Compounds, Compositions, and Methods of Using Them

Abstract

The present disclosure relates to bicyclic compounds, pharmaceutically acceptable salts thereof, and pharmaceutical preparations thereof. Also described herein are compositions and the use of such compounds in methods of treating diseases and conditions mediated by defective CFTR activity, particularly cystic fibrosis.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit and priority of U.S. Provisional Application No. 63 / 350,970, filed on June 10, 2022, the content of which is hereby incorporated by reference in its entirety.

Background Art

[0002] Background Cystic fibrosis (CF), an autosomal recessive disorder, is caused by a functional defect in the cAMP - activated cell membrane chloride channel, cystic fibrosis transmembrane conductance regulator (CFTR), and results in lung and other complications. The gene encoding CFTR has been identified and sequenced (see Gregory, R. J. et al. (1990) Nature 347:382 - 386 (Non - Patent Document 1); Rich, D. P. et al. (1990) Nature 347:358 - 362 (Non - Patent Document 2), (Riordan, J. R. et al. (1989) Science 245:1066 - 1073 (Non - Patent Document 3)). CFTR, a member of the ATP - binding cassette (ABC) superfamily, is composed of two six - transmembrane domains (MSD1 and MSD2), two nucleotide - binding domains (NBD1 and NBD2), a regulatory region (R), and four cytoplasmic loops (CL1 - 4). The CFTR protein is mainly located in the apical membrane of epithelial cells, where it functions to conduct anions, including chloride, bicarbonate, and thiocyanate, across the cell membrane. CFTR may have a regulatory role for other electrolyte channels, including the epithelial sodium channel ENaC.

[0003] In patients with cystic fibrosis, the absence or dysfunction of CFTR results in exocrine gland dysfunction and multi - system diseases (characterized by pancreatic insufficiency and malabsorption), as well as abnormal mucociliary clearance, suppression of mucus secretion, chronic lung infections and inflammation, reduced lung function, and ultimately respiratory failure in the lungs.

[0004] While more than 1,900 mutations have been identified in the CFTR gene, only limited details are known about how each CFTR mutation can affect channel function. (Derichs, European Respiratory Review, 22:127, 58 - 65 (2013) (Non - Patent Document 4)). The most frequent CFTR mutation is the in - frame deletion of phenylalanine at residue 508 in the first nucleotide - binding domain (NBD1), ΔF508. More than 70% of patients with cystic fibrosis have a deletion at residue 508 in at least one CFTR allele. The loss of this important phenylalanine causes NBD1 to be conformationally unstable at physiological temperature, compromising the integrity of the inter - domain interface between NBD1 and the second transmembrane domain (ICL4) of CFTR. The ΔF508 mutation causes the production of misfolded CFTR protein, which instead of migrating to the cell membrane, is retained in the endoplasmic reticulum and targeted for degradation by the ubiquitin - proteasome system.

[0005] The loss of functional CFTR channels in the cell membrane disrupts ionic homeostasis and airway surface hydration, leading to reduced lung function. Reduced periciliary liquid volume and increased mucus viscosity impede mucociliary clearance, leading to chronic infections and inflammation. In the lungs, the loss of CFTR function results in numerous physiological effects downstream of altered anion conductance that lead to dysfunction of additional organs, such as the pancreas, intestine, and gallbladder.

[0006] By studying the mechanistic aspects of CFTR misfolding and correction, small molecules have been identified as CF modulators that can act as stabilizers.

[0007] Despite the identification of compounds that modulate CFTR, a cure for this life - threatening disease, as well as the identification of new compounds and new methods of therapy, are needed as much as new ways to treat or attenuate the severity of cystic fibrosis and other CFTR - mediated conditions and diseases in patients.

Prior Art Documents

Non-Patent Documents

[0008]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Summary of the Invention

[0009] Summary This disclosure includes a compound of formula (I) or (II) TIFF2025519597000001.tif64165, or a pharmaceutically acceptable salt thereof. Further, this disclosure includes, inter alia, pharmaceutical compositions, methods of using and making a compound of formula (I) or (II).

Modes for Carrying Out the Invention

[0010] Detailed Description In some embodiments, this disclosure includes a compound of formula (I) or (II) TIFF2025519597000002.tif64165, or a pharmaceutically acceptable salt thereof: A is selected from the group consisting of an optionally substituted 3 - to 10 - membered carbocyclic ring, an optionally substituted 3 - to 10 - membered heterocyclic ring, an optionally substituted phenyl, and an optionally substituted 5 - to 10 - membered heteroaryl; L is selected from the group consisting of a bond, -O-, -S-, -S(O)2-, -CH2-, -C(O)-, -N(H)-, and -N(H)C(O)-; W is selected from the group consisting of -O-, -S-, -S(O)-, -S(O)2-, -N(H)-, and an optionally substituted 3- to 6-membered heterocyclylene; X 1 is N or C(H); X 2 is selected from the group consisting of -CH2-, -N(H)-, and -N(1-3 alkyl)-; Y 1 is selected from the group consisting of -C(H)=, -C(F)=, and -N=; Y 2 is selected from the group consisting of -C(H)=, -C(F)=, and -N=; Y 3 is selected from the group consisting of -C(H)=, -C(F)=, and -N=; Y 4 is selected from the group consisting of -C(H)=, -C(F)=, and -N=; Z is selected from the group consisting of -C(H)=, -C(F)=, and -N=; Each R a is independently selected from the group consisting of halogen, an optionally substituted C1-C3 aliphatic, an optionally substituted 5- to 7-membered heterocyclyl, an optionally substituted 5- to 6-membered heteroaryl, and -COOH; R b is selected from the group consisting of -CN, an optionally substituted C1-C6 aliphatic, an optionally substituted C1-C6 haloaliphatic, and an optionally substituted 3- to 7-membered heterocyclyl; R e1 is selected from the group consisting of hydrogen, C1-C5-alkyl, and C3-C5-cycloalkyl; R e2 is selected from the group consisting of hydrogen, C1-C5-alkyl, and C3-C5-cycloalkyl; wherein R e1 and R e2together with the atoms to which they are attached, optionally together, form an optionally substituted 3- to 6-membered carbocyclic ring; m is from 0 to 2; and n is from 0 to 5.

[0011] In some embodiments, the present disclosure includes a compound of formula (I) or a pharmaceutically acceptable salt thereof: A is selected from the group consisting of an optionally substituted 3- to 10-membered carbocyclic, an optionally substituted 3- to 10-membered heterocyclic, an optionally substituted aryl, and an optionally substituted 5- to 10-membered heteroaryl; L is selected from the group consisting of a bond, -O-, -S-, -S(O)2-, -CH2-, -C(O)-, and -N(H)-; X is N or C; Y 1 is selected from the group consisting of -C(H)=, -C(F), and -N=; Y 2 is selected from the group consisting of -C(H)=, -C(F), and -N=; Y 3 is selected from the group consisting of -C(H)=, -C(F), and -N=; Y 4 is selected from the group consisting of -C(H)=, -C(F), and -N=; Z is selected from the group consisting of -C(H)=, -C(F)=, and -N=; Each R a is independently selected from the group consisting of halogen, optionally substituted C1-C3 aliphatic, and -COOH; R e1 is selected from the group consisting of hydrogen, C1-C5-alkyl, and C3-C5-cycloalkyl; R e2 is selected from the group consisting of hydrogen, C1-C5-alkyl, and C3-C5-cycloalkyl; m is from 0 to 2; and n is from 0 to 5.

[0012] In some embodiments, the present disclosure includes a compound represented by formula (I-a) or (II-a) or a pharmaceutically acceptable salt thereof, as represented by TIFF2025519597000004.tif64165.

[0013] In some embodiments, the present disclosure includes a compound of formula (I-a’) or a pharmaceutically acceptable salt thereof, as represented by TIFF2025519597000005.tif79165.

[0014] In some embodiments, the present disclosure includes a compound represented by formula (I-a1) or (I-a2) or a pharmaceutically acceptable salt thereof, as represented by TIFF2025519597000006.tif64165.

[0015] In some embodiments, the present disclosure includes a compound represented by formula (I-b1) or (I-b2) or a pharmaceutically acceptable salt thereof, as represented by TIFF2025519597000007.tif64165.

[0016] A In some embodiments, A is selected from the group consisting of an optionally substituted 3- to 10-membered carbocyclic ring, an optionally substituted 3- to 10-membered heterocyclic ring, an optionally substituted phenyl, and an optionally substituted 5- to 10-membered heteroaryl. In some embodiments, A is selected from the group consisting of an optionally substituted 3- to 10-membered carbocyclic ring, an optionally substituted 3- to 10-membered heterocyclic ring, an optionally substituted aryl, and an optionally substituted 5- to 10-membered heteroaryl. In some embodiments, A is selected from the group consisting of an optionally substituted 5- to 8-membered carbocyclic ring, an optionally substituted 5- to 7-membered heterocyclic ring, and an optionally substituted phenyl. In some embodiments, A is an optionally substituted 5- to 8-membered carbocyclic ring. In some embodiments, A is an optionally substituted 5- to 7-membered heterocyclic ring. In some embodiments, A is an optionally substituted phenyl. In some embodiments, A is selected from the group consisting of an optionally substituted cyclohexyl, an optionally substituted bicyclo[1.1.1]pentyl, an optionally substituted bicyclo[2.2.2]octyl, an optionally substituted piperidinyl, and an optionally substituted phenyl. In some embodiments, A is selected from the group consisting of TIFF2025519597000008.tif99165.

[0017] In some embodiments, A is selected from the group consisting of TIFF2025519597000009.tif104165.

[0018] L In some embodiments, L is selected from the group consisting of a bond, -O-, -S-, -S(O)2-, -CH2-, -C(O)-, -N(H)-, and -N(H)C(O)-. In some embodiments, L is selected from the group consisting of a bond, -O-, -S-, -S(O)2-, -CH2-, -C(O)-, and -N(H)-. In some embodiments, L is selected from the group consisting of -S(O)2-, -CH2-, and -C(O)-. In some embodiments, L is -O-. In some embodiments, L is -S-. In some embodiments, L is -S(O)2-. In some embodiments, L is -CH2-. In some embodiments, L is -C(O)-. In some embodiments, L is -N(H)-.

[0019] X 1 and X 2 In some embodiments, X 1 is N or C(H). In some embodiments, X 1 is N. In some embodiments, X 1 is C(H).

[0020] In some embodiments, X 2 is selected from the group consisting of -CH2-, -N(H)-, and -N(C 1~3 alkyl)-. In some embodiments X 2 is -CH2-. In some embodiments, X 2 is -N(H)-. In some embodiments X 2 is -N(C 1~3 alkyl)-. In some embodiments, it is -N(Me)-.

[0021] Y 1 In some embodiments, Y 1 is selected from the group consisting of -C(H)=, -C(F), and -N=. In some embodiments, Y 1 is -C(H)=. In some embodiments, Y 1is -C(F)=. In some embodiments, Y 1 is -N=.

[0022] Y 2 In some embodiments, Y 2 is selected from the group consisting of -C(H)=, -C(F), and -N=. In some embodiments, Y 2 is -C(H)=. In some embodiments, Y 2 is -C(F)=. In some embodiments, Y 2 is -N=.

[0023] Y 3 In some embodiments, Y 3 is selected from the group consisting of -C(H)=, -C(F), and -N=. In some embodiments, Y 3 is -C(H)=. In some embodiments, Y 3 is -C(F)=. In some embodiments, Y 3 is -N=.

[0024] Y 4 In some embodiments, Y 4 is selected from the group consisting of -C(H)=, -C(F), and -N=. In some embodiments, Y 4 is -C(H)=. In some embodiments, Y 4 is -C(F)=. In some embodiments, Y 4 is -N=.

[0025] Z In some embodiments, Z is selected from the group consisting of -C(H)=, -C(F), and -N=. In some embodiments, Z is -C(H)=. In some embodiments, Z is -C(F)=. In some embodiments, Z is -N=.

[0026] R a In some embodiments, each R a is independently selected from the group consisting of halogen, optionally substituted C1-C3 aliphatic, optionally substituted 5-7 membered heterocyclyl, optionally substituted 5-6 membered heteroaryl, and -COOH. In some embodiments, each R a is independently selected from the group consisting of halogen, optionally substituted C1-C3 aliphatic, and -COOH. In some embodiments, each R a is independently selected from the group consisting of optionally substituted C1-C3 aliphatic, or -COOH. In some embodiments, each R a is independently selected from optionally substituted C1-C3 aliphatic. In some embodiments, each R a is independently selected from optionally substituted halogen. In some embodiments, each R a is independently selected from the group consisting of methyl and -COOH. In some embodiments, R a is methyl. In some embodiments, R a is -COOH. In some embodiments, R a is optionally substituted 5-6 membered heterocyclyl. In some embodiments, R a is TIFF2025519597000010.tif27165.

[0027] R e1 In some embodiments, R e1 is selected from the group consisting of hydrogen, C1-C5-alkyl, and C3-C5-cycloalkyl. In some embodiments, R e1 is hydrogen. In some embodiments, R e1 is C1-C5-alkyl. In some embodiments, R e1 is C1-C3-alkyl. In some embodiments, R e1 is methyl.

[0028] R e2 In some embodiments, R e2 is selected from the group consisting of hydrogen, C1-C5-alkyl, and C3-C5-cycloalkyl. In some embodiments, R e2 is hydrogen. In some embodiments, R e2 is C1-C5-alkyl. In some embodiments, R e2 is C1-C3-alkyl. In some embodiments, R e2 is methyl.

[0029] M In some embodiments, m is from 0 to 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0030] N In some embodiments, n is from 0 to 5. In some embodiments, n is from 0 to 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5.

[0031] The present disclosure includes the compounds of Table 1.

[0032]

Table 1

[0033] Definition As used herein, the term "aliphatic" or "aliphatic group" means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is completely saturated or contains one or more units of unsaturation and that is not aromatic (also referred to herein as "carbocyclic", "alicyclic" or "cycloalkyl") and that has a single point of attachment to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains from 1 to 6 aliphatic carbon atoms. In some embodiments, the aliphatic group contains from 1 to 5 aliphatic carbon atoms. In other embodiments, the aliphatic group contains from 1 to 4 aliphatic carbon atoms. In still other embodiments, the aliphatic group contains from 1 to 3 aliphatic carbon atoms, and in still other embodiments, the aliphatic group contains from 1 to 2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocyclic" or "carbosilyl") is completely saturated or contains one or more units of unsaturation but is not completely aromatic and has a single point of attachment to the remainder of the molecule and refers to a monocyclic or bicyclic C3-C 10 hydrocarbon. The terms "alicyclic", "carbocyclic", and "carbosilyl" are used interchangeably herein and also include groups in which a carbocyclic ring is fused to one or more alicyclic rings. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and their hybrids, such as, for example, (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0034] The term "haloaliphatic" refers to an aliphatic substituted with one or more halogen atoms.

[0035] The term "haloalkyl" refers to a straight-chain or branched alkyl group substituted with one or more halogen atoms.

[0036] As used herein, the term "alkyl" is a branched or unbranched saturated hydrocarbon group having a specified number of carbon atoms. In some embodiments, alkyl refers to a branched or unbranched saturated hydrocarbon group having three carbon atoms (C3). In some embodiments, alkyl refers to a branched or unbranched saturated hydrocarbon group having six carbon atoms (C6). In some embodiments, the term "alkyl" includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, and hexyl.

[0037] As used herein, the term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n -(where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3). A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced by substituents. Suitable substituents include those described below for substituted aliphatic groups. The term "halogen" means F, Cl, Br, or I.

[0038] The term "aryl", used alone or as part of a larger moiety such as "aralkyl", "aralkoxy", or "aryloxyalkyl", is a monocyclic and bicyclic ring system having a total of 5 to 14 ring members, wherein at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring". In certain embodiments of the present disclosure, "aryl" refers to an aromatic ring system including, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, etc., which may carry one or more substituents. Also within the scope of the term "aryl", as used herein, are groups in which the aromatic ring is fused to one or "more than one" aromatic ring above, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, etc.

[0039] The terms "heteroaryl" and "heteroal-" when used alone or as part of a larger moiety, e.g., "heteroalkyl", or "heteroalkoxy", have 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; have 6, 10, or 14 π electrons shared in a cyclic array; and refer to a group having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen or sulfur and any quaternized form of basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroal-" also include, as used herein, groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the linking radical or point is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups can be mono- or bicyclic. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring", "heteroaryl group", or "heteroaromatic", and any of these terms includes substituted or unsubstituted rings containing groups in which a heteroaryl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings. The term "heteroalkyl" refers to an alkyl group substituted by heteroaryl, where the alkyl and heteroaryl moieties are independently optionally substituted.

[0040] As used herein, the terms "heterocyclic", "heterocyclyl", "heterocyclic radical", and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated and that, in addition to carbon atoms, has one or more, preferably 1 to 4, of the heteroatoms defined above. When used with respect to the ring atoms of a heterocyclic ring, the term "nitrogen" includes substituted nitrogen. By way of example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur or nitrogen, nitrogen can be N (such as in 3,4-dihydro-2H-pyrrolyl), NH (such as in pyrrolidinyl), or + NR (such as in TV-substituted pyrrolidinyl). The heterocyclic ring can be attached to its pendant group by any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms can optionally be substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocyclic", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety", and "heterocyclic radical" are used interchangeably herein and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as, for example, indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the linking radical or point is on the heterocyclyl ring. A heterocyclyl group can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, where the alkyl and heterocyclyl moieties can each optionally be substituted independently.

[0041] The complex cyclic ring can be bonded to the pentant group by any heteroatom or carbon atom that provides a stable structure, and any of the ring atoms may be optionally substituted. Examples of such saturated or partially unsaturated complex cyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle", "heterocyclyl", "heterocyclic ring", "heterocyclic group", "heterocyclic moiety", and "heterocyclic radical" are used interchangeably herein, and also include groups in which the heterocyclic ring is fused to one or more aryl, heteroaryl, or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the bonding radical or point is on the heterocyclic ring. The heterocyclyl group can be mono- or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by heterocyclyl, where the alkyl and heterocyclyl moieties may be independently optionally substituted.

[0042] As used herein, the term "partially unsaturated" refers to a ring moiety containing at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple unsaturated sites, but as defined herein, is not intended to include aryl or heteroaryl moieties.

[0043] As described herein, the compounds of the present disclosure may contain "optionally substituted" moieties. Generally, the term "substituted", whether or not preceded by the term "optionally", means that one or more hydrogens of the designated moiety are replaced by suitable substituents. Unless otherwise indicated, an "optionally substituted" group may have suitable substituents at each substitutable position of the group, and when a plurality of positions in any given structure are substituted with a plurality of substituents selected from the designated groups, the substituents may be the same or different for each position. Combinations of substituents contemplated by the present disclosure preferably result in the formation of stable or chemically feasible compounds. The term "stable", as used herein, refers to compounds that are not substantially modified when subjected to the conditions necessary for their generation, detection, and in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0044] Suitable monovalent substituted groups on a substitutable carbon atom of an "optionally substituted" group are, independently, halogen; -(CH2) 0~4 R ° ; -(CH2) 0~4 OR ° ; -O(CH2) 0~4 R ° , -O-(CH2) 0~4 C(O)OR ° ; -(CH2) 0~4 CH(OR ° )2; -(CH2) 0~4 SR ° ; R ° that may be substituted with -(CH2) 0~4 Ph; R ° that may be substituted with -(CH2) 0~4 O(CH2) 0~1 Ph; R ° that may be substituted with -CH=CHPh; R ° that may be substituted with -(CH2) 0~4 O(CH2) 0~1-pyridyl; -NO2; -CN; -N3; -(CH2) 0~4 N(R ° )2; -(CH2) 0~4 N(R ° )C(O)R ° ; -N(R ° )C(S)R ° ; -(CH2) 0~4 N(R ° )C(O)NR ° 2; -N(R ° )C(S)NR ° 2; -(CH2) 0~4 N(R ° )C(O)OR ° ; -N(R ° )N(R ° )C(O)R ° ; -N(R ° )N(R ° )C(O)NR ° 2; -N(R ° )N(R ° )C(O)OR ° ; -(CH2) 0~4 C(O)R ° ; -C(S)R ° ; -(CH2) 0~4 C(O)OR ° ; -(CH2) 0~4 C(O)SR ° ; -(CH2) 0~4 C(O)OsiR ° 3; -(CH2) 0~4 OC(O)R ° ; -OC(O)(CH2) 0~4 SR ° 、SC(S)SR ° ; -(CH2) 0~4 SC(O)R ° ; -(CH2) 0~4 C(O)NR ° 2; -C(S)NR ° 2; -C(S)SR ° ; -SC(S)SR ° 、-(CH2) 0~4 OC(O)NR ° 2; -C(O)N(OR ° )R ° ; -C(O)C(O)R °;-C(O)CH2C(O)R ° ;-C(NOR ° )R ° ;-(CH2) 0~4 SSR ° ;-(CH2) 0~4 S(O)2R ° ;-(CH2) 0~4 S(O)2OR ° ;-(CH2) 0~4 OS(O)2R ° ;-S(O)2NR ° 2;-(CH2) 0~4 S(O)R ° ;-N(R ° )S(O)2NR ° 2;-N(R ° )S(O)2R ° ;-N(OR ° )R ° ;-C(NH)NR2;-P(O)2R ° ;-P(O)R ° 2;-OP(O)R ° 2;-OP(O)(OR ° )2;SiR ° 3;-(C 1~4 linear or branched alkylene)O-N(R ° )2; or -(C 1~4 linear or branched alkylene)C(O)O-N(R ° )2, and each R ° may be substituted as defined below and is independently hydrogen, C 1~6 aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, -CH2-(5- to 6-membered heteroaryl ring), or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definition, two independent occurrences of R ° together with their intervening atom(s) (if any) form a 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur that may be substituted as defined below.

[0045] R °(or R ° A suitable monovalent substituent on the ring) formed by incorporating two independent entities of ° along with their intervening atoms is, independently, halogen, -(CH2) 0~2 R ● , -(haloR ● ), -(CH2) 0~2 OH, -(CH2) 0~2 OR ● , -(CH2) 0~2 CH(OR ● )2; -O(haloR ● ), -CN, -N3, -(CH2) 0~2 C(O)R ● , -(CH2) 0~2 C(O)OH, -(CH2) 0~2 C(O)OR ● , -(CH2) 0~2 SR ● , -(CH2) 0~2 SH, -(CH2) 0~2 NH2, -(CH2) 0~2 NHR ● , -(CH2) 0~2 NR ● 2, -NO2, -SiR ● 3, -OsiR ● 3, -C(O)SR ● , -(C 1~4 linear or branched alkylene)C(O)OR ● , or -SSR ● wherein each R ● is unsubstituted or, when preceded by "halo", is substituted with only one or more halogens, and is independently selected from C 1~4 aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on the saturated carbon atoms of R ° include =O and =S.

[0046] Suitable divalent substituents on the saturated carbon atom of the "optionally substituted" group include the following: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, -O(C(R*2)) 2~3 O-, or -S(C(R*2)) 2~3 where each independent occurrence of R* is hydrogen, C which may be substituted as defined below 1~6 aliphatic, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to an adjacent substitutable carbon of the "optionally substituted" group include -O(CR*2) 2~3 O-, where each independent occurrence of R* is hydrogen, C which may be substituted as defined below 1~6 aliphatic, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0047] Suitable substituents on the aliphatic group of R* include halogen, -R ● , -(haloR ● ), -OH, -OR ● , -O(haloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each of R ● is unsubstituted or, when preceded by "halo", is substituted by only one or more halogens and independently is C 1~4 aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0048] Suitable substituents on the substitutable nitrogen of the "optionally substituted" group include -R † , -NR † 2, -C(O)R †, -C(O)OR † , -C(O)C(O)R † , -C(O)CH2C(O)R † , -S(O)2R † , -S(O)2NR † 2, -C(S)NR † 2, -C(NH)NR † 2, or -N(R † )S(O)2R † is included; each R † is, independently, hydrogen, C 1~6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definition, two independent occurrences of R † together with their intervening atom(s), if any, form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0049] R † Suitable substituents on the aliphatic group of R ● include halogen, -R ● , -(haloR ● ), -OH, -OR ● , -O(haloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● 2, or -NO2, and each of R ● is unsubstituted or, when preceded by "halo", is substituted with only one or more halogens and is independently C 1~4 aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0050] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc. within the scope of sound medical judgment and which are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19 (incorporated herein by reference). Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc.

[0051] Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium and N(C 1~4The (alkyl)4 salt is included. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0052] In the description of the listing of chemical groups in any definition of a variable element herein, the definition of that variable element is included as any single group or combination of the listed groups. In the description of embodiments for a variable element herein, the embodiment is included as any single embodiment or as a combination with any other embodiment or part thereof.

[0053] The term "biological sample", as used herein, includes, but is not limited to, cell cultures or extracts thereof; biopsy materials or extracts thereof obtained from mammals; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. Examples of such purposes include, but are not limited to, blood transfusions, organ transplants, biological sample preservation, and biological assays.

[0054] As used herein, "therapeutically effective amount" means the amount of a substance (e.g., therapeutic agent, composition, and / or formulation) that elicits a desired biological response. In some embodiments, the therapeutically effective amount of a substance, when administered as part of a dosing regimen to a subject suffering from or susceptible to a disease, disorder, and / or condition, is an amount sufficient to treat and / or diagnose the onset of the disease, disorder, and / or condition. As will be understood by those skilled in the art, the effective amount of a substance can vary depending on factors such as the desired biological endpoint, the substance being delivered, the target cell or tissue, etc. For example, the effective amount of a compound provided in a formulation for treating a disease, disorder, and / or condition is an amount that reduces, ameliorates, alleviates, reduces, and / or reduces the frequency of occurrence of one or more symptoms or characteristics of the disease, disorder, and / or condition. In some embodiments, "therapeutically effective amount" is at least the minimum amount of a provided compound or composition containing the provided compound that is sufficient to treat one or more symptoms of a CFTR-related disease or disorder.

[0055] The terms "treat", "treatment" or "treating" mean reducing, suppressing, attenuating, alleviating, halting, or stabilizing the onset or progression of a disease (e.g., a disease or disorder described herein), attenuating the severity of the disease, or improving the symptoms associated with the disease. Treatment includes treating the symptoms of a disease, disorder or condition. Without being bound by any theory, in some embodiments, treating includes increasing CFTR activity deficiency. When administered prior to the clinical signs of an undesirable condition (e.g., a disease or other undesirable condition of a subject), then the treatment is prophylaxis (i.e., protecting the subject against developing the undesirable condition), while when administered after the signs of the undesirable condition, the treatment is therapy (i.e., intended to attenuate, improve, or stabilize an existing undesirable condition or its side effects).

[0056] The term "subject" for which administration is contemplated includes humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, toddlers, adolescents) or adult subjects (e.g., young adults, middle-aged adults or elderly adults)) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals relevant commercially, e.g., cows, pigs, horses, sheep, goats, cats, and / or dogs; and / or birds relevant commercially, e.g., chickens, ducks, geese, quails, and / or turkeys, but is not limited thereto. Preferred subjects are humans.

[0057] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound(s) being formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the compounds disclosed herein include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin, but are not limited thereto.

[0058] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester or other derivative of a compound of the present disclosure that, when administered to a recipient, is capable of providing, directly or indirectly, the compound of the present disclosure or its active metabolite or residue.

[0059] The term "dosage unit form" as used herein refers to physically discrete units of the drug appropriate for the patient to be treated. However, it will be understood that the total daily usage of the compounds and compositions of the present disclosure will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination with or concurrently with the specific compound employed, as well as other factors well known in the medical arts.

[0060] A "response" to a treatment method can include, among other things, a decrease or improvement in negative symptoms, a decrease in the progression of a disease or its symptoms, an increase in beneficial symptoms or clinical outcomes, a reduction in side effects, stabilization of a disease, or partial or complete relief of a disease.

[0061] As used herein, "CFTR" means cystic fibrosis transmembrane conductance regulator. Defects in the function of the CFTR ion channel result in loss-of-function mutations of CFTR. Such mutations lead to exocrine gland dysfunction, abnormal mucociliary clearance, and cause cystic fibrosis. The most common CFTR mutation in patients with cystic fibrosis (CF) results in a specific deletion of 3 nucleotides of the codon for phenylalanine at position 508. This mutation, found in approximately 70% of CF patients worldwide, is designated "ΔF508". The ΔF508 mutation reduces the stability of the CFTR NBD1 domain and limits CFTR domain-to-domain assembly. Since CF is an autosomal recessive disease, CF patients carrying the ΔF508 CFTR mutation should also have a second defective copy of CFTR. Approximately 2,000 different CFTR mutations that cause CF have been identified in CF patients. CF patients carrying the ΔF508 CFTR mutation can be homozygous for that mutation (ΔF508 / ΔF508). CF patients can also be ΔF508 heterozygous if the second CFTR allele such a patient has instead contains a different CFTR loss-of-function mutation. Such CFTR mutations include, but are not limited to, G542X, G551D, N1303K, W1282X, R553X, R117H, R1162X, R347P, G85E, R560T, A455E, ΔI507, G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P, and G1349D.

[0062] As used herein, the term "CFTR modulator" refers to a compound that increases the activity of CFTR. In certain embodiments, a CFTR modulator is a CFTR corrector or enhancer or a dual-acting compound having the activities of a corrector and an enhancer.

[0063] As used herein, the term "CFTR corrector" refers to a compound that increases the amount of functional CFTR protein at the cell surface and thus improves CFTR channel function. A CFTR corrector partially "rescues" the misfolding of CFTR, thereby enabling the maturation and functional expression of CFTR proteins bearing mutations that cause CF on the cell surface. Examples of correctors include, but are not limited to, VX-809, VX-661, VX-152, VX-440, VX-983, and GLPG2222. Such compounds can interact directly with the CFTR protein and modify its folding and conformational maturation during synthesis.

[0064] As used herein, the term "CFTR potentiator" refers to a compound that increases the ion channel activity of CFTR proteins located on the cell surface, resulting in improved ion transport. A CFTR potentiator repairs the channel function defects caused by mutations. Examples of potentiators include, but are not limited to, ivacaftor (VX770), deuterated ivacaftor (CPT656), genistein, and GLPG1837.

[0065] As used herein, the term "CFTR pharmacological chaperone" (PC) refers to a compound that stabilizes the native state of the CFTR protein by binding directly to the protein.

[0066] As used herein, the term "CFTR protein homeostasis regulator" (PR) refers to a compound that improves the efficiency of protein folding within the cell. A PR can modify the activity of transcription, folding, and / or membrane trafficking mechanisms, as well as interfere with the degradation of conformers that are partially folded but functional in the endoplasmic reticulum (ER) or cell membrane.

[0067] As used herein, "CFTR disease or condition" refers to a disease or condition associated with a deficiency in CFTR activity, such as cystic fibrosis, congenital bilateral absence of the vas deferens (CBAVD), acute, recurrent, or chronic pancreatitis, bronchiectasis, asthma, allergic bronchopulmonary aspergillosis, smoking lung diseases such as chronic obstructive pulmonary disease (COPD), chronic rhinosinusitis, dry eye disease, protein C deficiency, abetalipoproteinemia, lysosomal storage diseases, type 1 chylomicronemia, mild lung disease, lipid processing deficiencies, hereditary angioedema, coagulation / fibrinolysis, hereditary hemochromatosis, CFTR-related metabolic syndrome, chronic bronchitis, constipation, pancreatic insufficiency, hereditary emphysema, and Sjogren's syndrome.

[0068] As used herein, the terms "combination", "combined", and related terms refer to the simultaneous or sequential administration of therapeutic agents in accordance with the present disclosure. For example, the compounds of the present disclosure can be administered with another therapeutic agent, either simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present disclosure provides a single unit dosage form comprising the provided compound, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0069] Alternative embodiments In alternative embodiments, the compounds described herein can also include one or more isotope substitutions. For example, hydrogen can be 2 H (D or deuterium) or 3 H (T or tritium); carbon can be, for example, 13 C or 14 C; oxygen can be, for example, 18 O; nitrogen can be, for example, 15 N, etc. In other embodiments, specific isotopes (e.g., 3 H, 13 C, 14 C, 18 O, or 15N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of the element occupying a specific site of the compound.

[0070] Pharmaceutical composition In some embodiments, the present disclosure provides a composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the amount of the compound in the compositions contemplated herein is such that it is effective to measurably modulate CFTR, or a variant thereof, in a biological sample or patient. In certain embodiments, the amount of the compound in the compositions of the present disclosure is such that it is effective to measurably modulate CFTR, or a variant thereof, in a biological sample or patient. In certain embodiments, the compositions contemplated by the present disclosure are formulated for administration to a patient in need of such a composition. In some embodiments, the compositions contemplated by the present disclosure are formulated for oral administration to a patient.

[0071] In some embodiments, the amount of the compound in the compositions contemplated herein is such that it is effective to measurably modulate a protein, particularly CFTR, or a variant thereof, in a biological sample or patient. In certain embodiments, the amount of the compound in the compositions of the present disclosure is such that it is effective to measurably modulate CFTR, or a variant thereof, in a biological sample or patient.

[0072] In some embodiments, the compositions of the present disclosure can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. In some preferred embodiments, the compositions are administered orally, intraperitoneally or intravenously. In some embodiments, the sterile injectable form of the composition comprising one or more compounds of formula (A) can be an aqueous or oily suspension. In some embodiments, the suspension can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. In some embodiments, the sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. In some embodiments, acceptable vehicles and solvents that can be used include water, Ringer's solution and isotonic sodium chloride solution. In some embodiments, additional examples include, but are not limited to, sterile fixed oils conventionally used as a solvent or suspending medium.

[0073] As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intraliver, intralesional and intracranial injection or infusion techniques.

[0074] The pharmaceutically acceptable compositions comprising one or more compounds of formula (A) can be administered orally in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In some embodiments, carriers used include lactose and corn starch. Lubricants, such as magnesium stearate, are also typically added. In some embodiments, useful diluents include lactose and dried corn starch. In some embodiments, when an aqueous suspension is required for oral use, the active ingredient is combined with emulsifying and suspending agents. In some embodiments, certain sweetening, flavoring or coloring agents can also be added.

[0075] Alternatively, a pharmaceutically acceptable composition comprising a compound of formula (A) can be administered in the form of a suppository for rectal administration. These can be prepared by mixing the drug with suitable non-irritating excipients that are solid at room temperature but liquid at rectal temperature and will thus melt in the rectum to release the drug. Such substances include cocoa butter, beeswax and polyethylene glycol.

[0076] A pharmaceutically acceptable composition comprising a compound of formula (A) can also be administered topically, particularly when the target of treatment includes areas or organs that are readily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. In some embodiments, the pharmaceutically acceptable composition can be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the provided pharmaceutically acceptable composition can be formulated in a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0077] A pharmaceutically acceptable composition comprising a compound of formula (A) can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in physiological saline, using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0078] In some embodiments, the amount of the compounds of the present disclosure that can be combined with a carrier substance to produce a single dosage form composition will vary depending on the host being treated and the particular mode of administration. Preferably, the compositions provided should be formulated such that an inhibitor in an amount of 0.01 to 100 mg / kg body weight / day can be administered to a patient ingesting these compositions.

[0079] Methods of using the compounds of the present disclosure As discussed above, CFTR is composed of two six-transmembrane domains (MSD1 and MSD2), two nucleotide binding domains (NBD1 and NBD2), regulatory region I, and four cytoplasmic loops (CL1-4). The CFTR protein is mainly located in the apical membrane of epithelial cells, where it functions to conduct anions, including chloride, bicarbonate, and thiocyanate, in and out of the cell. The most frequent CFTR mutation is the in-frame deletion of phenylalanine at residue 508 in the first nucleotide binding domain (NBD1) (ΔF508). The mutation has several deleterious effects on the production of CFTR in the ER, its correct folding, its movement to the cell membrane, and its normal function as an ion channel for the cell.

[0080] One such negative effect is that the NBD1 domain is partially or misfolded, which is recognized as an abnormal protein within the cell and tagged for removal by ER-associated degradation (ERAD) via the ubiquitin-proteasome system (UPS). If a partially or misfolded CFTR protein emerges from the ER, the protein must translocate to the cell membrane via complex glycosylation within the Golgi compartment and be functionally inserted. In wild-type CFTR, only 20-40% of CFTR reaches the cell membrane, suggesting that CFTR has an energetic stability of individual NBDs, slow domain assembly, and relatively rapid ERAD kinetics, all of which contribute to inefficient folding and sensitize CFTR to structural fluctuations due to mutations.

[0081] In wild-type CFTR, the NBD1 domain folds co-translationally, while other domains fold post-translationally. Mutated ΔF508 CFTR has a NBD1 folding defect, but its backbone structure and thermodynamic stability are the same as those of wild-type CFTR. In the delayed folding kinetics, mutated ΔF508 CFTR NBD1 has an increased folding activation energy. The lack of proper folding will expose hydrophobic residues on the surface of NBD1, leading to aggregation with other CFTR proteins. Therefore, the aggregation temperature of mutated CFTR decreases from 41 °C to 33 °C. This level of instability results in a higher percentage of misfolded mutant CFTR at physiological temperature (37 °C in humans). Mutant CFTR has both kinetic and thermodynamic folding defects. CFTR stabilizers can address these folding defects, but it has been shown that complete energetic correction of mutant NBD1 folding does not result in CFTR biosynthesis processing, and similarly emphasizes the need for interface stability.

[0082] The disclosed CFTR modifiers can interact with the NBD domain to stabilize the correct folding position R so that CFTR is not labeled for elimination from the cell. By preserving the correct folding, CFTR can function as a chloride ion channel at wild-type levels. In some embodiments, the disclosed CFTR modifiers can improve the performance of wild-type CFTR.

[0083] CFTR stabilizers can function in combination with other therapeutic agents such as CFTR modifiers that promote the excretion of Δ508CFTR from the ER and its accumulation in the cell membrane. Increasing the amount of CFTR cell surface expression can result in improved chloride conductance after channel activation by both potentiators and cAMP agonists. Therefore, disclosed herein are combinations of CFTR stabilizers with CFTR modifiers and potentiators, optionally accompanied by a cAMP agonist or another therapeutic agent described below.

[0084] Disclosed herein is a method of treating a CFTR activity defect in a cell, the method comprising contacting the cell with a compound of formula (A) or a pharmaceutically acceptable salt thereof. In certain embodiments, contacting the cell is performed in a subject in need thereof, thereby treating a disease or disorder mediated by a CFTR activity defect.

[0085] Also disclosed herein is a method of treating a disease or disorder mediated by a CFTR activity defect, the method comprising administering a compound of formula (A) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is a mammal, preferably a human. In some embodiments, the disease is related to the control of fluid volume passing through an epithelial membrane, particularly obstructive airway diseases such as CF or COPD.

[0086] Such diseases and conditions include, but are not limited to, cystic fibrosis, asthma, smoking-induced COPD, chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), mild lung disease, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), liver disease, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, protein C deficiency, hereditary angioedema type 1, lipid processing deficiencies, familial hypercholesterolemia, type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, I-cell disease / pseudo-Hurler, mucopolysaccharidoses, Sandhoff disease / Tay-Sachs disease, Crigler-Najjar type II, multiple endocrine neoplasia / hypoinsulinemia, diabetes, Laron-type dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, diabetes insipidus (DI), neurophyseal DI, nephrogenic DI, Charcot-Marie-Tooth syndrome, Pelizaeus-Merzbacher disease, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, some polyglutamine neuropathies, Huntington's disease, spinocerebellar degeneration type I, bulbospinal muscular atrophy, dentatorubal pallidoluysian, myotonic dystrophy, spongiform encephalopathies, hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler-Scheinker syndrome, COPD, dry eye disease, Sjogren's disease, osteoporosis, osteopenia, bone healing and bone growth, bone repair, bone regeneration, reduction of bone resorption, increase of bone deposition, Gorham syndrome, chloride channelopathy, congenital myotonia, Bartter syndrome type III, Dent disease, startle disease, epilepsy, startle disease, lysosomal storage diseases, Angelman syndrome, primary ciliary dyskinesia (PCD), PCD with inversion, PCD without inversion, and immotile cilia.

[0087] Such diseases and conditions include, but are not limited to, cystic fibrosis, congenital bilateral absence of the vas deferens (CBAVD), acute, recurrent, or chronic pancreatitis, diffuse bronchiectasis, asthma, allergic bronchopulmonary aspergillosis, chronic obstructive pulmonary disease (COPD), chronic rhinosinusitis, dry eye disease, protein C deficiency, abetalipoproteinemia, lysosomal storage disorders, type 1 chylomicronemia, mild pulmonary disease, lipid processing defects, hereditary angioedema type 1, coagulation / fibrinolysis, hereditary hemochromatosis, CFTR-related metabolic syndrome, chronic bronchitis, constipation, pancreatic insufficiency, hereditary emphysema, and Sjogren's syndrome. In some embodiments, the disease is cystic fibrosis.

[0088] Disclosed herein is a method of treating cystic fibrosis, the method comprising administering to a subject in need thereof a compound disclosed herein or a pharmaceutically acceptable salt thereof. Also disclosed herein is a method of attenuating the severity of cystic fibrosis, the method comprising administering to a subject in need thereof a compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is human. In some embodiments, the subject is at risk of developing cystic fibrosis and the administration is performed prior to the onset of symptoms of cystic fibrosis in the subject.

[0089] Disclosed herein is a compound disclosed herein for use in treating a disease or condition mediated by CFTR activity deficiency. Also disclosed herein is the use of a compound disclosed herein for the manufacture of a medicament for treating a disease or condition mediated by CFTR activity deficiency.

[0090] Disclosed herein are kits for use in measuring the activity of CFTR or a fragment thereof in a biological sample, either in vitro or in vivo. The kit may comprise (i) a compound disclosed herein, or a pharmaceutical composition comprising the disclosed compound, and (ii) instructions for a) contacting the compound or composition with a biological sample; and b) measuring the activity of the CFTR or a fragment thereof. In some embodiments, the biological sample is a biopsy material or extract obtained from a mammal; blood, saliva, urine, feces, semen, tears, other body fluids, or an extract thereof. In some embodiments, the mammal is a human.

[0091] Combination treatment As used herein, the term "combination therapy" means administering to a subject (e.g., a human) two or more CFTR modulators, or a CFTR modulator and an agent, such as an antibiotic, an EnaC inhibitor, a GSNO (S-nitrosothiol, s-nitroglutathione) reductase inhibitor, and a CRISPR Cas modification therapy or system (described in US2007 / 0022507, etc.). In some embodiments, the combination therapy includes administering a compound described herein in combination with a compound that modulates CFTR protein or ABC protein activity (e.g., as described in WO2018167690A1, etc.).

[0092] In certain embodiments, a method of treating a disease or condition mediated by CFTR activity deficiency comprises administering a compound disclosed herein together with one or more other therapeutic agent(s). In some embodiments, one other therapeutic agent is administered. In other embodiments, at least two other therapeutic agents are administered.

[0093] In certain embodiments, a method of preventing a disease or condition mediated by CFTR activity deficiency comprises administering a compound disclosed herein together with one or more other therapeutic agent(s). In some embodiments, one other therapeutic agent is administered. In other embodiments, at least two other therapeutic agents are administered.

[0094] Additional therapeutic agents include, for example, EnaC inhibitors, mucolytics, regulators of mucus rheology, bronchodilators, antibiotics, anti-infective agents, anti-inflammatory agents, ion channel regulators, therapeutic agents used in gene or mRNA therapy, agents that reduce airway surface liquid and / or reduce airway surface pH, CFTR modifiers, and CFTR potentiators, or other agents that modulate CFTR activity. Other therapeutic agents include liposomal composition components, such as those described in WO2012 / 170889, hybrid oligonucleotides that facilitate RNA cleavage, such as those described in WO2016 / 130943, and single-stranded oligonucleotides that modulate gene expression as described in WO2016 / 130929.

[0095] In some embodiments, at least one additional therapeutic agent is selected from one or more CFTR regulators, one or more CFTR modifiers, and one or more CFTR potentiators.

[0096] Non-limiting examples of additional therapeutic agents include VX-770 (Ivacaftor), VX-809 (Lumacaftor, 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-1-carboxamido)-3-methylpyridin-2-yl)benzoic acid), VX-661 (Tezacaftor, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane-1-carboxamide), VX-983, VX-152, VX-440, VX-445, VX-659, VX-371, Orkambi, Ataluren (PTC 124) (3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid), PTI-130 (Proteostasis), PTI-801, PTI-808, PTI-428, N91115.74 (Carbosustat), the QBW251 (Novartis) compound described in WO2011113894, the Compound N30 Pharmaceuticals (e.g., WO2014 / 186704), deuterated ivacaftor (e.g., CTP-656 or VX-561), GLPG2222, GLPG2451, GLPG3067, GLPG2851, GLPG2737, GLPG 1837 (N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-5-carboxamide), GLPG2665 (Galapagos), FDL169 (Flatley Discovery lab), FDL176, FDL438, FDL304, FD2052160, FD1881042, FD2027304, FD2035659, FD2033129, FD1860293, CFFT-Pot01, CFFT-Pot-02, P-1037, glycerol, phenylbutyrate, etc. are included.

[0097] Non-limiting examples of anti-inflammatory agents include N6022 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-carbamoyl-2-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid), ibuprofen, Lenabasum (anabasum), Acebilustat (CTX-4430), LAU-7b, POL6014, docosahexaenoic acid, alpha-1 antitrypsin, sildenafil. Additional therapeutic agents also include mucolytics, modifiers of mucus rheology (e.g., hypertonic saline, mannitol, and oligosaccharide-based therapies), bronchodilators, anti-infective agents (e.g., tazobactam, piperacillin, rifampin, meropenem, ceftazidime, aztreonam, tobramycin, fosfomycin, azithromycin, amitriptyline, vancomycin, gallium, and colistin), anti-infective agents, anti-inflammatory agents, CFTR regulators other than the compounds of the present disclosure, and nutritional agents, but are not limited thereto. Additional therapeutic agents may include treatments for complications of cystic fibrosis such as pancreatic exocrine insufficiency that can be treated with pancrelipase or liprotamase.

[0098] Examples of CFTR potentiators include, but are not limited to, Ivacaftor (VX-770), CTP-656, NVS-QBW251, FD1860293, GLPG2451, GLPG1837, and N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-5-carboxamide. Examples of potentiators are also disclosed in the publications: WO2005120497, WO2008147952, WO2009076593, WO2010048573, WO2006002421, WO2008147952, WO2011072241, WO2011113894, WO2013038373, WO2013038378, WO2013038381, WO2013038386, WO2013038390, WO2014180562, WO2015018823, and U.S. Patent Application Publication Nos. 14 / 271,080, 14 / 451,619, and 15 / 164,317.

[0099] Non-limiting examples of correctors include Lumacaftor (VX-809), 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-{1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl}cyclopropanecarboxamide (VX-661), VX-983, GLPG2222, GLPG2665, GLPG2737, VX-152, VX-440, FDL169, FDL304, FD2052160, and FD2035659. Examples of correctors are also disclosed in US20160095858A1, and US Application Serial Nos. 14 / 925,649 and 14 / 926,727.

[0100] In certain embodiments, the additional therapeutic agent is a CFTR amplifier. CFTR amplifiers enhance the effects of known CFTR modulators, such as potentiators and correctors. Examples of CFTR amplifiers include PTI130 and PTI-428. Examples of amplifiers are also disclosed in the publications: WO2015138909 and WO2015138934.

[0101] In certain embodiments, the additional therapeutic agent is an agent that reduces the activity of epithelial sodium channel (EnaC) either directly by blocking the channel or indirectly by modulating proteases (e.g., serine proteases, channel activating proteases) that result in an increase in EnaC activity. Exemplification of such agents includes camostat (a trypsin-like protease inhibitor), QAU145, 552-02, GS-9411, INO-4995, Aerolytic, amiloride, AZD5634, and VX-371. Additional agents that reduce the activity of epithelial sodium channel (EnaC) can be found, for example, in PCT Publication Nos. WO2009074575 and WO2013043720; and U.S. Patent No. 8,999,976.

[0102] In one embodiment, the EnaC inhibitor is VX-371.

[0103] In one embodiment, the EnaC inhibitor is SPX-101 (S18).

[0104] Enumerated embodiments The present disclosure includes the enumerated embodiments 1 to 30: 1. Formula (I) A compound represented by TIFF2025519597000041.tif79165 or a pharmaceutically acceptable salt thereof: A is selected from the group consisting of an optionally substituted 3- to 10-membered carbocyclyl, an optionally substituted 3- to 10-membered heterocyclyl, an optionally substituted aryl, and an optionally substituted 5- to 10-membered heteroaryl; L is selected from the group consisting of a bond, -O-, -S-, -S(O)2-, -CH2-, -C(O)-, and -N(H)-; X is N or C; Y 1 is selected from the group consisting of -C(H)=, -C(F)=, and -N=; Y 2 is selected from the group consisting of -C(H)=, -C(F)=, and -N=; Y 3 is selected from the group consisting of -C(H)=, -C(F)=, and -N=; Y 4 is selected from the group consisting of -C(H)=, -C(F)=, and -N=; Z is selected from the group consisting of -C(H)=, -C(F)=, and -N=; Each R a is independently selected from the group consisting of halogen, optionally substituted C1-C3 aliphatic, and -COOH; R e1 is selected from the group consisting of hydrogen, C1-C5-alkyl, and C3-C5-cycloalkyl; R e2 is selected from the group consisting of hydrogen, C1-C5-alkyl, and C3-C5-cycloalkyl; m is 0 to 2; and n is 0 to 5. 2. The compound is (I-a) or (I-b) The compound according to Embodiment 1 represented by TIFF2025519597000042.tif79165, or a pharmaceutically acceptable salt thereof. 3. The compound is formula (I-b1) or (I-b2) The compound according to Embodiment 1 represented by TIFF2025519597000043.tif64165, or a pharmaceutically acceptable salt thereof. 4. The compound according to any one of Embodiments 1 to 3, wherein X is C. 5. The compound according to any one of Embodiments 1 to 4, wherein L is -O-. 6. The compound according to any one of Embodiments 1 to 3, wherein X is N. 7. The compound according to any one of Embodiments 1 to 6, wherein L is selected from the group consisting of -S(O)2-, -CH2-, and -C(O)-. 8. The compound according to any one of Embodiments 1 to 6, wherein L is -CH2-. 9. The compound according to any one of Embodiments 1 to 8, wherein A is selected from the group consisting of an optionally substituted 5- to 8-membered carbocyclic ring, an optionally substituted 5- to 7-membered heterocyclic ring, and an optionally substituted phenyl. 10. The compound according to any one of Embodiments 1 to 8, wherein A is selected from the group consisting of an optionally substituted cyclohexyl, an optionally substituted bicyclo[1.1.1]pentyl, an optionally substituted bicyclo[2.2.2]octyl, an optionally substituted piperidinyl, and an optionally substituted phenyl. 11. A is The compound according to any one of Embodiments 1 to 8, selected from the group consisting of TIFF2025519597000044.tif99165. 12. Each R a is independently selected from the group consisting of methyl and -COOH, the compound according to any one of Embodiments 1 to 11. 13. n is 1 to 5, and at least one example of R a is -COOH, the compound according to any one of Embodiments 1 to 12. 14.R a is the compound according to Embodiment 11 which is -COOH. 15.Y 1 is -C(H)= or -N=, and Y 2 is the compound according to any one of Embodiments 1 to 14 which is -C(H)= or -N=. 16.Y 1 is -C(H)=, and Y 2 is the compound according to any one of Embodiments 1 to 14 which is -C(H)=. 17.Y 1 is -N=, and Y 2 is the compound according to any one of Embodiments 1 to 14 which is -C(H)=. 18.Y 1 is -C(H)=, and Y 2 is the compound according to any one of Embodiments 1 to 14 which is -N=. 19.Y 1 is -N=, and Y 2 is the compound according to any one of Embodiments 1 to 14 which is -N=. 20. Z is the compound according to any one of Embodiments 1 to 19 which is -C(H)=. 21. Z is the compound according to any one of Embodiments 1 to 19 which is -N=. 22. Z is the compound according to any one of Embodiments 1 to 19 which is -C(F)=. 23. as follows: Compounds selected from the group consisting of TIFF2025519597000045.tif207165, TIFF2025519597000046.tif226165, TIFF2025519597000047.tif227165, TIFF2025519597000048.tif228165, TIFF2025519597000049.tif232165, TIFF2025519597000050.tif226165, TIFF2025519597000051.tif228165, TIFF2025519597000052.tif232165, TIFF2025519597000053.tif232165, TIFF2025519597000054.tif227165, TIFF2025519597000055.tif228165, TIFF2025519597000056.tif227165, TIFF2025519597000057.tif86165, or a pharmaceutically acceptable salt thereof. 24. A pharmaceutical composition comprising the compound according to any one of embodiments 1 to 23 and a pharmaceutically acceptable adjuvant. 25. A method for treating a CFTR-mediated disease or disorder, the method comprising administering to a patient in need thereof the compound according to any one of embodiments 1 to 23 or the pharmaceutical composition according to embodiment 24. 26. The disease or condition is selected from cystic fibrosis, asthma, smoking-induced COPD, chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility caused by congenital absence of the vas deferens (CBAVD), mild lung disease, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), liver disease, hereditary emphysema, hereditary hemochromatosis, coagulation / fibrinolysis deficiency, protein C deficiency, type 1 hereditary angioedema, lipid processing deficiency, familial hypercholesterolemia, type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage disease, I-cell disease / pseudo-Hurler, mucopolysaccharidosis, Sandhoff disease / Tay-Sachs disease, Crigler-Najjar type II, multiple endocrine neoplasia / hypoinsulinemia, diabetes, Laron-type dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, glycosylation CDG type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, diabetes insipidus (DI), neurogenic osseous dysplasia DI, nephrogenic DI, Charcot-Marie-Tooth syndrome, Pelizaeus-Merzbacher disease, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, some polyglutamine neuropathies, Huntington's disease, spinocerebellar degeneration type I, bulbospinal muscular atrophy, dentatorubral-pallidoluysian atrophy, myotonic dystrophy, spongiform encephalopathy, hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler-Scheinker syndrome, COPD, dry eye disease, Sjogren's disease, osteoporosis, osteopenia, bone healing and bone growth, bone repair, bone regeneration, reduction of bone resorption, increase in bone deposition, Gorham syndrome, chloride channelopathy, congenital myotonia, Bartter syndrome type III, Dent disease, startle disease, epilepsy, startle disease, lysosomal storage disease, Angelman syndrome, primary ciliary dyskinesia (PCD), PCD with inversion, PCD without inversion, and ciliary dysplasia, the method according to embodiment 25. 27. The method according to embodiment 25 or 26, wherein the disease or condition is selected from cystic fibrosis, congenital bilateral absence of the vas deferens (CBAVD), acute, recurrent, or chronic pancreatitis, diffuse bronchiectasis, asthma, allergic bronchopulmonary aspergillosis, chronic obstructive pulmonary disease (COPD), chronic rhinosinusitis, dry eye disease, protein C deficiency, abetalipoproteinemia, lysosomal storage disease, type 1 chylomicronemia, mild lung disease, lipid processing deficiency, hereditary angioedema type 1, coagulation / fibrinolysis, hereditary hemochromatosis, CFTR-related metabolic syndrome, chronic bronchitis, constipation, pancreatic insufficiency, hereditary emphysema, and Sjögren's syndrome. 28. The method according to any one of embodiments 25 to 27, wherein the disease or condition is cystic fibrosis. 29. A method of treating cystic fibrosis in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1 to 23 or a pharmaceutical composition according to embodiment 24. 30. The method according to embodiment 29, wherein the subject is a human.

Examples

[0105] Illustration General procedure Preparation of intermediates Schemes A - D show methods for the preparation of intermediates A - D commonly used for the synthesis of compounds of formula (I) and / or (II) which are readily prepared from commercially available starting materials or by known reactions well known to those skilled in the art.

[0106] Scheme A. Preparation of Intermediate A TIFF2025519597000058.tif84165 Scheme A shows the synthetic method for the preparation of Intermediate A. As shown in Scheme A, commercially available or readily prepared starting material 1 is condensed with hydrazine 2 carrying an appropriate protecting group P, such as 4-methoxybenzyl, using a dehydrating reagent, such as 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetan-2,4-disulfide, while heating (step 1) to provide compound 3. Compound 3 can be alkylated with alkylating agent 4 at its piperidine nitrogen with removal of the protecting group 4-methoxybenzyl under the reaction conditions (step 2) to obtain intermediate A.

[0107] Scheme B. Preparation of Intermediate B TIFF2025519597000059.tif53165 Similar to Scheme A, commercially available or readily prepared starting material 1 is condensed with arylhydrazine 5 carrying the appropriate group required by formula (I) under heating conditions to obtain intermediate B (G 2 = F, Cl, Br, and I). This intermediate can be further converted to a hydroxyl group (intermediate B, G 2 = OH) by being catalyzed by a palladium-mediated reagent (step 2). For example, bromide can be converted to hydroxyl by being catalyzed by a Pd catalyst, such as tris(dibenzylideneacetone)dipalladium, by using cesium hydroxide monohydrate.

[0108] Scheme C. Preparation of Intermediate C TIFF2025519597000060.tif120165 Scheme C shows intermediate C (G 3=OH, NH2, Cl, Br, I, OT, OM). The preparation of aryl halide 6 (X = Cl, Br, I) is shown. Aryl halide 6 can be converted to alkyl aryl ketone via available methods known to those skilled in the art, such as coupling with 1-ethoxyvinyltri-n-butyltin or treating halide 6 with nBuLi followed by addition of acyl halide (step 1) to obtain ketone 7. Compound 7 can be reduced with a reducing agent, such as sodium borohydride (step 2), to obtain achiral intermediate C. Ketone 7 can also be reduced via an enantioselective protocol, such as reduction with BH3·Me2S catalyzed by (S)-2-methyl-CBS oxazaborolidine, to obtain enantiomerically pure alcohol intermediate C (G 3 =OH) in good yield and high ee. This intermediate can be easily converted to chloride or bromide (step 3). Ketone 7 is condensed with chiral auxiliary 8 (step 4), and then subjected to reduction or carbon anion addition conditions to generate intermediate C (G 3 =NH2). Alternatively, halide 6 is converted to aryl aldehyde 9 (step 5). Compound 9 is condensed with chiral auxiliary 8 catalyzed by titanium(IV) isopropoxide (step 6) to obtain compound 10. Addition of Grignard or similar metal agent to compound 10 (step 7) generates intermediate C (G 3 =NH2). Intermediate D can be synthesized via the following methods (Schemes Da - Dc). The choice of method is determined by the nature and position of Y (Y 1 ~Y 4 ).

[0109] Scheme Da. Preparation of Intermediate D (Method 1) As shown in Scheme Da, en-1,3-dione 11 is condensed with appropriately protected hydrazine 2 (step 1) to generate intermediate D-1. This intermediate (D-1) is coupled with appropriately substituted aryl analog 12 (step 2) to obtain intermediate D (G 2= Cl, Br, I, OH, NH2) is generated. The selection of reaction conditions is determined by the nature of functional group G 4 and Y 2 / Y 3 is determined by the nature of / Y. For example, when 12 is 3,5-dichloropyridazine, the direct halogen substitution between intermediate D-1 and 12 (G 4 = Br) can be carried out by using the catalyst Cs2CO3 with heating. Intermediate D (G 2 = Cl, Br, I) can be further converted to other intermediates D (G 2 = OH) (step 3) and D (G 2 = Cl, Br, I; G 4 = OH, NH2, Cl, Br, I) (step 4) to meet the coupling needs of the next step of the reaction (see Schemes 1 - 6).

[0110] Scheme Db. Preparation of Intermediate D (Method 2) TIFF2025519597000062.tif99165 Scheme Db shows an alternative method for preparing intermediate D. En-1,3-dione 11 is condensed with arylhydrazine 13 having the desired functional group (G 2 ) (step 1) to directly form intermediate D (G2 = Cl, Br, I, OH, NH2). When arylhydrazine 13 is not commercially available, it can be easily prepared via a halogen substitution reaction between 14 and protected hydrazine (step 2) or an amination reaction by treating arylamine 15 with sodium nitrite salt / SnCl2 / HCl (step 3).

[0111] Scheme Dc. Preparation of Intermediate D (X = Br, I) TIFF2025519597000063.tif49165 Scheme Dc shows another method for preparing intermediate D (X = Br, I). 1,3-dione 16 is condensed with DMF-DMA (step 1) to form compound 17. This compound is condensed with hydrazine hydrate and then cyclized (step 2) to produce compound 18. Halogenation of 18 with NBS or NIS (step 3) yields the desired intermediate D (X = Br, I).

[0112] Representative scheme for the synthesis of exemplary compounds of the present disclosure The compounds of formula (I) and / or (II) of the better disclosure can be better understood in combination with the following synthetic schemes (Schemes 1-6) and the methods indicating the means by which the compounds can be synthesized. The starting materials for the reaction schemes described herein are prepared according to the methods described for intermediate preparation (Schemes A-D), or in some examples are commercially available substances. These schemes are representative schemes that do not purport to include all of the methods used for the synthesis of the exemplary compounds of the present disclosure. The synthesis of some compounds may lie outside the scope of Schemes 1-6. In this case, refer to the examples.

[0113] Scheme 1. Synthesis of the compound of formula (I) (X 1 = N (starting from intermediate A)). TIFF2025519597000064.tif99165 As shown in Scheme 1, intermediate A can be condensed with substituted aryl 12 under appropriate reaction conditions (step 1) to obtain compound 1-1. This compound is further coupled with intermediate C (step 2), and after removal of the carboxylic acid protecting group, such as methyl or ethyl, a compound of formula (I) (X 1 = N) can be obtained. The selection of reagents and reaction conditions in step 2 is determined by the nature of the functional groups G 2 , G 3 and Y 2 / Y 3 ). For example, G 2 and G 3When both are hydroxyl groups, Mitsunobu reaction conditions are applicable. In this case, R e1 and R e2 The chirality of the carbon atom bearing the substituent will be inverted. G 2 When G is halogen, G 3 should be a hydroxyl or amino group, and appropriate substitution reaction conditions should be selected. In this case, R e1 and R e2 The chirality of the carbon atom bearing the substituent is maintained. Similarly, when G 2 is hydroxyl, then G 3 should be an appropriate leaving group, such as halogen, OT, or OM, to ensure that a substitution reaction occurs.

[0114] Scheme 2. Synthesis of the compound of formula (I) (X 1 =N (starting from Intermediate B)). TIFF2025519597000065.tif135165 Scheme 2 shows an alternative synthetic sequence to that described in Scheme 1 for synthesizing the compound of formula (I) (X 1 =N). In Scheme 2, Intermediate B is coupled with Intermediate C (Step 1) to obtain Compound 2-1. The selection of reaction conditions is also determined in this case, as in Step 2 of Scheme 1, by the functional groups involved in the reaction known to those skilled in the art in a similar manner to obtain Compound 2-1. Then Compound 2-1 is coupled with Reagent 4 (Step 2, Scheme 2) to obtain the compound of formula (I) (X 1 =N).

[0115] Scheme 3. Synthesis of the compound of formula (I) (X 1 =C) (Method 1) TIFF2025519597000066.tif140165 As shown in Scheme 3, Intermediate D (G 2 =Cl, Br, I, OH, NH2; G 5 =OH, NH2, Cl, Br, I) is coupled with Compound 4 (Step 1) to produce Compound 3-1. The selection of reaction conditions / reagents is based on the functional group G1 -G 3 is determined by. For example, when G 3 is OH or NH2, then G 1 should be a leaving group to ensure that the substitution reaction occurs. When G 5 is Cl, Br, I, then G 1 should be S, OH, or NH2 to enable the substitution reaction to occur. Compound 3-1 is condensed with intermediate C under the same conditions as in Scheme 1, Step 2 (Step 2) to give a compound of formula (I) (X 1 = carbon).

[0116] Scheme 4. Synthesis of the compound of formula (I) (X = C) (Method 2) TIFF2025519597000067.tif145165 Scheme 4 shows an alternative synthetic sequence to that described in Scheme 3 for synthesizing the compound of formula (I) (X 1 = carbon). In Scheme 4, intermediate D (G 2 = Cl, Br, I, OH, NH2) is coupled with intermediate C under substitution reaction conditions (Step 1) (Step 1) to give compound 4-1. Reduction of compound 4-1 (Step 2) is carried out under achiral conditions using a reducing agent, for example, sodium borohydride, or under enantioselective conditions by using chiral catalysis, for example, (R,R)-TsDPEN-RuCl(p-cymene), to provide alcohol 4-2 (* indicates an enantiomerically pure analog). Compound 4-2 is then coupled with reagent 4 (Step 3) to give a compound of formula (I) (X 1 = carbon). Alternatively, alcohol 4-2 is converted to a halide or a suitable leaving group (e.g., OT or OM) 4-3 (G 5 = Cl, Br, I, OT, OM) (Step 4), which is then reacted with reagent 4 (G 1 = OH, NH2) (Step 5) to give a compound of formula (I) (X 1 = carbon).

[0117] Scheme 5. Synthesis of the compound of formula (I) (X = C) (Method 3) TIFF2025519597000068.tif149165In some other cases, alternative synthetic sequences are used to successfully synthesize the compounds of formula (I) as shown in Scheme 5. In Scheme 5, compound 12 is condensed with enantiomerically pure alcohol or amine intermediate C with inversion of stereochemistry under Mitsunobu reaction conditions (step 1) (G 2 =OH and G 3 =OH) to give compound 5-1 (W = O). When G 3 is an amino group, G 2 should be a halide. In this case, a Pd-mediated backward coupling reaction is used with retention of stereochemistry to produce compound 5-1 (W = O or NH). Bromide 5-1 is converted to a boronic acid or boronic acid ester (5-2) (step 2), which is then coupled with intermediate D-1 under backward coupling reaction conditions (step 3) to produce compound 5-3. Compound 5-3 can be reduced via the conditions described in step 2 of Scheme 3 (step 4) to give alcohol 5-4. Then reagent 4 is used according to the method described in step 3 or step 4 of Scheme 4, and the reaction conditions shown in step 3 of Scheme 3 are applied to introduce the side chain into compound 5-4 (step 5) to provide the compound of formula (I).

[0118] Scheme 6. Synthesis of Compounds of Formula (II) (X = C) TIFF2025519597000069.tif120165Scheme 6 shows the synthesis of compounds of formula (II) (X = C). In step 1, the pyrazole nitrogen (intermediate D, X = Br, I) is alkylated catalyzed by a strong base, such as sodium hydride, to give compound 6-1. This compound can be coupled with 12 (G 4 =B(OH)2) under standard Suzuki coupling conditions known to those skilled in the art (step 2) to give compound 6-2. The remainder of the steps and the strategy (reaction sequence) are the same as those of Schemes 1-5. Enantiomerically pure examples and synthetic intermediates in the present disclosure can be achieved either via chiral separation, e.g., via chiral HPLC or SFC, or via enantioselective reactions.

[0119] Analytical procedures High-performance liquid chromatography-mass spectrometry (LC-MS) for determining the compound retention time (RT) and related mass ions was performed using one of the following methods.

[0120] LC-MS Method 1: Mobile phase: A: water (0.01% TFA). B: ACN (0.01% TFA). Gradient: 5% - 95% B in 1.5 minutes. Flow rate: 2.0 mL / min. Column: Sunfire C18, 4.6×50 mm, 3.5 μm. Oven temperature: 50 °C. Mass range: 110 - 1000. UV (214 nm, 254 nm). LC-MS Method 2: Column: Xbridge C18(2) (4.6×50 mm, 3.5 μm Mobile phase: H2O (10 mmol NH4HCO3) (A) / ACN (B). Elution program: Gradient of 10 to 95% B in 1.5 minutes at 1.8 mL / min. Temperature: 50 °C. Detection: UV (214 nm, 254 nm) and MS (ESI, positive mode, 103 - 800 amu).

[0121] LC-MS Method 3: Mobile phase: A: water (0.01% TFA) B: ACN (0.01% TFA). Gradient: 5% - 95% B in 1.5 minutes. Flow rate: 2.0 mL / min. Column: Sunfire C18, 3.5 μm 4.6×50 mm. Oven temperature: 50 °C. Mass range: 110 - 1000 : 214 nm; 254 nm. LC-MS Method 4: Column: Xbridge C18(2) (4.6×50 mm, 3.5 μm). Mobile phase: H2O (10 mmol NH4HCO3) (A) / ACN (B). Elution program: Gradient of 5 to 90% B in 1.4 minutes at 1.8 mL / min. Temperature: 50 °C. Detection: UV (214 nm, 254 nm) and MS (ESI, positive mode, 105 - 900 amu).

[0122] 1 1H NMR spectra were collected at 400 MHz using an ASW 5 mm probe on a Gemini 400 or Varian Mercury 400 spectrometer (unless otherwise described), and were usually recorded at ambient temperature in a deuterated solvent such as D2O, DMSO-d6, CH3OH-d4 or CDCl3, unless otherwise described. Chemical shift values (δ) are reported in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard. Abbreviations: ACN: Acetonitrile Boc: tert-Butyloxycarbonyl DEA: Diethylamine DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene DCE: 1,2-Dichloroethane DCM: Dichloromethane DIAD: Diisopropyl azodicarboxylate DMAP: 4-Dimethylaminopyridine DMSO: Dimethyl sulfoxide dppf: 1,1’-Bis(diphenylphosphino)ferrocene EA: Ethyl acetate ee: Enantiomeric excess ESI: Electrospray ionization HPLC: High performance liquid chromatography LC-MS: Liquid chromatography - mass spectrometry MsCl: Methanesulfonyl chloride Pd / C: Palladium on carbon rt: Room temperature PE: Petroleum ether SFC: Supercritical fluid chromatography TBS: tert-Butyldimethylsilyl TIPS: Triisopropylsilyl THF: Tetrahydrofuran THP: Tetrahydropyran Ts: Tosyl

[0123] General disclaimer regarding stereochemistry It is understood that the absolute stereochemistry for all intermediates and examples described in this specification has not been determined. The assignment of R or S to the chiral center(s), if any, is entirely arbitrary and is only for the purpose of distinguishing the different fractions (P1 and P2) eluted from either flash column chromatography or prep-HPLC, or chiral HPLC, or SFC. There is no correlation between P1 or P2 and the designation of S or R. Methods for determining the absolute stereochemistry of enantiomerically enriched samples are known to those skilled in the art.

[0124] Both ChemDraw and Mol2Nam from OpenEye Scientific software are used to create the names of compounds. In case of inconsistency, the structure shall prevail.

[0125] Preparation of Intermediates Preparation of Intermediate A-1 Methyl 3-((3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-b]pyridin-7-yl)methyl)bicyclo[1.1.1]pentane-1-carboxylate TIFF2025519597000070.tif53165 Step 1. Synthesis of 1-(4-methoxybenzyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine TIFF2025519597000071.tif A mixture of 3-(2,2,2-trifluoroacetyl)piperidin-2-one (2500 mg, 12.8 mmol) and (4-methoxybenzyl)hydrazine hydrochloride (2685 mg, 15.4 mmol) in toluene (50 mL) was stirred at 60 °C for 1 h and concentrated. A solution of (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetan-2,4-disulfide) (10364 mg, 25.6 mmol) in THF (50 mL) was added and the mixture was stirred at 70 °C for 12 h. The mixture was concentrated and the crude product was purified by silica gel column chromatography (PE:EA = 5:1) to give the title compound (1.90 g, 48% yield) as a yellow solid. LC-MS (Method 1): retention time = 2.21 min. MS (ESI) m / z 312.0 [M+H] + 。

[0126] Step 2. Synthesis of 3-((1-(4-methoxybenzyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-b]pyridin-7-yl)methyl)bicyclo[1.1.1]pentane-1-carboxylic acid TIFF2025519597000072.tif To a solution of 1-[(4-methoxyphenyl)methyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[3,4-b]pyridine (810 mg, 2.60 mmol) in THF (5 mL) were added methyl 3-(bromomethyl)bicyclo[1.1.1]pentane-1-carboxylate (570 mg, 2.60 mmol) and t-BuOK (7.8 mL, 7.81 mmol, 1 M in THF). The reaction was stirred at room temperature for 2 h. The mixture was concentrated and the crude was purified by flash chromatography (10 - 50% EA in heptane) to give 3-[[1-[(4-methoxyphenyl)methyl]-3-(trifluoromethyl)-5,6-dihydro-4H-pyrazolo[3,4-b]pyridin-7-yl]methyl]bicyclo[1.1.1]pentane-1-carboxylic acid (820 mg, 72% yield) as a white solid. LC-MS (Method 1): Retention time = 2.08 minutes. MS (ESI) m / z 436.3 [M+H] + 。

[0127] Step 3. Synthesis of methyl 3-((1-(4-methoxybenzyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-b]pyridin-7-yl)methyl)bicyclo[1.1.1]pentane-1-carboxylate TIFF2025519597000073.tif48165 A solution of 3-((1-(4-methoxybenzyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-b]pyridin-7-yl)methyl)bicyclo[1.1.1]pentane-1-carboxylic acid (820 mg, 1.88 mmol) in methanol (5 mL) and THF (5 mL) was added dropwise with trimethylsilyldiazomethane (1.9 mL, 3.77 mmol, 2 M), and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated. The crude product was purified by flash chromatography (10 - 20% EA in heptane) to give the title compound (790 mg, 93% yield) as a white solid. LC-MS (Method 1): Retention time = 2.25 minutes. MS (ESI) m / z 450.3 [M+H] + 。

[0128] Step 4. Synthesis of methyl 3-((3-(trifluoromethyl)-5,6-dihydro-1H-pyrazolo[3,4-b]pyridin-7(4H)-yl)methyl)bicyclo[1.1.1]pentane-1-carboxylate A solution of methyl 3-((1-(4-methoxybenzyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-b]pyridin-7-yl)methyl)bicyclo[1.1.1]pentane-1-carboxylate (470 mg, 1.05 mmol) in chloroform (4 mL) was added trifluoroacetic acid (2.0 mL, 26.0 mmol), and the mixture was stirred at 80 °C for 5 h. The mixture was concentrated. The crude product was purified by flash chromatography eluting with 10 - 20% ethyl acetate in heptane to yield the title compound (170 mg, 49% yield) as a white solid. LC-MS (method 4): retention time = 1.97 min. MS (ESI) m / z 330.2 [M+H] + 。 1 H NMR (500 MHz, DMSO-d6) δ 12.42 (s, 1H), 3.57 (s, 3H), 3.29 (s, 2H), 3.17 - 3.10 (m, 2H), 2.46 - 2.50 (m, 2H), 1.92 (s, 6H), 1.85 - 1.77 (m, 2H). The following intermediates were prepared according to a protocol similar to that of Intermediate A-1. TIFF2025519597000075.tif154165

[0129] Preparation of Intermediate B-1 3-(3-(Trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridin-1-yl)phenol TIFF2025519597000076.tif32165Step 1. Synthesis of 1-(3-bromophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[3,4-b]pyridine (Intermediate B-1a) A solution of 3-(2,2,2-trifluoroacetyl)piperidin-2-one (1500 mg, 7.69 mmol) and (3-bromophenyl)hydrazine (2157 mg, 11.5 mmol) in toluene (10 mL) was stirred at 60 °C for 2 h and then the solvent was evaporated. The residue was dissolved in THF (20 mL). To this solution was added (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide) (4664 mg, 11.5 mmol). The reaction mixture was stirred at 55 °C for 12 h. The reaction mixture was then concentrated in vacuo. The residue was purified by silica gel column chromatography (0 - 35% ethyl acetate in heptane) to give the title compound B-1a (1200 mg, 43% yield) as a colorless oil. LC-MS (Method 3): retention time = 2.26 min. MS (ESI) m / z 345 / 347 [M+H] + 。

[0130] Step 2. Synthesis of 3-[3-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[3,4-b]pyridin-1-yl]phenol TIFF2025519597000078.tif32165A solution of 1-(3-bromophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[3,4-b]pyridine (500 mg, 1.44 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was added with cesium hydroxide monohydrate (728 mg, 4.33 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (31 mg, 0.0722 mmol), and then tris(dibenzylideneacetone)dipalladium (66 mg, 0.0722 mmol) under Ar. The reaction mixture was stirred at 100 °C for 12 h. Then water (30 mL) was added and the mixture was extracted with EA (2 × 40 mL). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, and then concentrated in vacuo. The residue was purified by combiflash (A: water (10 mmol / L NH4HCO3); B: ACN) to give the title compound (300 mg, 73% yield) as a yellow solid. LC-MS (method 1): retention time = 1.98 min. MS (ESI) m / z 284.0 [M+H] + 。

[0131] Preparation of Intermediate B-2 5-(3-(Trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridin-1-yl)pyridin-3-ol TIFF2025519597000079.tif32165The title compound was synthesized in essentially the same manner as the preparation of Intermediate B-1. LC-MS (method 1): retention time = 1.76 min. MS (ESI) m / z 285.0 [M+H] + 。

[0132] Preparation of Intermediate C-1 1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)ethan-1-ol TIFF2025519597000080.tif27165Step 1. Synthesis of 1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)ethan-1-one A solution of 1-ethoxyvinyltri-n-butyltin (1.7 mL, 4.93 mmol) in toluene (20 mL) was added with 2,2-difluoro-5-iodo-1,3-benzodioxole (1.40 g, 4.93 mmol) and Pd(PPh3)2Cl2 (138 mg, 0.20 mmol). The reaction mixture was stirred at 90 °C for 12 h under N2 and then cooled to room temperature. HCl (30 mL, 60.0 mmol) was added and stirred for 0.5 h. The mixture was extracted with EA (3 × 30 mL). The organic layers were combined, washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash column chromatography eluting with 5% ethyl acetate in isohexane to afford the title compound (950 mg, 95% yield) as a colorless oil. LC-MS (Method 1): retention time = 2.02 min. MS (ESI) m / z 201.0 (M+H) + 。 1 H NMR (500 MHz, CDCl3) δ 7.77 (dd, J = 8.3, 1.6 Hz, 1H), 7.69 (d, J = 1.6 Hz, 1H), 7.14 (d, J = 8.3 Hz, 1H), 2.60 (s, 3H).

[0133] Step 2. Synthesis of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethan-1-ol To a solution of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)pyridine (900 mg, 4.50 mmol) in methanol (10 mL) was added NaBH4 (340 mg, 8.99 mmol) at 0 °C and stirred for 2 h. Then the mixture was poured into water (40 mL) and extracted with EA (3 × 30 mL). The organic layers were combined, washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash column chromatography eluting with 10% ethyl acetate in isohexane to afford the title compound (860 mg, 94.6% yield) as a colorless oil. LC-MS (Method 1): Retention time = 1.94 min. MS(ESI)m / z 185.0(M-H2O+H) + .

[0134] Preparation of intermediate C-1R I-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethan-1-ol TIFF2025519597000083.tif27165Step 1. Synthesis of (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethan-1-ol TIFF2025519597000084.tif27165N2 A solution of (S)-2-methyl-CBS oxazaborolidine (reference 1) [(8.25 g, 0.03 mol) in DCM (200 mL) was added to BH3 . Me2S (150 mL, 2M in DCM) was added at 0° C. The reaction was stirred at room temperature for 0.5 h, then a solution of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethan-1-one (product of step 1 of preparation of intermediate C-1, 60 g, 0.30 mol) in DCM (300 mL) was added dropwise at 0° C. for 1 h. The reaction mixture was stirred at room temperature for 4 h. The reaction was quenched at 0° C. by addition of MeOH and then concentrated in vacuo to give a residue which was purified by flash silica gel column chromatography (0% to 10% ethyl acetate in petroleum ether) to provide the title compound (56 g, 92% yield) as a light yellow liquid. LC-MS: retention time = 1.75 min. MS(ESI)m / z 185.0[M-H2O+H] + .

[0135] Preparation of intermediate C-1S (S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethan-1-ol TIFF2025519597000085.tif27165 Intermediate C-1S was synthesized in essentially the same manner as intermediate C-1R, except that in step 1, (R)-2-methyl-CBS oxazaborolidine (Reference 1) was used. TIFF2025519597000086.tif143165

[0136] Preparation of Intermediate C-4 5-(1-Chloroethyl)-2,2-difluorobenzo[d][1,3]dioxole TIFF2025519597000087.tif27165To a solution of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethanol (Intermediate C-1) (1.00 eq, 6.00 g, 29.7 mmol) and triethylamine (3.00 eq, 12 mL, 89.0 mmol) in DCM (120 mL) was added methanesulfonyl chloride (1.50 eq, 3.5 mL, 44.5 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 4 h. The mixture was then diluted with water (50 mL) and extracted with DCM (3 × 80 mL). The combined organic phases were washed with brine and dried over Na2SO4. The organics were concentrated in vacuo. The residue was purified by flash column chromatography (PE:EA = 5:1) to afford 5-(1-chloroethyl)-2,2-difluoro-1,3-benzodioxole (5.00 g, 22.7 mmol, 76.3% yield) as a colorless oil. LC-Mass Method 1: Retention time = 2.15 min. MS (ESI) m / z: Not observed.

[0137] Preparation of Intermediate C-4R (R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)propan-1-ol TIFF2025519597000088.tif27165Step 1. Synthesis of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)propan-1-ol A solution of 2,2-difluoro-1,3-benzodioxole-5-carbaldehyde (3000 mg, 16.1 mmol) in THF (30 mL) was added with ethylmagnesium bromide (48 mL, 48.4 mmol). The reaction mixture was stirred at room temperature for 1 h. Then it was quenched with aqueous NH4Cl solution and extracted with EA (10 mL×3). The combined organic solutions were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 - 10% ethyl acetate in heptane) to give the title compound (2500 mg, 71.7% yield) as a colorless oil. LCMS (method 4): retention time = 1.80 min. MS (ESI) m / z 199.1 [M+H-H2O] + 。

[0138] Step 2. Synthesis of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)propan-1-one Manganese dioxide (5027 mg, 57.8 mmol) was added to a solution of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)propan-1-ol (2500 mg, 11.6 mmol) in DCM (30 mL). The suspension was stirred at room temperature for 12 h. Then the solid was removed by filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (0 - 5% ethyl acetate in heptane) to give the title compound (2000 mg, 80.7% yield) as a colorless oil. LCMS (method 4): retention time = 1.94 min. MS (ESI) m / z: not observed.

[0139] Step 3. Synthesis of (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)propan-1-ol In a solution of DCM (25 mL) under 27165N2, 1-(2,2-difluoro-1,3-benzodioxol-5-yl)propan-1-one (2200 mg, 10.30 mmol) and (s)-methyloxazaborolidine (0.31 mL, 1.03 mmol), borane-methyl sulfide complex (0.98 mL, 10.30 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched at 0 °C by the addition of MeOH and then concentrated in vacuo to give a residue, which was purified by flash silica gel column chromatography (ethyl acetate in petroleum ether from 0% to 10%) to afford the title compound (2000 mg, 88.3% yield) as a colorless liquid. LCMS (Method 2): retention time = 1.83 min. MS (ESI) m / z 199.1 [M - H2O + H] + 。

[0140] Preparation of Intermediate C-6a TIFF2025519597000092.tif Step 1. Synthesis of (R,E)-N-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methylene)-2-methylpropane-2-sulfinamide To a solution of R-2-methylpropane-2-sulfinamide (SM-1) (3256 mg, 26.9 mmol) in THF (50 mL), 2,2-difluoro-1,3-benzodioxole-5-carbaldehyde (5000 mg, 26.9 mmol) and titanium(IV) isopropoxide (16 mL, 53.7 mmol) were added. The reaction mixture was stirred at 60 °C for 2 hours. Then the solid was removed by filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (0 - 20% ethyl acetate in heptane) to yield the title compound (5800 mg, 74.6% yield) as a yellow oil. LCMS (Method 4): retention time = 2.09 min. MS (ESI) m / z 290.0 [M + H] + 。

[0141] Synthesis of 2.N-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethyl)-2-methylpropan-2-sulfinamide TIFF2025519597000094.tif27165A solution of (R,E)-N-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methylene)-2-methylpropan-2-sulfinamide (5800 mg, 20.0 mmol) in THF (60 mL) was added with methylmagnesium bromide (20 mL, 60.1 mmol) at -20 °C under N2. The reaction mixture was stirred at room temperature for 1 h. Then the reaction was quenched with aqueous NH4Cl solution and extracted with EA (10 mL × 3). The EA solution was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 - 10% ethyl acetate in heptane) to give the title compound (4500 mg, 73.5% yield) as a yellow oil. LCMS (method 4): retention time = 1.91 min. MS (ESI) m / z 306.1 [M + H] + 。

[0142] Synthesis of (S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethan-1-amine TIFF2025519597000095.tif27165Hydrochloric acid (18 mL, 73.7 mmol) was added to a solution of N-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethyl]-2-methyl-propan-2-sulfinamide (4500 mg, 14.7 mmol) in 1,4-dioxane (18 mL). The solution was stirred at room temperature for 2 h. The solvent was removed. EA (20 mL) was added to this residue and concentrated in vacuo. Another portion of EA (20 mL) was added and concentrated again to give the title compound (3000 mg, 85.7% yield) as a white solid. LCMS (method 4): retention time = 1.60 min. MS (ESI) m / z 185.1 [M + H - NH2] + 。

[0143] Preparation of Intermediate C-6b (S)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-2-methylpropan-1-amine hydrochloride TIFF2025519597000096.tif27165 Intermediate C-6b was synthesized as a white solid in 86.9% yield in essentially the same manner as Intermediate C-6a. LCMS (Method 4): Retention time = 1.86 min. MS (ESI) m / z 213.1 [M-H2O+H]+.

[0144] Preparation of Intermediate C-6c (S)-Cyclopropyl(2,2-difluorobenzo[d][1,3]dioxol-5-yl)methanamine hydrochloride TIFF2025519597000097.tif32165 Intermediate C-6b was synthesized as a white solid in 84% yield in essentially the same manner as Intermediate C-6c. LCMS (Method 4): Retention time = 1.75 min. MS (ESI) m / z 211.1 [M-NH3+H]+.

[0145] Preparation of Intermediate C-6d (S)-1-(2,2,6-Trifluorobenzo[d][1,3]dioxol-5-yl)ethan-1-amine TIFF2025519597000098.tif27165 Step 1. Synthesis of 4-bromo-5-fluorobenzene-1,2-diol A solution of 1-bromo-2-fluoro-4,5-dimethoxy-benzene (1.00 eq, 15.00 g, 63.8 mmol) in DCM (200 mL) was added with boron tribromide (1.50 eq, 9.0 mL, 95.7 mmol, 1 M in dichloromethane) at 0 °C. The reaction mixture was stirred at room temperature for 4 h. Methanol (50 mL) was added to the mixture at 0 °C, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluted with DCM. The desired fractions were combined and concentrated in vacuo until dry to afford 4-bromo-5-fluoro-benzene-1,2-diol (13.00 g, 62.8 mmol, 98.4% yield) as a brown oil. LC-MS method 1: retention time = 1.50 min. MS (ESI) m / z 207.0, 209.0 [M+H] + 。

[0146] Step 2. Synthesis of 5-bromo-6-fluorobenzene[d][1,3]dioxole-2-thione A solution of 4-bromo-5-fluoro-benzene-1,2-diol (1.00 eq, 15.00 g, 72.5 mmol) and 4-dimethylaminopyridine (4.00 eq, 35412 mg, 290 mmol) in DCM (150 mL) was added with thiophosgene (2.50 eq, 14 mL, 181 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 12 h. The mixture was filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (10:1). The desired fractions were concentrated in vacuo until dry to afford 5-bromo-6-fluoro-1,3-benzodioxole-2-thione (15.00 g, 60.2 mmol, 83.1% yield) as a white solid. LC-MS method 2: retention time = 1.86 min. MS (ESI) m / z 249.0, 251 [M+H] + 。

[0147] Step 3. Synthesis of 5-bromo-2,2,6-trifluorobenzene[d][1,3]dioxole A suspension of 1,3-dibromo-5,5-dimethylhydantoin (3.00 eq, 51660 mg, 181 mmol) in DCM (150 mL) was added with hydrogen fluoride-pyridine (3.00 eq, 17907 mg, 181 mmol) (70%) at -78 °C under nitrogen. The reaction mixture was stirred for 30 minutes. A solution of 5-bromo-6-fluoro-1,3-benzodioxole-2-thione (1.00 eq, 15.00 g, 60.2 mmol) in DCM (50 mL) was added to this solution at -78 °C. The reaction mixture was stirred at room temperature for 12 hours. The organic layer was washed with water (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE. The desired fraction was concentrated in vacuo until dry to afford 5-bromo-2,2,6-trifluoro-1,3-benzodioxole (12.00 g, 47.1 mmol, 78.1% yield) as a colorless oil. LC-MS Method 1: Retention time = 2.13 min. MS (ESI) m / z 255.0, 257 [M+H] + 。

[0148] Step 4.1 - Synthesis of (2,2,6-trifluorobenzo[d][1,3]dioxol-5-yl)ethan-1-one A solution of 5-bromo-2,2,6-trifluoro-1,3-benzodioxole (1.00 eq, 12.00 g, 47.1 mmol) and 1-ethoxyvinyltri-n-butyltin (1.00 eq, 16 mL, 47.1 mmol) in toluene (100 mL) was added bis(triphenylphosphine)palladium(II) chloride (0.0363 eq, 1200 mg, 1.71 mmol) under nitrogen. The reaction mixture was stirred at 90 °C for 12 h. 2M HCl (100 mL) was added to the mixture at 0 °C, stirred for 30 min, and then extracted with EA (100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with PE / EA (10:1). The desired fraction was concentrated in vacuo until dry to give 1-(2,2,6-trifluoro-1,3-benzodioxol-5-yl)pyridine (8.00 g, 36.7 mmol, 77.9% yield) as a colorless oil. LC-MS Method 1: Retention time = 1.85 min. MS (ESI) m / z 219.0 [M+H] + 。

[0149] Step 5. Synthesis of (S)-2-methyl-N-((S)-1-(2,2,6-trifluorobenzo[d][1,3]dioxol-5-yl)ethyl)propane-2-sulfinamide A solution of 1-(2,2,6-trifluoro-1,3-benzodioxol-5-yl)pyridine (1.00 eq, 5.00 g, 22.9 mmol) and (S)-2-methylpropane-2-sulfinamide (1.50 eq, 4167 mg, 34.4 mmol) in THF (50 mL) was added with titanium tetraethoxide (2.00 eq, 10458 mg, 45.8 mmol). The reaction mixture was stirred at 60 °C for 12 h. Sodium borohydride (1.10 eq, 954 mg, 25.2 mmol) was added portionwise to the mixture at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Water (20 mL) was added to the mixture at 0 °C, stirred for 30 min, and filtered. The filtrate was diluted with EA (50 mL). The organic solution was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography eluted with PE / EA (2:1). The desired fraction was concentrated in vacuo until dry to afford the title compound (5.00 g, 15.5 mmol, 67.5% yield) as a white solid. LC-MS method 2: retention time = 1.85 min. MS (ESI) m / z 324.0 [M+H] + 。

[0150] Step 6. Synthesis of (S)-1-(2,2,6-trifluorobenzo[d][1,3]dioxol-5-yl)ethan-1-amine A solution of (S)-2-methyl-N-((S)-1-(2,2,6-trifluorobenzo[d][1,3]dioxol-5-yl)ethyl)propane-2-sulfinamide (1.00 eq, 5.00 g, 15.5 mmol) in methanol (20 mL) was added with hydrogen chloride (4.0 M in 1,4-dioxane, 20 mL). The reaction mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure. The residue was dissolved in an aqueous solution of Na2CO3 (20 mL) and extracted with EA (50 mL). The EA solution was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo until dry to obtain (1S)-1-(2,2,6-trifluoro-1,3-benzodioxol-5-yl)ethanamine (3.20 g, 14.6 mmol, 94.4% yield) as a yellow oil. LC-MS method 1: retention time = 1.22 min. MS (ESI) m / z 203.3 [M+H-NH2] + 。

[0151] Preparation of Intermediate D-1 3-(Trifluoromethyl)-1,4,5,6-tetrahydro-7H-indazol-7-one TIFF2025519597000105.tif32165 Step 1. Synthesis of 3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-indazol-7-one A solution of 2-(benzyloxy)-6-(2,2,2-trifluoroacetyl)cyclohex-2-en-1-one (6000 mg, 20.0 mmol) and (4-methoxybenzyl)hydrazine (3041 mg, 20.0 mmol) in ethanol (60 mL) was added triethylamine (2.8 mL, 20.0 mmol). The reaction mixture was stirred at 80 °C for 8 hours. TFA (20 mL) was added to this reaction mixture at 80 °C and stirred for 2 hours. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (ethyl acetate in petroleum ether from 0% to 20%) to afford a crude product, which was further purified by prep-HPLC (NH4HCO3 as modifier) to give the title compound (1400 mg, 34% yield) as a white solid. LC-MS (Method 2): retention time = 1.46 min. MS (ESI) m / z 204.9 [M+H] + 。

[0152] Preparation of Intermediate D-1b 1-(3-Bromo-4-fluorophenyl)-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid TIFF2025519597000107.tif37165 Step 1. Synthesis of Ethyl 2-(3-(benzyloxy)-2-oxocyclohex-3-en-1-yl)-2-oxoacetate A solution of 2-benzyloxycyclohex-2-en-1-one (1.00 eq, 5000 mg, 24.7 mmol) in THF (50 mL) was slowly added with lithium bis(trimethylsilyl)amide (1.50 eq, 6205 mg, 37.1 mmol) at -50 °C. The solution was stirred at room temperature for 0.5 h. Diethyl oxalate (1.20 eq, 4.1 mL, 29.7 mmol) was then slowly added and the mixture was stirred at room temperature overnight. The reaction was quenched with aqueous NH4Cl and the aqueous phase was extracted with EA (10 mL×3). The combined organic solutions were washed with brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 - 15% ethyl acetate in heptane) to give the title compound ethyl 2-(3-benzyloxy-2-oxo-cyclohex-3-en-1-yl)-2-oxo-acetate (6000 mg, 19.8 mmol, 80.3% yield) as a yellow oil. LC-MS (Method 2): retention time = 1.26 min. MS (ESI) m / z 303.1 [M+H] + 。

[0153] Step 2. Synthesis of ethyl 1-(3-bromo-4-fluorophenyl)-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate (3-Bromo-4-fluoro-phenyl)hydrazine (1.10 eq, 2238 mg, 10.9 mmol) was added to a solution of ethyl 2-(3-benzyloxy-2-oxo-cyclohex-3-en-1-yl)-2-oxo-acetate (1.00 eq, 3000 mg, 9.92 mmol) in ethanol (30 mL). The reaction was stirred at 80 °C overnight. The solution was cooled to room temperature during which a yellow solid precipitated. The solid was filtered and dried in vacuo to give the title compound ethyl 1-(3-bromo-4-fluoro-phenyl)-7-oxo-5,6-dihydro-4H-indazole-3-carboxylate (1800 mg, 4.72 mmol, 47.6% yield) as a yellow solid. LC-MS (Method 2): Retention time = 2.01 minutes. MS (ESI) m / z 381.0, 383 [M+H] + 。

[0154] Synthesis of 3-(3-bromo-4-fluorophenyl)-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid TIFF2025519597000110.tif32165 To a solution of ethyl 1-(3-bromo-4-fluorophenyl)-7-oxo-5,6-dihydro-4H-indazole-3-carboxylate (1.00 eq, 800 mg, 2.10 mmol) in methanol (10 mL) was added sodium hydroxide (3.00 eq, 252 mg, 6.30 mmol). The solution was stirred at room temperature for 2 hours. The solvent was then removed and the pH was adjusted to <2 with 2N HCl. The aqueous solution was extracted with EA (25 mL × 3). The organic solution was washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo to give the title compound 1-(3-bromo-4-fluorophenyl)-7-oxo-5,6-dihydro-4H-indazole-3-carboxylic acid (610 mg, 1.73 mmol, 82.3% yield) as a yellow solid. LC-MS (Method 2): Retention time = 1.24 minutes. MS (ESI) m / z 352.9, 354.9 [M+H] + 。

[0155] Preparation of Intermediate D-1c 1-(3-bromo-4-fluorophenyl)-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carbonitrile TIFF2025519597000111.tif32165 Step 1. Synthesis of 1-(3-bromo-4-fluorophenyl)-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide In a solution of 1-(3-bromo-4-fluoro-phenyl)-7-oxo-5,6-dihydro-4H-indazole-3-carboxylic acid (1.00 eq, 600 mg, 1.70 mmol) in 32165 DMF (5 mL), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.50 eq, 969 mg, 2.55 mmol), N,N-diisopropylethylamine (3.00 eq, 0.89 mL, 5.10 mmol), and ammonium chloride (2.00 eq, 182 mg, 3.40 mmol) were added. The reaction mixture was stirred at room temperature overnight. It was then quenched with aqueous NH4Cl solution (20 mL). The aqueous solution was extracted with EA (25 mL × 3). The combined organic solutions were washed with brine (20 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 - 50% ethyl acetate in heptane) to give the title compound 1-(3-bromo-4-fluoro-phenyl)-7-oxo-5,6-dihydro-4H-indazole-3-carboxamide (420 mg, 1.19 mmol, 70.2% yield) as a yellow solid. LC-MS (Method 2): Retention time = 1.67 min. MS (ESI) m / z 351.9, 353.9 [M+H] + 。

[0156] Step 2. Synthesis of 1-(3-bromo-4-fluorophenyl)-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carbonitrile TIFF2025519597000113.tif A solution of 1-(3-bromo-4-fluoro-phenyl)-7-oxo-5,6-dihydro-4H-indazole-3-carboxamide (1.00 eq, 420 mg, 1.19 mmol) in 37165 DMF (5 mL) was added with 2,4,6-trichloro-1,3,5-triazine (2.00 eq, 440 mg, 2.39 mmol) at 0 °C and stirred for 1 hour. Then water (20 mL) was added and the mixture was extracted with EA (25 mL × 3). The combined organic solutions were washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 - 40% ethyl acetate in heptane) to give 1-(3-bromo-4-fluoro-phenyl)-7-oxo-5,6-dihydro-4H-indazole-3-carbonitrile (360 mg, 1.08 mmol, 90.3% yield) as a white solid. LC-MS (Method 2): retention time = 1.97 min. MS (ESI) m / z 333.7, 335.7 [M+H] + 。

[0157] Preparation of Intermediate D-1d 1-(4-Fluoro-3-hydroxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carbonitrile TIFF2025519597000114.tif Step 1. Synthesis of 1-(4-fluoro-3-hydroxy-phenyl)-7-oxo-5,6-dihydro-4H-indazole-3-carbonitrile TIFF2025519597000115.tif32165A solution of 1-(3-bromo-4-fluoro-phenyl)-7-oxo-5,6-dihydro-4H-indazole-3-carbonitrile (Intermediate D-1d) (360 mg, 1.08 mmol) in 1,4-dioxane (3 mL) was added with cesium carbonate (878 mg, 2.69 mmol), water (58 mg, 3.23 mmol), and [9-[di-tert-butyl-[6-methoxy-3-methyl-2-(2,4,6-triisopropylphenyl)phenyl]-λ5-phosphanyl]-8-aza-9λ4-paradatoricyclo[8.4.0.02,7]tetradeca-1(10),2,4,6,11,13-hexaene-9-yl]methanesulfonate (90 mg, 0.11 mmol) at room temperature under N2. The reaction mixture was stirred at 100 °C for 1 h. The mixture was concentrated and purified by reverse-phase combiflash (0.01 N NH4HCO3 in ACN) to give 1-(4-fluoro-3-hydroxy-phenyl)-7-oxo-5,6-dihydro-4H-indazole-3-carbonitrile (150 mg, 51.3%) as a yellow solid. LCMS (Method 4): Rt 1.55 min. MS (ESI) m / z 272.1 [M+H] + 。

[0158] Preparation of Intermediate D-2 1-(3-Hydroxyphenyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-indazol-7-one TIFF2025519597000116.tif32165Step 1. Synthesis of 1-(3-bromophenyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-indazol-7-one (Intermediate D-2a) A solution of 2-benzyloxy-6-(2,2,2-trifluoroacetyl) cyclohex-2-en-1-one (7.90 g, 26.5 mmol) in 32165 DMF (80 mL) was added to (3-bromophenyl) hydrazine (4.95 g, 26.5 mmol). The reaction was stirred overnight at room temperature under Ar. The mixture was then diluted with water (800 mL) and extracted with EA (150 mL × 3). The combined organic layers were washed with brine (300 mL) and dried over Na2SO4. The residue was concentrated under vacuum and purified by flash chromatography (Biotage, 120 g silica gel column @ 80 mL / min, eluted with 0 - 30% ethyl acetate in petroleum for 20 minutes) to give the title compound intermediate D-2a (4.81 g, 51% yield) as a pale yellow oil. LC-MS (Method 1): Retention time = 2.23 min. MS (ESI) m / z 359 / 361 [M+H] + 。

[0159] Step 2. Synthesis of 1-(3-hydroxyphenyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-indazol-7-one The title compound was prepared by following the protocol described for the preparation of intermediate D-1d. LC-MS (Method 2): Retention time = 1.91 min. MS (ESI) m / z 297.2 [M+H] + 。

[0160] Preparation of intermediate D-2b 1-(3-bromophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-ol TIFF2025519597000119.tif32165 Step 1. Synthesis of 1-(3-bromophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-ol TIFF2025519597000120.tifA solution of 1-(3-bromophenyl)-3-(trifluoromethyl)-5,6-dihydro-4H-indazol-7-one (1.00 eq, 14.00 g, 39.0 mmol) in ethanol (100 mL) was added with sodium borohydride (3.00 eq, 4.42 g, 117 mmol) at 0 °C under N₂. The reaction mixture was stirred at room temperature under N₂ for 1 hour. NH₄Cl aqueous solution (30 mL) and water (100 mL) were added to the mixture. The mixture was extracted with EA (70 mL × 3). The EA layer was washed with brine (80 mL) and concentrated in vacuo. Then the crude product was purified by flash column chromatography eluting with 20% ethyl acetate in isohexane to give 1-(3-bromophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-ol (13.00 g, 36.0 mmol, 92.3% yield) as a white solid.

[0161] Preparation of Intermediate D-3 1-(4-Fluoro-3-hydroxyphenyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-indazol-7-one TIFF2025519597000121.tifStep 1. Synthesis of (3-bromo-4-fluorophenyl)hydrazine TIFF2025519597000122.tifSodium nitrite (4358 mg, 63.2 mmol) was added portionwise to a solution of 3-bromo-4-fluoro-aniline (10000 mg, 52.6 mmol) in concentrated aqueous HCl (100 mL) at -10 °C. The reaction mixture was stirred at -10 °C for 1 hour. Then stannous chloride (II) (44908 mg, 237 mmol) in concentrated aqueous HCl (90 mL) was added at -10 °C. The reaction mixture was stirred at room temperature for 8 hours. The aqueous phase was treated with NaOH until a pH of 14 was achieved and then extracted with ethyl acetate (3 × 80 mL). The organic layers were combined and concentrated. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether from 0% to 21%) to afford the title compound (10500 mg, 92% yield) as a grey solid. LC-MS (Method 1): Retention time = 1.39 minutes. MS (ESI) m / z 205 / 207 [M+H] + 。

[0162] Synthesis of (3-Bromo-4-fluorophenyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-indazol-7-one (Intermediate D-3a) in Step 2.1 TIFF2025519597000123.tif32165 To a solution of (3-Bromo-4-fluoro-phenyl)hydrazine (6000 mg, 29.3 mmol) in ethanol (60 mL) was added 2-Benzyloxy-6-(2,2,2-trifluoroacetyl)cyclohex-2-en-1-one (10474 mg, 35.1 mmol). The reaction mixture was stirred at room temperature for 8 hours. The reaction mixture was concentrated in vacuo to give a residue, which was purified by flash chromatography on silica gel (ethyl acetate in petroleum ether from 0% to 20%) to afford the title compound (3500 mg, 31% yield) as a white solid. LC-MS (Method 3): Retention time = 2.23 minutes. MS (ESI) m / z 377 / 379 [M+H] + 。

[0163] Synthesis of (4-Fluoro-3-hydroxyphenyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-indazol-7-one in Step 3.1 TIFF2025519597000124.tif32165A solution of 1-(3-bromo-4-fluoro-phenyl)-3-(trifluoromethyl)-5,6-dihydro-4H-indazol-7-one (Intermediate D-3a) (5000 mg, 13.3 mmol) in 1,4-dioxane (50 mL) and water (10 mL) was added with 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (563 mg, 1.33 mmol), cesium hydroxide monohydrate (6679 mg, 39.8 mmol), and Pd2(dba)3 (500 mg, 0.5 mmol). The reaction mixture was stirred at 80 °C for 8 h. The reaction mixture was concentrated in vacuo to give a residue, which was purified by prep-HPLC (using NH4HCO3 as the modifier) to afford the title compound (2000 mg, 47% yield) as a white solid. LC-MS (Method 3): retention time = 1.98 min. MS (ESI) m / z 315.2 [M+H] + 。

[0164] Preparation of Intermediate D-4 1-(2-Hydroxypyridin-4-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-indazol-7-one TIFF2025519597000125.tif32165Step 1. Synthesis of 4-bromo-2-(1-phenylethoxy)pyridine TIFF2025519597000126.tif27165Cesium carbonate (111081 mg, 341 mmol) was added to a solution of 4-bromo-2-fluoro-pyridine (20000 mg, 114 mmol) and 1-phenylethanol (13908 mg, 114 mmol) in DMF (200 mL). The mixture was then stirred at 100 °C overnight. The crude product was then purified by flash chromatography eluting with 10% ethyl acetate in isohexane to afford the title compound (29000 mg, 92% yield) as a yellow solid. LC-MS (Method 1): retention time = 2.45 min. MS (ESI) m / z 174.1 / 176.1 (M-PhCHMe+H) + 。

[0165] Synthesis of 2.tert-Butyl 1-(2-(1-phenylethoxy)pyridin-4-yl)hydrazinecarboxylate TIFF2025519597000127.tif271651, To a solution of 4-bromo-2-(1-phenylethoxy)pyridine (15000 mg, 53.9 mmol) in 1,4-dioxane (150 mL) were added tert-butyl N-aminocarbamate (8553 mg, 64.7 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (3120 mg, 5.39 mmol), tris(dibenzylideneacetone)dipalladium (4938 mg, 5.39 mmol), and cesium carbonate (52714 mg, 162 mmol). The mixture was then stirred at 100 °C overnight under Ar. The crude product was then purified by flash column chromatography eluting with 10% ethyl acetate in isohexane to give the title compound (16000 mg, 90% yield) as a yellow solid. LC-MS (Method 1): Retention time = 2.11 min. MS (ESI) m / z 330 [M+H] + 。

[0166] Synthesis of 1-(2-Hydroxypyridin-4-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-indazol-7-one TIFF2025519597000128.tif371652,2,2-Trifluoroethanol (100 mL) was added to a solution of tert-butyl 1-(2-(1-phenylethoxy)pyridin-4-yl)hydrazinecarboxylate (10 g, 30.4 mmol) and 2-(benzyloxy)-6-(2,2,2-trifluoroacetyl)cyclohex-2-en-1-one. Sulfuric acid (25 mL) was then added. The mixture was then stirred at 80 °C overnight. The mixture was poured into water (500 mL), the pH was adjusted to 8 - 9 with NaHCO3, and then extracted with EA (3 × 50 mL). The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was then purified by flash column chromatography eluting with 10% ethyl acetate in isohexane to give the title compound (5 g, 55% yield) as a yellow solid. LC-MS (Method 1): retention time = 1.72 min. MS (ESI) m / z 298.3 [M+H] +

[0167] Preparation of Intermediate D-5 1-(5-Hydroxy-3-pyridyl)-3-(trifluoromethyl)-5,6-dihydro-4H-indazol-7-one TIFF2025519597000129.tif32165Step 1. Synthesis of tert-butyl 1-(5-bromopyridin-3-yl)hydrazine-1-carboxylate A solution of 3,5-dibromopyridine (10.0 g, 42.2 mmol) and tert-butyl N-aminocarbamate (5.58 g, 42.2 mmol) in 1,4-dioxane (100 mL) was added with cesium carbonate (41.26 g, 127 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2.44 g, 4.22 mmol) and tris(dibenzylideneacetone)dipalladium(0) (3.87 g, 4.22 mmol). The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated. The residue was purified by flash chromatography (PE:EA = 5:1) to give the title compound (4.10 g, 33% yield) as a yellow solid. LC-MS (Method 3): retention time = 1.92 min. MS (ESI) m / z 288.1 / 290.1 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.36 (d, J = 1.9 Hz, 1H), 8.15 (t, J = 1.9 Hz, 1H), 5.20 (s, 2H), 1.48 (s, 9H).

[0168] Step 2. Synthesis of 1-(5-bromopyridin-3-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-indazol-7-one A solution of tert-butyl 1-(5-bromopyridin-3-yl)hydrazine-1-carboxylate (4.10 g, 14.2 mmol) and 2-benzyloxy-6-(2,2,2-trifluoroacetyl)cyclohex-2-en-1-one (4.67 g, 15.7 mmol) in 2,2,2-trifluoroethanol (20 mL, 265 mmol) was added dropwise with sulfuric acid (5.0 mL, 93.8 mmol) at 0 °C. The reaction mixture was stirred at 80 °C for 6 hours and then cooled. 6N aqueous sodium hydroxide solution was added dropwise to this solution at 0 °C. After the addition, the mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (PE:EA = 5:1) to give the title compound (3.50 g, 65% yield) as a yellow solid. LC-MS (Method 3): retention time = 2.11 min. MS (ESI) m / z 360.0 / 362.0 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 8.87 (d, J = 2.0 Hz, 1H), 8.81 (d, J = 2.0 Hz, 1H), 8.44 (t, J = 2.0 Hz, 1H), 2.91 (t, J = 5.9 Hz, 2H), 2.65 - 2.58 (m, 2H), 2.20 - 2.12 (m, 2H).

[0169] Step 3. Synthesis of 1-(5-hydroxy-3-pyridyl)-3-(trifluoromethyl)-5,6-dihydro-4H-indazol-7-one TIFF2025519597000132.tif32165 A solution of 1-(5-bromopyridin-3-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-indazol-7-one (3.50 g, 9.72 mmol) in 1,4-dioxane (15 mL) and water (5 mL) was added with 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (413 mg, 0.972 mmol), tris(dibenzylideneacetone)dipalladium (890 mg, 0.972 mmol) and cesium hydroxide monohydrate (4.90 g, 29.2 mmol). The reaction mixture was stirred at 100 °C for 1 h. The reaction mixture was concentrated and the residue was purified by reverse-phase flash chromatography (C18) (0.1% NH4HCO3 in water, 10 - 100% acetonitrile) to give the title compound (1.15 g, 40% yield) as an off-white solid. LC-MS (Method 3): retention time = 1.81 min. MS (ESI) m / z 298.2 [M+H] + 。 1 H NMR (500 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.26 (d, J = 2.0 Hz, 1H), 8.22 (d, J = 0.7 Hz, 1H), 7.36 (t, 1H), 2.90 (t, J = 5.7 Hz, 2H), 2.63 - 2.57 (m, 2H), 2.19 - 2.11 (m, 2H).

[0170] Preparation of Intermediate D-6 1-(6-Chloropyridazin-4-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-indazol-7-one TIFF2025519597000133.tif32165 Step 1. Synthesis of 1-(6-chloropyridazin-4-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-indazol-7-one A solution of 3,5-dichloropyridazine (1.82 g, 12.2 mmol) in DMF (30 mL) was added with 3-(trifluoromethyl)-1,4,5,6-tetrahydroindazol-7-one (Intermediate D-1) (2.50 g, 12.2 mmol) and cesium carbonate (7980 mg, 24.5 mmol). The reaction mixture was stirred at 80 °C for 2 h and then poured into water (200 mL). The solution was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography (PE:EA = 5:1) to give the title compound (1300 mg, 32% yield) as a yellow solid. LC-MS (Method 2): retention time = 1.99 min. MS (ESI) m / z 317.1 [M+H] + 。

[0171] Preparation of Intermediate D-7 1-(4-Hydroxypyridin-2-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-indazol-7-one TIFF2025519597000135.tif37165 Step 1. Synthesis of 1-(4-bromopyridin-2-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-indazol-7-one (Intermediate D-7a) In a solution of (4-bromo-2-pyridyl)hydrazine (630 mg, 3.35 mmol) and 2-benzyloxy-6-(2,2,2-trifluoroacetyl)cyclohex-2-en-1-one (1049 mg, 3.52 mmol) in TFE / H2SO4 (v / v = 3:1) (10 mL). The reaction mixture was stirred at 80 °C for 8 h. Water (20 mL) was added to the reaction mixture and the mixture was adjusted to pH = 8 by the addition of saturated aqueous sodium hydrogen carbonate. It was then extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue which was purified by flash silica gel column chromatography (ethyl acetate in petroleum ether from 0% to 25%) to afford the title compound (830 mg, 67.4% yield) as a yellow rubbery solid. LCMS (Method 2): retention time = 1.95 min. MS (ESI) m / z 359.9 [M+H] + 。

[0172] Step 2. Synthesis of 1-(4-hydroxypyridin-2-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-indazol-7-one In a solution of 1-(4-bromo-2-pyridyl)-3-(trifluoromethyl)-5,6-dihydro-4H-indazol-7-one (830 mg, 2.30 mmol), cesium hydroxide monohydrate (1161 mg, 6.91 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (98 mg, 0.23 mmol), and tris(dibenzylideneacetone)dipalladium (106 mg, 0.12 mmol) in 1,4-dioxane (10 mL) / water (2 mL) under 32165N2. The reaction mixture was stirred at 80 °C for 8 hours. The reaction mixture was added with water (20 mL), and then extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a residue, which was purified by prep-HPLC (NH4HCO3 conditions) to give the title compound (230 mg, 32.9% yield) as a gray solid. LCMS (Method 2): Retention time = 1.27 min. MS (ESI) m / z 298.0 [M+H] + 。

[0173] Preparation of Intermediate D-8 1-(6-Hydroxypyridin-2-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-indazol-7-one TIFF2025519597000138.tif37165

[0174] Preparation of Intermediate D-8a 1-(6-Bromopyridin-2-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-indazol-7-one Intermediates D-8 and D-8a were prepared according to the same procedure as for the preparation of Intermediates D-7 and D-7a in TIFF2025519597000139.tif32165. Intermediate D-8: LCMS (Method 2): Retention time = 1.50 min. MS (ESI) m / z 298.0 [M+H] + 。 Intermediate D-8a: LCMS (Method 2): Retention time = 1.96 min. MS (ESI) m / z 360.0 [M+H] + 。

[0175] Preparation of Intermediate D-9 1-(5-Hydroxypyridazin-3-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-indazol-7-one TIFF2025519597000140.tif37165 Intermediate D-9 was prepared as a white solid in essentially the same manner as Intermediate D-4 (410 mg, 1.37 mmol, 26.4% yield). LC-Mass (Method 1): Retention time = 1.68 min. MS (ESI) m / z 299.1 [M+H] + 。 1 1H NMR (400 MHz, MeOH-d4) δ 8.54 (d, J = 2.6 Hz, 1H), 6.99 (d, J = 2.6 Hz, 1H), 2.97 (t, J = 6.0 Hz, 2H), 2.69 - 2.63 (m, 2H), 2.29 - 2.20 (m, 2H).

[0176] Preparation of Intermediate D-10 1-(5-Fluoro-4-hydroxypyridin-2-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-indazol-7-one TIFF2025519597000141.tif32165 Step 1. Synthesis of 4-chloro-5-fluoro-2-hydrazinylpyridine A mixture of 4-chloro-2,5-difluoro-pyridine (1.00 eq, 4.00 g, 26.8 mmol) in IPA (15 mL) and hydrazine hydrate (2.00 eq, 2.6 mL, 53.5 mmol) was stirred at room temperature for 72 h. The mixture was concentrated under vacuum. The residue was purified by reverse-phase flash chromatography (C18) (0.1% NH4HCO3 in water, 10 - 100% acetonitrile) to give 4-chloro-5-fluoro-2-pyridyl)hydrazine (1.00 g, 6.19 mmol, 23.1% yield) as a white solid. LC-Mass (Method 2): Retention time = 1.29 min. MS (ESI) m / z 162.1 [M+H] + 。

[0177] Step 2.1 - Synthesis of (4-chloro-5-fluoropyridin-2-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-indazol-7-one A solution of (4-chloro-5-fluoro-2-pyridyl)hydrazine (1.00 eq, 1.30 g, 8.05 mmol) and 2-benzyloxy-6-(2,2,2-trifluoroacetyl)cyclohex-2-en-1-one (1.10 eq, 2.64 g, 8.85 mmol) in 2,2,2-trifluoroethanol (32.9 eq, 20 mL, 265 mmol) was added dropwise with sulfuric acid (11.7 eq, 5.0 mL, 93.8 mmol) at 0 °C. The reaction was stirred at 80 °C for 6 h. An aqueous sodium hydroxide solution (6N) was added dropwise to the reaction mixture at 0 °C. The mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (PE:EA = 5:1) to give 1-(4-chloro-5-fluoro-2-pyridyl)-3-(trifluoromethyl)-5,6-dihydro-4H-indazol-7-one (1.30 g, 3.90 mmol, 48.4% yield) as a yellow solid. LC-Mass (Method 1): Retention time = 2.07 min. MS (ESI) m / z 334.0 [M+H]+ .

[0178] Synthesis of 3.1-(5-Fluoro-4-hydroxypyridin-2-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-indazol-7-one TIFF2025519597000144.tif37165 A solution of 1-(4-chloro-5-fluoro-2-pyridyl)-3-(trifluoromethyl)-5,6-dihydro-4H-indazol-7-one (1.00 eq, 90 mg, 0.270 mmol) in 1,4-dioxane (15 mL) and water (5.00 eq, 24 mg, 1.35 mmol) was added with cesium carbonate (3.00 eq, 264 mg, 0.809 mmol) and RockPhos Pd G3 (CAS#: 2009020-38-4) (0.10 eq, 23 mg, 0.0270 mmol) (). The reaction mixture was stirred at 100 °C for 30 minutes under nitrogen. The mixture was concentrated and purified by flash column chromatography (DCM:MeOH = 10:1) to obtain the crude product. The crude product was further purified by reverse phase flash chromatography (C18) (0.1% NH4HCO3 in water, 10 - 100% acetonitrile) to obtain 1-(5-fluoro-4-hydroxy-2-pyridyl)-3-(trifluoromethyl)-5,6-dihydro-4H-indazol-7-one (20 mg, 0.0634 mmol, 23.5% yield) as a white solid. LC-Mass (Method 1): Retention time = 1.82 minutes. MS (ESI) m / z 316.1 [M+H] + .

[0179] Preparation of Intermediate D-11 3-Iodo-1,5,6,7-tetrahydroindazol-4-one TIFF2025519597000145.tif32165 Step 1. Synthesis of 2-(dimethylaminomethylene)cyclohexane-1,3-dione A solution of cyclohexane-1,3-dione (18.0 g, 161.00 mmol) in DMF-DMA (45 mL, 336.00 mmol) was stirred at 80 °C for 2 hours. The mixture was concentrated to obtain a residue, which was washed with petroleum ether (100 mL × 2) and filtered to give 2-(dimethylaminomethylene)cyclohexane-1,3-dione (24.0 g, 84.9% yield) as a yellow solid. LCMS (Method 1): retention time = 1.11 min. MS (ESI) m / z 168.2 [M+H] + 。

[0180] Step 2. Synthesis of 1,5,6,7-tetrahydroindazol-4-one Acetic acid (21 mL) and hydrazine hydrate (3588 mg, 71.80 mmol) were added to a solution of 2-(dimethylaminomethylene)cyclohexane-1,3-dione (24.0 g, 144.00 mmol) in ethanol (300 mL). The reaction mixture was stirred at 80 °C for 16 hours. The mixture was concentrated to obtain a residue, which was purified by flash column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 1,5,6,7-tetrahydroindazol-4-one (8.0 g, 40.9%) as a yellow solid. LCMS (Method 1): retention time = 1.12 min. MS (ESI) m / z 137.1 [M+H] + 。

[0181] Step 3. Synthesis of 3-iodo-1,5,6,7-tetrahydroindazol-4-one A solution of 1,5,6,7 - tetrahydroindazol - 4 - one (8.0 g, 58.80 mmol) in DMF (200 mL) was added to n - iodosuccinimide (16.0 g, 71.10 mmol). The reaction mixture was stirred at 80 °C for 8 h. The mixture was washed with water (1000 mL) and extracted with ethyl acetate (300 mL×3). The combined organic phases were concentrated to give a residue, which was purified by flash column chromatography (petroleum ether / ethyl acetate = 2 / 1) to afford 3 - iodo - 1,5,6,7 - tetrahydroindazol - 4 - one (3000 mg, 18.5%) as a pale yellow solid. LCMS (Method 1): retention time = 1.44 min. MS (ESI) m / z 263.0 [M + H] + 。

[0182] Preparation of Intermediate E1 Methyl 4 - ((1 - (2 - hydroxypyridin - 4 - yl) - 3 - (trifluoromethyl) - 4,5,6,7 - tetrahydro - 1H - pyrazolo[4,3 - c]pyridin - 7 - yl)oxy)benzoate TIFF2025519597000149.tif58165 Step 1. Synthesis of tert - butyl 3 - bromo - 4 - oxo - piperidine - 1 - carboxylate Bromine (1.10 eq, 0.057 mL, 1.10 mmol) was added dropwise to a stirred solution of 1 - boc - 4 - piperidone (1.00 eq, 200 mg, 1.00 mmol) in chloroform (2 mL) at 0 °C under N2. Stirring was continued at 0 °C for 15 min, then gradually warmed to room temperature and stirred for 16 h. TLC showed one non - polar spot. The sample was used in the next step of the reaction without purification and characterization.

[0183] Step 2. Synthesis of tert - butyl 3 - (4 - (methoxycarbonyl)phenoxy) - 4 - oxopiperidine - 1 - carboxylate TIFF2025519597000151.tif To a solution of tert-butyl 3-bromo-4-oxo-piperidine-1-carboxylate (5000 mg, 18.00 mmol) and methyl 4-hydroxybenzoate (3009 mg, 19.8 mmol) in acetonitrile (50 mL) was added potassium carbonate (4969 mg, 36.00 mmol). The reaction mixture was stirred at 85 °C for 8 hours. The reaction mixture was concentrated in vacuo to afford the title compound (5800 mg, 78.5% yield) as a yellow solid. LCMS (Method 2): retention time = 1.88 min. MS (ESI) m / z 294.1 [M+H-tBu] + 。

[0184] Step 3. Synthesis of tert-butyl 3-(4-(methoxycarbonyl)phenoxy)-4-oxo-5-(2,2,2-trifluoroacetyl)piperidine-1-carboxylate TIFF2025519597000152.tif To a solution of tert-butyl 3-(4-methoxycarbonylphenoxy)-4-oxo-piperidine-1-carboxylate (4100 mg, 11.70 mmol) and ethyl trifluoroacetate (2.8 mL, 23.50 mmol) in THF (45 mL) was added lithium diisopropylamide (2514 mg, 23.50 mmol) at -78 °C under N2. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo to afford the title compound (5000 mg, 76.5% yield) as a yellow solid. LCMS (Method 2): retention time = 1.51 min. MS (ESI) m / z 446.0 [M+H] + 。

[0185] Step 4. Synthesis of tert-butyl 1-(2-hydroxypyridin-4-yl)-7-(4-(methoxycarbonyl)phenoxy)-3-(trifluoromethyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate A solution of tert-butyl 3-(4-methoxycarbonylphenoxy)-4-oxo-5-(2,2,2-trifluoroacetyl)piperidine-1-carboxylate (5000 mg, 11.20 mmol) in acetic acid (50 mL) was added with tert-butyl N-amino-N-[2-(1-phenylethoxy)-4-pyridyl]carbamate (4068 mg, 12.30 mmol) and (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetan-2,4-disulfide) (9081 mg, 22.50 mmol). The reaction mixture was stirred at 80 °C for 8 hours. The reaction mixture was concentrated in vacuo to give a residue, which was purified by flash silica gel column chromatography (ethyl acetate in petroleum ether from 0% to 100%) to afford the title compound (2700 mg, 36.0% yield) as a yellow solid. LCMS (Method 1): Retention time = 1.97 min. MS (ESI) m / z 535.0 [M+H] + 。

[0186] Step 5. Synthesis of methyl 4-((1-(2-hydroxypyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-7-yl)oxy)benzoate tert-Butyl 1-(2-hydroxy-4-pyridyl)-7-(4-methoxycarbonylphenoxy)-3-(trifluoromethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (2700 mg, 5.05 mmol) was dissolved in HCl (4 M, 30 mL) in 1,4-dioxane. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo to give a residue, which was purified by flash silica gel column chromatography (methanol in dichloromethane from 0% to 7%) to afford the title compound (650 mg, 23.7% yield) as a yellow solid. LCMS (Method 2): Retention time = 1.46 min. MS (ESI) m / z 435.1 [M+H] + 。

[0187] Examples 1 and 2 (R)-3-((1-(6-(1-(2,2-Difluoro-[1,3]dioxolo[4,5-c]pyridin-6-yl)ethoxy)pyridazin-4-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-b]pyridin-7-yl)methyl)bicyclo[1.1.1]pentane-1-carboxylic acid TIFF2025519597000155.tif53165(S)-3-((1-(6-(1-(2,2-Difluoro-[1,3]dioxolo[4,5-c]pyridin-6-yl)ethoxy)pyridazin-4-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-b]pyridin-7-yl)methyl)bicyclo[1.1.1]pentane-1-carboxylic acid TIFF2025519597000156.tif53165Step 1. Synthesis of methyl 3-((1-(6-chloropyridazin-4-yl)-3-(trifluoromethyl)-5,6-dihydro-1H-pyrazolo[3,4-b]pyridin-7(4H)-yl)methyl)bicyclo[1.1.1]pentane-1-carboxylate TIFF2025519597000157.tif48165To a solution of methyl 3-[[3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-b]pyridin-7-yl]methyl]bicyclo[1.1.1]pentane-1-carboxylate (Intermediate A-1) (370 mg, 1.12 mmol) in DMF (5 mL) were added 5-bromo-3-chloro-pyridazine (261 mg, 1.35 mmol) and Cs2CO3 (549 mg, 1.69 mmol). The reaction was stirred at 70 °C for 2 h. The reaction mixture was poured into water (50 mL) and extracted with EA (3 × 30 mL). The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography (10 - 20% EA in heptane) to give the title compound (50 mg, 10% yield) as a white solid. LC-MS (Method 3): retention time = 2.30 min. MS (ESI) m / z 442.2 [M+H]+ .

[0188] Process 2. Synthesis of (R)-3-((1-(6-(1-(2,2-difluoro-[1,3]dioxolo[4,5-c]pyridin-6-yl)ethoxy)pyridazin-4-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-b]pyridin-7-yl)methyl)bicyclo[1.1.1]pentane-1-carboxylic acid and (S)-3-((1-(6-(1-(2,2-difluoro-[1,3]dioxolo[4,5-c]pyridin-6-yl)ethoxy)pyridazin-4-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-b]pyridin-7-yl)methyl)bicyclo[1.1.1]pentane-1-carboxylic acid TIFF2025519597000158.tif A solution of 1-(2,2-difluoro-[1,3]dioxolo[4,5-c]pyridin-6-yl)ethanol (Intermediate C-2) (46 mg, 0.226 mmol) in THF (3 mL) was added with NaH (9.1 mg, 0.226 mmol) at 0 °C and stirred at room temperature for 30 minutes. Then methyl 3-[[1-(6-chloropyridazin-4-yl)-3-(trifluoromethyl)-5,6-dihydro-4H-pyrazolo[3,4-b]pyridin-7-yl]methyl]bicyclo[1.1.1]pentane-1-carboxylate (50 mg, 0.113 mmol) was added. The reaction solution was stirred at room temperature for 1 hour. The solution was concentrated and purified by Prep-HPLC to obtain 18 mg of the product as a white solid. This enantiomeric mixture was separated by SFC to obtain the title compound having a first fraction designated as P1 (7.2 mg, 11% yield, white solid) and a second fraction designated as P2 (7.8 mg, 12% yield, white solid). Chiral HPLC: Column: OJ-3 4.6×100 mm 3 μm; Cosolvent: MeOH [0.2% NH3 (7 M in MeOH)]. P1: Retention time = 0.940 min LC-MS (Method 2): Retention time = 1.77 min. MS (ESI) m / z 595.2 [M+H] + . 1 1H NMR (500 MHz, CH3OH-d4) δ 9.32 (d, J = 2.0 Hz, 1H), 8.40 (s, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.56 (s, 1H), 6.39 (q, J = 6.6 Hz, 1H), 3.30 - 3.25 (m, 2H), 2.92 (s, 2H), 2.64 (t, J = 6.3 Hz, 2H), 2.03 - 1.95 (m, 6H), 1.86 - 1.79 (m, 2H), 1.76 (d, J = 6.6 Hz, 3H). P2: Retention time = 2.196 minutes. LC-MS (Method 2): Retention time = 1.77 minutes. MS (ESI) m / z 595.2 [M+H] + . 1 1H NMR (500 MHz, CH3OH-d4δ 9.32 (d, J = 2.0 Hz, 1H), 8.40 (s, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.56 (s, 1H), 6.39 (q, J = 6.6 Hz, 1H), 3.30 - 3.25 (m, 2H), 2.92 (s, 2H), 2.64 (t, J = 6.3 Hz, 2H), 2.03 - 1.95 (m, 6H), 1.86 - 1.79 (m, 2H), 1.76 (d, J = 6.6 Hz, 3H).

[0189] Examples 3 and 4 (R)-4-((1-(6-(1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridazin-4-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-b]pyridin-7-yl)methyl)benzoic acid TIFF2025519597000159.tif58165(S)-4-((1-(6-(1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridazin-4-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-b]pyridin-7-yl)methyl)benzoic acid TIFF2025519597000160.tif58165Examples 3 and 4 were synthesized according to the procedures for the synthesis of Examples 1 and 2. Chiral Prep conditions: Column: IG 20×250 mm, 10 μm; Mobile phase: CO2 / MeOH (0.2% ammonia in methanol) = 65 / 35. P1: Retention time = 1.51 min LC-MS (Method 2): Retention time = 1.86 min. MS (ESI) m / z 604 [M+H] + 。 1 1H NMR (500 MHz, CH3OH-d4) δ 9.28 (d, J = 2.0 Hz, 1H), 8.05 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 2.0 Hz, 1H), 7.45 (d, J = 7.9 Hz, 2H), 7.12 - 6.99 (m, 3H), 6.24 (q, J = 6.4 Hz, 1H), 4.11 (s, 2H), 3.29 - 3.25 (m, 2H), 2.74 - 2.62 (m, 2H), 1.87 - 1.72 (m, 2H), 1.56 (d, J = 6.0 Hz, 3H). P2: Retention time = 2.21 min LC-MS (Method 2): Retention time = 1.86 min. MS (ESI) m / z 604 [M+H] + 。 11H NMR (500 MHz, CH3OH-d4) δ 9.28 (d, J = 2.0 Hz, 1H), 8.05 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 2.0 Hz, 1H), 7.45 (d, J = 7.9 Hz, 2H), 7.12 - 6.99 (m, 3H), 6.24 (q, J = 6.4 Hz, 1H), 4.10 (s, 2H), 3.29 - 3.25 (m, 2H), 2.74 - 2.62 (m, 2H), 1.87 - 1.72 (m, 2H), 1.56 (d, J = 6.0 Hz, 3H).

[0190] Examples 5 and 6 (R)-3-((1-(6-(1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridazin-4-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-b]pyridin-7-yl)methyl)bicyclo[1.1.1]pentane-1-carboxylic acid TIFF2025519597000161.tif53165(S)-3-((1-(6-(1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridazin-4-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-b]pyridin-7-yl)methyl)bicyclo[1.1.1]pentane-1-carboxylic acid TIFF2025519597000162.tif53165Examples 5 and 6 were synthesized by following the procedure for the synthesis of Examples 1 and 2. P1. Retention time = 0.991 min. (SFC method: (R,R)Whelk-O1 4.6×100mm 3.5μm). LC-MS (method 2): Retention time = 1.84 min. MS (ESI) m / z 594.1 [M+H] + . 11H NMR (500 MHz, CH3OH-d4) δ 9.29 (d, J = 1.8 Hz, 1H), 7.64 (d, J = 1.9 Hz, 1H), 7.40 (d, J = 1.3 Hz, 1H), 7.35 (d, J = 8.3 Hz, 1H), 7.17 (d, J = 8.3 Hz, 1H), 6.42 (q, J = 6.5 Hz, 1H), 3.29 - 3.23 (m, 2H), 2.89 (s, 2H), 2.63 (t, J = 6.3 Hz, 2H), 1.97 (s, 6H), 1.84 - 1.78 (m, 2H), 1.73 (d, J = 6.5 Hz, 3H). P2: Retention time = 1.556 min. (SFC method: (R,R)Whelk - O1 4.6×100mm 3.5μm). LC - MS (Method 2): Retention time = 1.84 min. MS(ESI) m / z 594.1 [M + H] + . 1 1H NMR (500 MHz, CH3OH-d4) δ 9.29 (d, J = 1.8 Hz, 1H), 7.64 (d, J = 1.8 Hz, 1H), 7.40 (d, J = 1.8 Hz, 1H), 7.35 (dd, J = 8.3 Hz, 1.8 Hz, 1H), 7.17 (d, J = 8.3 Hz, 1H), 6.42 (q, J = 6.5 Hz, 1H), 3.29 - 3.23 (m, 2H), 2.89 (s, 2H), 2.63 (t, J = 6.3 Hz, 2H), 1.97 (s, 6H), 1.84 - 1.78 (m, 2H), 1.73 (d, J = 6.5 Hz, 3H).

[0191] Example 7 4 - ((1 - (2 - ((S)-1 - (2,2 - difluorobenzo[d][1,3]dioxol - 5 - yl)ethoxy)pyridin - 4 - yl)-3 - (trifluoromethyl)-1,4,5,6 - tetrahydro - 7H - pyrazolo[3,4 - b]pyridin - 7 - yl)methyl)cyclohexane - 1 - carboxylic acid Example 7 was synthesized by following the procedure for the synthesis of Examples 1 and 2. Chiral Prep conditions: Column: AD-3 4.6×100 mm, 3 μm. Retention time = 1.86 min. LC-MS (Method 2): Retention time = 1.87 min. MS (ESI) m / z 609.3 [M+H] + . 1 1H NMR (400 MHz, CH3OH-d4) δ 8.18 (d, J = 5.2 Hz, 1H), 7.32 (s, 1H), 7.24 - 7.27 (m, 2H), 7.20 (s, 1H), 7.14 (d, J = 8.0 Hz, 1H), 6.24 (q, J = 6.0 Hz, 1H), 3.24 (d, J = 4.4 Hz, 2H), 2.62 (t, J = 6.4 Hz, 2H), 2.55 (d, J = 7.2 Hz, 2H), 1.58 - 2.04 (m, 11H), 1.28 - 1.37 (m, 2H), 0.66 - 0.71 (m, 2H).

[0192] Example 8 4-[[1-[2-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-4-pyridyl]-3-(trifluoromethyl)-5,6-dihydro-4H-pyrazolo[3,4-b]pyridin-7-yl]methyl]benzoic acid TIFF2025519597000164.tif58165 Step 1. Synthesis of methyl 4-((1-(2-fluoropyridin-4-yl)-3-(trifluoromethyl)-5,6-dihydro-1H-pyrazolo[3,4-b]pyridin-7(4H)-yl)methyl)benzoate A solution of methyl 4-[[3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-b]pyridin-7-yl]methyl]benzoate (Intermediate A-2) (1.00 g, 2.95 mmol) in DCM (20 mL) was added with (2-fluoropyridin-4-yl)boronic acid (831 mg, 5.89 mmol), copper(II) acetate (268 mg, 1.47 mmol) and TEA (0.41 mL, 2.95 mmol). The solution was stirred at room temperature for 3 days. The solution was concentrated and the crude product was purified by flash chromatography eluting with 15% EA in PE to afford the title compound (100 mg, 8% yield) as a white solid. LC-MS (Method 2): retention time = 1.88 min. MS (ESI) m / z 435 [M+H] + 。

[0193] Step 2. Synthesis of (S)-4-((1-(2-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-5,6-dihydro-1H-pyrazolo[3,4-b]pyridin-7(4H)-yl)methyl)benzoic acid To a solution of (1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethanol (Intermediate C-1S) (67 mg, 0.331 mmol) in THF (2 mL) was added NaH (14 mg, 0.55 mmol) and the solution was stirred at room temperature for 1 h. Then methyl 4-[[1-(2-fluoropyridin-4-yl)-3-(trifluoromethyl)-5,6-dihydro-4H-pyrazolo[3,4-b]pyridin-7-yl]methyl]benzoate (product from Step 1) (120 mg, 0.276 mmol) was added to the solution and the mixture was stirred at room temperature for 12 h. Water (20 mL) was added and the mixture was extracted with EA (2 × 20 mL). The organics were then separated, dried (Na2SO4) and then concentrated to dryness. The crude product was then purified by prep-TLC (EA / MeOH = 15 / 1) to afford the title compound (21 mg, 12% yield) as a white solid. LC-MS (Method 1): Retention time = 1.95 min. MS (ESI) m / z 603.1 [M+H] + 。 1 H NMR (500 MHz, CH3OH-d4) δ 8.07 (d, J = 5.6 Hz, 1H), 8.01 (d, J = 7.9 Hz, 2H), 7.42 (d, J = 7.8 Hz, 2H), 7.35 (s, 1H), 7.32 (d, J = 5.6 Hz, 1H), 7.08 (s, 1H), 7.06 - 6.99 (m, 2H), 6.07 (q, J = 6.5 Hz, 1H), 4.10 - 3.97 (m, 2H), 3.24 - 3.19 (m, 2H), 2.71 - 2.62 (m, 2H), 1.86 - 1.71 (m, 2H), 1.51 (d, J = 6.5 Hz, 3H).

[0194] Example 9 4-[[1-[2-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-4-pyridyl]-3-(trifluoromethyl)-5,6-dihydro-4H-pyrazolo[3,4-b]pyridin-7-yl]methyl]bicyclo[2.2.2]octane-1-carboxylic acid Example 9 was synthesized by using the same protocol as in Example 8. TIFF2025519597000167.tif58165 LC-MS (Method 2): Retention time = 1.89 min. MS (ESI) m / z 635.3 [M+H] + 。 11H NMR (400 MHz, CH3OH-d4) δ 8.20 (d, J = 5.6 Hz, 1H), 7.32 (s, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.11-7.16 (m, 2H), 7.04 (s, 1H), 6.24 (q, J = 6.4 Hz, 1H), 3.30-3.33 (m 2H), 2.62 (t, J = 6.4 Hz, 2H), 2.56 (d, J = 4.4 Hz, 2H), 1.82-1.85 (m, 2H), 1.61-1.65(m, 9H), 1.22-1.26 (m, 6H).

[0195] Example 10 3-[[1-[3-[1-(2,2-Difluoro-1,3-benzodioxol-5-yl)ethoxy]phenyl]-3-(trifluoromethyl)-5,6-dihydro-4H-pyrazolo[3,4-b]pyridin-7-yl]methyl]bicyclo[1.1.1]pentane-1-carboxylic acid TIFF2025519597000168.tif53165 Step 1. Synthesis of 1-[3-[1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[3,4-b]pyridine A solution of 3-[3-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[3,4-b]pyridin-1-yl]phenol (Intermediate B-1) (300 mg, 1.06 mmol), 1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethanol (Intermediate C-1) (321 mg, 1.59 mmol) and triphenylphosphine (556 mg, 2.12 mmol) in THF (5 mL) was added with diisopropyl azodicarboxylate (0.41 mL, 2.12 mmol) at 0 °C under Ar. The reaction mixture was stirred at 0 °C for 2 h. Then water (30 mL) was added. The solution was extracted with EA (2 × 30 mL), washed with brine (30 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by combiflash (A: water (10 mmol / L NH4HCO3) B: ACN) to give the title compound (330 mg, 65% yield) as a yellow solid. LC-MS (Method 1): retention time = 2.39 min. MS (ESI) m / z 468.0 [M+H] + 。

[0196] Step 2. Synthesis of methyl 3-[[1-[3-[1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]phenyl]-3-(trifluoromethyl)-5,6-dihydro-4H-pyrazolo[3,4-b]pyridin-7-yl]methyl]bicyclo[1.1.1]pentane-1-carboxylate TIFF2025519597000170.tifA solution of methyl 3-[[1-(3-hydroxyphenyl)-3-(trifluoromethyl)-5,6-dihydro-4H-pyrazolo[3,4-b]pyridin-7-yl]methyl]bicyclo[1.1.1]pentane-1-carboxylate (110 mg, 0.261 mmol) and methyl 3-(bromomethyl)bicyclo[1.1.1]pentane-1-carboxylate (158 mg, 0.720 mmol) in THF (10 mL) was added with potassium tert-butoxide (1.8 mL, 1.80 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. Then water (30 mL) was added. The solution was extracted with EA (2 × 30 mL), washed with brine (30 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by combiflash (A: water (10 mmol / L NH4HCO3); B: ACN) to give the title compound (60 mg, 36% yield) as a yellow solid. LC-MS (Method 1): retention time = 2.54 min. MS (ESI) m / z 606.0 [M+H] + 。

[0197] Step 3. Synthesis of 3-[[1-[3-[1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]phenyl]-3-(trifluoromethyl)-5,6-dihydro-4H-pyrazolo[3,4-b]pyridin-7-yl]methyl]bicyclo[1.1.1]pentane-1-carboxylic acid TIFF2025519597000171.tif53165A solution of methyl 3-[[1-[3-[1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]phenyl]-3-(trifluoromethyl)-5,6-dihydro-4H-pyrazolo[3,4-b]pyridin-7-yl]methyl]bicyclo[1.1.1]pentane-1-carboxylate (11 mg, 0.0186 mmol) in methanol (1 mL), THF (1 mL) and water (0.5 mL) was added with lithium hydroxide monohydrate (2.3 mg, 0.0559 mmol), and the resulting mixture was stirred at room temperature for 4 h. Then the reaction mixture was concentrated in vacuo. The residue was purified by Prep-HPLC (A: water (10 mmol / L NH4HCO3); B: ACN) to give the title compound (6.0 mg, 52% yield) as a white solid. LC-MS (Method 1): retention time = 1.87 min. MS (ESI) m / z 592.2 [M+H] + 。

[0198] Example 11 3-[[1-[3-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]phenyl]-3-(trifluoromethyl)-5,6-dihydro-4H-pyrazolo[3,4-b]pyridin-7-yl]methyl]bicyclo[1.1.1]pentane-1-carboxylic acid TIFF2025519597000172.tif48165Step 1. Synthesis of 1-[3-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[3,4-b]pyridine In a solution of 3-[3-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[3,4-b]pyridin-1-yl]phenol (Intermediate B-1) (100 mg, 0.353 mmol), (1R)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethanol (Intermediate C-1R) (86 mg, 0.424 mmol) and triphenylphosphine (139 mg, 0.530 mmol) in 32165 THF (5 mL), diisopropyl azodicarboxylate (0.10 mL, 0.530 mmol) was added at 0 °C under N2. The reaction mixture was stirred at room temperature for 4 h. Then water (20 mL) was added. The resulting mixture was extracted with EA (3 × 20 mL). The combined organic extracts were combined, washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EA = 2:1) to give the title compound (100 mg, 61% yield) as a yellow solid. LC-MS (Method 1): retention time = 1.94 min. MS (ESI) m / z 468.0 [M+H] + 。

[0199] Step 2. Synthesis of 3-[[1-[3-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]phenyl]-3-(trifluoromethyl)-5,6-dihydro-4H-pyrazolo[3,4-b]pyridin-7-yl]methyl]bicyclo[1.1.1]pentane-1-carboxylic acid A solution of 1-[3-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[3,4-b]pyridine (100 mg, 0.214 mmol) and methyl 3-(bromomethyl)bicyclo[1.1.1]pentane-1-carboxylate (52 mg, 0.235 mmol) in THF (2 mL) was added potassium tert-butoxide (0.53 mL, 0.535 mmol), and the resulting mixture was stirred at room temperature for 14 h. Then water (20 mL) was added and the mixture was extracted with EA (3×20 mL). The EA solution was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (A: water (10 mmol / L NH4HCO3); B: ACN) to give the title compound (30 mg, 24% yield) as a white solid. LC-MS (Method 2): retention time = 1.865 min. MS (ESI) m / z 591.8 [M+H] + 。 1 H NMR (400 MHz, CH3OH-d4) δ: 7.36 (t, J = 8.1 Hz, 1H), 7.29 (s, 1H), 7.27 - 6.90 (m, 5H), 5.50 (q, J = 6.3 Hz, 1H), 3.23 - 3.15 (m, 2H), 2.62 (dd, J = 13.9, 6.6 Hz, 4H), 1.88 - 1.74 (m, 2H), 1.65 (s, 6H), 1.62 (d, J = 6.3 Hz, 3H).

[0200] Example 12 (S)-4-((1-(5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-3-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-b]pyridin-7-yl)methyl)benzoic acid TIFF2025519597000175.tif58165 The labeled compound was synthesized in essentially the same manner as in Example 11. Chiral method: Column name: (R,R) WHELK-O1 4.6×100mm 3.5μm Solvent: MeOH [0.2% NH3 (7M in MeOH)]; Retention time = 2.963 min; ee = 100%. LC-MS (Method 3): Retention time = 1.86 min. MS (ESI) m / z 603.1 [M+H] + . 1 1H NMR (400 MHz, CH3OH-d4) δ: 8.44 (S, 1H), 8.17 (S, 1H), 7.89 (d, J = 8 Hz, 2H), 7.67 (s, 1H), 7.24 (s, 1H), 7.13 - 7.08 (m, 4H), 5.43 (dd, J = 12.4 Hz, 6 Hz, 1H), 3.81 (dd, J = 23.2 Hz, 7.6 Hz, 2H), 3.18 (t, J = 6 Hz, 2H), 2.62 (t, J = Hz, 2H), 1.72 - 1.68 (m, 2H), 1.59 (d, J = 6.4 Hz, 3H).

[0201] Example 13 trans-4-[[1-[5-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-3-pyridyl]-3-(trifluoromethyl)-5,6-dihydro-4H-pyrazolo[3,4-b]pyridin-7-yl]methyl]cyclohexanecarboxylic acid TIFF2025519597000176.tif58165 The labeled compound was synthesized in essentially the same manner as in Example 11. Chiral method: Column name: AS-3 4.6×100mm 3μm. Solvent: MeOH [0.2% NH3 (7M in MeOH)]; Retention time = 1.467 min; ee = 100%. LC-MS (Method 2): Retention time = 1.67 min. MS (ESI) m / z 608.8 [M+H] + . 11H NMR (400 MHz, CH3OH-d4) δ: 8.32 (dd, J = 6.8 Hz, 4.4 Hz, 2H), 7.58 - 7.67 (m, 1H), 7.35 (s, 1H), 7.29 - 7.27 (m, 1H), 7.22 - 7.20 (m, 1H), 5.62 (dd, J = 6.8 Hz, 1H), 3.19 - 3.17 (m, 2H), 2.63 (t, J = 6.0 Hz, 1H), 2.33 (d, J = 7.2 Hz, 2H), 1.93 - 1.79 (m, 5H), 1.67 (d, J = 6.0 Hz, 3H), 1.49 - 1.46 (m, 2H), 1.33 - 1.24 (m, 3H), 0.41 - 0.38 (m, 2H).

[0202] Example 14 (S)-4-((1-(5-(1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-3-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-b]pyridin-7-yl)methyl)bicyclo[2.2.2]octane-1-carboxylic acid The labeled compound was synthesized in essentially the same manner as in Example 11. TIFF2025519597000177.tif58165 LC-MS (Method 4): retention time = 1.83 min. MS (ESI) m / z 635.2 [M+H] + . 11H NMR (400 MHz, CH3OH-d4) δ: 8.38 (d, J = 2.4 Hz, 1H), 8.22 (d, J = 2.0 Hz, 1H), 7.46 (t, J = 2.4 Hz, 1H), 7.37 (d, J = 2.4 Hz, 1H), 7.31 - 7.28 (m, 1H), 7.22 - 7.20 (m, 1H), 5.62 (dd, J = 12.8 Hz, 6.4 Hz, 4H), 3.20 - 3.17 (m, 2H), 2.62 (t, J = 6.4 Hz, 2H), 2.32 (dd, J = 28.4 Hz, 13.6 Hz, 2H), 1.82 - 1.80 (m, 2H), 1.67 (d, J = 6.0 Hz, 3H), 1.56 (t, J = 8.0 Hz, 6H), 1.00 - 0.96 (m, 6H).

[0203] Example 15 (S)-4-(1-(3-(1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine-7-carbonyl)benzoic acid TIFF2025519597000178.tif58165Step 1. Synthesis of methyl (S)-4-(1-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine-7-carbonyl)benzoate TIFF2025519597000179.tif A solution of (S)-1-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine (the product of step 1 of Example 11) (250 mg, 0.40 mmol) in pyridine (2 mL) was added with methyl 4-(chlorocarbonyl)benzoate (118 mg, 0.60 mmol) and DMAP (49 mg, 0.40 mmol). The solution was stirred at 100 °C for 48 h. Then water (20 mL) was added and the mixture was extracted with EA (2 × 20 mL). The organic phase was washed with brine and dried over Na2SO4. The organics were concentrated under vacuum. The residue was purified by flash column chromatography (PE:EA = 2:1) to give the title compound (50 mg, 15% yield) as a white solid. LC-MS (Method 4): retention time = 2.37 min. MS (ESI) m / z 630.1 [M+H] + 。

[0204] Step 2. Synthesis of (S)-4-(1-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine-7-carbonyl)benzoic acid TIFF2025519597000180.tif To a solution of methyl (S)-4-(1-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine-7-carbonyl)benzoate (50 mg, 0.08 mmol) in MeOH (2 mL), THF (2 mL) and H2O (1 mL) was added LiOH .H2O (6 mg, 0.16 mmol) was added. The solution was stirred at room temperature for 1 hour. Then the solution was quenched with 1 N aqueous HCl to adjust the pH to 3 and extracted with EA (3 × 30 mL). The organic phase was washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by prep-HPLC to obtain the title compound (18.5 mg, 39% yield) as a white solid. LC-MS (Method 2): Retention time = 1.62 min. MS (ESI) m / z 615.7 [M+H] + 。 1 1H NMR (500 MHz, DMSO-d6, T60) δ: 7.85 (d, J = 7.6 Hz, 2H), 7.35 - 7.27 (m, 4H), 7.20 - 7.13 (m, 2H), 6.84 - 6.82 (m, 3H), 5.44 (dd, J = 12.4, 6.0 Hz, 1H), 3.91 (br, 2H), 2.77 (t, J = 6.4 Hz, 2H), 1.95 - 1.93 (m, 2H), 1.49 (d, J = 6.4 Hz, 3H).

[0205] Example 16 (S)-4-(1-(5-(1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-3-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine-7-carbonyl)benzoic acid The title compound was synthesized in essentially the same manner as in Example 15. LC-MS (Method 4): Retention time = 1.60 min. MS (ESI) m / z 617.2 [M+H] + 。 11H NMR (400 MHz, DMSO-d6, T60) δ: 8.23 - 8.19 (m, 2H), 7.92 (d, J = 8.0 Hz, 2H), 7.44 - 7.32 (m, 5H), 7.25 (d, J = 6.8 Hz, 1H), 5.61 (dd, J = 12.4 Hz, 6.4 Hz, 1H), 4.00 - 3.89 (m, 2H), 2.80 (t, J = 6.4 Hz, 2H), 1.96 (t, J = 5.6 Hz, 2H), 1.55 (d, J = 6.4 Hz, 3H).

[0206] Example 17 trans-4-[1-[5-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-3-pyridyl]-3-(trifluoromethyl)-5,6-dihydro-4H-pyrazolo[3,4-b]pyridine-7-carbonyl]cyclohexanecarboxylic acid TIFF2025519597000182.tif58165 The labeled compound was synthesized in essentially the same manner as in Example 15. LC-MS (Method 4): Retention time = 1.60 min. MS (ESI) m / z 623.2 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ: 8.30 (dd, J = 13.6 Hz, 10.8 Hz, 2H), 7.52 - 7.50 (m, 2H), 7.40 - 7.32 (m, 2H), 5.71 (dd, J = 12.4 Hz, 6.0 Hz, 1H), 3.96 (br, 2H), 2.75 (t, J = 6.4 Hz, 1H), 2.54 (br, 1H), 2.10 - 2.05 (m, 1H), 1.94 - 1.83 (m, 4H), 1.63 - 1.13 (m, 7H), 1.15 - 1.09 (m, 2H).

[0207] Example 18 (S)-1-(1-(3-(1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine-7-carbonyl)piperidine-4-carboxylic acid TIFF2025519597000183.tif58165Step 1. Synthesis of trichloromethyl (S)-1-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)phenyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-b]pyridine-7-carboxylate TIFF2025519597000184.tif48165To a solution of (S)-1-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine (product of Step 1 of Example 11) (100 mg, 0.21 mmol) in anhydrous THF (5 mL) was added triphosgene (424 mg, 1.07 mmol) and TEA (108 mg, 1.07 mmol). The solution was stirred at room temperature for 18 h. The solution was then concentrated under vacuum to give crude trichloromethyl (S)-1-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)phenyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-b]pyridine-7-carboxylate as a yellow oil.

[0208] Step 2. Synthesis of methyl (S)-1-(1-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine-7-carbonyl)piperidine-4-carboxylate A solution of (S)-1-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)phenyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-b]pyridine-7-carboxylate (crude product obtained in Step 1) in DCM (5 mL) was added with methyl piperidine-4-carboxylate (153 mg, 1.07 mmol) and TEA (108 mg, 1.07 mmol). The solution was stirred at room temperature for 1 hour. Then water (20 mL) was added and the mixture was extracted with EA (2 × 20 mL). The organic phase was washed with brine and dried over Na2SO4. The organics were concentrated under vacuum. The residue was purified by flash column chromatography (PE:EA = 1:1) to give the title compound (70 mg, 52% yield) as a white solid. LC-MS (Method 2): retention time = 2.30 min. MS (ESI) m / z 637.2 [M+H] + 。

[0209] Step 3. Synthesis of (S)-1-(1-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine-7-carbonyl)piperidine-4-carboxylic acid A solution of methyl (S)-1-(1-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine-7-carbonyl)piperidine-4-carboxylate (70 mg, 0.11 mmol) in MeOH (2 mL), THF (2 mL) and H2O (1 mL) was added with LiOH .H2O (9 mg, 0.22 mmol) was added. The solution was stirred at room temperature for 1 hour. Then the solution was quenched with 1 N aqueous HCl to adjust the pH to 3 and extracted with EA (3 × 30 mL). The organic phase was washed with brine and dried over Na2SO4. The organic matter was concentrated under vacuum. The residue was purified by prep-HPLC to obtain the title compound (33.4 mg, 49% yield) as a white solid. LC-MS (Method 2): Retention time = 1.72 min. MS (ESI) m / z 623.1 [M+H] + 。 1 1H NMR (400 MHz, CH3OH-d4) δ: 7.31 - 7.27 (m, 2H), 7.23 - 7.21 (m, 1H), 7.15 - 7.13 (m, 1H), 7.04 - 6.98 (m, 2H), 6.91 - 6.88 (m, 1H), 5.49 (dd, J = 12.8 Hz, 6.4 Hz, 1H), 3.80 (br, 2H), 3.61 (br, 2H), 2.89 (br, 2H), 2.72 (t, J = 6.4 Hz, 2H), 2.45 - 2.39 (m, 1H), 1.87 - 1.76 (m, 4H), 1.60 (d, J = 6.8 Hz, 3H), 1.46 (br, 2H).

[0210] Example 19 4 - ((1 - (3 - (1 - (2,2 - Difluorobenzo[d][1,3]dioxol - 5 - yl)ethoxy)phenyl)-3 - (trifluoromethyl)-4,5,6,7 - tetrahydro - 1H - indazol - 7 - yl)oxy)benzoic acid TIFF2025519597000187.tif58165Step 1. Synthesis of tert - butyl 4 - ((1 - (3 - bromophenyl)-3 - (trifluoromethyl)-4,5,6,7 - tetrahydro - 1H - indazol - 7 - yl)oxy)benzoate In a solution of 1-(3-bromophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-ol (Intermediate D-2b) (720 mg, 1.99 mmol), tert-butyl 4-hydroxybenzoate (581 mg, 2.99 mmol) and triphenylphosphine (1046 mg, 3.99 mmol) in THF (20 mL), DIAD (0.78 mL, 3.99 mmol) was added dropwise at 0 °C. The solution was then stirred at room temperature overnight. The solution was poured into water (50 mL) and extracted with EA (3 × 30 mL). The organic matter was washed with 30 mL of brine. The organic matters were combined, dried (Na2SO4), and concentrated until dry. The crude product was then purified by flash column chromatography eluting with 10% ethyl acetate in isohexane to give the title compound (490 mg, 46% yield) as a yellow solid. LC-MS (Method 1): retention time = 2.63 min. MS (ESI) m / z 559 / 561 [M+Na] + 。

[0211] Step 2. Synthesis of tert-butyl 4-((1-(3-hydroxyphenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)benzoate A solution of tert-butyl 4-[[1-(3-bromophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl]oxy]benzoate (440 mg, 0.819 mmol) in 1,4-dioxane (3.5 mL) and water (1.5 mL) was added with KOH (92 mg, 1.64 mmol), tris(dibenzylideneacetone)dipalladium (75 mg, 0.0819 mmol), and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (35 mg, 0.0819 mmol). The solution was stirred at 100 °C under N2 for 1 h. The solution was poured into water (30 mL) and extracted with EA (3 × 20 mL). The organic layers were combined, washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash column chromatography eluting with 10% ethyl acetate in isohexane to afford the title compound (270 mg, 69% yield) as a white solid. LC-MS (Method 2): retention time = 2.06 min. MS (ESI) m / z 419.1 (M - tert-butyl) + .

[0212] Step 3. Synthesis of tert-butyl 4-((1-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)benzoate TIFF2025519597000190.tifA solution of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethanol (Intermediate C-1) (202 mg, 0.999 mmol), tert-butyl 4-[[1-(3-hydroxyphenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]benzoate (237 mg, 0.500 mmol) and triphenylphosphine (524 mg, 2.00 mmol) in 53165 THF (10 mL) was added dropwise with DIAD (0.39 mL, 2.00 mmol) at 0 °C. The solution was then stirred at room temperature overnight. The solution was poured into water (50 mL) and extracted with EA (3 × 30 mL). The organics were combined, washed with 30 mL of brine, dried (Na2SO4) and concentrated to dryness. The crude product was then purified by flash column chromatography eluting with 10% ethyl acetate in isohexane to give the title compound (250 mg, 41% yield) as a white solid. LC-MS (Method 1): Retention time = 2.73 min. MS (ESI) m / z 681.2 (M+Na) + 。 1 H NMR (500 MHz, DMSO-d6) δ 7.81 (dd, J = 13.8, 8.8 Hz, 2H), 7.33 - 7.19 (m, 3H), 7.15 - 7.02 (m, 3H), 6.98 (d, J = 7.6 Hz, 2H), 6.89 (d, J = 8.3 Hz, 1H), 5.83 (s, 0.5H), 5.65 (s, 0.5H), 5.40 - 5.30 (m, 1H), 2.79 (d, J = 15.8 Hz, 1H), 2.68 - 2.55 (m, 1H), 2.18 - 2.04 (m, 1H), 1.96 - 1.77 (m, 3H), 1.50 (d, J = 6.9 Hz, 9H), 1.37 (dd, J = 11.9, 6.3 Hz, 3H). (A mixture of four diastereomers).

[0213] Synthesis of 4.4 - ((1 - (3 - (1 - (2,2 - Difluorobenzo[d][1,3]dioxol - 5 - yl)ethoxy)phenyl) - 3 - (trifluoromethyl) - 4,5,6,7 - tetrahydro - 1H - indazol - 7 - yl)oxy)benzoic acid TIFF2025519597000191.tif48165To a solution of tert - butyl 4 - [[1 - [3 - [1 - (2,2 - difluoro - 1,3 - benzodioxol - 5 - yl)ethoxy]phenyl] - 3 - (trifluoromethyl) - 4,5,6,7 - tetrahydroindazol - 7 - yl]oxy]benzoate (200 mg, 0.304 mmol) in 1,4 - dioxane (10 mL) and water (3 mL) was added KOH (256 mg, 4.56 mmol), and the solution was stirred at 100 °C for 19 h. The solution was purified by prep - HPLC to give the title compound (60 mg, 33% yield) as a white solid. LC - MS (Method 2): Retention time = 1.66 min. MS (ESI) m / z 603.2 (M + H) + 。 Δ 7.97 - 7 / 88 (m, 2H), 7.30 - 7.08 (m, 5H), 6.99 - 6.81 (m, 4H), 5.58 (s, 0.5H), 5.45 (s, 0.5H), 5.20 - 5.08 (m, 1H), 2.88 - 2.84 (m, 1H), 2.69 - 2.53 (m, 1H), 2.30 - 2.25 (m, 1H), 2.09 - 1.70 (m, 3H), 1.44 (d, J = 6.4 Hz, 1.5H), 1.39 (d, J = 6.4 Hz, 1.5H) (a mixture of four diastereomers)

[0214] Example 20 4 - ((1 - (3 - ((2,2 - Difluorobenzo[d][1,3]dioxol - 5 - yl)methoxy)phenyl) - 3 - (trifluoromethyl) - 4,5,6,7 - tetrahydro - 1H - indazol - 7 - yl)oxy)benzoic acid TIFF2025519597000192.tif48165The title compound was synthesized in essentially the same manner as in Example 19. LC-MS (Method 2): Retention time = 1.61 minutes. MS (ESI) m / z 589.1 [M+H] + 。 1 H NMR (400 MHz, CH3OH-d4 δ 7.92 (d, J = 8.8 Hz, 2H), 7.32 (t, J = 8.1 Hz, 1H), 7.23 - 7.07 (m, 4H), 7.03 - 6.90 (m, 4H), 5.65 (d, J = 3.2 Hz, 1H), 4.77 (d, J = 11.6 Hz, 1H), 4.60 (d, J = 11.6 Hz, 1H), 2.90 - 2.86 (m, 1H), 2.67 - 2.59 (m, 1H), 2.31 - 2.26 (m, 1H), 2.12 - 1.96 (m, 1H), 1.89 - 1.84 (m, 2H).

[0215] Examples 21 and 22 4 - [[1 - [2 - [(1R)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-4-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]benzoic acid TIFF2025519597000193.tif581654 - [[1 - [2 - [(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-4-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]benzoic acid TIFF2025519597000194.tif58165 Step 1. Synthesis of 1-(2-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-indazol-7-one A solution of 1-(2-hydroxy-4-pyridyl)-3-(trifluoromethyl)-5,6-dihydro-4H-indazol-7-one (Intermediate D-4) (4000 mg, 13.5 mmol) in 63165 THF (50 mL) was added with 1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethanol (Intermediate C-1) (3265 mg, 16.1 mmol) and triphenylphosphine (4236 mg, 16.1 mmol). After cooling the solution to 0 °C, diethyl azodicarboxylate (2.6 mL, 16.1 mmol) was added dropwise at 0 °C, and then the mixture was stirred at 25 °C for 1 hour. The solution was concentrated, and then the crude product was purified by flash column chromatography eluted with 10% ethyl acetate in isohexane to obtain a racemic compound (4500 mg, 69% yield), which was purified by SFC to obtain two enantiomers of the title compound each having a first fraction designated as P1 (2100 mg, 47% yield) and a second fraction designated as P2 (2000 mg, 44% yield). LC-MS (Method 2): retention time = 2.36 min. MS (ESI) m / z 482.0 (M+H) + 。

[0216] Step 2a. Synthesis of 1-(2-((R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-ol A solution of 1-[2-[(1R)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-4-pyridyl]-3-(trifluoromethyl)-5,6-dihydro-4H-indazol-7-one (Intermediate P1 in Step 1) (400 mg, 0.831 mmol) in methanol (10 mL) was added with sodium borohydride (126 mg, 3.32 mmol). Then the solution was stirred at room temperature for 2 hours under Ar. The reaction was quenched with water. Then the mixture was diluted with water (50 mL) and extracted with EA (3×50 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (Biotage, 40 g silica gel column @ 60 mL / min, eluted with 0 - 30% ethyl acetate in petroleum ether for 20 minutes) to give the title compound (360 mg, 83% yield) as a pale yellow oil. LC-MS (Method 1): Retention time = 2.38 min. MS (ESI) m / z 484.3 (M + H) + 。

[0217] Step 2b. Synthesis of 1-(2-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-ol Using the starting material of 1-[2-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-4-pyridyl]-3-(trifluoromethyl)-5,6-dihydro-4H-indazol-7-one (Intermediate P2 in Step 1), a diastereomeric labeled mixture was obtained as a pale yellow oil (350 mg, 83% yield) by the same protocol as described in Step 2a. LC-MS (Method 1): Retention time = 2.38 min. MS (ESI) m / z 484.3 (M + H) + 。

[0218] Synthesis of Methyl 4-((1-(2-((R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)benzoate TIFF2025519597000198.tif53165To a solution of 1-[2-[(1R)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-4-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-ol (intermediate from Step 2a) (100 mg, 0.207 mmol) in THF (3 mL) were added methyl 4-hydroxybenzoate (38 mg, 0.248 mmol) and triphenylphosphine (71 mg, 0.269 mmol). The solution was then cooled to 0 °C and DEAD (0.049 mL, 0.310 mmol) was added dropwise under N2. The solution was stirred at 25 °C for 1 - 2 h. The reaction solution was then diluted with aqueous NH4Cl solution. The solution was extracted with EA (3 × 15 mL). The organic layers were combined, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (EA:PE = 1:8) to give a diastereomeric mixture of the title compound (50 mg, 16% yield) as a white solid. LC-MS (Method 2): Retention time = 2.65 min. MS (ESI) m / z 618.2 (M+H) + 。

[0219] Synthesis of Methyl 4-((1-(2-((S)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)benzoate Using the starting material of [[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-4-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-ol (intermediate from step 2b), a diastereomeric mixture of labeled compounds was obtained as a white solid (60 mg, 23% yield) by the same protocol as described in step 3a. LC-MS (method 2): retention time = 2.65 min. MS (ESI) m / z 618.2 (M+H) + 。

[0220] Step 4a. Synthesis of 4-((1-(2-((R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)benzoic acid To a solution of methyl 4-[[1-[3-[(1R)-1-(2,2,6-trifluorobenzo[d][1,3]dioxol-5-yl)ethoxy]phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl]oxy]benzoate (intermediate from step 3a) (50 mg, 0.0946 mmol) in methanol (2 mL), THF (2 mL) and water (1 mL) was added LiOH (9.1 mg, 0.378 mmol). The solution was stirred at 25 °C for 12 h, then the solution was concentrated under vacuum and purified by prep-HPLC to give the labeled compound (28 mg, 48% yield) as a white solid. LC-MS (method 1): retention time = 2.38 min. MS (ESI) m / z 604.2 (M+H) + 。

[0221] Step 4b. Synthesis of 4-((1-(2-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)benzoic acid Using the starting material of TIFF2025519597000201.tif58165 methyl 4-[[1-[3-[(1S)-1-(2,2,6-trifluoro-1,3-benzodioxol-5-yl)ethoxy]phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]benzoate (intermediate from step 3b), a diastereomeric labeled mixture was obtained as a white solid (34 mg, 69% yield) by the same protocol as described in step 2a. LC-MS (method 1): retention time = 1.62 min. MS (ESI) m / z 604.1 (M+H) + 。

[0222] Examples 23 and 24 4-[[(7R)-1-[2-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-4-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]benzoic acid TIFF2025519597000202.tif58165 4-[[(7S)-1-[2-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-4-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]benzoic acid TIFF2025519597000203.tif58165 Synthetic method 1. Step 1. Synthesis of methyl 4-((1-(2-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)benzoate A solution of 1-[2-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-4-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-ol (800 mg, 1.65 mmol) (Intermediate from Examples 21 and 22, Step 2b) in THF (10 mL) was added with methyl 4-hydroxybenzoate (302 mg, 1.99 mmol) and PPh3 (521 mg, 1.99 mmol). The solution was stirred at 0 °C for 5 minutes, then DEAD (0.31 mL, 1.99 mmol) was added dropwise at 0 °C. The solution was then stirred at 25 °C for 1 hour. The solution was concentrated, and the crude product was purified by flash column chromatography eluting with 10% ethyl acetate in isohexane to give a mixture of diastereomers (650 mg, 69% yield), which was further separated by SFC to give the title compound having a first fraction designated as P1 (300 mg, 47%; yellow oil), and a second fraction as P2 (300 mg, 44%; yellow oil). LC-MS (Method 1): Retention time = 2.65 minutes. MS (ESI) m / z 618.2 [M+H] + .

[0223] Step 2a. Synthesis of 4-(((S)-1-(2-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)benzoic acid TIFF2025519597000205.tif A solution of methyl 4-(((S)-1-(2-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)benzoate (P1, an intermediate from the above step 1) (300 mg, 0.486 mmol) in methanol (10 mL), THF (10 mL) and water (5 mL) was added with lithium hydroxide (47 mg, 1.94 mmol). The solution was then stirred at 25 °C overnight. The solution was concentrated under vacuum and purified by prep-HPLC to obtain the title compound (185 mg, 48% yield) as a white solid. LC-MS (Method 1): retention time = 1.86 min. MS (ESI) m / z 602.0 [M-H] + 。 1 1H NMR (500 MHz, CH3OH-d4) δ 8.06 (d, J = 7.5 Hz, 1H), 8.03 (d, J = 11 Hz, 2H), 7.16 (dd, J = 7.0, 2.5 Hz, 1H), 7.12 (dd, J = 7.0, 5.0 Hz, 2H), 7.05 (d, J = 1.7 Hz, 1H), 7.03 - 6.87 (m, 3H), 6.03 (q, J = 8.0 Hz, 1H), 5.74 (t, J = 4.5 Hz, 1H), 2.87 (d, J = 21 Hz, 1H), 2.63 (ddd, J = 16.7, 11.0, 5.7 Hz, 1H), 2.29 (d, J = 17 Hz, 1H), 2.00 (dd, J = 12.2, 6.9 Hz, 1H), 1.95-1.75 (m, 2H), 1.43 (d, J = 8.0 Hz, 3H).

[0224] Step 2b. Synthesis of 4-(((R)-1-(2-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)benzoic acid Using the starting material of TIFF2025519597000206.tif58165 methyl 4-(((R)-1-(2-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)benzoate (P2, an intermediate from Step 1 above), the title compound was obtained as a white solid by the same protocol as described in Step 2a (158 mg, 54% yield). LCMS (Method 1): Retention time = 1.71 min. MS (ESI-) m / z 602 [M-H] - . 1 H NMR (400 MHz, CD3OD) δ 7.93 (dd, J = 20.9, 8.8 Hz, 2H), 7.30 - 6.81 (m, 9H), 5.51 (m, 1H), 5.15 (ddd, J = 26.7, 12.5, 6.2 Hz, 1H), 2.86 (d, J = 16.3 Hz, 1H), 2.69 - 2.53 (m, 1H), 2.27 (d, J = 14.3 Hz, 1H), 2.09 - 1.70 (m, 3H), 1.42 (dd, J = 21.4, 6.3 Hz, 3H).

[0225] Example 24, Synthetic Method 2. Step 1. Synthesis of 4-bromo-2-(1-phenylethoxy)pyridine A solution of 4-bromo-2-fluoro-pyridine (20.0 g, 114 mmol) and 1-phenylethanol (13.9 g, 114 mmol) in DMF (200 mL) was added with Cs2CO3 (111 g, 342 mmol). The reaction mixture was stirred at 100 °C overnight. The mixture was poured into water (2 L) and extracted with EA (200 mL×3). The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was then purified by flash column chromatography eluting with 10% ethyl acetate in PE to afford the title compound (29.0 g, 91.8%) as a yellow solid. LCMS (Method 1): retention time = 2.45 min. MS (ESI) m / z 174.1, 176.1 [M-103] + 。

[0226] Step 2. Synthesis of tert-butyl 1-(2-(1-phenylethoxy)pyridin-4-yl)hydrazinecarboxylate A solution of 4-bromo-2-(1-phenylethoxy)pyridine (15.0 g, 53.9 mmol) in 1,4-dioxane (150 mL) was added with tert-butyl N-aminocarbamate (8.6 g, 64.7 mmol), XantPhos (3.1 g, 5.39 mmol), tris(dibenzylideneacetone)dipalladium (4.9 g, 5.39 mmol), and Cs2CO3 (52.8 g, 162 mmol). The mixture was then stirred at 100 °C overnight under Ar. The mixture was poured into water (2 L) and extracted with EA (200 mL×3). The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was then purified by flash column chromatography eluting with 10% ethyl acetate in PE to afford the title compound (16.0 mg, 90.1%) as a yellow solid. LCMS (Method 1): retention time = 2.11 min. MS (ESI) m / z 226 [M-103] + 。

[0227] Synthesis of 3.1-(2-Hydroxypyridin-4-yl)-3-(trifluoromethyl)-5,6-dihydro-1H-indazol-7(4H)-one To a solution of tert-butyl N-amino-N-[2-(1-phenylethoxy)-4-pyridyl]carbamate (10.0 g, 30.4 mmol) in 2,2,2-trifluoroethanol (100 mL) was added sulfuric acid (25 mL). The mixture was then stirred at 80 °C overnight. The mixture was poured into water (500 mL), the pH was adjusted to 8 - 9 with NaHCO3, and then extracted with EA (50 mL × 3). The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was then purified by flash column chromatography eluting with 10% ethyl acetate in PE to afford the title compound (5.0 g, 55.4%) as a yellow solid. LCMS (Method 1): Retention time = 1.72 min. MS (ESI) m / z 298.3 [M+H] + 。

[0228] Synthesis of (S)-1-(2-(1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-5,6-dihydro-1H-indazol-7(4H)-one A solution of 1-(2-hydroxy-4-pyridyl)-3-(trifluoromethyl)-5,6-dihydro-4H-indazol-7-one (4000 mg, 13.5 mmol) in THF (50 mL) was added with R-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethan-1-ol (Intermediate C-1R) (3265 mg, 16.1 mmol) and PPh3 (4236 mg, 16.1 mmol). After cooling the mixture to 0 °C, DEAD (2.6 mL, 16.1 mmol) was added dropwise at 0 °C, and then the mixture was stirred at room temperature for 1 h under N2. The mixture was concentrated, and then the crude product was purified by flash column chromatography eluting with 10% ethyl acetate in PE to give the crude compound (4.5 g, ee 90%). This crude compound was further purified by SFC to afford the title compound (3.2 g, 49%, ee >99%) as a white solid. LCMS (Method 2): retention time = 2.36 min. MS (ESI) m / z 298.0 (M - 183) + 。

[0229] Step 5. Synthesis of (7R)-1-(2-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-ol In a 37165200 mL reactor, the product from Step 4 (5.0 g, 10.4 mmol) was suspended in IPA (yellow suspension) (10 vol) at room temperature. TEA (0.6 vol) and the catalyst (R,R)-TsDPEN-RuCl(p-cymene) (0.006 wt) were added to the mixture, and 3 cycles of vacuum / nitrogen exchange were applied. Formic acid (0.4 vol) was gradually added to the mixture over 10 minutes. (Exothermic reaction from 20 to 25 °C). The temperature was raised to 45 °C, and the solution was stirred for 4 hours. The reaction mixture was concentrated under vacuum. Water (10 vol) was added, the pH was adjusted to 7 - 8 with 5% aqueous NaHCO3, and then extracted with EA (2 vol × 3). The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash column chromatography eluting with 20% ethyl acetate in isohexane to give the title compound (3.0 g, 60%) as a yellow solid. LCMS (Method 1): Retention time = 1.73 min. MS (ESI) m / z 300 [M - 183] + 。

[0230] Step 6. Synthesis of methyl 4 - (((S)-1-(2-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)benzoate In a solution of R-1-(2-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-ol (3000 mg, 6.2 mmol) in THF (10 mL), methyl 4-hydroxybenzoate (1.1 g, 7.4 mmol) and PPh3 (2.4 g, 9.3 mmol) were added. The mixture was cooled to 0 °C, and DEAD (1.6 g, 9.3 mmol) was added dropwise at 0 °C under N2. The mixture was then stirred at room temperature for 1 hour. The mixture was concentrated, and the crude product was purified by flash column chromatography eluting with 10% ethyl acetate in PE to give the title compound (3.0 g, 79%) as a white solid. LCMS (Method 1): retention time = 2.65 min. MS (ESI) m / z 434.2 [M - 183] + 。

[0231] Step 7. Synthesis of 4-(((S)-1-(2-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)benzoic acid To a solution of methyl 4-[[(7S)-1-[2-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-4-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]benzoate (3.0 g, 4.86 mmol) in methanol (20 mL), THF (20 mL) and water (10 mL), lithium hydroxide (465 mg, 19.4 mmol) was added. The reaction was stirred at 25 °C overnight. The mixture was then concentrated, and the crude product was purified by pre-HPLC (NH4HCO3) to give the title compound (2204 mg, 75.2%) as a white solid. Analysis (LCMS and 1The 1H NMR is identical to the sample obtained through Synthesis Method 1.

[0232] Examples 25 and 26 4-[[(7S)-1-[3-[(1S)-1-(2,2-Difluoro-1,3-benzodioxol-5-yl)ethoxy]phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]benzoic acid TIFF2025519597000214.tif581654-[[(7R)-1-[3-[(1S)-1-(2,2-Difluoro-1,3-benzodioxol-5-yl)ethoxy]phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]benzoic acid TIFF2025519597000215.tif58165 The title compound was synthesized in essentially the same manner as in Examples 23 and 24. P1: 115.5 mg, 70%, white solid. LC-MS (Method 2): retention time = 1.63 min. MS (ESI) m / z 603.2 [M+H] + . 1 1H NMR (500 MHz, CH3OH-d4) δ 7.98 (d, J = 8.7 Hz, 2H), 7.22 - 7.18 (m, 1H), 7.12 - 6.90 (m, 7H), 6.86 (d, J = 8.5 Hz, 1H), 5.49 (s, 1H), 5.17 (q, J = 6.3 Hz, 1H), 2.89 - 2.83 (m, 1H), 2.65 - 2.58 (m, 1H), 2.27 - 2.22 (m, 1H), 2.01 - 1.89 (m, 3H), 1.41 (d, J = 6.3 Hz, 3H). P2: 105 mg, 67% yield, white solid. LC-MS (Method 2): retention time = 1.63 min. MS (ESI) m / z 603.2 [M+H] + . 11H NMR (500 MHz, CH3OH-d4) δ 7.97 (d, J = 8.7 Hz, 2H), 7.22-7.18 (m, 1H), 7.12-6.90 (m, 7H), 6.86 (d, J = 8.4 Hz, 1H), 5.49 (s, 1H), 5.17 (q, J = 6.3 Hz, 1H), 2.89-2.83 (m, 1H), 2.67-2.50 (m, 1H), 2.27-2.22 (m, 1H), 2.01-1.89 (m, 3H), 1.41 (d, J = 6.3 Hz, 3H).

[0233] Example 27 4-[[(7S)-1-[5-[(1S)-1-(2,2-Difluoro-1,3-benzodioxol-5-yl)ethoxy]-3-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]benzoic acid The labeled compound was synthesized in essentially the same manner as in Examples 23 and 24. TIFF2025519597000216.tif58165 Chiral method: Column name: OX-H 4.6×100mm 5μm. Solvent: EtOH[0.2%NH3(in MeOH 7M)]; Retention time = 2.39 minutes; ee = 100%. LC-MS (Method 4): Retention time = 1.85 minutes. MS (ESI) m / z 604.1 [M+H] + . 11H NMR (500 MHz, CH3OH-d4) δ 8.31 (d, J = 2.0 Hz, 1H), 8.19 (d, J = 2.5 Hz, 1H), 7.99 (d, J = 8.7 Hz, 2H), 7.52 (t, J = 2.3 Hz, 1H), 7.11 (dd, J = 14.0, 4.9 Hz, 2H), 6.97 (dd, J = 9.4, 2.2 Hz, 3H), 5.60 (t, J = 3.1 Hz, 1H), 5.19 (q, J = 6.3 Hz, 1H), 2.87 (d, J = 16.0 Hz, 1H), 2.62 (ddd, J = 16.7, 10.9, 5.8 Hz, 1H), 2.27 (d, J = 14.2 Hz, 1H), 2.05-1.92 (m 3H), 1.44 (d, J = 6.3 Hz, 3H)

[0234] Examples 28 and 29 4-((1-(3-((R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)benzoic acid TIFF2025519597000217.tif581654-((1-(3-((S)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)benzoic acid TIFF2025519597000218.tif58165The diastereomeric labeled mixture was synthesized in essentially the same manner as in Examples 21 and 22. P1: LC-MS (Method 1): Retention time = 2.33 min. MS (ESI) m / z 603.3 [M+H] + . 11H NMR (400 MHz, CH3OH-d4) δ 7.98 (d, J = 8.8 Hz, 1H), 7.92 (s, J = 8.8 HZ, 1H), 7.23 - 7.18 (m, 1H), 7.15 - 6.84 (m, 8H), 5.66 (s, 0.5H), 5.50 (d, J = 2.8 Hz, 0.5H), 5.22 - 5.17 (m, 1H), 2.89 - 2.84 (m, 1H), 2.63 - 2.62 (m, 1H), 2.26 - 2.22 (m, 1H), 2.04 - 1.77 (m, 3H), 1.44 - 1.39 (m, 3H) ppm。 P2: LC-MS (Method 1): Retention time = 2.33 min. MS (ESI) m / z 603.3 [M+H]+。 1 1H NMR (400 MHz, CH3OH-d 4) δ 8.09 - 7.87 (m, 2H), 7.23 - 7.18 (m, 1H), 7.14 - 6.84 (m, 8H), 5.66 (s, 0.5H), 5.51 (d, J = 2.8 Hz, 0.5H), 5.23 - 5.18 (m, 1H), 2.89 - 2.83 (m, 1H), 2.70 - 2.53 (m, 1H), 2.36 - 2.17 (m, 1H), 2.11 - 1.78 (m, 3H), 1.46 - 1.40 (m, 3H)。

[0235] Examples 30 and 31 4 - ((1 - (3 - ((R)-1 - (2,2 - difluoro - [1,3]dioxolo[4,5 - c]pyridin - 6 - yl)ethoxy)phenyl)-3 - (trifluoromethyl)-4,5,6,7 - tetrahydro - 1H - indazol - 7 - yl)oxy)benzoic acid TIFF2025519597000219.tif581654 - ((1 - (3 - ((S)-1 - (2,2 - difluoro - [1,3]dioxolo[4,5 - c]pyridin - 6 - yl)ethoxy)phenyl)-3 - (trifluoromethyl)-4,5,6,7 - tetrahydro - 1H - indazol - 7 - yl)oxy)benzoic acid TIFF2025519597000220.tif58165 The diastereomeric labeled mixture was synthesized in essentially the same manner as in Examples 21 and 22. P1: LC-MS (Method 2): Retention time = 1.53 min. MS (ESI) m / z 604.2 [M+H] + 。 1 1H NMR (500 MHz, CH3OH-d4) δ 8.36 (d, J = 3.7 Hz, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 8.7 Hz, 1H), 7.34 - 7.03 (m, 4H), 6.97 (d, J = 8.4 Hz, 1H), 6.93 - 6.81 (m, 2H), 5.67 (s, 0.5H), 5.54 (s, 0.5H), 5.26 - 5.20 (m, 1H), 2.90 - 2.80 (m, 1H), 2.69 - 2.57 (m, 1H), 2.26 - 2.20 (m, 1H), 2.08 - 1.82 (m, 3H), 1.50 - 1.45 (m, 3H) (mixture of two diastereomers). P2: LC-MS (Method 2): Retention time = 1.53 min. MS (ESI) m / z 604.2 [M+H] + 。 1 1H NMR (500 MHz, CH3OH-d4) δ 8.36 (d, J = 3.6 Hz, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.31 - 7.02 (m, 4H), 6.97 (d, J = 8.8 Hz, 1H), 6.93 - 6.80 (m, 2H), 5.67 (s, 0.5H), 5.54 (d, J = 2.4 Hz, 0.5H), 5.26 - 5.21 (m, 1H), 2.89 - 2.82 (m, 1H), 2.69 - 2.58 (m, 1H), 2.27 - 2.20 (m, 1H), 2.02 - 1.86 (m, 3H), 1.50 - 1.45 (m, 3H) ppm. (mixture of two diastereomers)

[0236] Examples 32 and 33 4-((1-(3-((R)-1-(2,2,6-Trifluorobenzo[d][1,3]dioxol-5-yl)ethoxy)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)benzoic acid TIFF2025519597000221.tif531654-((1-(3-((S)-1-(2,2,6-Trifluorobenzo[d][1,3]dioxol-5-yl)ethoxy)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)benzoic acid TIFF2025519597000222.tif58165The labeled compound was synthesized in essentially the same manner as in Examples 21 and 22. P1: LC-MS (Method 1): Retention time = 2.38 min. MS (ESI) m / z 621.2 [M+H] + 。 1 H NMR (500 MHz, CH3OH-d4) δ 7.92 (m, 8.7 Hz, 2H), 7.26 - 6.90 (m, 6H), 6.86 (dd, J = 11.8, 4.5 Hz, 2H), 5.71 - 5.24 (m, 2H), 2.87 (d, J = 16.8 Hz, 1H), 2.63 (d, J = 6.1 Hz, 1H), 2.25 (t, J = 13.9 Hz, 1H), 2.12 - 1.71 (m, 3H), 1.46 (dd, J = 23.2, 6.3 Hz, 3H). P2: LC-MS (Method 1): Retention time = 2.38 min. MS (ESI) m / z 621.2 [M+H] + 。 11H NMR (500 MHz, CH3OH-d4) δ 7.91 (m, 2H), 7.31 - 6.98 (m, 5H), 6.98 - 6.75 (m, 3H), 5.50 (m, 2H), 2.86 (d, J = 17.0 Hz, 1H), 2.61 (td, J = 10.9, 5.0 Hz, 1H), 2.27 (d, J = 11.5 Hz, 1H), 2.16 - 1.68 (m, 3H), 1.46 (dd, J = 27.5, 6.3 Hz, 3H).

[0237] Examples 34 and 35 2-Methyl-4-[[1-[3-[(1R)-1-(2,2,6-trifluoro-1,3-benzodioxol-5-yl)ethoxy]phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]benzoic acid TIFF2025519597000223.tif531652-Methyl-4-[[1-[3-[(1S)-1-(2,2,6-trifluoro-1,3-benzodioxol-5-yl)ethoxy]phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]benzoic acid TIFF2025519597000224.tif53165The diastereomeric labeled mixture was synthesized in essentially the same manner as in Examples 21 and 22. P1: LC-MS (Method 4): Retention time = 1.99 min. MS (ESI) m / z 635.1 [M+H] + . 1 1H NMR (400 MHz, CH3OH-d4) δ: 7.61 - 7.45 (m, 1H), 7.30 - 7.04 (m, 5H), 6.92 - 6.83 (m, 1H), 6.73 - 6.57 (m, 2H), 5.56 (m, 1H), 5.51 - 5.35 (m, 1H), 2.85 (m, 1H), 2.60 (m, 1H), 2.45 (m, 3H), 2.34 - 2.17 (m, 1H), 2.10 - 1.66 (m, 3H), 1.51 (m, 3H). P2: LC-MS (Method 4): Retention time = 2.02 min. MS (ESI) m / z 635.1 [M+H] + 。 1 1H NMR (400 MHz, CH3OH-d4) δ: 7.60 - 7.46 (m, 1H), 7.28 - 7.06 (m, 5H), 6.90 (m, 1H), 6.67 (m, 2H), 5.63 - 5.52 (m, 1H), 5.45 (m, 1H), 2.85 (m, 1H), 2.59 (s, 1H), 2.45 (dm, 2H), 2.23 (s, 1H), 1.84 (m, 3H), 1.51 (m, 3H).

[0238] Example 36 4-(((S)-1-(3-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)-4-fluorophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)benzoic acid TIFF2025519597000225.tif53165 Step 1. Synthesis of (S)-1-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)-4-fluorophenyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-indazol-7-one A solution of 1-(4-fluoro-3-hydroxy-phenyl)-3-(trifluoromethyl)-5,6-dihydro-4H-indazol-7-one (Intermediate D-3) (3000 mg, 9.55 mmol) and (1R)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethanol (Intermediate C-1R) (2123 mg, 10.50 mmol) in THF (40 mL) was added with triphenylphosphine (7512 mg, 28.60 mmol) and diethyl azodicarboxylate (2.3 mL, 14.30 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo. The residue was purified by flash silica gel column chromatography (ethyl acetate in petroleum ether from 0% to 15%) to afford the title compound (4500 mg, 92.7% yield) as a brown oil. LCMS (Method 2): retention time = 2.43 min. MS (ESI) m / z 499.0 [M+H] + 。

[0239] Step 2. Synthesis of (R)-1-(3-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)-4-fluorophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-ol A solution of 1-[3-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-4-fluorophenyl]-3-(trifluoromethyl)-5,6-dihydro-4H-indazol-7-one (4000 mg, 8.03 mmol) and ((R,R)-2-amino-1,2-diphenylethyl)[(4-tolyl)sulfonyl]amide](p-cymene)ruthenium(II) chloride (153 mg, 0.24 mmol) in IPA (50 mL) was added with triethylamine (3.0 mL, 21.50 mmol) and formic acid (2.0 mL, 52.10 mmol), and stirred for 2 h. The reaction mixture was concentrated in vacuo. The residue was purified by flash silica gel column chromatography (ethyl acetate in petroleum ether from 0% to 10%) to afford the title compound (4000 mg, 97.6% yield) as a yellow oil. LCMS (method 2): retention time = 2.37 min. MS (ESI) m / z 501.0 [M+H] + 。

[0240] Step 3. Synthesis of methyl 4-(((S)-1-(3-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)-4-fluorophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)benzoate A solution of (7R)-1-[3-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-4-fluoro-phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-ol (3000 mg, 6.00 mmol) and methyl 4-hydroxybenzoate (1003 mg, 6.59 mmol) in THF (35 mL) was added with triphenylphosphine (4718 mg, 18.00 mmol) and diethyl azodicarboxylate (1.4 mL, 8.99 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo. The residue was purified by flash silica gel column chromatography (ethyl acetate in petroleum ether from 0% to 8%) to afford the title compound (3000 mg, 77.3% yield) as a pale yellow oil. LCMS (Method 2): retention time = 2.69 min. MS (ESI) m / z 635.0 [M+H] + .

[0241] Step 4. Synthesis of 4-(((S)-1-(3-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)-4-fluorophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)benzoic acid A solution of methyl 4-[[(7S)-1-[3-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-4-fluorophenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]benzoate (3000 mg, 4.73 mmol) in methanol (20 mL) / THF (20 mL) / water (10 mL) was added with lithium hydroxide monohydrate (992 mg, 23.60 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (NH4HCO3 conditions) to afford the crude product. The crude product was purified by SFC to give the title compound (2010 mg, 68.5% yield) as a white solid. LCMS (Method 2): retention time = 1.81 min. MS (ESI) m / z 621.1 [M+H] + 。 1 1H NMR (400 MHz, MeOH-d4) δ 8.00 - 7.89 (m, 2H), 7.18 - 7.07 (m, 4H), 7.06 - 6.98 (m, 2H), 6.91 (d, J = 8.9 Hz, 2H), 5.46 (d, J = 2.9 Hz, 1H), 5.04 (q, J = 6.4 Hz, 1H), 2.84 (d, J = 12.7 Hz, 1H), 2.58 (ddd, J = 16.8, 10.9, 5.8 Hz, 1H), 2.22 (d, J = 14.2 Hz, 1H), 2.06 - 1.73 (m, 3H), 1.39 (d, J = 6.3 Hz, 3H). Examples 36a - 36m were synthesized using essentially the same protocol as in Example 36.

[0242] Example 36a 4-[[(7S)-1-[2-[(1S)-1-(2,2,6-trifluoro-1,3-benzodioxol-5-yl)ethoxy]-4-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]benzoic acid TIFF2025519597000230.tif58165LCMS (Method 1): Retention time = 1.87 minutes. MS (ESI) m / z 620.0 [M-H] - 。 Chiral method: Column name: OZ 4.6 * 100 mm 5 μm Solvent: MeOH [0.2% NH3 (7M in MeOH)]; Detected at 1.086 minutes; ee: 98.84%. 1 H NMR (400 MHz, MeOH-d4) δ 8.04 (dd, J = 15.7, 7.2 Hz, 3H), 7.17 (dd, J = 5.6, 1.8 Hz, 1H), 7.12 - 6.99 (m, 4H), 6.89 (d, J = 5.7 Hz, 1H), 6.27 (q, J = 6.5 Hz, 1H), 5.78 (d, J = 3.2 Hz, 1H), 2.87 (d, J = 16.8 Hz, 1H), 2.72 - 2.54 (m, 1H), 2.35 - 2.24 (m, 1H), 2.07 - 1.87 (m, 3H), 1.44 (d, J = 6.5 Hz, 3H).

[0243] Example 36b 4 - [[(7S)-1-[4-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-2-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]benzoic acid TIFF2025519597000231.tif58165LCMS (Method 2): Retention time = 1.87 minutes. MS (ESI) m / z 604.0 [M+H] + 。 11H NMR (400 MHz, MeOH-d4) δ 7.88 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 5.8 Hz, 1H), 7.33 (d, J = 2.2 Hz, 1H), 7.25 (d, J = 1.3 Hz, 1H), 7.17 (dt, J = 18.2, 4.9 Hz, 2H), 6.88 (d, J = 8.9 Hz, 2H), 6.71 (dd, J = 5.8, 2.3 Hz, 1H), 6.42 (s, 1H), 5.57 (q, J = 6.3 Hz, 1H), 2.82 (d, J = 15.7 Hz, 1H), 2.58 (dd, J = 14.9, 7.7 Hz, 1H), 2.28 - 2.13 (m, 1H), 2.03 - 1.81 (m, 3H), 1.60 (d, J = 6.4 Hz, 3H).

[0244] Example 36c 4-[[(7S)-1-[6-[(1S)-1-(2,2-Difluoro-1,3-benzodioxol-5-yl)ethoxy]-2-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]benzoic acid TIFF2025519597000232.tif58165LCMS (Method 2): Retention time = 1.83 min. MS (ESI) m / z 602.0 [M-H] + . 11H NMR (400 MHz, MeOH-d4) δ 7.76 (t, J = 8.0 Hz, 1H), 7.70 (d, J = 8.7 Hz, 2H), 7.25 (d, J = 7.7 Hz, 1H), 7.16 - 7.00 (m, 3H), 6.73 (d, J = 8.2 Hz, 1H), 6.67 (d, J = 8.8 Hz, 2H), 6.07 (s, 1H), 5.77 (q, J = 6.3 Hz, 1H), 2.83 (d, J = 16.4 Hz, 1H), 2.71 - 2.55 (m, 1H), 2.24 (d, J = 13.9 Hz, 1H), 2.01 (m, 3H), 1.41 (d, J = 6.4 Hz, 3H).

[0245] Example 36d 4-[[(7S)-1-[6-Fluoro-5-[(1S)-1-(2,2,6-trifluoro-1,3-benzodioxol-5-yl)ethoxy]-3-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]benzoic acid TIFF2025519597000233.tif58165As a white solid (31 mg, 63.16% yield). LCMS (method 2): Retention time = 1.80 min. MS (ESI) m / z 640.0 [M+H] + . 11H NMR (400 MHz, MeOH-d4) δ 7.93 (d, J = 8.8 Hz, 2H), 7.89 (s, 1H), 7.59 (dd, J = 8.5, 2.1 Hz, 1H), 7.25 (d, J = 5.7 Hz, 1H), 7.11 (d, J = 9.0 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 5.62 (s, 1H), 5.44 (q, J = 6.2 Hz, 1H), 2.85 (d, J = 16.5 Hz, 1H), 2.66 - 2.56 (m, 1H), 2.23 (d, J = 11.7 Hz, 1H), 2.02 - 1.84 (m, 3H), 1.46 (t, J = 6.9 Hz, 3H).

[0246] Example 36e 4 - [[(7S)-1-[5-[(1S)-1-(2,2,6-Trifluoro-1,3-benzodioxol-5-yl)ethoxy]-3-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]benzoic acid TIFF2025519597000234.tif58165LCMS (method 2): LC retention time 1.76, MS (ESI): m / z 622 [M + H]+. 1 1H NMR (400 MHz, MeOH-d4) δ 8.33 (d, J = 1.8 Hz, 1H), 8.17 (d, J = 2.5 Hz, 1H), 7.96 (d, J = 8.8 Hz, 2H), 7.55 (t, J = 2.3 Hz, 1H), 7.12 (dd, J = 10.0, 7.4 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 5.66 (d, J = 3.2 Hz, 1H), 5.55 (q, J = 6.3 Hz, 1H), 2.87 (d, J = 16.2 Hz, 1H), 2.71 - 2.49 (m, 1H), 2.24 (dd, J = 14.8, 11.4 Hz, 1H), 2.11 - 1.82 (m, 3H), 1.47 (t, J = 11.0 Hz, 3H).

[0247] Example 36f 4-[[(7S)-1-[6-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-5-fluoro-2-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]benzoic acid TIFF2025519597000235.tif58165LCMS (method 4): retention time = 1.80 min. MS (ESI) m / z 620.1 [M-H] - 。 1 H NMR (400 MHz, MeOH-d4) δ 7.71 (d, J = 8.8 Hz, 2H), 7.64 (dd, J = 9.3, 8.5 Hz, 1H), 7.26 (dd, J = 8.4, 2.6 Hz, 1H), 7.14 (d, J = 8.5 Hz, 2H), 7.07 (dd, J = 8.3, 1.5 Hz, 1H), 6.67 (d, J = 8.8 Hz, 2H), 5.96 (t, J = 3.7 Hz, 1H), 5.86 (q, J = 6.4 Hz, 1H), 2.90-2.80 (m, 1H), 2.71-2.59 (m, 1H), 2.31-2.20 (m, 1H), 2.12-1.86 (m, 3H), 1.46 (d, J = 6.5 Hz, 3H).

[0248] Example 36g 4-[[(7S)-1-[3-[(1S)-1-(2,2,6-trifluoro-1,3-benzodioxol-5-yl)ethoxy]phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]benzoic acid TIFF2025519597000236.tif58165LCMS (method 2): retention time = 1.78 min. MS (ESI) m / z 621.0 [M+H] + 。 11H NMR (400 MHz, MeOH-d4) δ 7.96 (d, J = 8.8 Hz, 2H), 7.23 (t, J = 8.1 Hz, 1H), 7.08 (dd, J = 15.3, 8.4 Hz, 3H), 6.98 (d, J = 8.9 Hz, 2H), 6.93 (d, J = 5.7 Hz, 1H), 6.83 (dd, J = 8.3, 1.9 Hz, 1H), 5.53 (s, 1H), 5.47 (q, J = 6.3 Hz, 1H), 2.88 (d, J = 15.3 Hz, 1H), 2.68-2.56 (m, 1H), 2.27 (d, J = 13.7 Hz, 1H), 2.09-1.81 (m, 3H), 1.43 (d, J = 6.3 Hz, 3H).

[0249] Example 36h 4-(((S)-1-(5-((S)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridazin-3-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)benzoic acid Example 36h was synthesized using a procedure similar to that of Example 36 by condensing Intermediate D-9 with Intermediate C-1R. After chiral reduction and coupling, followed by ester hydrolysis, the title compound was obtained as a white solid in 44.34% yield. LCMS (Method 2): Retention time = 1.79 min. MS (ESI) m / z 603.0 [M-H] - . 11H NMR (400 MHz, MeOH-d4) δ 8.76 (d, J = 2.6 Hz, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.55 (d, J = 2.6 Hz, 1H), 7.36 (d, J = 1.4 Hz, 1H), 7.28 (dd, J = 8.3, 1.6 Hz, 1H), 7.20 (d, J = 8.3 Hz, 1H), 6.96 (d, J = 8.8 Hz, 2H), 6.56 (s, 1H), 5.75 (q, J = 6.3 Hz, 1H), 2.84 (d, J = 15.9 Hz, 1H), 2.70-2.53 (m, 1H), 2.32-2.17 (m, 1H), 2.07-1.82 (m, 3H), 1.68 (d, J = 6.4 Hz, 3H).

[0250] Example 36i 4-[[(7S)-1-[4-[(1S)-1-(2,2-Difluoro-1,3-benzodioxol-5-yl)ethoxy]-5-fluoro-2-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]benzoic acid Example 36i was synthesized using a procedure similar to that of Example 36 by condensing Intermediate D-10 with Intermediate C-1R. After chiral reduction and coupling, followed by ester hydrolysis, the title compound was obtained as a white solid in 37.98% yield. LCMS (Method 2): retention time = 1.86 min. MS (ESI) m / z 620.0 [M-H] - . 11H NMR (400 MHz, MeOH-d4) δ 7.95 (d, J = 8.8 Hz, 2H), 7.64 (d, J = 2.5 Hz, 1H), 7.49 (d, J = 6.1 Hz, 1H), 7.32 (d, J = 1.5 Hz, 1H), 7.26 (dd, J = 8.3, 1.6 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 6.42 (s, 1H), 5.70 (q, J = 6.3 Hz, 1H), 2.82 (d, J = 16.7 Hz, 1H), 2.63-2.51 (m, 1H), 2.28-2.17 (m, 1H), 2.03-1.85 (m, 3H), 1.67 (d, J = 6.4 Hz, 3H).

[0251] Example 36j 4-[[(7S)-1-[4-Fluoro-3-[(1S)-1-(2,2,6-trifluoro-1,3-benzodioxol-5-yl)ethoxy]phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]benzoic acid TIFF2025519597000239.tif58165LCMS (method 2): retention time = 1.83 min. MS (ESI) m / z 639.0 [M+H] + . 1 1H NMR (400 MHz, MeOH) δ 7.92 (d, J = 8.8 Hz, 2H), 7.23-7.14 (m, 2H), 7.14-7.00 (m, 3H), 6.92 (d, J = 8.8 Hz, 2H), 5.50 (s, 1H), 5.35 (q, J = 6.2 Hz, 1H), 2.84 (d, J = 14.1 Hz, 1H), 2.63-2.53 (m, 1H), 2.22 (d, J = 13.9 Hz, 1H), 1.98-1.82 (m, 3H), 1.40 (d, J = 6.3 Hz, 3H).

[0252] Example 36k 4-[[(7S)-1-[2-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)propoxy]-4-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]benzoic acid TIFF2025519597000240.tif58165LCMS (Method 2): Retention time = 1.90 min. MS (ESI) m / z 616.0 [M-H] + 。 1 H NMR (400 MHz, MeOH-d4) δ 8.09-7.98 (m, 3H), 7.14 (dd, J = 5.6, 1.8 Hz, 1H), 7.07 (dd, J = 8.6, 3.7 Hz, 3H), 7.01-6.96 (m, 2H), 6.92 (dd, J = 8.3, 1.5 Hz, 1H), 5.81 (t, J = 6.5 Hz, 1H), 5.74 (s, 1H), 2.87 (d, J = 15.9 Hz, 1H), 2.70-2.53 (m, 1H), 2.29 (d, J = 11.8 Hz, 1H), 2.08-1.65 (m, 5H), 0.79 (t, J = 7.4 Hz, 3H).

[0253] Example 36l 4-[[(7S)-1-[6-[(1S)-1-(2,2,6-trifluoro-1,3-benzodioxol-5-yl)ethoxy]-2-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]benzoic acid TIFF2025519597000241.tif58165LCMS (Method 4): Retention time = 1.81 min. MS (ESI) m / z 620.1 [M-H] + 。

[0254] Example 36m 4-[[(7S)-1-[5-Fluoro-6-[(1S)-1-(2,2,6-trifluoro-1,3-benzodioxol-5-yl)ethoxy]-2-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]benzoic acid TIFF2025519597000242.tif58165LCMS (Method 4): Retention time = 1.81 min. MS (ESI) m / z 638.2 [M-H] + 。 1 H NMR (400 MHz, MeOH-d4) δ 7.72 - 7.61 (m, 3H), 7.32 - 7.23 (m, 2H), 7.16 (d, J = 9.1 Hz, 1H), 6.61 (d, J = 8.8 Hz, 2H), 6.10 (q, J = 6.4 Hz, 1H), 5.95 (t, J = 4.0 Hz, 1H), 2.83 (dt, J = 16.0, 4.4 Hz, 1H), 2.73 - 2.60 (m, 1H), 2.30 - 2.20 (m, 1H), 2.19 - 2.08 (m, 1H), 2.03 - 1.87 (m, 2H), 1.49 (d, J = 6.4 Hz, 3H).

[0255] Examples 37 and 38 trans-4-((1-(3-((R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)cyclohexane-1-carboxylic acid TIFF2025519597000243.tif58165trans-4-((1-(3-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)cyclohexane-1-carboxylic acid Synthesis of (R)-1-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)phenyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-indazol-7-one and (S)-1-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)phenyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-indazol-7-one, Project 58165, TIFF2025519597000244.tif To a solution of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethanol (Intermediate C-1) (1.84 g, 9.11 mmol), 1-(3-hydroxyphenyl)-3-(trifluoromethyl)-5,6-dihydro-4H-indazol-7-one (Intermediate D-2) (1.80 g, 6.08 mmol), and PPh3 (2.39 g, 9.11 mmol) in THF (20.0 mL) was added DEAD (1.9 mL, 12.2 mmol) at 0 °C. The reaction mixture was stirred for 2 h. The solution was then diluted with water (30.0 mL) and extracted with EA (3 × 50 mL). The organic layer was washed with brine (30 mL), dried over Na2SO4, and concentrated. The residue was purified by chiral prep-HPLC (water (A) / ACN (B) with 0.01% TFA, flow rate: 80 mL / min) to give the title compound having a first fraction designated as P1 (480 mg, 37% yield; pale yellow oil) and a second fraction designated as P2 (450 mg, 37% yield; pale yellow oil). LC-MS (Method 1): retention time = 2.38 min. MS (ESI) m / z 481.2 [M+H] + 。

[0256] Step 2a. Synthesis of 1-(3-((R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-ol In a solution of (R)-1-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)phenyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-indazol-7-one (Intermediate P1 from Step 1) (370 mg, 0.770 mmol) in methanol (4.0 mL), NaBH4 (44 mg, 1.16 mmol) was added at 0 °C. The solution was then stirred at room temperature for 1 hour under Ar. The reaction mixture was diluted with water (10 mL) and extracted with EA (3 × 10 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4, and concentrated. The residue was purified by flash chromatography (Biotage, 40 g silica gel column @ 60 mL / min, eluted with 0 - 30% ethyl acetate in petroleum ether for 20 minutes) to give a diastereomeric mixture of the title compound (350 mg, 94% yield) as a pale yellow oil. LC-MS (Method 1): Retention time = 2.07 min. MS (ESI) m / z 483.1 [M+H] + 。

[0257] Step 2b. Synthesis of 1-(3-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-ol Using the starting material (S)-1-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)phenyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-indazol-7-one (Intermediate P2 from Step 1), the title compound was obtained as a pale yellow oil (380 mg, 94% yield) by the same protocol as described in Step 2a. LC-MS (Method 1): Retention time = 2.09 min. MS (ESI) m / z 483.3 [M+H] + 。

[0258] Synthesis of 3a.7-chloro-1-(3-((R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole TIFF2025519597000248.tifTo a solution of 1-(3-((R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-ol (product obtained in Step 2a) (150 mg, 0.249 mmol) and TEA (0.2 mL, 0.622 mmol) in DCM (2 mL) was added MsCl (0.1 mL, 0.373 mmol). The solution was then stirred at room temperature for 2 h under Ar. The residue was concentrated in vacuo and purified by flash chromatography (Biotage, 40 g silica gel column @ 60 mL / min, eluted with 0 - 30% ethyl acetate in petroleum ether for 20 min) to give the title compound (120 mg, 77% yield) as a pale yellow oil. LC-MS (Method 2): Retention time = 2.16 min. MS (ESI) m / z 501.4 [M+H] + 。

[0259] Synthesis of 3b.7-chloro-1-(3-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole TIFF2025519597000249.tifUsing 1-(3-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-ol (product obtained in Step 2b) (120 mg, 0.249 mmol) as the starting material, the title compound was obtained as a pale yellow oil (95 mg, 76% yield) by the same protocol as described in Step 3a. LC-MS (Method 2): Retention time = 2.14 minutes. MS (ESI) m / z 501.1 [M+H] + 。

[0260] Step 4a. Synthesis of trans-ethyl 4-((1-(3-((R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)cyclohexane-1-carboxylate TIFF2025519597000250.tif58165A solution of 7-chloro-1-(3-((R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (the product obtained in Step 3a) (120 mg, 0.240 mmol) and ethyl trans-4-hydroxycyclohexanecarboxylate (65 mg, 0.379 mmol) in DCM (1 mL) was added with 2,6-di-tert-butylpyridine (91 mg, 0.474 mmol) and silver trifluoromethanesulfonate (73 mg, 0.285 mmol). The solution was then stirred at 0 °C for 2 hours under Ar. The solution was filtered. The filtrate was concentrated under vacuum. The residue was purified by HPLC (Biotage, 40 g silica gel column @ 60 mL / min, eluted with 0 - 100% ethyl acetate in petroleum ether for 20 minutes) to give the title compound (64 mg, 43% yield) as a pale yellow oil. LC-MS (Method 2): Retention time = 2.25 minutes. MS (ESI) m / z 637.3 [M+H] + 。

[0261] Step 4b. Synthesis of trans-ethyl 4-((1-(3-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)cyclohexane-1-carboxylate Using the starting material of TIFF2025519597000251.tif481657-chloro-1-(3-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (the product obtained in Step 3b), the title compound was obtained as a pale yellow oil (50 mg, 41% yield) by the same protocol as described in Step 4a. LC-MS (Method 2): Retention time = 2.27 min. MS (ESI) m / z 637.5 [M+H] + 。

[0262] Synthesis of trans-4-((1-(3-((R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)cyclohexane-1-carboxylic acid To a solution of ethyl trans-4-((1-(3-((R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)cyclohexane-1-carboxylate (the product obtained in Step 4a) (64 mg, 0.0785 mmol) in methanol (1 mL) and THF (1 mL) was added LiOH (2.0 mL, 0.785 mmol) at 0 °C. The solution was then stirred at room temperature for 1 hour under N2. Aqueous HCl (2 M, 2 ml) was added thereto to adjust the pH to 7. The solution was then extracted with EA (3 × 5 mL). The organic layer was washed with brine (3 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by pre-HPLC to obtain the title compound (27.6 mg, 41% yield) as a white solid. LC-MS (Method 2): Retention time = 1.88 min. MS (ESI) m / z 609.0 [M+H] + 。 11H NMR (500 MHz, CH3OH-d4) δ 7.42-7.36 (m, 1H), 7.34-6.99 (m, 6H), 5.55-5.49 (m, 1H), 4.73 (s, 0.5H), 4.34 (s, 0.5H), 3.15-3.08 (m, 1H), 2.75-2.68 (m, 1H), 2.54-2.47 (m, 1H), 2.16-1.96 (m, 2H), 1.94-1.53 (m, 9H), 1.46-0.96 (m, 4H), 0.74-0.49 (m, 1H).

[0263] Synthesis of 5b. trans-4-((1-(3-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)cyclohexane-1-carboxylic acid TIFF2025519597000253.tif58165 A diastereomeric mixture of the title compound was obtained as a white solid (12.4 mg, 26% yield) using the same protocol as described in Step 5a by hydrolyzing ethyl trans-4-((1-(3-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)cyclohexane-1-carboxylate (the product obtained in Step 4b). LC-MS (Method 2): retention time = 1.91 min. MS (ESI) m / z 609.0 [M+H] + . 11H NMR (500 MHz, CH3OH-d4) δ 7.42 - 7.36 (m, 1H), 7.35 - 7.02 (m, 6H), 5.56 - 5.46 (m, 1H), 4.74 (s, 0.5H), 4.34 (s, 0.5H), 3.15 - 3.10 (m, 0.5H), 2.91 - 2.86 (m, 0.5H), 2.78 - 2.70 (m, 1H), 2.56 - 2.48 (m, 1H), 2.10 - 1.97 (m, 2H), 1.95 - 1.55 (m, 9H), 1.34 - 1.24 (m, 1.5H), 1.18 - 0.98 (m, 2.5H), 0.77 - 0.61 (m, 1H).

[0264] Examples 39 and 40 3 - ((1 - (2 - ((R) - 1 - (2,2 - difluorobenzo[d][1,3]dioxol - 5 - yl)ethoxy)pyridin - 4 - yl) - 3 - (trifluoromethyl) - 4,5,6,7 - tetrahydro - 1H - indazol - 7 - yl)oxy)bicyclo[1.1.1]pentane - 1 - carboxylic acid TIFF2025519597000254.tif531653 - ((1 - (2 - ((S) - 1 - (2,2 - difluorobenzo[d][1,3]dioxol - 5 - yl)ethoxy)pyridin - 4 - yl) - 3 - (trifluoromethyl) - 4,5,6,7 - tetrahydro - 1H - indazol - 7 - yl)oxy)bicyclo[1.1.1]pentane - 1 - carboxylic acid TIFF2025519597000255.tif53165Step 1a. Synthesis of 7 - chloro - 1 - (2 - ((R) - 1 - (2,2 - difluorobenzo[d][1,3]dioxol - 5 - yl)ethoxy)pyridin - 4 - yl) - 3 - (trifluoromethyl) - 4,5,6,7 - tetrahydro - 1H - indazole A solution of 1-[2-[(1R)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-4-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-ol (Intermediate from Steps 2a of Examples 21 and 22) (200 mg, 0.414 mmol) in DCM (5 mL) was added with MsCl (0.039 mL, 0.496 mmol) and TEA (0.17 mL, 1.24 mmol). The solution was then stirred at room temperature for 2 hours under Ar. The solution was quenched with water. The solution was diluted with water (10 mL) and extracted with EA (3×50 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, concentrated under vacuum, and the crude product was purified by flash chromatography (Biotage, 40 g silica gel column @ 60 mL / min, eluted with 0 - 30% ethyl acetate in petroleum ether for 20 minutes) to obtain the title compound (200 mg, 51% yield) as a pale yellow oil. LC-MS (Method 1): Retention time = 2.18 min. MS (ESI) m / z 318.1 (M+H) + 。

[0265] Step 1b. Synthesis of 7-chloro-1-(2-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole Using 1-[2-[(1R)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-4-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-ol (Intermediate from Steps 2b of Examples 21 and 22) (200 mg, 0.414 mmol) as the starting material, the title compound was obtained as a pale yellow oil (200 mg, 51% yield) by the same protocol as described in Step 1a. LC-MS (Method 1): Retention time = 2.18 min. MS (ESI) m / z 318.1 (M+H) + 。

[0266] Step 2a. Synthesis of Methyl 3-((1-(2-((R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)bicyclo[1.1.1]pentane-1-carboxylate To a solution of 2,6-Di-tert-butylpyridine (95 mg, 0.498 mmol) in DCM (5 mL) was added 7-Chloro-1-[2-[(1R)-1-(2,2-Difluoro-1,3-benzodioxol-5-yl)ethoxy]-4-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazole (product of Step 1a) (100 mg, 0.199 mmol), Methyl 3-hydroxybicyclo[1.1.1]pentane-1-carboxylate (31 mg, 0.219 mmol) and AgOTf (77 mg, 0.299 mmol). The solution was then stirred at room temperature for 2 hours under Ar. The reaction was quenched with water. The solution was diluted with water (10 mL) and extracted with EA (3 × 50 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (Biotage, 40 g silica gel column @ 60 mL / min, eluted with 0 - 30% ethyl acetate in petroleum ether over 20 minutes) to give the title compound (50 mg, 31% yield) as a white solid. LC-MS (Method 1): Retention time = 2.22 min. MS (ESI) m / z 424.1 [M - 183] + 。

[0267] Step 2b. Synthesis of Methyl 3-((1-(2-((S)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)bicyclo[1.1.1]pentane-1-carboxylate TIFF2025519597000259.tif48165 Using 7-chloro-1-(2-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (the product of step 1b) as the starting material, the title compound was obtained as a white solid (60 mg, 33.21% yield) by the same protocol as described in step 2a. LC-MS (Method 1): Retention time = 2.22 min. MS (ESI) m / z 424.1 (M - 183) + 。

[0268] Step 3a. Synthesis of 3-((1-(2-(R-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)bicyclo[1.1.1]pentane-1-carboxylic acid TIFF2025519597000260.tif53165 Lithium hydroxide monohydrate (11 mg, 0.263 mmol) was added to a solution of methyl 3-[[1-[2-[(1R)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-4-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]bicyclo[1.1.1]pentane-1-carboxylate (the product from step 2a) (40 mg, 0.0658 mmol) in a mixture of methanol (5 mL) and water (1 mL). The reaction mixture was stirred at room temperature for 2 h. The solution was concentrated under vacuum and purified by prep-HPLC to give the title compound (20 mg, 52% yield) as a white solid. LC-MS (Method 1): Retention time = 1.78 min. MS (ESI) m / z 592.0 (M - H) + 。 11H NMR (500 MHz, CD3OD) δ 8.22 (d, J = 5.6 Hz, 1H), 7.35 - 7.25 (m, 2H), 7.24 - 7.20 (m, 1H), 7.18 (dd, J = 7.0, 1.6 Hz, 1H), 7.14 (d, J = 8.3 Hz, 1H), 6.26 (dq, J = 9.3, 6.5 Hz, 1H), 4.88 (dt, J = 10.2, 3.5 Hz, 1H), 2.76 (m, 1H), 2.55 (d, J = 10.0 Hz, 1H), 2.20 (m, 7H), 2.01-1.79 (m, 2H), 1.80-1.68 (m, 1H), 1.66 (d, J = 6.5 Hz, 3H).

[0269] Step 3b. Synthesis of 3-((1-(2-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)bicyclo[1.1.1]pentane-1-carboxylic acid The title compound was obtained as a white solid (10 mg, 18% yield) (60 mg, 0.0988 mmol) by the same protocol as described in Step 3a above via hydrolysis of methyl 3-[[1-[2-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-4-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]bicyclo[1.1.1]pentane-1-carboxylate (product from Step 2b). LC-MS (Method 1): retention time = 1.78 min. MS (ESI) m / z 592.0 (M-H) + . 11H NMR (500 MHz, CD3OD) δ 8.22 (d, J = 5.6 Hz, 1H), 7.35 - 7.26 (m, 2H), 7.24 - 7.20 (m, 1H), 7.18 (dd, J = 6.9, 1.6 Hz, 1H), 7.14 (d, J = 8.3 Hz, 1H), 6.26 (m, 1H), 4.91 - 4.86 (m, 1H), 2.76 (m, 1H), 2.54 (s, 1H), 2.37 - 2.06 (m, 7H), 1.90 (m, 2H), 1.75 (m, 1H), 1.66 (d, J = 6.5 Hz, 3H).

[0270] Examples 41 and 42 3-[[1-[3-[(1R)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]bicyclo[1.1.1]pentane-1-carboxylic acid TIFF2025519597000262.tif531653-[[1-[3-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]bicyclo[1.1.1]pentane-1-carboxylic acid TIFF2025519597000263.tif53165 The title compounds were synthesized in essentially the same manner as in Examples 39 and 40. P1: LC-MS (Method 2): retention time = 1.54 min. MS (ESI) m / z 593.2 [M+H] + . 11H NMR (400 MHz, CH3OH-d4) δ 7.42 - 7.21 (m, 3H), 7.19 - 6.99 (m, 4H), 5.53 (dq, J = 12.8, 6.4 Hz, 1H), 4.67 (dt, J = 51.7, 3.2 Hz, 1H), 2.80 - 2.71 (m, 1H), 2.51 (m, 1H), 2.12 - 1.68 (m, 10H), 1.63 (d, J = 6.3 Hz, 3H). P2: LC-MS (Method 2): Retention time = 1.52 min. MS (ESI) m / z 593.2 [M+H] + . 1 1H NMR (500 MHz, CH3OH-d4) δ 7.41 - 7.22 (m, 3H), 7.18 - 7.00 (m, 4H), 5.53 (dq, J = 12.8, 6.3 Hz, 1H), 4.67 (dt, J = 62.0, 4.0 Hz, 1H), 2.76 (d, J = 15.5 Hz, 1H), 2.58 - 2.46 (m, 1H), 2.12 - 1.68 (m, 10H), 1.66 - 1.60 (m, 3H).

[0271] Examples 43 and 44 trans-4-((1-(2-(R-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)cyclohexane-1-carboxylic acid TIFF2025519597000264.tif58165trans-4-((1-(2-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)cyclohexane-1-carboxylic acid TIFF2025519597000265.tif58165The title compounds were synthesized in essentially the same manner as in Examples 39 and 40. P1: LC-MS (Method 1): Retention time = 1.67 min. MS (ESI) m / z 610.2 (M+H) + 。 1 H NMR (500 MHz, CH3OH-d4) δ 8.21 (dd, J = 5.9, 2.1 Hz, 1H), 7.32 (s, 1H), 7.29 - 7.21 (m, 3H), 7.15 (dd, J = 8.3, 4.1 Hz, 1H), 6.25 (q, J = 6.3 Hz, 1H), 4.89 (dd, J = 8.8, 5.6 Hz, 1H), 3.52 - 3.35 (m, 1H), 2.75 (d, J = 16.1 Hz, 1H), 2.62 - 2.43 (m, 1H), 2.21 (d, J = 13.8 Hz, 1H), 2.11 (m, 1H), 2.02 - 1.68 (m, 7H), 1.69 - 1.57 (m, 3H), 1.54 - 1.14 (m, 3H), 1.14 - 0.92 (m, 1H). P2: LC-MS (Method 1): Retention time = 1.67 min. MS (ESI) m / z 610.2 (M+H) + 。 1 H NMR (500 MHz, CH3OH-d4) δ 8.21 (dd, J = 5.8, 2.1 Hz, 1H), 7.33 (s, 1H), 7.29 - 7.20 (m, 3H), 7.15 (dd, J = 8.2, 4.2 Hz, 1H), 6.26 (q, J = 6.5 Hz, 1H), 4.90 (s, 1H), 3.55 - 3.38 (m, 1H), 2.75 (d, J = 16.0 Hz, 1H), 2.55 (dd, J = 19.5, 12.6 Hz, 1H), 2.20 (d, J = 14.6 Hz, 1H), 2.11 (m, 1H), 1.82 (m, 7H), 1.65 (dd, J = 6.5, 2.1 Hz, 3H), 1.55 - 1.14 (m, 3H), 1.17 - 0.87 (m, 1H).

[0272] Examples 45 and 46 3-[[1-[2-[(1R)-1-(2,2-difluoro-[1,3]dioxolo[4,5-c]pyridin-6-yl)ethoxy]-4-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]bicyclo[1.1.1]pentane-1-carboxylic acid TIFF2025519597000266.tif531653-[[1-[2-[(1S)-1-(2,2-difluoro-[1,3]dioxolo[4,5-c]pyridin-6-yl)ethoxy]-4-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]bicyclo[1.1.1]pentane-1-carboxylic acid TIFF2025519597000267.tif53165 The labeled compound was synthesized in essentially the same manner as in Examples 39 and 40. P1: LCMS (Method 2): Retention time = 1.47 min. MS (ESI) m / z 595.2 [M+H] + 。 1 1H NMR (400 MHz, CH3OH-d4) δ: 8.39 (s, 1H), 8.18 (d, J = 5.3 Hz, 1H), 7.49 (d, J = 3.6 Hz, 1H), 7.28 - 7.23 (m, 2H), 6.26 - 6.20 (m, 1H), 4.95 - 4.91 (m, 1H), 2.79 - 2.73 (m, 1H), 2.63 - 2.48 (m, 1H), 2.26 - 2.13 (m, 7H), 1.99 - 1.73 (m, 3H), 1.69 (d, J = 6.6 Hz, 3H) ppm. (A mixture of two diastereomers) P2: LCMS (Method 2): Retention time = 1.47 min. MS (ESI) m / z 595.2 [M+H] + 。 11H NMR (400 MHz, CH3OH-d4) δ: 8.38 (s, 1H), 8.23 - 8.10 (m, 1H), 7.49 (d, J = 3.7 Hz, 1H), 7.29 - 2.22 (m, 2H), 6.31 - 6.20 (m, 1H), 4.95 - 4.91 (m, 1H), 2.79 - 2.72 (m, 1H), 2.60 - 2.51 (m, 1H), 2.26 - 2.09 (m, 7H), 2.05 - 1.71 (m, 3H), 1.69 (d, J = 6.6 Hz, 3H) ppm。

[0273] Examples 47 and 48 trans-4-((1-(2-(R-1-(2,2-difluoro-[1,3]dioxolo[4,5-c]pyridin-6-yl)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)cyclohexane-1-carboxylic acid TIFF2025519597000268.tif58165trans-4-((1-(2-((S)-1-(2,2-difluoro-[1,3]dioxolo[4,5-c]pyridin-6-yl)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)cyclohexane-1-carboxylic acid TIFF2025519597000269.tif58165The title compounds were synthesized in essentially the same manner as in Examples 39 and 40. P1: LC-MS (Method 4): retention time = 1.98 min. MS (ESI) m / z 611.1 [M+H] + 。 11H NMR (400 MHz, CH3OH-d4) ) δ 8.43 (d, J = 1.4 Hz, 1H), 8.22 (d, J = 5.2 Hz, 1H), 7.52 (d, J = 4.8 Hz, 1H), 7.36 (s, 1H), 7.30 (d, J = 5.6 Hz, 1H), 6.32 - 6.23 (m, 1H), 4.94 (d, J = 4.1 Hz, 1H), 3.50 (t, J = 10.5 Hz, 1H), 2.83 - 2.76 (m, 1H), 2.64 - 2.57 (m, 1H), 2.30 - 2.09 (m, 2H), 2.05 - 1.77 (m, 7H), 1.71 (d, J = 6.6 Hz, 3H), 1.54 - 1.27 (m, 3H), 1.12 - 1.00 (m, 1H). P2: LC-MS (Method 4): Retention time = 1.98 min. MS (ESI) m / z 611.1 [M+H] + . 1 1H NMR (400 MHz, CH3OH-d4) δ 8.43 (s, 1H), 8.22 (d, J = 5.3 Hz, 1H), 7.52 - 3.46 (m, 1H), 7.36 (s, 1H), 7.30 (d, J = 5.6 Hz, 1H), 6.35 - 6.22 (m, 1H), 5.00 - 4.91 (m, 1H), 3.50 (t, J = 10.4 Hz, 1H), 2.79 (d, J = 15.9 Hz, 1H), 2.69 - 2.52 (m, 1H), 2.32 - 2.09 (m, 2H), 2.06 - 1.76 (m, 7H), 1.71 (d, J = 6.5 Hz, 3H), 1.58 - 1.42 (m, 1H), 1.39 - 1.28 (m, 2H), 1.11 - 1.00 (m, 1H).

[0274] Examples 49 and 50 4 - [[1 - [5 - [(1R)-1-(2,2 - difluoro - 1,3 - benzodioxol - 5 - yl)ethoxy]-3 - pyridyl]-3-(trifluoromethyl)-4,5,6,7 - tetrahydroindazol - 7 - yl]oxy]benzoic acid TIFF2025519597000270.tif581654-[[1-[5-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-3-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]benzoic acid TIFF2025519597000271.tif58165 The labeled compound was synthesized in essentially the same manner as in Examples 39 and 40. P1: LC-MS (Method 3): Retention time = 2.28 min. MS (ESI) m / z 604.3 [M+H] + 。 1 1H NMR (500 MHz, CH3OH-d4) δ 8.31 (dd, J = 14.3, 2.0 Hz, 1H), 8.17 (dd, J = 9.7, 2.6 Hz, 1H), 8.01 - 7.91 (m, 2H), 7.53 (dt, J = 19.2, 2.3 Hz, 1H), 7.20 - 6.88 (m, 5H), 5.68 (dt, J = 65.6, 3.0 Hz, 1H), 5.24 (p, J = 6.3 Hz, 1H), 2.91-2.82 (m, 1H), 2.69-2.59 (m, 1H), 2.29-2.20 (m, 1H), 2.04-1.86 (m, 3H), 1.48 (dd, J = 15.7, 6.3 Hz, 3H). P2: LC-MS (Method 3): Retention time = 2.28 min. MS (ESI) m / z 604.3 [M+H] + 。 11H NMR (500 MHz, CH3OH-d4) δ 8.30 (dd, J = 13.3, 1.7 Hz, 1H), 8.17 (dd, J = 6.0, 2.4 Hz, 1H), 7.96 (dd, J = 24.0, 8.7 Hz, 2H), 7.53 (dt, J = 17.8, 2.1 Hz, 1H), 7.19 - 6.90 (m, 5H), 5.70 (d, J = 66.6 Hz, 1H), 5.31 - 5.25 (m, 1H), 2.91 - 2.83 (m, 1H), 2.69 - 2.59 (m, 1H), 2.29 - 2.19 (m, 1H), 2.04 - 1.88 (m, 3H), 1.49 (dd, J = 13.7, 6.3 Hz, 3H).

[0275] Examples 51 and 52 3 - ((R)-1-(2-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)bicyclo[1.1.1]pentane-1-carboxylic acid TIFF2025519597000272.tif531653 - (((S)-1-(2-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)bicyclo[1.1.1]pentane-1-carboxylic acid Synthesis of Methyl 3-(((S)-1-(2-((S)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)bicyclo[1.1.1]pentane-1-carboxylate and Methyl 3-(((R)-1-(2-((S)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)bicyclo[1.1.1]pentane-1-carboxylate A sample (300 mg) of Methyl 3-((1-(2-((S)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)bicyclo[1.1.1]pentane-1-carboxylate (from Steps 2b of Examples 39 and 40) was separated by chiral-HPLC (column name: OD-H 4.6×100 mm, 5 μm; processing method: AS1 Acq. Method settings: 10%B3 vial: 2:F, 3 co-solvent: isopropanol 0.5% NH3 (7M in MeOH)] injection volume: 5.00 μl. Channel name: PDA Ch2 254 nm@4.8 nm. Run time: 6.0 minutes. Processing channel specification: PDA Ch2 254 nm@4.8 nm. Flow rate: 3.0 mL / min) to provide a labeled compound having a first fraction designated as P1 (140 mg, 0.23 mmol) and a second fraction designated as P2 (120 mg, 0.20 mmol) for both compounds as white solids. LC-MS (Method 2): Retention time = 2.28 minutes. MS (ESI) m / z 423.8 [M - 185 + H] + 。

[0276] Synthesis of 2a.3-(((S)-1-(2-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)bicyclo[1.1.1]pentane-1-carboxylic acid TIFF2025519597000275.tif53165Lithium hydroxide monohydrate (48 mg, 1.15 mmol) was added to a solution of methyl 3-[[(7S)-1-[2-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-4-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]bicyclo[1.1.1]pentane-1-carboxylate (P1, an intermediate from Step 1) (140 mg, 0.23 mmol) in methanol (4 mL), THF (4 mL), and water (2 mL). The solution was stirred at room temperature for 8 hours. Water (10 mL) was added to the reaction solution, the pH was adjusted to 5 with aqueous HCl (2 M), and then the solution was extracted with ethyl acetate (3 × 15 mL). The organic layer was concentrated. The crude product was purified by prep-HPLC (NH4HCO3 conditions) to give the title compound (115 mg, 84% yield) as a white solid. LC-MS (Method 2): retention time = 1.78 min. MS (ESI) m / z 592.0 [M-H] + . 1 H NMR (400 MHz, CH3OH-d4) δ 8.19 (d, J = 5.6 Hz, 1H), 7.33-7.26 (m, 2H), 7.20 (dd, J = 5.6, 1.8 Hz, 1H), 7.16 (d, J = 1.6 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 6.24 (q, J = 6.6 Hz, 1H), 4.84 (d, J = 3.3 Hz, 1H), 2.73 (d, J = 16.5 Hz, 1H), 2.53 (m, 1H), 2.16 (m, 7H), 1.95-1.66 (m, 3H), 1.63 (d, J = 6.5 Hz, 3H).

[0277] Process 2b. Synthesis of 3-((R)-1-(2-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)bicyclo[1.1.1]pentane-1-carboxylic acid TIFF2025519597000276.tif53165 Methyl 3-[[(7R)-1-[2-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-4-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]bicyclo[1.1.1]pentane-1-carboxylate (P2, an intermediate in Step 1) (120 mg, 0.20 mmol) was hydrolyzed according to the same protocol as described in Step 2a to give the title compound as a white solid (101 mg, 84% yield). LC-MS (Method 1): Retention time = 1.78 min. MS (ESI) m / z 592.0 [M-H] + 。 1 1H NMR (400 MHz, CH3OH-d4) δ 8.19 (d, J = 5.6 Hz, 1H), 7.31 (d, J = 1.5 Hz, 1H), 7.26 (dd, J = 8.4, 1.6 Hz, 1H), 7.23-7.16 (m, 2H), 7.12 (d, J = 8.3 Hz, 1H), 6.22 (q, J = 6.5 Hz, 1H), 4.86-4.82 (m, 1H), 2.74 (d, J = 15.7 Hz, 1H), 2.53 (m, 1H), 2.18 (m, 7H), 1.97-1.66 (m, 3H), 1.63 (d, J = 6.5 Hz, 3H).

[0278] Examples 53 and 54 trans-4-(((R)-1-(2-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)cyclohexane-1-carboxylic acid TIFF2025519597000277.tif58165trans-4-(((S)-1-(2-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)cyclohexane-1-carboxylic acid TIFF2025519597000278.tif58165The labeled compound was synthesized in essentially the same manner as in Examples 51 and 52. P1: LC-MS (Method 1): Retention time = 1.88 min. MS (ESI) m / z 608.0 (M-H) + 。 1 H NMR (500 MHz, CH3OH-d4) δ 8.21 (d, J = 5.5 Hz, 1H), 7.32 (s, 1H), 7.27 (d, J = 7.9 Hz, 2H), 7.24 (dd, J = 5.5, 1.5 Hz, 1H), 7.17 (d, J = 8.3 Hz, 1H), 6.25 (q, J = 6.5 Hz, 1H), 4.85 (d, J = 3.3 Hz, 1H), 3.46 (t, J = 10.6 Hz, 1H), 2.75 (d, J = 16.6 Hz, 1H), 2.55 (ddd, J = 16.3, 10.2, 5.8 Hz, 1H), 2.22 (d, J = 14.1 Hz, 1H), 2.08 (t, J = 11.8 Hz, 1H), 1.91 (t, J = 25.9 Hz, 3H), 1.82 (d, J = 9.5 Hz, 3H), 1.68 (dd, J = 30.1, 10.1 Hz, 4H), 1.54 - 1.39 (m, 1H), 1.39 - 1.19 (m, 2H), 1.06 (dd, J = 21.8, 11.0 Hz, 1H). P2: LC-MS (Method 1): Retention time = 1.89 minutes. MS (ESI) m / z 608.0 (M-H) + 。 1 H NMR (500 MHz, CH3OH-d4) δ 8.21 (d, J = 5.3 Hz, 1H), 7.32 (s, 1H), 7.29 - 7.20 (m, 3H), 7.15 (d, J = 8.3 Hz, 1H), 6.25 (q, J = 6.5 Hz, 1H), 4.89 (d, J = 1.5 Hz, 1H), 3.54 - 3.36 (m, 1H), 2.75 (d, J = 16.1 Hz, 1H), 2.55 (ddd, J = 16.4, 10.4, 5.9 Hz, 1H), 2.22 (d, J = 14.2 Hz, 1H), 2.10 (t, J = 11.8 Hz, 1H), 1.88 (dt, J = 44.3, 16.0 Hz, 6H), 1.70 (dd, J = 27.7, 14.7 Hz, 1H), 1.64 (d, J = 6.5 Hz, 3H), 1.34 (tdd, J = 22.1, 17.1, 10.7 Hz, 3H), 1.16 - 0.92 (m, 1H).

[0279] Examples 55 and 56 (1S,4r)-4-(((S)-1-(6-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridazin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)cyclohexane-1-carboxylic acid (P1) TIFF2025519597000279.tif58165(1R,4r)-4-(((R)-1-(6-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridazin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)cyclohexane-1-carboxylic acid (P2) Synthesis of TIFF2025519597000280.tif58165 Project 1. (S)-1-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridazin-4-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-indazol-7-one To a solution of 1-(6-chloropyridazin-4-yl)-3-(trifluoromethyl)-5,6-dihydro-4H-indazol-7-one (Intermediate D-6) (1.35 g, 4.26 mmol) in dry toluene (20 mL) were added (1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethanol (Intermediate C-1S) (948 mg, 4.69 mmol), 5-[bis(1,1-dimethylethyl)phosphino]-1′,3′,5′-triphenyl-1,4′-bi-1H-pyrazole (108 mg, 0.213 mmol), cesium carbonate (2778 mg, 8.53 mmol) and palladium(II) acetate (48 mg, 0.213 mmol). The solution was stirred at 90 °C for 4 h under N2. The solution was concentrated and the crude product was purified by flash column chromatography eluting with 15% ethyl acetate in PE and then further purified by SFC to give (S)-1-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridazin-4-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-indazol-7-one (930 mg, 45%, ee>99%) as a white solid. LC-MS (Method 2): Retention time = 2.29 min. MS (ESI) m / z 483.1 [M+H] + 。

[0280] Step 2. Synthesis of 1-(6-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridazin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-ol A solution of (S)-1-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridazin-4-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-indazol-7-one (640 mg, 1.33 mmol) in IPA (10 mL) was added with triethylamine (4.30 mmol) and RuCl[(R,R)-Tsdpen](p-cymene)(Reference 2) (3.0 mg, 0.00475 mmol), and then formic acid (0.40 mL, 10.4 mmol) was added dropwise while maintaining the temperature below 25 °C. The reaction mixture was stirred at 45 °C for 4 hours. The reaction mixture was concentrated, and the crude product was purified by flash column chromatography eluted with 30% ethyl acetate in PE to obtain the title compound (585 mg, 91% yield) as a white solid. LC-MS (Method 2): retention time = 2.26 min. MS (ESI) m / z 485.2 [M+H] + 。

[0281] Step 3. Synthesis of 7-chloro-1-(6-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridazin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole A solution of 1-(6-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridazin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-ol (600 mg, 1.24 mmol) in DCM (10 mL) was added with methanesulfonyl chloride (0.24 mL, 3.10 mmol) and TEA (0.52 mL, 3.72 mmol) at 0 °C. Then the solution was stirred at room temperature for 3 hours. The reaction solution was concentrated. The crude product was purified by flash column chromatography eluted with 15% EA in PE to obtain the title compound (570 mg, 92% yield) as a white solid. LC-MS (Method 2): Retention time = 2.37 min. MS (ESI) m / z 503 [M+H] + 。

[0282] Step 4. Synthesis of Ethyl (1S,4r)-4-(((S)-1-(6-((S)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridazin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)cyclohexane-1-carboxylate and Ethyl (1R,4r)-4-(((R)-1-(6-((S)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridazin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)cyclohexane-1-carboxylate TIFF2025519597000284.tif42165To a solution of 7-Chloro-1-(6-((S)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridazin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (product of Step 3) (200 mg, 0.398 mmol) in DCM (10 mL) were added Ethyl trans-4-hydroxycyclohexanecarboxylate (75 mg, 0.438 mmol), 2,6-Di-tert-butylpyridine (228 mg, 1.19 mmol) and Silver trifluoromethanesulfonate (123 mg, 0.477 mmol). The solution was stirred at room temperature for 3 hours. The solution was concentrated and the crude product was purified by flash column chromatography eluting with 15% EA in PE to give 100 mg of a white solid which was further purified by SFC to give both compounds as white solids having a first fraction designated as P1 (40 mg, 16% yield) and a second fraction designated as P2 (40 mg, 15% yield). SFC Method: IC 4.6×100 mm, 3 μm; MeOH [0.2% NH3 (7M in MeOH)]. P1: LC-MS (Method 2): Retention time = 2.08 min. MS (ESI) m / z 661 [M+Na] + 。 P2: LC-MS (Method 2): Retention time = 2.08 min. MS (ESI) m / z 661 [M+Na] + 。

[0283] Step 5a. Synthesis of (1S,4r)-4-(((S)-1-(6-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridazin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)cyclohexane-1-carboxylic acid TIFF2025519597000285.tif53165 To a solution of ethyl (1S,4r)-4-(((S)-1-(6-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridazin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)cyclohexane-1-carboxylate (Intermediate P1 in Step 4) (40 mg, 0.0626 mmol) in methanol (1 mL) and THF (1 mL) was added aqueous LiOH (2 M, 1 mL), and the solution was stirred at room temperature for 4 h. The pH of the solution was adjusted to 6. The crude product was purified by prep-HPLC to give the title compound (22 mg, 58% yield) as a white solid. LC-MS (Method 1): Retention time = 1.86 min. MS (ESI) m / z 611 [M+H] + 。 11H NMR (500 MHz, CH3OH-d4) δ 9.24 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.38 (d, J = 1.4 Hz, 1H), 7.32 (dd, J = 8.3, 1.4 Hz, 1H), 7.20 (d, J = 8.3 Hz, 1H), 6.42 (q, J = 6.5 Hz, 1H), 4.99 (t, J = 3.4 Hz, 1H), 3.65 - 3.54 (m, 1H), 2.83 - 2.70 (m, 1H), 2.62 - 2.51 (m, 1H), 2.27 (dd, J = 11.3, 5.7 Hz, 1H), 2.15 - 2.01 (m, 2H), 2.01 - 1.89 (m, 4H), 1.88 - 1.66 (m, 5H), 1.56 - 1.41 (m, 2H), 1.37 - 1.23 (m, 1H), 1.23 - 1.10 (m, 1H).

[0284] Step 5b. Synthesis of (1R,4r)-4-(((R)-1-(6-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridazin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)cyclohexane-1-carboxylic acid The title compound was obtained as a white solid (21 mg, 55% yield) by the same protocol as described in Step 5a via hydrolysis of ethyl (1R,4r)-4-(((R)-1-(6-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridazin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)cyclohexane-1-carboxylate (intermediate P2 from Step 4) (40 mg, 0.0626 mmol). LC-MS (Method 1): retention time = 1.81 min. MS (ESI) m / z 611 [M + H] + . 11H NMR (500 MHz, CH3OH-d4) δ 9.21 (d, J = 1.9 Hz, 1H), 7.73 (d, J = 1.9 Hz, 1H), 7.38 (s, 1H), 7.34 (dd, J = 8.4, 1.2 Hz, 1H), 7.20 (d, J = 8.3 Hz, 1H), 6.45 (q, J = 6.4 Hz, 1H), 4.97 (t, J = 3.3 Hz, 1H), 3.62 - 3.55 (m, 1H), 2.80-2.71 (m, 1H), 2.62-2.52 (m, 1H), 2.29-2.20 (m, 1H), 2.13-2.01 (m, 2H), 2.00-1.88 (m, 4H), 1.88-1.69 (m, 5H), 1.56-1.41 (m, 2H), 1.34-1.23 (m, 1H), 1.21-1.11 (m, 1H).

[0285] Examples 57 and 58 4-[[(7S)-1-[5-[(1S)-1-(2,2-Difluoro-1,3-benzodioxol-5-yl)ethoxy]-3-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]bicyclo[2.2.2]octane-1-carboxylic acid (P1) TIFF2025519597000287.tif581654-[[(7R)-1-[5-[(1S)-1-(2,2-Difluoro-1,3-benzodioxol-5-yl)ethoxy]-3-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]bicyclo[2.2.2]octane-1-carboxylic acid (P2) TIFF2025519597000288.tif53165The title compound was synthesized by following the procedure in Examples 55 and 56 to give the final acid as a diastereomeric mixture (90 mg, 0.142 mmol), which was separated by chiral-HPLC to give the title compound having a first fraction designated as P1 (27 mg, 30% yield; white solid) and a second fraction designated as P2 (26 mg, 29% yield; white solid). P1: Chiral method: Column name: IH 4.6×100mm 5μm. Solvent: IPA[0.2% NH3 (7M in MeOH)]; Retention time = 2.334 min; ee = 100%. LC-MS (Method 4): Retention time = 1.91 min. MS (ESI) m / z 636.2 [M+H] + 。 1 H NMR (500 MHz, CH3OH-d4) δ 8.40 (d, J = 2.4 Hz, 1H), 8.30 (d, J = 1.5 Hz, 1H), 7.52 (t, J = 2.2 Hz, 1H), 7.36 (d, J = 1.5 Hz, 1H), 7.28 (dd, J = 8.3, 1.5 Hz, 1H), 7.19 (d, J = 8.3 Hz, 1H), 5.67 (q, J = 6.3 Hz, 1H), 4.98 (t, J = 3.7 Hz, 1H), 2.70 (d, J = 15.9 Hz, 1H), 2.53 (dt, J = 14.9, 7.6 Hz, 1H), 2.00 - 1.85 (m, 3H), 1.81 - 1.74 (m, 1H), 1.69 (dd, J = 10.0, 7.2 Hz, 9H), 1.26 (ddd, J = 15.9, 8.6, 3.2 Hz, 3H), 1.15 (ddd, J = 15.2, 10.1, 3.1 Hz, 3H). P2: Chiral method: Column name: IH 4.6×100mm 5μm. Solvent: IPA[0.2% NH3 (7M in MeOH)]; Retention time = 3.310 min; ee = 99.02%. LC-MS (Method 4): Retention time = 1.91 min. MS (ESI) m / z 636.2 [M+H] + 。 11H NMR (500 MHz, CH3OH-d4) δ 8.40 (s, 1H), 8.29 (s, 1H), 7.56 (t, J = 2.1 Hz, 1H), 7.42 (d, J = 1.3 Hz, 1H), 7.34 (dd, J = 8.3, 1.4 Hz, 1H), 7.25 (d, J = 8.3 Hz, 1H), 5.63 (q, J = 6.3 Hz, 1H), 4.62 (d, J = 3.7 Hz, 1H), 2.71 (d, J = 15.9 Hz, 1H), 2.59 - 2.47 (m, 1H), 1.98 - 1.73 (m, 4H), 1.68 (dd, J = 11.0, 4.8 Hz, 9H), 1.22 (dt, J = 10.6, 5.9 Hz, 3H), 1.12 (dt, J = 12.2, 5.5 Hz, 3H).

[0286] Examples 59 and 60 4 - (((S)-1-(5-((S)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)-6-fluoropyridin-3-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)bicyclo[2.2.2]octane-1-carboxylic acid (P1) TIFF2025519597000289.tif531654 - (((R)-1-(5-((S)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)-6-fluoropyridin-3-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)bicyclo[2.2.2]octane-1-carboxylic acid (P2) TIFF2025519597000290.tif58165 The labeled compounds were synthesized in essentially the same manner as in Examples 55 and 56. P1: LC-MS (Method 2): Retention time = 1.87 min. MS (ESI) m / z 654.1 [M+H] + . 11H NMR (400 MHz, CH3OH-d4) δ 7.89 (t, J = 1.9 Hz, 1H), 7.56 (dd, J = 8.7, 2.1 Hz, 1H), 7.34 (d, J = 1.4 Hz, 1H), 7.27 (dd, J = 8.3, 1.5 Hz, 1H), 7.19 (d, J = 8.3 Hz, 1H), 5.67 (q, J = 6.3 Hz, 1H), 4.93 (d, J = 3.6 Hz, 1H), 2.68 (d, J = 15.5 Hz, 1H), 2.50 (dd, J = 15.2, 7.8 Hz, 1H), 1.96 - 1.82 (m, 3H), 1.79-1.61 (m, 10H), 1.25-1.13 (m, 3H), 1.12-0.99 (m, 3H). P2: LC-MS (Method 2): Retention time = 1.86 min. MS (ESI) m / z 654.2 [M+H] + . 1 1H NMR (400 MHz, CH3OH-d4) δ 7.86 (t, J = 1.9 Hz, 1H), 7.63 (dd, J = 8.7, 2.1 Hz, 1H), 7.44 (d, J = 1.4 Hz, 1H), 7.35 (dd, J = 8.3, 1.5 Hz, 1H), 7.29 (d, J = 8.3 Hz, 1H), 5.60 (q, J = 6.3 Hz, 1H), 4.43 (d, J = 3.2 Hz, 1H), 2.70 (d, J = 15.4 Hz, 1H), 2.59-2.40 (m, 1H), 1.97-1.85 (m, 2H), 1.81-1.64 (m, 11H), 1.16 (m,3H), 1.04 (m, 3H).

[0287] Example 61 4-(((S)-1-(6-((S)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridazin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)benzoic acid The labeled compound was synthesized in essentially the same manner as in Examples 55 and 56 using TIFF2025519597000291.tif58165. LC-MS (Method 1): retention time = 1.86 min. MS (ESI) m / z 605.0 [M+H] + 。 1 1H NMR (400 MHz, CH3OH-d4) δ 9.15 (d, J = 2.1 Hz, 1H), 8.01 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 2.1 Hz, 1H), 7.17 (m, 2H), 7.02 (m, 3H), 6.17 (q, J = 6.4 Hz, 1H), 5.79 (s, 1H), 2.87 (d, J = 15.9 Hz, 1H), 2.73 - 2.56 (m, 1H), 2.37 - 2.23 (m, 1H), 2.07 - 1.93 (m, 3H), 1.52 (d, J = 6.5 Hz, 3H).

[0288] Examples 62 and 63 3-(((S)-1-(6-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridazin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)bicyclo[1.1.1]pentane-1-carboxylic acid (P1) TIFF2025519597000292.tif53165 3-(((R)-1-(6-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridazin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)bicyclo[1.1.1]pentane-1-carboxylic acid (P2) The labeled compound was synthesized in essentially the same manner as in Examples 55 and 56 using TIFF2025519597000293.tif53165. P1: LC-MS (Method 1): retention time = 1.85 min. MS (ESI) m / z 595.1 [M+H] + 。 SFC conditions: IH 4.6 * 100 mm, 5 μm; rt = 1.96 min 1 H NMR (500 MHz, CH3OH-d4) δ 9.19 (d, J = 2.0 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.41 (s, 1H), 7.35 (dd, J = 8.3, 1.3 Hz, 1H), 7.17 (d, J = 8.3 Hz, 1H), 6.43 (q, J = 6.5 Hz, 1H), 5.00 (t, J = 3.6 Hz, 1H), 2.84 - 2.68 (m, 1H), 2.64 - 2.50 (m, 1H), 2.31 - 2.12 (m, 7H), 2.02 - 1.78 (m, 3H), 1.75 (d, J = 6.5 Hz, 3H). P2: LC-MS (Method 1): Retention time = 1.85 min. MS (ESI) m / z 595.1 [M+H] + 。 SFC conditions: IH 4.6 × 100 mm, 5 μm; Retention time = 1.53 min 1 H NMR (500 MHz, CH3OH-d4) δ 9.19 (d, J = 1.8 Hz, 1H), 7.55 (d, J = 1.9 Hz, 1H), 7.40 (s, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 6.45 (q, J = 6.5 Hz, 1H), 4.97 (t, J = 3.5 Hz, 1H), 2.80 - 2.71 (m, 1H), 2.60 - 2.50 (m, 1H), 2.31 - 2.12 (m, 7H), 2.00 - 1.76 (m, 3H), 1.75 (d, J = 6.5 Hz, 3H).

[0289] Examples 64 and 65 4-(((S)-1-(2-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)bicyclo[2.2.2]octane-1-carboxylic acid TIFF2025519597000294.tif581654-(((R)-1-(2-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)bicyclo[2.2.2]octane-1-carboxylic acid TIFF2025519597000295.tif58165 The labeled compound was synthesized in essentially the same manner as in Examples 55 and 56. P1: LC-MS (Method 1): Retention time = 1.93 min. MS (ESI) m / z 634.0 (M-H) + 。 1 1H NMR (500 MHz, CH3OH-d4) δ 8.22 (d, J = 5.5 Hz, 1H), 7.33 (s, 1H), 7.28 (dd, J = 8.3, 1.2 Hz, 1H), 7.21 (s, 1H), 7.20 - 7.14 (m, 2H), 6.26 (q, J = 6.4 Hz, 1H), 5.10 - 4.96 (m, 1H), 2.72 (d, J = 16.0 Hz, 1H), 2.53 (ddd, J = 15.8, 9.7, 5.8 Hz, 1H), 2.18 - 2.04 (m, 1H), 1.95 (d, J = 13.0 Hz, 1H), 1.81 (t, J = 8.0 Hz, 8H), 1.65 (t, J = 11.5 Hz, 3H), 1.62 - 1.41 (m, 6H). P2: LC-MS (Method 1): Retention time = 1.96 min. MS (ESI) m / z 634.0 (M-H) + 。 11H NMR (500 MHz, CH3OH-d4) δ 8.22 (d, J = 5.5 Hz, 1H), 7.33 (s, 1H), 7.27 (d, J = 8.4 Hz, 1H), 7.23 - 7.14 (m, 3H), 6.25 (q, J = 6.5 Hz, 1H), 5.03 (d, J = 27.7 Hz, 1H), 2.73 (d, J = 15.5 Hz, 1H), 2.54 (dt, J = 22.3, 8.0 Hz, 1H), 2.14 (d, J = 11.7 Hz, 1H), 2.07 - 1.87 (m, 1H), 1.89 - 1.71 (m, 8H), 1.71 - 1.38 (m, 9H).

[0290] Examples 66 and 67 trans-4-[[(7S)-1-[5-[(1S)-1-(2,2-Difluoro-1,3-benzodioxol-5-yl)ethoxy]-3-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]cyclohexanecarboxylic acid (P1) TIFF2025519597000296.tif58165trans-4-[[(7R)-1-[5-[(1S)-1-(2,2-Difluoro-1,3-benzodioxol-5-yl)ethoxy]-3-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]cyclohexanecarboxylic acid (P2) TIFF2025519597000297.tif53165The labeled compounds were synthesized in essentially the same manner as in Examples 55 and 56. P1: Chiral method: Column name: IH 4.6×100mm 5μm. Solvent: MeOH[0.1% NH3 (7M in MeOH)]; Retention time = 1.934 min; ee = 99.96%. LC-MS (Method 4): Retention time = 1.88 min. MS (ESI) m / z 610.1 [M+H] + . 11H NMR (500 MHz, CH3OH-d4) δ 8.38 (s, 2H), 7.61 (t, J = 2.1 Hz, 1H), 7.35 (d, J = 1.3Hz, 1H), 7.28 (dd, J = 8.3, 1.3 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 5.66 (q, J = 6.3 Hz, 1H), 4.78 (t, J = 3.5 Hz, 1H), 3.26-3.18 (m, 1H), 2.73 (d, J = 16.2 Hz, 1H), 2.60-2.49 (m, 1H), 2.12-1.98 (m, 2H), 1.92-1.76 (m, 5H), 1.75-1.63 (m, 4H), 1.43-1.29 (m, 2H), 1.21 (qd, J = 13.1, 3.4 Hz, 1H), 1.11-0.99 (m, 1H), 0.57 (qd, J = 12.8, 3.6 Hz, 1H). P2: Chiral method: Column name: IH 4.6×100mm 5μm. Solvent: MeOH[0.1%NH3 (7M in MeOH)]; Retention time = 2.344 min; ee = 99.12%. LC-MS (Method 4): Retention time = 1.87 min. MS (ESI) m / z 610.1 [M+H] + . 11H NMR (500 MHz, CH3OH-d4) δ 8.37 (d, J = 18.3 Hz, 2H), 7.60 (s, 1H), 7.39 (d, J = 1.3Hz, 1H), 7.31 (dd, J = 8.3, 1.2 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H), 5.63 (q, J = 6.3 Hz, 1H), 4.45 (t, J = 3.4 Hz, 1H), 3.08 - 2.97 (m, 1H), 2.74 (d, J = 16.2 Hz, 1H), 2.54 (ddd, J = 16.2, 10.2, 5.9 Hz, 1H), 2.10 - 2.02 (m, 2H), 1.92 - 1.64 (m, 9H), 1.32 (ddd, J = 15.4, 13.2, 3.3 Hz, 1H), 1.24 - 1.06 (m, 3H), 0.67 - 0.55 (m, 1H).

[0291] Example 68 4 - (((S)-1-(5-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)-6-fluoropyridin-3-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)benzoic acid TIFF2025519597000298.tif58165 Step 1. Synthesis of (S)-5-bromo-3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)-2-fluoropyridine A solution of 5-bromo-2-fluoro-pyridin-3-ol (700 mg, 3.65 mmol) and (1R)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethanol (Intermediate C-1R) (884 mg, 4.38 mmol) in THF (15 mL) was added with PPh3 (2869 mg, 10.9 mmol) and DIAD (0.87 mL, 5.47 mmol) at 0 °C. The solution was stirred at room temperature for 1 hour. The reaction solution was concentrated in vacuo to give a residue, which was purified by flash silica gel column chromatography (ethyl acetate in petroleum ether from 0% to 15% yield) to afford the title compound (1400 mg, 97% yield) as a yellow oil. LC-MS (Method 3): retention time = 1.88 min. MS (ESI) m / z 376 / 378.0 [M+H] + 。

[0292] Step 2. Synthesis of (S)-(5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)-6-fluoropyridin-3-yl)boronic acid To a solution of 5-bromo-3-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-2-fluoro-pyridine (1300 mg, 3.46 mmol) in 1,4-dioxane (20 mL) were added bis(pinacolato)diboron (1053 mg, 4.15 mmol), potassium acetate (678 mg, 6.91 mmol), and Pd(dppf)2Cl2 (130 mg). The solution was stirred at 80 °C for 8 hours. The reaction solution was concentrated in vacuo to give a residue, which was purified by flash silica gel column chromatography (ethyl acetate in petroleum ether from 0% to 12% yield) to afford a crude product, which was then purified by prep-HPLC to afford the title compound (1000 mg, 85% yield) as a yellow oil. LC-MS (Method 1): retention time = 1.95 min. MS (ESI) m / z 342.0 [M+H] + 。

[0293] Step 3. Synthesis of (S)-1-(5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)-6-fluoropyridin-3-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-indazol-7-one To a solution of [5-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-6-fluoro-3-pyridyl]boronic acid (550 mg, 1.61 mmol) in DCE (15 mL) was added 3-(trifluoromethyl)-1,4,5,6-tetrahydroindazol-7-one (Intermediate D-1) (329 mg, 1.61 mmol), copper(II) acetate (146 mg, 0.806 mmol), and triethylamine (0.25 mL, 1.77 mmol). The solution was stirred at room temperature for 8 hours. The reaction solution was concentrated in vacuo to give a residue, which was purified by prep-HPLC (modified NH4HCO3) to afford a crude product, and then purified by SFC to give the title compound (450 mg, 56% yield) as a brown oil. LC-MS (Method 4): retention time = 2.34 min. MS (ESI) m / z 500.1 [M+H] + .

[0294] Step 4. Synthesis of R-1-(5-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)-6-fluoropyridin-3-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-ol TIFF2025519597000302.tif37165 times, then to a solution of 1-[5-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-6-fluoro-3-pyridyl]-3-(trifluoromethyl)-5,6-dihydro-4H-indazole-7-one (70 mg, 0.140 mmol) and bis(dichloro(η6-p-cymene)ruthenium)(1R,2R)-N-p-toluenesulfonyl-1,2-diphenylethylenediamine (5 mg) in IPA (5 mL) under N2, triethylamine (0.30 mL, 2.15 mmol) and formic acid (0.20 mL, 5.21 mmol) were added while maintaining the temperature below 45 °C under N2. The solution was stirred at 45 °C for 4 hours. The reaction solution was concentrated in vacuo to give a residue, which was purified by flash silica gel column chromatography (ethyl acetate in petroleum ether from 0% to 20%) to afford the title compound (60 mg, 86% yield) as a pale yellow oil. LC-MS (Method 2): retention time = 2.05 min. MS (ESI) m / z 501.8 [M+H] + 。

[0295] Step 5. Synthesis of methyl 4-(((S)-1-(5-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)-6-fluoropyridin-3-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)benzoate A solution of (7R)-1-[5-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-6-fluoro-3-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-ol (60 mg, 0.120 mmol) and methyl 4-hydroxybenzoate (22 mg, 0.144 mmol) in THF (5 mL) at 58 - 165 °C was added with triphenylphosphine (63 mg, 0.239 mmol) and diethyl azodicarboxylate (0.028 mL, 0.180 mmol). The solution was stirred at room temperature for 1 hour. The reaction solution was concentrated in vacuo to give a residue, which was purified by prep-HPLC (modified NH4HCO3) to afford the title compound (40 mg, 53% yield) as a white solid. LC-MS (Method 2): retention time = 2.60 min. MS (ESI) m / z 452.1 [M - 185 + H] + 。

[0296] Step 6. Synthesis of 4-(((S)-1-(5-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)-6-fluoropyridin-3-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)benzoic acid A solution of methyl 4-[[(7S)-1-[5-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-6-fluoro-3-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]benzoate (40 mg, 0.0629 mmol) in THF (5 mL) and water (1 mL) was added lithium hydroxide monohydrate (13 mg, 0.315 mmol). The solution was stirred at room temperature for 8 h. Water (10 mL) was added to the reaction solution. The pH was adjusted to 5 with aqueous HCl (2 M) and then extracted with ethyl acetate (3 × 10 mL). The organic layers were combined, concentrated and purified by prep-HPLC (NH4HCO3 modifier) to afford the title compound (25 mg, 63% yield) as a white solid. LC-MS (Method 2): retention time = 1.79 min. MS (ESI) m / z 620.0 [M-H] + 。 1 1H NMR (400 MHz, CH3OH-d4) δ 7.96 (d, J = 8.8 Hz, 2H), 7.86 (t, J = 2.0 Hz, 1H), 7.55 (dd, J = 8.6, 2.2 Hz, 1H), 7.14 (t, J = 4.9 Hz, 2H), 7.06 (dd, J = 8.3, 1.6 Hz, 1H), 6.95 (d, J = 8.9 Hz, 2H), 5.59 (d, J = 3.4 Hz, 1H), 5.15 (q, J = 6.4 Hz, 1H), 2.85 (d, J = 16.2 Hz, 1H), 2.61 (ddd, J = 16.2, 10.4, 5.9 Hz, 1H), 2.23 (d, J = 11.4 Hz, 1H), 2.13 - 1.80 (m, 3H), 1.47 (d, J = 6.3 Hz, 3H).

[0297] Example 69 4-[[1-[5-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-3-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]amino]benzoic acid TIFF2025519597000305.tif58165Step 1. Synthesis of 1-[5-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-3-pyridyl]-3-(trifluoromethyl)-5,6-dihydro-4H-indazol-7-one TIFF2025519597000306.tif32165To a solution of 1-(5-hydroxy-3-pyridyl)-3-(trifluoromethyl)-5,6-dihydro-4H-indazol-7-one (Intermediate D-5) (2.90 g, 9.76 mmol) in anhydrous THF (20 mL) were added (1R)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethanol (Intermediate C-1R) (2.37 g, 11.7 mmol) and triphenylphosphine (3.84 g, 14.6 mmol) with stirring at 0 °C under a nitrogen atmosphere. Diethyl azodicarboxylate (2.3 mL, 14.6 mmol) was added dropwise to this solution over a period of 10 minutes, and the reaction was monitored by LC-MS. After completion, the reaction solution was concentrated. The residue was purified by reverse-phase flash chromatography (C18) (0.1% NH4HCO3, 10 - 100% ACN) to give a crude product (3.2 g, ee = 75.88%). The crude product was separated by chiral-HPLC (IG 20×250 mm, 10 μm) to give the title compound (2.70 g, 57% yield) as a white solid. Chiral method: Column name: IG 4.6×100 mm 5 μm. Solvent: MeOH [0.2% NH3 (7M in MeOH)]; Retention time = 1.632 min; ee = 99.88%. LC-MS (Method 4): Retention time = 2.29 min. MS (ESI) m / z 482.1 [M+H] + 。

[0298] Synthesis of (7R)-1-[5-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-3-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-ol TIFF2025519597000307.tif32165IPA(25 mL) A solution of 1-[5-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-3-pyridyl]-3-(trifluoromethyl)-5,6-dihydro-4H-indazol-7-one (2.50 g, 5.19 mmol) was added with triethylamine (1.5 mL, 10.8 mmol) and RuCl(p-cymene)[(R,R)-Ts-DPEN] (CAS No.: 192139-92-7) (33 mg, 0.0519 mmol) at 0 °C, and the solution was stirred at this temperature for 10 minutes under a nitrogen atmosphere. Formic acid (1.0 mL, 26.1 mmol) was gradually added dropwise to this solution. Then the solution was stirred at 45 °C for 8 hours. The reaction was monitored by LC-MS. After completion, the solution was diluted with water (30 mL) and extracted with EA (3 × 30 mL). The organic phases were combined, washed with brine, and dried over Na2SO4. The organic solution was concentrated under vacuum. The residue was purified by flash column chromatography (PE:EA = 1:1) to obtain the title compound (2.50 g, 99.58% yield) as a white solid. Chiral method: Column name: AD-H 4.6×100 mm 5 μm. Solvent: MeOH[0.2% NH3 (7M in MeOH)]; Retention time = 1.6 minutes; ee = 100%. LC-MS (Method 3): Retention time = 1.87 minutes. MS (ESI) m / z 484.1 [M+H] + 。

[0299] Synthesis of (7S)-7-chloro-1-[5-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-3-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazole A solution of (7R)-1-[5-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-3-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-ol (1.50 g, 3.10 mmol) and triethylamine (1.3 mL, 9.31 mmol) in DCM (50 mL) was added methanesulfonyl chloride (0.48 mL, 6.21 mmol) at 0 °C. The solution was stirred at room temperature for 4 h. Then the solution was diluted with water (20 mL) and extracted with DCM (3×30 mL). The organic extracts were combined, washed with brine, and dried over Na2SO4. The organic solution was concentrated under vacuum. The residue was purified by flash column chromatography (PE:EA = 5:1) to give the title compound (1.50 g, 96% yield) as a colorless oil. LC-MS (method 3): retention time = 1.98 min. MS (ESI) m / z 502.1 [M+H] + 。

[0300] Step 4. Synthesis of methyl 4-[[1-[5-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-3-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]amino]benzoate To a solution of (7S)-7-chloro-1-[5-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-3-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazole (150 mg, 0.299 mmol) and methyl 4-aminobenzoate (54 mg, 0.359 mmol) in DMF (2 mL) were added potassium carbonate (207 mg, 1.49 mmol) and potassium iodide (25 mg, 0.149 mmol). The solution was stirred at 60 °C for 30 min. The reaction solution was concentrated and purified by reverse phase flash chromatography (C18) (0.1% NH4HCO3 in water, 10~100% ACN) to give the title compound (80 mg, 43% yield) as a white solid. LC-MS (Method 3): Retention time = 1.95 minutes. MS (ESI) m / z 617.2 [M+H] + 。

[0301] Step 5.4 - Synthesis of [[1-[5-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-3-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]amino]benzoic acid TIFF2025519597000310.tif53165 Aqueous sodium hydroxide (1.2 mL, 2.4 mmol, 2 M) was added to a solution of methyl 4-[[1-[5-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-3-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]amino]benzoate (50 mg, 0.0811 mmol) in methanol (1.5 mL) and THF (1.5 mL) at 0 °C. The reaction solution was then stirred at room temperature for 5 hours. The reaction was monitored by LC-MS. After completion of the reaction, the solution was adjusted to pH 5 - 6 by adding citric acid. The solution was then diluted with water (10 mL) and extracted with ethyl acetate (3 × 20 mL). The organic extracts were combined, washed with brine, and dried over Na2SO4. The organic solution was concentrated under vacuum. The residue was purified by reverse-phase flash chromatography (C18) (0.1% NH4HCO3 in water, 10 - 100% ACN) to give the title compound (29 mg, 60% yield) as a white solid. LC-MS (Method 3): Retention time = 1.82 minutes. MS (ESI) m / z 603.1 [M+H] + 。 11H NMR (500 MHz, CH3OH-d4) δ 8.36 (dd, J = 28.5, 1.9 Hz, 1H), 8.13 (dd, J = 25.1, 2.5 Hz, 1H), 7.81 (dd, J = 23.9, 8.7 Hz, 2H), 7.67 (dt, J = 22.0, 2.3 Hz, 1H), 7.17 - 7.03 (m, 2H), 6.98 (d, J = 8.3 Hz, 1H), 6.63 (dd, J = 17.9, 8.8 Hz, 2H), 5.15 (dq, J = 43, 6 Hz, 1H), 4.92 (dd, J = 45, 3.5 Hz, 1H), 2.82 (d, J = 17.1 Hz, 1H), 2.62 (m, 1H), 2.07 (m, 1H), 1.89 (m, 3H), 1.44 (dd, J = 22.1, 6.3 Hz, 3H).

[0302] Example 70 4 - ((1 - (3 - ((S) - 1 - (2,2 - difluorobenzo[d][1,3]dioxol - 5 - yl)ethoxy)phenyl) - 3 - (trifluoromethyl) - 4,5,6,7 - tetrahydro - 1H - indazol - 7 - yl)thio)benzoic acid TIFF2025519597000311.tif53165 Step 1. Synthesis of 4 - [[1 - [3 - [(1S) - 1 - (2,2 - difluoro - 1,3 - benzodioxol - 5 - yl)ethoxy]phenyl] - 3 - (trifluoromethyl) - 4,5,6,7 - tetrahydroindazol - 7 - yl]sulfanyl]benzoic acid A solution of 7-chloro-1-[3-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazole (from the intermediate of Step 3b of Examples 37 and 38) (150 mg, 0.299 mmol) and 4-mercaptobenzoic acid (55 mg, 0.359 mmol) in DMF (2 mL) was added with potassium carbonate (207 mg, 1.50 mmol) and potassium iodide (25 mg, 0.150 mmol). The solution was stirred at 60 °C for 30 minutes. The reaction solution was concentrated and the residue was purified by reverse-phase flash chromatography (C18) (0.1% NH4HCO3 in water, 10 - 100% ACN) to obtain the title compound (150 mg, 81% yield) as a white solid. LC-MS (Method 4): retention time = 1.96 minutes. MS (ESI) m / z 619.1 [M+H] + 。 1 H NMR (500 MHz, CH3OH-d4) δ 7.83 - 7.75 (m, 2H), 7.33 (td, J = 8.2, 1.7 Hz, 1H), 7.22 (dd, J = 8.1, 1.5 Hz, 1H), 7.18 - 6.97 (m, 7H), 5.43 (dq, J = 22.0, 6.4 Hz, 1H), 4.51 (m 1H), 2.77 (d, J = 15.8 Hz, 1H), 2.60 - 2.50 (m, 1H), 2.13 - 2.00 (m, 3H), 1.96 - 1.87 (m, 1H), 1.57 (dd, J = 8.4, 6.4 Hz, 3H).

[0303] Example 71 4-[[1-[3-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]sulfonyl]benzoic acid Synthesis of [[1-[3-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]sulfonyl]benzoic acid in TIFF2025519597000313.tif53165 Project 1.4- To a solution of 4-[[1-[3-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]sulfanyl]benzoic acid (Example 70) (60 mg, 0.0970 mmol) in DCM (3 mL) was added 3-chloroperoxybenzoic acid (33 mg, 0.194 mmol). The solution was stirred at room temperature for 4 hours. The reaction was monitored by LC-MS. After completion of the reaction, the reaction solution was concentrated and the residue was purified by reverse-phase flash chromatography (C18) (0.1% NH4HCO3 in water, 10 - 100% ACN) to give the title compound (26 mg, 41.0% yield) as a white solid. LC-MS (Method 4): Retention time = 1.87 min. MS (ESI) m / z 651.1 [M+H] + 。 1 H NMR (500 MHz, CH3OH-d4) δ 7.88 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 1H), 7.32 - 7.10 (m, 5H), 6.95 - 6.70 (m, 3H), 5.45 (dq, J = 37.2, 6.3 Hz, 1H), 5.09 (d, J = 3.6 Hz, 0.46H), 4.58 (d, J = 3.8 Hz, 0.55H), 2.82 (dd, J = 16.7, 6.2 Hz, 1H), 2.71 - 2.55 (m, 2H), 2.38 - 2.24 (m, 1H), 2.16 - 2.01 (m, 1H), 1.98 - 1.87 (m, 1H), 1.62 (dd, J = 12.1, 6.4 Hz, 3H).

[0304] Examples 72 and 73 4-[[(7R)-1-[2-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-4-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]sulfanyl]benzoic acid TIFF2025519597000315.tif581654-[[(7S)-1-[2-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-4-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]sulfanyl]benzoic acid TIFF2025519597000316.tif53165Step 1. Synthesis of 4-(((S)-1-(2-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)thio)benzoic acid and 4-(((R)-1-(2-((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethoxy)pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)thio)benzoic acid TIFF2025519597000317.tif42165The title compound having a first fraction designated as P1 (27.1 mg, 12% yield; white solid) and a second fraction designated as P2 (26.9 mg, 13%; white solid) separated by SFC from Example 71 P1: LC-MS (Method 2): Retention time = 1.88 min. MS (ESI) m / z = 618.0 (M-H) + 。 11H NMR (400 MHz, CH3OH-d4) δ 8.19-8.07 (m, 1H), 7.89 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.30-7.17 (m, 3H), 7.14 (dd, J = 8.3, 1.7 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 6.15 (q, J = 6.5 Hz, 1H), 5.03 (s, 1H), 2.80 (d, J = 16.3 Hz, 1H), 2.60 (dd, J = 16.4, 10.2 Hz, 1H), 2.15 (s, 3H), 1.94 (s, 1H), 1.59 (d, J = 6.5 Hz, 3H). P2: LC-MS (Method 2): Retention time = 1.87 min. MS (ESI) m / z = 618.0 (M-H) + . 1 1H NMR (400 MHz, CH3OH-d4) δ 8.12 (d, J = 5.6 Hz, 1H), 7.89 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.29-7.19 (m, 3H), 7.20-7.04 (m, 2H), 6.13 (q, J = 6.5 Hz, 1H), 4.92 (d, J = 3.2 Hz, 1H), 2.79 (d, J = 16.1 Hz, 1H), 2.68-2.50 (m, 1H), 2.26-2.02 (m, 3H), 1.95 (d, J = 12.4 Hz, 1H), 1.56 (d, J = 6.5 Hz, 3H).

[0305] Example 74 (P1 and P2) 3-[[(7S)-1-[5-[(1S)-1-(2,2,6-Trifluoro-1,3-benzodioxol-5-yl)ethoxy]-3-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]bicyclo[1.1.1]pentane-1-carboxylic acid TIFF2025519597000318.tif531653-[(7R)-1-[5-[(1S)-1-(2,2,6-Trifluoro-1,3-benzodioxol-5-yl)ethoxy]-3-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]bicyclo[1.1.1]pentane-1-carboxylic acid TIFF2025519597000319.tif53165Step 1. Synthesis of 7-chloro-1-[5-[(1S)-1-(2,2,6-trifluoro-1,3-benzodioxol-5-yl)ethoxy]-3-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazole TIFF2025519597000320.tif37165To a solution of (7R)-1-[5-[(1S)-1-(2,2,6-trifluoro-1,3-benzodioxol-5-yl)ethoxy]-3-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-ol (synthesized as in Example 36, Step 2) (300 mg, 0.598 mmol) and triethylamine (0.25 mL, 1.80 mmol) in DCM (15 mL) was added methanesulfonyl chloride (0.061 mL, 0.778 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 4 h. Then the mixture was diluted with water (30 mL) and extracted with DCM (30 mL×3). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash column chromatography (PE:EA = 5:1) to give 7-chloro-1-[5-[(1S)-1-(2,2,6-trifluoro-1,3-benzodioxol-5-yl)ethoxy]-3-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazole (300 mg, 0.577 mmol, 96.4% yield) as a colorless oil. LCMS (Method 1): Retention time = 2.36 min. MS (ESI) m / z 520.0 [M+H] + .

[0306] Synthesis of Methyl 3-[[1-[5-[(1S)-1-(2,2,6-Trifluoro-1,3-benzodioxol-5-yl)ethoxy]-3-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]bicyclo[1.1.1]pentane-1-carboxylate To a solution of methyl 3-hydroxybicyclo[1.1.1]pentane-1-carboxylate (66 mg, 0.462 mmol) in dry 2,6-di-tert-butylpyridine (177 mg, 0.923 mmol) was added silver trifluoromethanesulfonate (198 mg, 0.769 mmol) at 0 °C, followed by dropwise addition of (7S)-7-chloro-1-[5-[(1S)-1-(2,2,6-trifluoro-1,3-benzodioxol-5-yl)ethoxy]-3-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazole (160 mg, 0.308 mmol). The reaction mixture was stirred at 0 °C for 1.5 h. Et3N was added to maintain basic conditions. The mixture was filtered through a pad of Celite. The filtrate was concentrated and purified by reverse-phase flash chromatography (C18) (0.1% NH4HCO3 in water, 10 - 100% acetonitrile) to give methyl 3-[[1-[5-[(1S)-1-(2,2,6-trifluoro-1,3-benzodioxol-5-yl)ethoxy]-3-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]bicyclo[1.1.1]pentane-1-carboxylate (120 mg, 0.192 mmol, 62.3% yield) as a white solid. LCMS (Method 1): retention time = 2.38 min. MS (ESI) m / z 626.0 [M+H] + .

[0307] Synthesis of 3-[[1-[5-[(1S)-1-(2,2,6-Trifluoro-1,3-benzodioxol-5-yl)ethoxy]-3-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]bicyclo[1.1.1]pentane-1-carboxylic Acid TIFF2025519597000322.tif53165 A solution of methyl 3-[[1-[5-[(1S)-1-(2,2,6-trifluoro-1,3-benzodioxol-5-yl)ethoxy]-3-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]bicyclo[1.1.1]pentane-1-carboxylate (120 mg, 0.192 mmol) in methanol (1.5 mL) and THF (1.5 mL) was added sodium hydroxide (2.9 mL, 5.76 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 5 h. The reaction was monitored by LCMS. The reaction mixture was adjusted to pH 5 - 6 by the addition of citric acid. Then the mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by reverse phase flash chromatography (C18) (0.1% NH4HCO3 in water, 10 - 100% acetonitrile) to give 3-[[1-[5-[(1S)-1-(2,2,6-trifluoro-1,3-benzodioxol-5-yl)ethoxy]-3-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]bicyclo[1.1.1]pentane-1-carboxylic acid (100 mg, 0.164 mmol, 85.2% yield) as a white solid. LCMS (Method 1): retention time = 2.22 min. MS (ESI) m / z 612.0 [M+H] + 。

[0308] Synthesis of [[(7S)-1-[5-[(1S)-1-(2,2,6-trifluoro-1,3-benzodioxol-5-yl)ethoxy]-3-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]bicyclo[1.1.1]pentane-1-carboxylic acid (P1) and 3-[[(7R)-1-[5-[(1S)-1-(2,2,6-trifluoro-1,3-benzodioxol-5-yl)ethoxy]-3-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]bicyclo[1.1.1]pentane-1-carboxylic acid (P2) TIFF2025519597000323.tif421653 - The crude product of [[1-[5-[(1S)-1-(2,2,6-trifluoro-1,3-benzodioxol-5-yl)ethoxy]-3-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]bicyclo[1.1.1]pentane-1-carboxylic acid (100 mg, 0.164 mmol) was separated by chiral SFC to give 3-[[(7S)-1-[5-[(1S)-1-(2,2,6-trifluoro-1,3-benzodioxol-5-yl)ethoxy]-3-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]bicyclo[1.1.1]pentane-1-carboxylic acid (27 mg, 0.0429 mmol, 26.2% yield) (P1) (ee: 100%) as a white solid and 3-[[(7R)-1-[5-[(1S)-1-(2,2,6-trifluoro-1,3-benzodioxol-5-yl)ethoxy]-3-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]bicyclo[1.1.1]pentane-1-carboxylic acid (26 mg, 0.0413 mmol, 25.2% yield) (P2) (ee: 95.9%) as a white solid. Chiral Prep SFC conditions: Apparatus: SFC-150 (Waters) Column: IG 20*250 mm, 10 μm Column temperature: 35 °C Mobile phase: CO2 / EtOH:n-hexane = 1:1(0.2% methanol ammonia (7M)) = 80 / 20 Flow rate: 100 g / min Back pressure: 100 bar Detection wavelength: 214 nm Cycle time: 6 minutes Sample solution: Dissolve 100 mg in 30 ml of methanol Injection volume: 0.6 ml P1: LCMS (method 2): Retention time = 1.72 minutes. MS (ESI) m / z 612.0 [M+H] + 。 Chiral method: Column name: IG 4.6*100 mm 3.5um Solvent: EtOH:n-hexane = 1:1 [0.2% NH3 (in MeOH 7M)]; Detected at 2.236 minutes; ee: 100% 1 H NMR (400 MHz, MeOH-d4) δ 8.40 (dd, J = 11.0, 1.9 Hz, 2H), 7.62 (s, 1H), 7.42 (d, J = 5.6 Hz, 1H), 7.18 (d, J = 9.0 Hz, 1H), 5.92 (q, J = 6.2 Hz, 1H), 4.82 (s, 1H), 2.77 (d, J = 16.1 Hz, 1H), 2.63 - 2.50 (m, 1H), 2.12 - 2.02 (m, 4H), 1.99 - 1.79 (m, 6H), 1.73 (d, J = 6.3 Hz, 3H). P2: LCMS (method 2): Retention time = 1.72 minutes. MS (ESI) m / z 612.0 [M+H] + 。 Chiral method: Column name: IG 4.6*100 mm 3.5um Solvent: EtOH:n-hexane = 1:1 [0.2% NH3 (in MeOH 7M)]; Detected at 2.931 minutes; ee: 95.88% 11H NMR (400 MHz, MeOH-d4) δ 8.40 (dd, J = 15.4, 2.0 Hz, 2H), 7.63 (s, 1H), 7.44 (d, J = 5.6 Hz, 1H), 7.19 (d, J = 9.1 Hz, 1H), 5.92 (q, J = 6.3 Hz, 1H), 4.78 (s, 1H), 2.77 (d, J = 16.6 Hz, 1H), 2.63 - 2.49 (m, 1H), 2.12 - 2.01 (m, 4H), 1.99 - 1.79 (m, 6H), 1.73 (d, J = 6.3 Hz, 3H). Examples 75 to 84 were synthesized according to the protocol described in the synthesis of Example 74.

[0309] Example 75 (P1 and P2) 3 - [[(7S)-1-[6-Fluoro-5-[(1S)-1-(2,2,6-trifluoro-1,3-benzodioxol-5-yl)ethoxy]-3-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]bicyclo[1.1.1]pentane-1-carboxylic acid TIFF2025519597000324.tif531653 - [[(7R)-1-[6-Fluoro-5-[(1S)-1-(2,2,6-trifluoro-1,3-benzodioxol-5-yl)ethoxy]-3-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]bicyclo[1.1.1]pentane-1-carboxylic acid TIFF2025519597000325.tif53165P1: LCMS (Method 2): Retention time = 1.75 min. MS (ESI) m / z 630.0 [M+H] + . 11H NMR (400 MHz, MeOH-d4) δ 7.96 (s, 1H), 7.58 (dd, J = 8.6, 2.1 Hz, 1H), 7.37 (d, J = 5.7 Hz, 1H), 7.12 (d, J = 9.0 Hz, 1H), 5.85 (q, J = 6.3 Hz, 1H), 4.74 (d, J = 3.7 Hz, 1H), 2.70 (d, J = 16.5 Hz, 1H), 2.48 (dd, J = 15.9, 8.9 Hz, 1H), 2.06-1.89 (m, 4H), 1.83 (d, J = 9.3 Hz, 6H), 1.68 (d, J = 6.3 Hz, 3H). P2: LCMS (Method 2): Retention time = 1.75 min. MS (ESI) m / z 630.0 [M+H] + . 1 1H NMR (400 MHz, MeOH-d4) δ 7.97 (t, J = 1.9 Hz, 1H), 7.62 (dd, J = 8.6, 2.1 Hz, 1H), 7.39 (d, J = 5.7 Hz, 1H), 7.13 (d, J = 9.1 Hz, 1H), 5.84 (q, J = 6.3 Hz, 1H), 4.65 (t, J = 3.5 Hz, 1H), 2.70 (d, J = 16.2 Hz, 1H), 2.58-2.42 (m, 1H), 2.05-1.93 (m, 4H), 1.91-1.75 (m, 6H), 1.68 (d, J = 6.3 Hz, 3H).

[0310] Example 76 (P1 and P2) 3-[[(7S)-1-[3-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-4-fluoro-phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]bicyclo[1.1.1]pentane-1-carboxylic acid TIFF2025519597000326.tif531653-[[(7R)-1-[3-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-4-fluorophenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]bicyclo[1.1.1]pentane-1-carboxylic acid TIFF2025519597000327.tif53165P1: LCMS (Method 2): Retention time = 1.74 min. MS (ESI) m / z 611.1 [M+H] + 。 1 H NMR (400 MHz, MeOH-d4) δ 7.33 (d, J = 1.6 Hz, 1H), 7.26 (ddd, J = 8.3, 7.2, 5.1 Hz, 2H), 7.19 - 7.13 (m, 2H), 7.07 (ddd, J = 8.6, 3.8, 2.5 Hz, 1H), 5.53 (q, J = 6.3 Hz, 1H), 4.44 (t, J = 3.3 Hz, 1H), 2.72 (d, J = 16.1 Hz, 1H), 2.48 (ddd, J = 16.4, 9.9, 6.5 Hz, 1H), 2.05 - 1.94 (m, 1H), 1.90 - 1.69 (m, 9H), 1.64 (d, J = 6.4 Hz, 3H). P2: LCMS (Method 2): Retention time = 1.74 min. MS (ESI) m / z 611.1 [M+H] + 。 1 H NMR (400 MHz, MeOH-d4) δ 7.34 - 7.15 (m, 4H), 7.15 - 7.01 (m, 2H), 5.56 (q, J = 6.3 Hz, 1H), 4.70 (t, J = 3.3 Hz, 1H), 2.72 (d, J = 16.3 Hz, 1H), 2.56 - 2.42 (m, 1H), 2.06 - 1.96 (m, 1H), 1.81 (m, 9H), 1.64 (d, J = 6.4 Hz, 3H).

[0311] Example 77 (P1 and P2) 3-[[(7S)-1-[6-[(1S)-1-(2,2-Difluoro-1,3-benzodioxol-5-yl)ethoxy]-2-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]bicyclo[1.1.1]pentane-1-carboxylic acid TIFF2025519597000328.tif53165 and 3-[[(7R)-1-[6-[(1S)-1-(2,2-Difluoro-1,3-benzodioxol-5-yl)ethoxy]-2-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]bicyclo[1.1.1]pentane-1-carboxylic acid TIFF2025519597000329.tif53165 P1: LC-Mass (Method 2): Retention time = 1.76 min. MS (ESI, negative) m / z 592.0 [M-H] + 。 Chiral method: Column name: OD 4.6×100mm 3μm; Solvent: MeOH [0.2% NH3 (7M in MeOH)]; Detection at 2.697 min; ee: 100%. 1 H NMR (400 MHz, MeOH-d4-d4) δ 7.95 - 7.85 (m, 1H), 7.40 (d, J = 1.5 Hz, 1H), 7.33 (dd, J = 8.3, 1.5 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H), 7.16 (d, J = 7.5 Hz, 1H), 6.99 (d, J = 8.2 Hz, 1H), 6.04 (q, J = 6.5 Hz, 1H), 4.81 (s, 1H), 2.74 (d, J = 16.1 Hz, 1H), 2.62 - 2.46 (m, 1H), 1.96 - 1.77 (m, 4H), 1.67 - 1.57 (m, 6H), 1.52 (m, 3H). P2: LC-Mass (Method 2): Retention time = 1.76 min. MS (ESI, negative) m / z 592.0 [M-H] + 。 Chiral method: Column name: OD 4.6×100 mm; 3 μm. Solvent: MeOH [0.2% NH3 (7 M in MeOH)]; Detection at 3.481 min; ee: 98.78%. 1 1H NMR (400 MHz, MeOH-d4) δ 7.86 (t, J = 7.9 Hz, 1H), 7.28 (d, J = 1.5 Hz, 1H), 7.23 - 7.13 (m, 2H), 7.07 (d, J = 8.3 Hz, 1H), 6.93 (d, J = 8.1 Hz, 1H), 6.13 (q, J = 6.6 Hz, 1H), 5.47 (t, J = 3.6 Hz, 1H), 2.74 (d, J = 16.4 Hz, 1H), 2.63 - 2.49 (m, 1H), 2.15 - 2.07 (m, 1H), 2.04 - 1.80 (m, 10H), 1.69 (d, J = 6.6 Hz, 3H).

[0312] Example 78 (P1 and P2) 2-[3-[[(7S)-1-[3-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-4-fluorophenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]-1-bicyclo[1.1.1]pentanyl]acetic acid TIFF2025519597000330.tif581652-[3-[[(7R)-1-[3-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-4-fluorophenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]-1-bicyclo[1.1.1]pentanyl]acetic acid TIFF2025519597000331.tif58165P1: LCMS (Method 4): Retention time = 1.82 min. MS (ESI) m / z 625.0 [M+H] + . 11H NMR (400 MHz, MeOH-d4) δ: 7.34 (d, J = 1.6 Hz, 1H), 7.30 - 7.22 (m, 2H), 7.21 - 7.14 (m, 2H), 7.08 (ddd, J = 8.6, 3.8, 2.5 Hz, 1H), 5.54 (q, J = 6.3 Hz, 1H), 4.39 (t, J = 3.3 Hz, 1H), 2.74 (d, J = 15.9 Hz, 1H), 2.55 - 2.47 (m, 1H), 2.45 (s, 2H), 2.03 (dd, J = 9.3, 5.9 Hz, 1H), 1.83 (dd, J = 14.2, 10.8 Hz, 2H), 1.71 - 1.63 (m, 4H), 1.61 (dd, J = 9.3, 1.0 Hz, 3H), 1.54 - 1.45 (m, 3H). P2: LCMS (Method 4): Retention time = 1.82 min. MS (ESI) m / z 625.0 [M+H] + . 1 1H NMR (400 MHz, MeOH-d4) δ: 7.33 - 7.21 (m, 3H), 7.20 - 7.13 (m, 2H), 7.10 (ddd, J = 8.6, 3.9, 2.5 Hz, 1H), 5.57 (q, J = 6.4 Hz, 1H), 4.68 (t, J = 3.3 Hz, 1H), 2.73 (d, J = 16.6 Hz, 1H), 2.56 - 2.48 (m, 1H), 2.47 (s, 2H), 2.04 (d, J = 11.3 Hz, 1H), 1.93 - 1.68 (m, 3H), 1.68 - 1.59 (m, 6H), 1.58 - 1.51 (m, 3H).

[0313] Example 79 (P1 and P2) 4 - [[(7S)-1-[5-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-6-fluoro-3-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]cyclohexanecarboxylic acid TIFF2025519597000332.tif581654-[[(7R)-1-[5-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-6-fluoro-3-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]cyclohexanecarboxylic acid TIFF2025519597000333.tif58165P1: LCMS (Method 1): LC retention time = 1.80 min, MS (ESI): m / z 628.0 [M+H] + 。 1 H NMR (400 MHz, MeOH-d4) δ 7.97 (s, 1H), 7.62 (dd, J = 8.6, 2.0 Hz, 1H), 7.33 (s, 1H), 7.30 - 7.24 (m, 1H), 7.19 (d, J = 8.3 Hz, 1H), 5.66 (q, J = 6.3 Hz, 1H), 4.73 (d, J = 3.8 Hz, 1H), 3.22 - 3.10 (m, 1H), 2.72 (d, J = 16.6 Hz, 1H), 2.60 - 2.44 (m, 1H), 2.00 (m, 2H), 1.91 - 1.74 (m, 5H), 1.70 (t, J = 8.8 Hz, 4H), 1.41 - 1.10 (m, 3H), 0.93 (ddd, J = 16.5, 13.0, 3.7 Hz, 1H), 0.41 (m, 1H). P2: LCMS (Method 1): LC retention time = 1.80 min, MS (ESI): m / z 628.0 [M+H]+. 11H NMR (400 MHz, MeOH-d4) δ 7.92 (t, J = 1.8 Hz, 1H), 7.65 (dd, J = 8.7, 2.1 Hz, 1H), 7.39 (d, J = 1.4 Hz, 1H), 7.31 (dd, J = 8.3, 1.5 Hz, 1H), 7.24 (d, J = 8.3 Hz, 1H), 5.61 (q, J = 6.3 Hz, 1H), 4.27 (t, J = 3.3 Hz, 1H), 2.92 (ddd, J = 14.5, 10.3, 4.0 Hz, 1H), 2.73 (d, J = 16.3 Hz, 1H), 2.52 (ddd, J = 16.2, 9.9, 6.0 Hz, 1H), 2.08 - 1.95 (m, 2H), 1.93 - 1.77 (m, 3H), 1.72 (dd, J = 13.2, 4.9 Hz, 6H), 1.39 - 1.00 (m, 4H), 0.53 (ddd, J = 23.2, 12.8, 3.7 Hz, 1H).

[0314] Example 80 (P1 and P2) 4 - [[(7S)-1-[2-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-6-fluoro-4-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]cyclohexanecarboxylic acid (P1) TIFF2025519597000334.tif581654 - [[(7R)-1-[2-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-6-fluoro-4-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]cyclohexanecarboxylic acid (P2) TIFF2025519597000335.tif58165P1: LCMS (Method 2): Retention time = 1.96 min. MS (ESI) m / z 628.1 [M+H] + . 11H NMR (400 MHz, MeOH-d4) δ 7.32 (s, 1H), 7.27 (d, J = 8.3 Hz, 1H), 7.21 (s, 1H), 7.17 (d, J = 8.3 Hz, 1H), 6.92 (s, 1H), 6.14 (q, J = 6.5 Hz, 1H), 4.86-4.85 (m, 1H), 3.51 (m, 1H), 2.74 (d, J = 16.6 Hz, 1H), 2.60-2.47 (m, 1H), 2.28-2.07 (m, 2H), 2.01-1.77 (m, 6H), 1.66 (m, 4H), 1.39 (m, 3H), 1.13 (m, 1H). P2: LCMS (Method 2): Retention time = 1.96 min. MS (ESI) m / z 628.1 [M+H] + . 1 1H NMR (400 MHz, MeOH-d4) δ 7.32 (s, 1H), 7.26 (dd, J = 8.3, 1.4 Hz, 1H), 7.17 (dd, J = 12.1, 4.6 Hz, 2H), 6.94 (s, 1H), 6.12 (q, J = 6.5 Hz, 1H), 4.90 (s, 1H), 3.50 (td, J = 10.5, 5.2 Hz, 1H), 2.73 (d, J = 16.3 Hz, 1H), 2.53 (m, 1H), 2.29-2.06 (m, 2H), 2.02-1.78 (m, 6H), 1.66 (m, 4H), 1.49-1.22 (m, 3H), 1.13 (m, 1H).

[0315] Example 81 (P1 and P2) 4-[[(7R)-1-[2-[(1S)-1-(2,2-Difluoro-1,3-benzodioxol-5-yl)ethoxy]-6-fluoro-4-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]bicyclo[2.2.2]octane-1-carboxylic acid TIFF2025519597000336.tif581654-[[(7S)-1-[2-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-6-fluoro-4-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]bicyclo[2.2.2]octane-1-carboxylic acid TIFF2025519597000337.tif58165P1: LCMS (Method 2): Retention time = 2.01 min. MS (ESI) m / z 652.0 [M-H] + 。 1 H NMR (400 MHz, MeOH-d4) δ: 7.34 (d, J = 1.4 Hz, 1H), 7.29 (dd, J = 8.3, 1.5 Hz, 1H), 7.16 (dd, J = 14.4, 4.7 Hz, 2H), 6.87 (s, 1H), 6.17 (q, J = 6.5 Hz, 1H), 5.05 (t, J = 3.7 Hz, 1H), 2.71 (d, J = 16.3 Hz, 1H), 2.60 - 2.46 (m, 1H), 2.10 (dd, J = 12.4, 5.6 Hz, 1H), 2.02 - 1.90 (m, 1H), 1.81 (m, 8H), 1.70 - 1.56 (m, 9H). P2: LCMS (Method 2): Retention time = 2.02 min. MS (ESI) m / z 652.0 [M-H] + 。 11H NMR (400 MHz, MeOH-d4) δ: 7.36 (d, J = 1.4 Hz, 1H), 7.29 (dd, J = 8.3, 1.5 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 7.12 (d, J = 1.0 Hz, 1H), 6.87 (s, 1H), 6.17 (q, J = 6.5 Hz, 1H), 5.10 (t, J = 3.6 Hz, 1H), 2.71 (d, J = 16.2 Hz, 1H), 2.62 - 2.44 (m, 1H), 2.08 (dd, J = 12.3, 5.6 Hz, 1H), 1.99 - 1.75 (m, 9H), 1.62 (m, 9H).

[0316] Example 82 (P1 and P2) 4-[[(7S)-1-[5-[(1S)-1-(2,2-Difluoro-1,3-benzodioxol-5-yl)ethoxy]-6-fluoro-3-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxymethyl]cyclohexanecarboxylic acid TIFF2025519597000338.tif581654-[[(7R)-1-[5-[(1S)-1-(2,2-Difluoro-1,3-benzodioxol-5-yl)ethoxy]-6-fluoro-3-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxymethyl]cyclohexanecarboxylic acid TIFF2025519597000339.tif58165P1: LCMS (Method 2): LC retention time 1.87, MS (ESI): m / z 642 [M+H] + . 11H NMR (400 MHz, MeOH-d4) δ 7.99 (d, J = 1.8 Hz, 1H), 7.69 (dd, J = 8.6, 2.1 Hz, 1H), 7.34 (d, J = 1.3 Hz, 1H), 7.25 (dt, J = 18.0, 9.0 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 5.64 (q, J = 6.3 Hz, 1H), 4.54 (t, J = 3.7 Hz, 1H), 3.31 (dd, J = 3.3, 1.6 Hz, 1H), 3.04 - 2.89 (m, 1H), 2.72 (d, J = 16.3 Hz, 1H), 2.60 - 2.47 (m, 1H), 2.07 (ddd, J = 12.2, 7.9, 3.6 Hz, 2H), 1.79 (ddd, J = 22.4, 14.7, 7.2 Hz, 5H), 1.67 (t, J = 12.2 Hz, 3H), 1.49 (dd, J = 34.1, 12.8 Hz, 2H), 1.36 - 1.16 (m, 3H), 0.87 - 0.67 (m, 2H). P2: LCMS (Method 2): LC retention time = 1.87, MS (ESI): m / z 642 [M+H] + . 11H NMR (400 MHz, MeOH-d4) δ 7.89 (t, J = 1.9 Hz, 1H), 7.68 (dd, J = 8.6, 2.1 Hz, 1H), 7.38 (t, J = 8.6 Hz, 1H), 7.33 (dd, J = 8.3, 1.5 Hz, 1H), 7.24 (d, J = 8.3 Hz, 1H), 5.61 (q, J = 6.3 Hz, 1H), 4.16 (t, J = 3.7 Hz, 1H), 3.12 (dd, J = 8.6, 5.6 Hz, 1H), 2.77 - 2.61 (m, 1H), 2.59 - 2.44 (m, 1H), 2.38 (dd, J = 8.5, 6.5 Hz, 1H), 2.13 - 1.97 (m, 2H), 1.92 - 1.62 (m, 8H), 1.48 - 1.37 (m, 1H), 1.37 - 1.17 (m, 3H), 1.16 - 1.02 (m, 1H), 0.76 - 0.50 (m, 2H).

[0317] Example 83 (P1 and P2) 3 - [[(7S)-1-[6-[(1S)-1-(2,2,6-Trifluoro-1,3-benzodioxol-5-yl)ethoxy]-2-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]cyclobutanecarboxylic acid (P1) TIFF2025519597000340.tif53165 and 3 - [[(7R)-1-[6-[(1S)-1-(2,2,6-Trifluoro-1,3-benzodioxol-5-yl)ethoxy]-2-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]cyclobutanecarboxylic acid (P2) TIFF2025519597000341.tif53165 P1: LCMS (Method 2): Retention time = 1.92 min: Detected peak 600.0 [M + H] + . 11H NMR (400 MHz, MeOH-d4) δ: 7.96 - 7.82 (m, 1H), 7.41 (d, J = 5.7 Hz, 1H), 7.24 (dt, J = 16.1, 7.9 Hz, 2H), 6.96 (t, J = 11.8 Hz, 1H), 6.22 (q, J = 6.5 Hz, 1H), 4.56 (t, J = 3.6 Hz, 1H), 3.79 - 3.59 (m, 1H), 2.72 (d, J = 16.4 Hz, 1H), 2.53 (dt, J = 9.7, 6.2 Hz, 2H), 2.04 (dq, J = 7.6, 4.1 Hz, 1H), 1.91 (ddd, J = 11.8, 9.7, 4.0 Hz, 3H), 1.82 - 1.53 (m, 6H), 1.38 - 1.12 (m, 1H). P2: LCMS (Method 2): Retention time = 1.92 min: Detected peak 600.0 [M + H] + . 1 1H NMR (400 MHz, MeOH-d4) δ: 7.86 (t, J = 8.0 Hz, 1H), 7.35 - 7.19 (m, 2H), 7.05 (d, J = 9.1 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.34 (q, J = 6.6 Hz, 1H), 5.50 (d, J = 3.5 Hz, 1H), 4.41 - 4.26 (m, 1H), 2.81 - 2.60 (m, 2H), 2.60 - 2.33 (m, 2H), 2.24 - 1.99 (m, 3H), 1.99 - 1.60 (m, 7H).

[0318] Example 84 (P1 and P2) 3 - [[(7S)-1 - [5 - fluoro - 6 - [(1S)-1 - (2,2,6 - trifluoro - 1,3 - benzodioxol - 5 - yl)ethoxy] - 2 - pyridyl] - 3 - (trifluoromethyl) - 4,5,6,7 - tetrahydroindazol - 7 - yl]oxy]cyclobutanecarboxylic acid (P1) TIFF2025519597000342.tif531653-[(7R)-1-[5-Fluoro-6-[(1S)-1-(2,2,6-trifluoro-1,3-benzodioxol-5-yl)ethoxy]-2-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]cyclobutanecarboxylic acid (P2) TIFF2025519597000343.tif53165P1: LCMS (Method 2): Retention time = 1.96 min. MS (ESI) m / z 616.2 [M-H] - 。 Chiral method: Column name: (R,R)Whelk-O1 4.6*100mm 3.5μm Solvent: MeOH[1%NH3 (7M in MeOH)]; Detected at 1.527 min; ee: 100% 1 H NMR (400 MHz, MeOH-d4) δ 7.77 (dd, J = 9.3, 8.5 Hz, 1H), 7.42 (d, J = 5.7 Hz, 1H), 7.25 (dd, J = 12.6, 5.8 Hz, 2H), 6.29 (q, J = 6.5 Hz, 1H), 4.46 (t, J = 3.7 Hz, 1H), 3.63 (p, J = 6.7 Hz, 1H), 2.78-2.65 (m, 1H), 2.61-2.47 (m, 2H), 2.03 (dq, J = 7.6, 4.1 Hz, 1H), 1.93-1.82 (m, 3H), 1.81-1.63 (m, 6H), 1.37-1.27 (m, 1H). P2: LCMS (Method 2): Retention time = 1.96 min. MS (ESI) m / z 616.2 [M-H] - 。 Chiral method: Column name: (R,R)Whelk-O1 4.6*100mm 3.5μm Solvent: EtOH[1%NH3 (7M in MeOH)]; Detected at 1.772 min; ee: 96.45% 11H NMR (400 MHz, MeOH-d4) δ 7.72 (dd, J = 9.3, 8.6 Hz, 1H), 7.33 - 7.25 (m, 2H), 7.06 (d, J = 9.1 Hz, 1H), 6.42 (q, J = 6.6 Hz, 1H), 5.38 (t, J = 3.4 Hz, 1H), 4.32 (p, J = 7.2 Hz, 1H), 2.77 - 2.66 (m, 2H), 2.59 - 2.47 (m, 1H), 2.41 (ddd, J = 11.1, 7.4, 4.3 Hz, 1H), 2.20 (ddd, J = 11.4, 7.4, 4.5 Hz, 1H), 2.14 - 2.03 (m, 2H), 1.95 - 1.64 (m, 7H).

[0319] Example 85 (P1 and P2) 3-[3-[[(7S)-1-[3-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-4-fluorophenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]-1-bicyclo[1.1.1]pentanyl]-2H-1,2,4-oxadiazol-5-one (P1) TIFF2025519597000344.tif63165 and 3-[3-[[(7R)-1-[3-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-4-fluorophenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]-1-bicyclo[1.1.1]pentanyl]-2H-1,2,4-oxadiazol-5-one (P2) TIFF2025519597000345.tif63165 Step 1. Synthesis of 3-[[1-(3-bromo-4-fluorophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]bicyclo[1.1.1]pentane-1-carboxamide A solution of 3-[[1-(3-bromo-4-fluoro-phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl]oxy]bicyclo[1.1.1]pentane-1-carboxylic acid (500 mg, 1.02 mmol) in DMF (10 mL) was added with ammonium chloride (66 mg, 1.23 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (369 mg, 1.53 mmol), and N,N-diisopropylethylamine (0.89 mL, 5.11 mmol). The reaction mixture was stirred at 25 °C for 12 h. Then the mixture was diluted with water (10 mL) and extracted with EA (20 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to afford 3-[[1-(3-bromo-4-fluoro-phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl]oxy]bicyclo[1.1.1]pentane-1-carboxamide (450 mg, 90.1%) as a white solid. LCMS: retention time = 1.95 min. MS(ESI) m / z 488 and 490 [M+H] + 。

[0320] Step 2. Synthesis of 3-[[1-(3-bromo-4-fluoro-phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl]oxy]bicyclo[1.1.1]pentane-1-carbonitrile A solution of 3-[[1-(3-bromo-4-fluoro-phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl]oxy]bicyclo[1.1.1]pentane-1-carboxamide (400 mg, 0.81 mmol) in 48165 DMF (8 mL) was added cyanuric chloride (66 mg, 3.28 mmol). The reaction mixture was stirred at 25 °C for 2 h. Then the mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0 - 100% ethyl acetate in heptane) to give 3-[[1-(3-bromo-4-fluoro-phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl]oxy]bicyclo[1.1.1]pentane-1-carbonitrile (380 mg, 98.6%) as a yellow oil. LCMS (Method 1): retention time = 2.26 min. MS (ESI) m / z 470.1, 472.1 [M+H] + .

[0321] Step 3. Synthesis of 3-[[1-(4-fluoro-3-hydroxy-phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl]oxy]bicyclo[1.1.1]pentane-1-carbonitrile A solution of 3-[[1-(3-bromo-4-fluoro-phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl]oxy]bicyclo[1.1.1]pentane-1-carbonitrile (350 mg, 0.74 mmol) in 1,4-dioxane (10 mL) was added with water (67 mg, 3.72 mmol), cesium carbonate (727 mg, 2.23 mmol) and Rockphos-Pd-G3 (35 mg). The reaction mixture was stirred at 100 °C for 0.5 h under N2. Then the solid was removed by filtration. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (0 - 100% ethyl acetate in heptane) to give 3-[[1-(4-fluoro-3-hydroxy-phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl]oxy]bicyclo[1.1.1]pentane-1-carbonitrile (300 mg, 98.9% yield) as a yellow oil. LCMS (method 2): retention time = 1.95 min. MS (ESI) m / z 408.0 [M+H] + 。

[0322] Step 4. Synthesis of 3-[[1-[3-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-4-fluoro-phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl]oxy]bicyclo[1.1.1]pentane-1-carbonitrile A solution of 3-[[1-(4-fluoro-3-hydroxy-phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]bicyclo[1.1.1]pentane-1-carbonitrile (200 mg, 0.49 mmol) in 53165 THF (5 mL) was added to (1R)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethanol (Intermediate C-1R) (119 mg, 0.59 mmol) and triphenylphosphine (258 mg, 0.98 mmol). The mixture was then cooled to 0 °C under N2, and diethyl azodicarboxylate (0.09 mL, 0.59 mmol) was added dropwise at 0 °C over 10 minutes. The reaction was then stirred at room temperature for 1 hour. The mixture was concentrated and the crude product was purified by flash column chromatography (ethyl acetate in PE: 0 - 25%) to give 3-[[1-[3-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-4-fluoro-phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]bicyclo[1.1.1]pentane-1-carbonitrile (260 mg, 89.5%) as a white solid. LCMS (Method 1): Retention time = 2.38 minutes. MS (ESI) m / z 592.0 [M+H] + .

[0323] Step 5. Synthesis of 3-[[1-[3-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-4-fluoro-phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]-N-hydroxy-bicyclo[1.1.1]pentane-1-carboxamidine A solution of 3-[[1-[3-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-4-fluorophenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl]oxy]bicyclo[1.1.1]pentane-1-carbonitrile (260 mg, 0.44 mmol) in ethanol (3 mL) was added with hydroxylamine (3.0 mL, 0.44 mmol). The reaction mixture was stirred at 80 °C for 1 hour. The mixture was concentrated and the crude product was purified by flash column chromatography (ethyl acetate in PE) to give 3-[[1-[3-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-4-fluorophenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl]oxy]-N-hydroxy-bicyclo[1.1.1]pentane-1-carboxamidine (200 mg, 72.8% yield) as a white solid. LCMS (Method 1): retention time = 2.03 min. MS (ESI) m / z 625.1 [M+H] + 。

[0324] Step 6. Synthesis of 3-[3-[[(7R)-1-[3-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-4-fluorophenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl]oxy]-1-bicyclo[1.1.1]pentanyl]-2H-1,2,4-oxadiazol-5-one and 3-[3-[[(7S)-1-[3-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-4-fluorophenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl]oxy]-1-bicyclo[1.1.1]pentanyl]-2H-1,2,4-oxadiazol-5-one A solution of 3-[[1-[3-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-4-fluoro-phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]-N-hydroxy-bicyclo[1.1.1]pentane-1-carboxamidine (48165) in ethyl acetate (10 mL) and methylthiohypofluorite (90 mg, 0.13 mmol) was added with N,N-carbonyldiimidazole (106 mg, 0.65 mmol). The reaction mixture was stirred at 65 °C for 12 h. The mixture was concentrated and the crude product was purified by flash column chromatography (ethyl acetate in PE: 0 - 15% in 20 min) to give the product (90 mg), which was separated by SFC to give 3-[3-[[(7R)-1-[3-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-4-fluoro-phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]-1-bicyclo[1.1.1]pentanyl]-2H-1,2,4-oxadiazol-5-one (P1) (38 mg, 44.9% yield) and 3-[3-[[(7S)-1-[3-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethoxy]-4-fluoro-phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]-1-bicyclo[1.1.1]pentanyl]-2H-1,2,4-oxadiazol-5-one (P2) (38 mg, 44.3% yield). Both products are white solids. P1: LCMS (method 1): retention time = 1.85 min. MS (ESI) m / z 651 [M+H] + 。 11H NMR (400 MHz, MeOH-d4) δ: 7.35 (d, J = 1.4 Hz, 1H), 7.33 - 7.24 (m, 2H), 7.23 - 7.17 (m, 2H), 7.15 (d, J = 3.8 Hz, 1H), 5.58 (dq, J = 12.7, 6.4 Hz, 1H), 4.52 (t, J = 3.2 Hz, 1H), 2.75 (d, J = 16.3 Hz, 1H), 2.60 - 2.43 (m, 1H), 2.12 - 1.94 (m, 4H), 1.96 - 1.71 (m, 6H), 1.66 (d, J = 6.3 Hz, 3H). P2: LCMS (Method 1): Retention time = 1.85 min. MS (ESI) m / z 651 [M+H] + . 1 1H NMR (400 MHz, MeOH-d4) δ: 7.36 - 7.17 (m, 4H), 7.17 - 7.03 (m, 2H), 5.59 (q, J = 6.3 Hz, 1H), 4.77 (d, J = 3.4 Hz, 1H), 2.74 (d, J = 16.4 Hz, 1H), 2.51 (dd, J = 16.2, 9.3 Hz, 1H), 2.13 - 1.96 (m, 4H), 1.87 (ddd, J = 39.4, 16.5, 6.4 Hz, 6H), 1.66 (d, J = 6.4 Hz, 3H).

[0325] Example 86 (P1 and P2) 3-[3-[[(7S)-1-[4-Fluoro-3-[(1S)-1-(2,2,6-trifluoro-1,3-benzodioxol-5-yl)ethoxy]phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]-1-bicyclo[1.1.1]pentanyl]-2H-1,2,4-oxadiazol-5-one TIFF2025519597000352.tif68165 and 3-[3-[[(7R)-1-[4-Fluoro-3-[(1S)-1-(2,2,6-trifluoro-1,3-benzodioxol-5-yl)ethoxy]phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]-1-bicyclo[1.1.1]pentanyl]-2H-1,2,4-oxadiazol-5-one Example 86 (P1 and P2) was synthesized in the same manner as Example 85 (P1 and P2). P1: LCMS (Method 1): Retention time = 1.85 min. MS (ESI) m / z 669.0 [M+H] + 。 1 1H NMR (400 MHz, MeOH-d4) δ: 7.40 (dd, J = 10.3, 5.6 Hz, 1H), 7.32 (dd, J = 10.7, 8.7 Hz, 1H), 7.24 - 7.08 (m, 3H), 5.81 (q, J = 6.3 Hz, 1H), 4.65 (t, J = 3.3 Hz, 1H), 2.76 (d, J = 16.6 Hz, 1H), 2.53 (ddd, J = 16.2, 9.7, 6.3 Hz, 1H), 2.16 - 1.93 (m, 7H), 1.81 (ddd, J = 25.8, 9.5, 3.2 Hz, 3H), 1.69 (d, J = 6.4 Hz, 3H). P2: LCMS (Method 1): Retention time = 1.85 min. MS (ESI) m / z 669.0 [M+H] + 。 11H NMR (400 MHz, MeOH-d4) δ: 7.40 (dd, J = 10.2, 5.7 Hz, 1H), 7.32 (dd, J = 10.7, 8.6 Hz, 1H), 7.24 - 7.03 (m, 3H), 5.82 (q, J = 6.3 Hz, 1H), 4.78 (d, J = 3.5 Hz, 1H), 2.75 (d, J = 16.2 Hz, 1H), 2.65 - 2.35 (m, 1H), 2.15 - 2.02 (m, 4H), 2.02 - 1.91 (m, 3H), 1.93 - 1.74 (m, 3H), 1.69 (d, J = 6.4 Hz, 3H).

[0326] Example 87 4 - [[(7S)-1-[2-[[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethyl]amino]-4-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-yl]oxy]benzoic acid TIFF2025519597000353.tif58165Step 1. Synthesis of (S)-4-bromo-N-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethyl)pyridin-2-amine TIFF2025519597000354.tif32165To a solution of (1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethanamine hydrochloride (Intermediate C-6a) (1000 mg, 4.21 mmol) in DMSO (15 mL) was added 4-bromo-2-fluoropyridine (2222 mg, 12.60 mmol) and cesium fluoride (1918 mg, 12.60 mmol). The reaction mixture was stirred at 100 °C for 8 h. Water (20 mL) was added and the aqueous solution was extracted with ethyl acetate (20 mL × 3). The organic solution was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash silica gel column chromatography (eluting with ethyl acetate in 0% to 25% petroleum ether) to afford the title compound (1000 mg, 63.2% yield) as a yellow oil. LCMS (Method 2): Retention time = 2.16 min. MS (ESI) m / z 357.0, 359.0 [M+H] + 。

[0327] Step 2. Synthesis of (S)-(2-((1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethyl)amino)pyridin-4-yl)boronic acid TIFF2025519597000355.tif321651,4-dioxane (15 mL) A solution of 4-bromo-N-[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethyl]pyridin-2-amine (1000 mg, 2.80 mmol) was added with bis(pinacolato)diboron (853 mg, 3.36 mmol), KOAc (550 mg, 5.60 mmol) and Pd(dppf)Cl2 (102 mg, 0.14 mmol) under N2. The reaction mixture was stirred at 80 °C for 8 h. The reaction mixture was concentrated under vacuum to obtain a residue, which was purified by flash silica gel column chromatography (eluting with 0% - 100% ethyl acetate in petroleum ether), followed by prep-HPLC (TFA conditions) to obtain the title compound (750 mg, 81.5% yield) as a brown solid. LCMS (Method 1): Retention time = 1.53 min. MS (ESI) m / z 323.0 [M+H] + 。

[0328] Step 3. Synthesis of (S)-1-(2-((1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethyl)amino)pyridin-4-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-indazol-7-one A solution of [2-[[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethyl]amino]-4-pyridyl]boronic acid (750 mg, 2.33 mmol), 3-(trifluoromethyl)-1,4,5,6-tetrahydroindazol-7-one (475 mg, 2.33 mmol) and copper(II) acetate (211 mg, 1.16 mmol) in 42165DCE (15 mL) was added with triethylamine (0.36 mL, 2.56 mmol) under O2. The reaction mixture was stirred at room temperature for 8 hours. The reaction mixture was concentrated in vacuo to give a residue, which was purified by flash silica gel column chromatography (eluting with 0% - 20% ethyl acetate in petroleum ether) to afford the title compound (85 mg, 7.5% yield) as a yellow solid. LCMS (Method 2): retention time = 2.22 min. MS (ESI) m / z 481.0 [M+H] + 。

[0329] Step 4. Synthesis of R-1-(2-(((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethyl)amino)pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-ol To a solution of 1-[2-[[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethyl]amino]-4-pyridyl]-3-(trifluoromethyl)-5,6-dihydro-4H-indazol-7-one (85 mg, 0.18 mmol) in 32165IPA (5 mL) was added RuCl(p-cymene)[(R,R)-Ts-DPEN] (5 mg) under N2, followed by the addition of triethylamine (0.30 mL, 2.15 mmol) and formic acid (0.20 mL, 5.21 mmol) portionwise. The reaction mixture was stirred at 45 °C for 2 hours. The reaction mixture was concentrated in vacuo to give a residue, which was purified by flash silica gel column chromatography (ethyl acetate in 0% to 15% petroleum ether) to afford the title compound (80 mg, 91.8% yield) as a brown oil. LCMS (Method 2): Retention time = 2.16 minutes. MS (ESI) m / z 483.0 [M+H] + 。

[0330] Step 5. Synthesis of methyl 4-(((S)-1-(2-(((S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethyl)amino)pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-yl)oxy)benzoate TIFF2025519597000358.tif58165A solution of (7R)-1-[2-[[(1S)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethyl]amino]-4-pyridyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-7-ol (80 mg, 0.17 mmol) in THF (5 mL) was added with methyl 4-hydroxybenzoate (28 mg, 0.18 mmol) under N2. The reaction mixture was stirred at 0 °C for 15 minutes. Then, triphenylphosphine (130 mg, 0.50 mmol) and diethyl azodicarboxylate (0.039 mL, 0.25 mmol) were added to the reaction mixture at 0 °C. The reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo to give a residue, which was purified by flash silica gel column chromatography (ethyl acetate in petroleum ether from 0% to 15%) to give the title compound (35 mg, 33.5% yield) as a yellow solid. LCMS (Method 2): Retention time = 2.49 minutes. MS (ESI) m / z 617.1 [M+H] + 。

[0331] Step 6. Synthesis of 4-(((S)-1-(2-(((S)-1-(2,2-diflu...

Claims

1. Equation (I) or Equation (II) Compounds represented by, or their pharmaceutically acceptable salts: A is selected from the group consisting of optionally substituted 3- to 10-membered carbocyclyls, optionally substituted 3- to 10-membered heterocyclyls, optionally substituted phenyls, and optionally substituted 5- to 10-membered heteroaryls; L is a bond, -O-, -S-, -S(O) ２ -ien-CH ２ Selected from the group consisting of -, -C(O)-, -N(H)-, and -N(H)C(O)-; W is -O-, -S-, -S(O)-, -S(O) ２ Selected from the group consisting of -, -N(H)-, and optionally substituted 3- to 6-membered heterocyclylenes; X １ is N or C(H); X ２ is, -CH ２ -, -N(H)-, and -N(C) １～３ Selected from the group consisting of alkyl)-; Y １ is selected from the group consisting of -C(H)=, -C(F)=, and -N=; Y ２ is selected from the group consisting of -C(H)=, -C(F)=, and -N=; Y ３ is selected from the group consisting of -C(H)=, -C(F)=, and -N=; Y ４ is selected from the group consisting of -C(H)=, -C(F)=, and -N=; Z is selected from the group consisting of -C(H)=, -C(F)=, and -N=; Each R ａ C may be a halogen or substituted C １ ~C ３ Independently selected from the group consisting of aliphatic, optionally substituted 5- to 7-membered heterocyclines, optionally substituted 5- to 6-membered heteroaryls, and -COOH; R ｂ -CN, C may be substituted. １ ~C ６ Aliphatic C, may be substituted. １ ~C ６ Selected from the group consisting of haloaliphatic and possibly substituted 3- to 7-membered heterocyclines; R ｅ１ is hydrogen, C １ ~C ５ - Alkyl and C ３ ~C ５ - Selected from the group consisting of cycloalkyl groups; R ｅ２ is hydrogen, C １ ~C ５ - Alkyl and C ３ ~C ５ - Selected from the group consisting of cycloalkyl groups; Here, R ｅ１ and R ｅ２ They, together with the atoms to which they are bonded, optionally form a substituted 3- to 6-membered carbocykyl ring; m is between 0 and 2; and n is between 0 and 5.

2. The compound according to claim 1, wherein W is -O-.

3. The compound according to claim 1, wherein W is selected from the group consisting of -N(H)-, -S(O)-, -S(O)2-, and -S-.

4. The aforementioned compound is of formula (I-a1) or (I-a2) The compound according to claim 1, represented by, or a pharmaceutically acceptable salt thereof.

5. Y １ is -C(H) = or -N = and Y ２ The compound according to claim 1 or 4, wherein is -C(H)= or -N=.

6. Y １ is -C(H) = and Y ２ The compound according to claim 1 or 4, wherein -C(H)=.

7. Y １ is -N = and Y ２ The compound according to claim 1 or 4, wherein -C(H)=.

8. Y １ is -C(H) = and Y ２ The compound according to claim 1 or 4, wherein -N =

9. Y １ is -N = and Y ２ The compound according to claim 1 or 4, wherein -N =

10. X １ The compound according to claim 1, wherein C is C.

11. X １ The compound according to claim 1, wherein is N.

12. The compound according to claim 1 or 4, wherein L is -O-.

13. The compound according to claim 1 or 4, wherein L is selected from the group consisting of -N(H)-, -S(O)2-, -CH2-, and -C(O)-.

14. The compound according to claim 1 or 4, wherein A is selected from the group consisting of optionally substituted cyclohexyl, optionally substituted bicyclo[1.1.1]pentyl, optionally substituted bicyclo[2.2.2]octyl, optionally substituted piperidinyl, and optionally substituted phenyl.

15. A is, A compound according to claim 14, selected from the group consisting of the following.

16. R ａ teeth, The compound according to claim 15, or -COOH.

17. R ｂ The compound according to claim 1 or 4, wherein the compound is selected from -CN and -CF3.

18. The compound according to claim 1 or 4, wherein Z is -C(H)=.

19. below: A compound selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition comprising the compound according to claim 1 or 19 and a pharmaceutically acceptable adjuvant.

21. A pharmaceutical composition for treating cystic fibrosis in a subject, comprising the compound described in claim 1 or 19.

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