Novel substituted 2,3,4,9-tetrahydro-1H-pyrido[3,4-B]indolecarboxylic acid derivatives, their preparation process and their therapeutic use

Abstract

As used herein, a compound of formula (I), or a pharmaceutically acceptable salt thereof: [Case 1] TIFF2025528250000186.tif54170 (wherein R1 and R2 independently represent a hydrogen atom or a deuterium atom; R3 represents a hydrogen atom or a -COOH group; R3' represents a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom, a cyano group, or a -COOH group; R3" represents a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom, or a cyano group; provided that either R3 or R3' is R represents a -COOH group, but not both -COOH groups, and R and R' do not simultaneously represent a hydrogen atom; R represents a hydrogen atom or a fluorine atom; R and R' independently represent a hydrogen atom or a fluorine atom; Y represents -CH-, -CH=, -CR=, -O-, or -NH-; R represents a fluorine atom or a (C-C) alkyl group; represents a single bond or a double bond; p is 0 or 1; and X represents -CH=, -N= or -CR"=, where R" represents a (C1-C3) alkyl group or a halogen atom such as a fluorine atom or a chlorine atom, a cyano group, or a (C1-C3) fluoroalkyl group such as trifluoromethyl; R7 independently represent a (C1-C3) alkyl group such as a methyl group, a halogen atom such as a fluorine atom, a cyano group, or a (C1-C3) fluoroalkyl group such as trifluoromethyl; n is 0, 1, or 2; R6 represents an optionally substituted (C1-C9) alkyl group, and R8 particularly represents a (C1-C6) alkyl group). Further disclosed are processes for the preparation of compounds of formula (I), or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them, and the use of compounds of formula (I) as inhibitors and degraders of estrogen receptors, particularly for the treatment of ovulation failure, cancer, endometriosis, osteoporosis, prostate hyperplasia, or inflammation.

Description

[Technical Field]

[0001] Disclosed herein are novel substituted 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indolecarboxylic acids, processes for their preparation, and their therapeutic use, particularly as anti-cancer agents through selective antagonism and degradation of estrogen receptors. [Background technology]

[0002] Estrogen receptors (ERs) belong to the steroid / nuclear receptor superfamily, which are involved in the regulation of eukaryotic gene expression, cell growth, and differentiation in target tissues. ERs exist in two forms: estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ), encoded by the ESR1 and ESR2 genes, respectively. ERα and ERβ are ligand-activated transcription factors activated by the hormone estrogen (17β-estradiol is the most potent estrogen produced in the body). In the absence of hormone, ERs are located mostly in the cytosol of cells. When the hormone estrogen binds to ERs, they translocate from the cytosol to the nucleus, form dimers, and subsequently bind to specific genomic sequences called estrogen response elements (EREs). The DNA / ER complex interacts with coregulators to regulate the transcription of target genes.

[0003] ERα is mainly expressed in reproductive tissues such as the uterus, ovaries, breast, bone, and white adipose tissue. Aberrant ERα signaling leads to the development of various diseases, such as cancer, metabolic and cardiovascular diseases, neurodegenerative diseases, inflammatory diseases, and osteoporosis.

[0004] ERα is expressed in less than 10% of normal breast epithelium but in approximately 50–80% of breast tumors. Such breast tumors with high levels of ERα are classified as ERα-positive breast tumors. The pathogenetic role of estrogen in breast cancer is well established, and modulation of ERα signaling remains the mainstay of breast cancer treatment for the majority of ERα-positive breast tumors. Currently, several strategies exist to inhibit the estrogen system in breast cancer, including: 1) blocking estrogen synthesis with aromatase inhibitors, which are used to treat patients with early-stage and advanced ERα-positive breast cancer; 2) antagonizing estrogen ligand binding to ERα with tamoxifen, which is used to treat patients with ERα-positive breast cancer in both premenopausal and postmenopausal settings; and 3) antagonizing and downregulating ERα levels with fulvestrant, which is used to treat breast cancer in patients whose disease has progressed despite endocrine therapy, such as tamoxifen or aromatase inhibitors.

[0005] Although these endocrine therapies have significantly contributed to reducing breast cancer incidence, approximately one-third or more of ERα-positive patients exhibit de novo resistance or develop resistance to existing therapies over time. Several mechanisms have been described to explain resistance to such hormone therapy, such as the hypersensitivity of ERα to low estrogen levels during aromatase inhibitor treatment, the switch in tamoxifen effect from antagonist to agonist during tamoxifen treatment, or the involvement of multiple growth factor receptor signaling pathways. Acquired mutations in ERα that occur after the initiation of hormone therapy may also play a role in treatment failure and cancer progression. Certain mutations in ERα, particularly those identified in the ligand-binding domain (LBD), confer the ability to bind DNA in the absence of ligand, conferring hormone independence in cells harboring such mutant receptors.

[0006] Most of the identified endocrine therapy resistance mechanisms rely on ERα-dependent activity. One novel strategy to combat such resistance is to block ERα signaling by removing ERα from tumor cells using selective estrogen receptor degraders (SERDs). Clinical and preclinical data have shown that a significant number of resistance pathways can be circumvented by the use of SERDs.

[0007] There remains a need to provide SERDs with good decomposition efficacy.

[0008] Documents WO 2017 / 140669 and WO 2018 / 091153 disclose several substituted 6,7-dihydro-5H-benzo[7]annulene compounds and substituted N-(3-fluoropropyl)-pyrrolidine derivatives useful as SERDs. Summary of the Invention [Means for solving the problem]

[0009] We have now discovered novel compounds capable of selectively antagonizing and degrading estrogen receptors (SERD compounds) for use in cancer therapy.

[0010] A compound of formula (I) or a pharmaceutically acceptable salt thereof: [ka] (In the formula, R1 and R2 independently represent a hydrogen atom or a deuterium atom; R3 represents a hydrogen atom or a -COOH group; - R3' represents a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom, a cyano group, or a -COOH group; R3″ represents a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom, or a cyano group; provided that either R3 or R3' represents -COOH, but not both of them represent -COOH, and R3 and R3' do not simultaneously represent a hydrogen atom; R4 represents a hydrogen atom or a fluorine atom; R5 and R5' independently represent a hydrogen atom or a fluorine atom; - Y represents -CH2-, -CH=, -CR9=, -O- or -NH-, where R9 represents a fluorine atom or a (C1-C3)alkyl group; - [ka] represents a single or double bond; - p is 0 or 1; - X represents -CH=, -N= or -CR"=, where R" represents a (C1-C3) alkyl group or a halogen atom, such as a fluorine atom or a chlorine atom, a cyano group, or a (C1-C3) fluoroalkyl group, such as trifluoromethyl; R7 independently represents a (C1-C3) alkyl group such as a methyl group, a halogen atom such as a fluorine atom, a cyano group, or a (C1-C3) fluoroalkyl group such as trifluoromethyl; - n is 0, 1 or 2; and R6 represents a (C1-C9) alkyl group, and the (C1-C9) alkyl group is selected from the group consisting of a halogen atom, a -cyano group, an -OR a group, -N(R a )2 groups, (C1-C9) alkyl groups, (C1-C9) alkoxy groups, (C1-C3) fluoroalkoxy groups, (C3-C9) cycloalkyl groups, (C3-C9) heterocyclic groups, (C6-C9) aryl groups, (C5-C 10 ) heteroaryl group, —C(O)R b group, -C(O)NR a group, -SO2CH3 group, and SO2NR a optionally substituted with 1 to 4 substituents independently selected from the group; -R arepresents a hydrogen atom, a (C1-C6) alkyl group, a (C2-C8) alkenyl group, a propargyl group, a (C3-C6) cycloalkyl group, or a (C3-C7) heterocycloalkyl group; and represents a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a cyano group, optionally substituted with one or more substituents independently selected from -OH groups, methoxy groups, and -SO2CH3 groups; -R b represents a hydrogen atom, an —O((C1-C3)alkyl) group, a (C1-C6)alkyl group, a (C2-C8)alkenyl group, a propargyl group, a —((C2-C6)alkene)-((C3-C6)cycloalkyl) group, a (C3-C6)cycloalkyl group, and a (C3-C7)heterocycloalkyl group, optionally substituted with one or more substituents independently selected from a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a cyano group, a —CH2F group, a —CHF2 group, a —CF3 group, a —CH2CF3 group, a —CH2CF2 group, a —CH2CH2F group, a —OH group, a methoxy group, and a —SO2CH3 group; and - R8 is a hydrogen atom, cyano group, (C1-C6) alkyl group, -CH2OH group, -CH2OCH3 group, -CH2CH2OH group, -C(CH3)2OH group, -CH(OH)CH(CH3)2 group, -C(CH3)2CH2OH group, -CH2CH2SO2CH3 group, -CH2OP(O)(OH)2 group, -CH2F group, -CHF 2 groups, -CH2NH2, -CH2NHSO2CH3 group, -CH2NHCH3 group, -CH2N(CH3)2 group, -CF3 group, -CH2CF3 group, -CH2CF2 group, -CH(CH3)CN group, -C(CH3)2CN group, -CH2CN group, -CO2H group, -COCH3 group, -CO2CH3 group, -CO2C(CH3)3 group, - Disclosed are compounds which represent a COCH(OH)CH group, a -CONH group, a -CONHCH group, a -CONHCHCH group, a -CONHCH(CH) group, a -CON(CH) group, a -C(CH)CONH group, a cyclopropyl group, a cyclopropylamido group, a cyclobutyl group, an oxetanyl group, an azetidinyl group, a 1-methylazetidin-3-yloxy group, an N-methyl-N-oxetan-3-ylamino group, an azetidin-1-ylmethyl group, a benzyloxyphenyl group, a pyrrolidin-1-yl group, a pyrrolidin-1-ylmethanone group, a piperazin-1-yl group, a morpholinomethyl group, a morpholinomethanone group, or a morpholino group.

[0011] As used herein, a compound of formula (I), or a pharmaceutically acceptable salt thereof: [ka] (In the formula, R1 and R2 independently represent a hydrogen atom or a deuterium atom; R3 represents a hydrogen atom or a -COOH group; - R3' represents a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom, a cyano group, or a -COOH group; R3″ represents a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom, or a cyano group; provided that either R3 or R3' represents -COOH, but not both of them represent -COOH, and R3 and R3' do not simultaneously represent a hydrogen atom; R4 represents a hydrogen atom or a fluorine atom; R5 and R5' independently represent a hydrogen atom or a fluorine atom; - Y represents -CH2-, -CH=, -CR9=, -O- or -NH-, where R9 represents a fluorine atom or a (C1-C3)alkyl group; - [ka] represents a single or double bond; - p is 0 or 1; - X represents -CH=, -N= or -CR"=, where R" represents a (C1-C3) alkyl group or a halogen atom, such as a fluorine atom or a chlorine atom, a cyano group, or a (C1-C3) fluoroalkyl group, such as trifluoromethyl; R7 independently represents a (C1-C3) alkyl group such as a methyl group, a halogen atom such as a fluorine atom, a cyano group, or a (C1-C3) fluoroalkyl group such as trifluoromethyl; - n is 0, 1 or 2; and R6 represents a (C1-C9) alkyl group, and the (C1-C9) alkyl group is selected from the group consisting of a halogen atom, a -cyano group, an -OR a group, -N(R a )2 groups, (C1-C9) alkyl groups, (C1-C9) alkoxy groups, (C1-C3) fluoroalkoxy groups, (C3-C9) cycloalkyl groups, (C3-C9) heterocyclic groups, (C6-C9) aryl groups, (C5-C 10 ) heteroaryl group, —C(O)R b group, -C(O)NR a group, -SO2CH3 group, and SO2NR a optionally substituted with 1 to 4 substituents independently selected from the group; -R a represents a hydrogen atom, a (C1-C6) alkyl group, a (C2-C8) alkenyl group, a propargyl group, a (C3-C6) cycloalkyl group, or a (C3-C7) heterocycloalkyl group; and represents a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a cyano group, optionally substituted with one or more substituents independently selected from -OH groups, methoxy groups, and -SO2CH3 groups; -R b represents a hydrogen atom, an —O((C1-C3)alkyl) group, a (C1-C6)alkyl group, a (C2-C8)alkenyl group, a propargyl group, a —((C2-C6)alkene)-((C3-C6)cycloalkyl) group, a (C3-C6)cycloalkyl group, and a (C3-C7)heterocycloalkyl group, optionally substituted with one or more substituents independently selected from a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a cyano group, a —CH2F group, a —CHF2 group, a —CF3 group, a —CH2CF3 group, a —CH2CF2 group, a —CH2CH2F group, a —OH group, a methoxy group, and a —SO2CH3 group; and - R8 is a hydrogen atom, cyano group, (C1-C6) alkyl group, -CH2OH group, -CH2OCH3 group, -CH2CH2OH group, -C(CH3)2OH group, -CH(OH)CH(CH3)2 group, -C(CH3)2CH2OH group, -CH2CH2SO2CH3 group, -CH2OP(O)(OH)2 group, -CH2F group, -C HF2 group, -CH2NH2, -CH2NHSO2CH3 group, -CH2NHCH3 group, -CH2N(CH3)2 group, -CF3 group, -CH2CF3 group, -CH2CF2 group, -CH(CH3)CN group, -C(CH3)2CN group, -CH2CN group, -CO2H group, -COCH3 group, -CO2CH3 group, -CO2C(CH3) a -COCH(OH)CH group, a -CONH group, a -CONHCH group, a -CONHCH2CH3 group, a -CONHCH(CH3)2 group, a -CON(CH3)2 group, a -C(CH3)2CONH2 group, a cyclopropyl group, a cyclopropylamido group, a cyclobutyl group, an oxetanyl group, an azetidinyl group, a 1-methylazetidin-3-yl)oxy group, an N-methyl-N-oxetan-3-ylamino group, an azetidin-1-ylmethyl group, a benzyloxyphenyl group, a pyrrolidin-1-yl group, a pyrrolidin-1-ylmethanone group, a piperazin-1-yl group, a morpholinomethyl group, a morpholinomethanone group, or a morpholino group; with the proviso that when p is 1, X is CH; Y is CH; R is COOH; R, R, R, R, R, R and R are H; R is F; n is 2; R is CH; and R does not represent a 2,2-difluoropropyl group, - when p is 0, X is CH; Y is NH; R3 is COOH; R1, R2, R3', R3'', R4, R5 and R5' are H; R7 is F; n is 2; R8 is CH3; and R6 does not represent a 2,2-difluoro-3-hydroxypropyl group).

[0012] The compounds of formula (I) may contain one or more asymmetric carbon atoms and therefore may exist in enantiomeric forms.

[0013] The compounds of formula (I) may also exist in tautomeric forms.

[0014] The compounds of formula (I) can exist in the form of bases, acids, zwitterions, or addition salts with acids or bases. Accordingly, there is provided herein a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0015] These salts may be prepared using pharmaceutically acceptable acids or bases, although other acid or base salts useful, for example, for purifying or isolating compounds of formula (I) are also provided.

[0016] Among the suitable salts of the compounds of formula (I), mention may be made of the hydrochloride salt. DETAILED DESCRIPTION OF THE INVENTION

[0017] As used herein, the following terms have the following definitions unless stated otherwise throughout the specification. halogen atoms: fluorine, chlorine, bromine or iodine atoms, in particular fluorine and chlorine atoms; - alkyl group: a linear or branched saturated hydrocarbon-based aliphatic group containing 1 to 9 carbons (written as "(C1-C9) alkyl") unless otherwise specified. Examples may include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl and isohexyl groups; - alkene group: a linear or branched, unsaturated or partially unsaturated aliphatic group containing conjugated or non-conjugated double bonds, containing 2 to 6 carbon atoms unless otherwise specified; - cycloalkyl group: unless otherwise specified, a saturated or partially unsaturated, unsubstituted or substituted monocyclic alkyl group containing 3 to 9 carbon atoms; - heterocyclic group: a 3-, 4-, 5-, 6-, 7-, 8-, or 9-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S, wherein the ring is saturated or unsaturated but not aromatic. A 3- or 4-membered ring may contain one heteroatom selected from the group consisting of O, N, and S. A 5-membered ring may contain zero or one double bond and one, two, or three heteroatoms selected from the group consisting of O, N, and S. A 6-, 7-, 8-, or 9-membered ring may contain zero, one, or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S; heterocycloalkyl groups: saturated or partially unsaturated 3- to 7-membered cycloalkyl groups containing 1 to 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, in particular oxygen or nitrogen; - Fluoroalkyl group: the alkyl group as defined above, in which the alkyl group is substituted with at least one fluorine atom. In other words, at least one hydrogen atom of the alkyl group is replaced with a fluorine atom. Examples include -CH2F, -CHF2, -CH2CHF2, -CH2CH2F, etc. When all hydrogen atoms belonging to the alkyl group are substituted with fluorine atoms, the fluoroalkyl group can be called a perfluoroalkyl group. Examples include a trifluoromethyl group or a trifluoroethyl group; - alkoxy group: -O-alkyl group, wherein the alkyl group is as defined above. Examples that may be mentioned, but are not limited to, are: methoxy, ethoxy, propoxy, isopropoxy, linear, secondary or tertiary butoxy, isobutoxy, pentoxy or hexoxy groups, etc.; - Fluoroalkoxy group: -O-alkyl group, where the alkyl group is as defined above and the alkyl group is substituted with at least one fluorine atom. In other words, at least one hydrogen atom of the alkyl group is substituted with a fluorine atom. Examples include -OCH2F, -OCHF2, -OCH2CH2F, etc. When all hydrogen atoms belonging to the alkyl group are substituted with fluorine atoms, the fluoroalkoxy group can be named a perfluoroalkoxy group. Examples include trifluoromethoxy group, etc.; - aryl group: a monocyclic or bicyclic aromatic group containing 6 or 9 carbon atoms; Heteroaryl group: a cyclic 5-10 membered aromatic group containing 2-9 carbon atoms and 1-3 heteroatoms such as nitrogen, oxygen or sulfur. Such nitrogen atoms may be substituted with oxygen atoms to form -NO bonds. Such -NO bonds can be converted into N-oxides (-N + -O - ) may be in the form of; - Zwitterion refers to an overall neutral molecule that has positive and negative charges and has acidic and basic groups.

[0018] In another embodiment, in the compounds of formula (I) as defined above, R3 represents a -COOH group. In another embodiment, in the compounds of formula (I) as defined above, R3' is a -COOH group. Thus, herein, compounds of formula (II) and (III): [ka] (In the formula, R1, R2, R3, R3', R3'', R4, R5, R5', R6, R7, R8, [ka] , Y, n and p are as defined in formula (I) above).

[0019] In another embodiment, the compound of formula (I) as defined above is a compound of formula (II).

[0020] In another embodiment, in the compounds of formula (I) or (II) as defined above, R3' and R3" both represent a hydrogen atom.

[0021] In another embodiment, in the compounds of formula (I) as defined above, R3 represents a -COOH group, and R3' and R3" both represent a hydrogen atom.

[0022] In another embodiment, in the compounds of formula (I) as defined above, R3' represents a -COOH group, and R' and R3'' both represent a hydrogen atom.

[0023] In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, R 1 and R 2 are hydrogen atoms.

[0024] In another embodiment, in a compound of formula (I), (II) or (III) as defined above, R4 represents a hydrogen atom.

[0025] In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, R5 and R5' represent a hydrogen atom.

[0026] In another embodiment, in a compound of formula (I), (II) or (III) as defined above, p is 0. In another embodiment, in a compound of formula (I) as defined above, p is 1.

[0027] In another embodiment, in the compounds of formula (I), (II) or (II) as defined above, X represents -CR"=, wherein R" represents a halogen atom, preferably a fluorine atom.

[0028] In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, X represents -CH=.

[0029] In another embodiment, in the compound of (I), (II) or (III) as defined above, R6 represents a (C1-C6) alkyl group, said (C1-C6) alkyl group being optionally substituted with 1 to 3 substituents independently selected from a fluorine atom, a methyl group and an —OH group.

[0030] In another embodiment, in the compounds of formula (I), (II) or (II) as defined above, R6 represents a -CH2-CF3 group, a -CH2-CF2-CH2-OH group or a -CH2-CF2-CH3 group.

[0031] In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, R7 is a halogen atom, preferably a fluorine atom.

[0032] In another embodiment, in a compound of formula (I), (II) or (III) as defined above, n is 0. In another embodiment, in a compound of formula (I), (II) or (III) as defined above, n is 1. In another embodiment, in a compound of formula (I), (II) or (III) as defined above, n is 2.

[0033] In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, R7 represents a fluorine atom and n is 1 or 2.

[0034] In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, R8 represents a (C1-C6) alkyl group, preferably a methyl group.

[0035] In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, Y represents -CH2-, -CH=, -O- or -NH-.

[0036] In another embodiment, in a compound of formula (I), (II) or (III) as defined above, Y represents -CH. In another embodiment, in a compound of formula (I), (II) or (III) as defined above, Y represents -CH=. In another embodiment, in a compound of formula (I), (II) or (III) as defined above, Y represents -O-. In another embodiment, in a compound of formula (I), (II) or (III) as defined above, Y represents -NH-.

[0037] In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, [ka] represents a single bond. [ka] represents a double bond.

[0038] In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, p is equal to 1.

[0039] Among the compounds of formula (I), (II) or (III) described herein, mention may be made in particular of the following compounds or their pharmaceutically acceptable salts, in particular their hydrochlorides: (1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid, (1) (1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid, (2) (1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid, (3) (1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid, (4) (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid, (5) (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid, (6) (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid, (7) (1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid, (8) (1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid, (9) (1R,3R)-1-(2,6-difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid, (10) (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid, (11) (1S,3S)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid, (12) (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-carboxylic acid, (13) (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid, (14) (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid, (15).

[0040] Another embodiment is a compound selected from the list above, or a pharmaceutically acceptable salt thereof, for use in therapy, particularly as an inhibitor and degrader of the estrogen receptor.

[0041] Another embodiment is a compound selected from the list above, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, in particular breast cancer.

[0042] Another embodiment is a method of inhibiting and degrading estrogen receptors, comprising administering to a subject, particularly a human, in need thereof a therapeutically effective amount of a compound selected from the list above, or a pharmaceutically acceptable salt thereof.

[0043] Another embodiment is a method of treating ovulatory dysfunction, cancer, endometriosis, osteoporosis, prostatic hyperplasia or inflammation, comprising administering to a subject, particularly a human, in need thereof a therapeutically effective amount of a compound selected from the list above, or a pharmaceutically acceptable salt thereof.

[0044] Another embodiment is a method of treating cancer, comprising administering to a subject, particularly a human, in need thereof a therapeutically effective amount of a compound selected from the list above, or a pharmaceutically acceptable salt thereof.

[0045] Another embodiment is a pharmaceutical composition comprising an active ingredient, an effective dose of a compound selected from the list above, or a pharmaceutically acceptable salt thereof, and also at least one pharmaceutically acceptable excipient.

[0046] The compounds of formula (I), (II) or (III) may be prepared by the following process.

[0047] Compounds of formula (I), (II), or (III) and other related compounds having different substituents are synthesized using the techniques and materials described below, or using methods and materials otherwise known to those skilled in the art. In addition, the solvents, temperatures, and other reaction conditions presented below may be varied as deemed appropriate by those skilled in the art.

[0048] The following general methods for preparing compounds of formula (I), (II) or (III), optionally modified by the use of appropriate reagents and conditions for the introduction of the various moieties found in formula (I), (II) or (III) as described below.

[0049] The following abbreviations and empirical formulas are used: AcOH acetic acid MeCN acetonitrile NH4HCO3 Ammonium Acetate NH4OAc Ammonium Bicarbonate NH4Cl Ammonium chloride BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) NiCl2.dtbbpy [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine]nickel(II) dichloride n-BuLi n-butyllithium CO Carbon monoxide CO2 Carbon dioxide Cs2CO3 Cesium Carbonate CuCl Copper chloride DCM dichloromethane SPhos 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl DIPEA Diisopropylethylamine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide EtOAc ethyl acetate HPLC High Performance Liquid Chromatography H2 Hydrogen HCl Hydrochloric acid Withdrawal from LG Group LiOH Lithium hydroxide MeOH Methanol MgSO4 Magnesium Sulfate MeMgCl Methylmagnesium chloride Pd / C Palladium Carbon Pd(OH)2 palladium hydroxide POCl3 Phosphorus oxychloride PtO2 platinum oxide K2CO3 Potassium Carbonate K3PO4 Potassium Phosphate LG leaving group NaHCO3 Sodium bicarbonate NaCl Sodium chloride NaBH3CN Sodium cyanoborohydride Na2SO4 Sodium Sulfate NaOH Sodium hydroxide SFC Supercritical Fluid Chromatography tBuBrettPhos Dimethoxy-2',4',6'-tris(1-methylethyl)[1,1'-biphenyl]-2-yl]bis(1,1-dimethylethyl)phosphine tBuBrettPd G3 [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate TBAF Tetra-n-butylammonium fluoride TMAD Tetramethylazodicarboxamide TEA Triethylamine TFA trifluoroacetic acid THF tetrahydrofuran PPh3 Triphenylphosphine RT room temperature

[0050] Scheme 1a Parts 1 and 2: Preparation of Compounds of Formula (II) - General Process [ka] [ka] Scheme 1a - Part 1 and Part 2 (R3a is a carboxylic acid ester such as -COOMe or -COOEt, and R1, R2, R3, R3', R3'', R4, R5, R5', R6, R7, R8, n, p, X, Y and [ka] is defined above), compound 1A can be converted to compound 1C in step 1 by treating it with compound 1B in the presence of methylmagnesium chloride (MeMgCl) and copper chloride (CuCl).

[0051] In step 2, compound 1C can be converted to compound 1D by carbonylation with carbon monoxide (OH) in MeOH or EtOH solution in the presence of a palladium catalyst, such as palladium acetate or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) complexed with DCM.

[0052] Compound 1D can be converted to compound 1E in step 3 by treatment with TFA or HCl or chlorotrimethylsilane.

[0053] Compound 1E can be converted to compound 1G in step 4 by treatment with compound 1F (R6-LG), where LG is a suitable leaving group, for example, a halogen atom such as iodo, bromo, or chloro or trifluoromethanesulfonate, in the presence of a suitable base, such as diisopropylethylamine (DIPEA), in a suitable solvent, such as DMF.

[0054] Compound 1G can be converted to compound 1J in step 5 by treating it with compound 1H in a Pictet-Spengler cyclization reaction in a suitable solvent, such as toluene, in the presence of an acid such as TFA or acetic acid, by heating the solvent to reflux.

[0055] Alternatively, in step 6, compound 1G can be treated with compound 1K in a Pictet-Spengler cyclization reaction in a suitable solvent, for example toluene, in the presence of an acid such as TFA or acetic acid by heating to reflux of the solvent, followed by a coupling reaction between the resulting compound 1L and one of compounds 1M under coupling reaction conditions in step 7 to give compound 1J.

[0056] Compound 1J can be converted to compound II in step 8 by treatment with an aqueous solution of sodium hydroxide (NaOH) or lithium hydroxide (LiOH) in MeOH or THF. Extraction of the product can provide the sodium or lithium salt of compound II. Acidification with aqueous HCl to pH 6-7 can provide the neutral form of compound II. Acidification with aqueous HCl to pH 1-2 can provide the hydrochloride salt of compound II. Purification of the eluate using HPLC in the presence of formic acid or trifluoroacetic acid can provide the formate or trifluoroacetate salt of compound II.

[0057] In the case of Y=CH=, compound II can be reduced by hydrogenation in step 9 over a catalyst such as Pd / C or platinum oxide (PtO) under hydrogen (H) pressure to give the corresponding saturated compound II'.

[0058] Alternatively, when Y=CH=, compound II' can be prepared in step 10 by hydrogenation of compound 1J over a catalyst such as Pd / C or platinum oxide (PtO) under hydrogen (H) pressure, followed by treatment with aqueous NaOH or LiOH in MeOH or THF. Extraction of the product can provide the sodium or lithium salt of compound II'. Acidification with aqueous HCl to pH 6-7 can provide the neutral form of compound II'. Acidification with aqueous HCl to pH 1-2 can provide the hydrochloride salt of compound II'. Purification of the eluate using HPLC in the presence of formic acid or trifluoroacetic acid can provide the formate or trifluoroacetate salt of compound II'.

[0059] Scheme 1b: Alternative process for preparing intermediate 1J [ka] Scheme 1b (R3a is a carboxylic acid ester such as -COOMe or -COOEt, and R1, R2, R3', R3'', R4, R5, R5', R6, R7, R8, n, p, X, Y and [ka] According to the above formula (wherein 1G is defined as above), compound 1G can be converted to compound 1N in step 1 by treating it with compound 1H' in a Pictet-Spengler cyclization reaction in a suitable solvent, for example toluene, in the presence of an acid such as TFA or acetic acid, by heating the solvent to reflux.

[0060] Alternatively, in step 2, compound 1L can be treated with one of compounds 1M' under coupling reaction conditions to give compound 1N in a coupling reaction.

[0061] Compound 1N can be converted to compound 1O in step 3 by treatment with TFA or HCl.

[0062] Compound 1O can be converted to compound 1J in step 4 by treatment with compound 1P in the presence of a base such as potassium carbonate (K2CO3) in DMF as a solvent, where W is Cl, Br, or I, or OSO2R (R = CH3, PhMe, CF3, or CF2CF2CF2CF3).

[0063] Scheme 1c: Alternative process for preparing intermediate 1E [ka] According to Scheme 1c (R3a is a carboxylic acid ester such as -COOMe or -COOEt, R8 is a methyl group, and R3' and R3'' are defined as above), compound 1Q can be converted to compound 1R in Step 1 under Vilsmeier-Haack reaction conditions in the presence of POCl3 and DMF.

[0064] Compound 1R can be converted to compound 1S in step 2 by treatment with nitroethane in the presence of ammonium acetate.

[0065] Compound 1S can be converted to compound 1T in step 3 by treatment with iron in the presence of an acid such as HCl.

[0066] Compound 1T can be converted to compound 1V in a reductive amination reaction in step 4 by treatment with compound 1U in the presence of NaBH3CN and acetic acid.

[0067] Compound 1E can be obtained in step 5 by hydrogenating compound 1V in the presence of a catalyst such as Pd / C or Pd(OH) 2 .

[0068] Scheme 1d Part 1 and Part 2: General process for preparing compounds of formula (III) [ka] [ka] Scheme 1d - Part 1 and Part 2 (R3a' is a carboxylic acid ester such as -COOMe or -COOEt, R8 is a methyl group, and R1, R2, R3, R3', R3'', R4, R5, R5', R6, R7, n, p, X, Y and [ka] According to the above formula (where 1W is defined as above), compound 1W can be converted to compound 1X in step 1 under Vilsmeier-Haack reaction conditions in the presence of POCl3 and DMF.

[0069] Compound 1X can be converted to compound 1Y in step 2 by treatment with nitroethane in the presence of ammonium acetate (NH4OAc).

[0070] Compound 1Y can be converted to compound 1Z in step 3 by treatment with iron (Fe) in the presence of an acid such as HCl.

[0071] Compound 1Z can be converted to compound 1Aa in a reductive amination reaction in step 4 by treating with compound 1U in the presence of NaBH3CN and acetic acid.

[0072] Compound 1Ab can be obtained in step 5 by hydrogenating compound 1Aa in the presence of a catalyst such as Pd / C or Pd(OH) 2 .

[0073] Compound 1Ab can be converted to compound 1Ac in step 6 by treatment with compound 1F (R6-LG), where LG is a suitable leaving group, for example, a halogen atom such as iodo, bromo, or chloro or trifluoromethanesulfonate, in the presence of a suitable base, such as diisopropylethylamine (DIPEA), in a suitable solvent, such as DMF.

[0074] According to Scheme 1d-part 2, compound 1Ac can be converted to compound 1Ae in step 7 by treating it with compound 1H in a Pictet-Spengler cyclization reaction in a suitable solvent, e.g., toluene, in the presence of an acid such as TFA or acetic acid, by heating the solvent to reflux.

[0075] Alternatively, in step 8, compound 1Ac can be treated with compound 1K in a Pictet-Spengler cyclization reaction in a suitable solvent, such as toluene, in the presence of an acid such as TFA or acetic acid by heating to reflux, followed by a coupling reaction between the resulting compound 1Ad and one of compounds 1M under coupling reaction conditions in step 9 to give compound 1Ae.

[0076] Compound 1Ae can be converted to compound III in step 10 by treatment with an aqueous solution of sodium hydroxide (NaOH) or lithium hydroxide (LiOH) in MeOH or THF. Extraction of the product can provide the sodium or lithium salt of compound III. Acidification with aqueous HCl to pH 6-7 can provide the neutral form of compound III. Acidification with aqueous HCl to pH 1-2 can provide the hydrochloride salt of compound III. Purification of the eluate using HPLC in the presence of formic acid or trifluoroacetic acid can provide the formate or trifluoroacetate salt of compound III.

[0077] In the case of Y=CH=, compound III can be reduced by hydrogenation in step 11 over a catalyst such as Pd / C or platinum oxide (PtO) under hydrogen (H) pressure to give the corresponding saturated compound III'.

[0078] Alternatively, when Y=CH=, compound III' can be prepared in step 12 by hydrogenation of compound 1Ae with a catalyst such as Pd / C or platinum oxide (PtO) under hydrogen (H) pressure, followed by treatment with aqueous NaOH or LiOH in MeOH or THF. Extraction of the product can provide the sodium or lithium salt of compound III'. Acidification with aqueous HCl to pH 6-7 can provide the neutral form of compound III'. Acidification with aqueous HCl to pH 1-2 can provide the hydrochloride salt of compound III'. Purification of the eluate using HPLC in the presence of formic acid or trifluoroacetic acid can provide the formate or trifluoroacetate salt of compound III'.

[0079] Scheme 1e: Alternative process for preparing intermediate 1Ae [ka] Scheme 1e (R3a is a carboxylic acid ester such as -COOMe or -COOEt, and R1, R2, R3, R3'', R4, R5, R5', R6, R7, R8, n, p, X, Y and [ka] According to the above formula (wherein 1Ac is defined as above), compound 1Ac can be converted to compound 1Af in step 1 by treating it with compound 1H' in a Pictet-Spengler cyclization reaction in a suitable solvent, for example toluene, in the presence of an acid such as TFA or acetic acid by heating the solvent to reflux.

[0080] Alternatively, in step 2, compound 1Ad can be treated with one of compounds 1M' under coupling reaction conditions to provide compound 1Af in a coupling reaction.

[0081] Compound 1Af can be converted to compound 1Ag in step 3 by treatment with TFA or HCl.

[0082] Compound 1Ag can be converted to compound 1Ae in step 4 by treatment with compound 1P in the presence of a base such as potassium carbonate (K2CO3) in DMF as a solvent, where W is Cl, Br, or I, or OSO2R (R = CH3, PhMe, CF3, or CF2CF2CF2CF3).

[0083] Also provided herein is a process for preparing a compound of formula (II) as defined above, wherein a compound of formula 1J: [ka] (In the formula, R1, R2, R3', R3'', R4, R5, R5', R6, R7, R8, [ka] wherein n, p, X and Y are as defined above and R3a is a carboxylic acid ester such as -COOMe or -COOEt) is converted to a compound of formula (II) in the presence of a hydroxide ion source such as NaOH or LiOH in methanol or THF solution, said step being optionally preceded by a step to obtain compound 1J, wherein compound 1L: [ka] wherein R, R, R, R, R, n, and X are defined as above, and R is a carboxylic acid ester such as -COOMe or -COOEt, can be converted under coupling reaction conditions to compound 1M: [ka] wherein R1, R2, R4, R5, R5' and p are as defined above.

[0084] Also provided herein is a process for preparing a compound of formula (II) as defined above, wherein a compound of formula 1J: [ka] (In the formula, R1, R2, R3', R3'', R4, R5, R5', R6, R7, R8, [ka] , n, p, X and Y are defined as above and R3a is a carboxylic acid ester such as -COOMe or -COOEt) is converted to a compound of formula (II) in the presence of a hydroxide ion source such as NaOH or LiOH in methanol or THF solution, said step being optionally preceded by a step to obtain a compound of formula 1J, wherein a compound of formula 1G: [ka] wherein R, R, R, and R are defined as above, and R is a carboxylic acid ester such as -COOMe or -COOEt, can be converted to compound 1H: [ka] (In the formula, R1, R2, R4, R5, R5', R7, X, Y, [ka] , n and p are as defined above).

[0085] Also provided herein is a process for preparing a compound of formula (II) as defined above, wherein a compound of formula 1J: [ka] (In the formula, R1, R2, R3', R3'', R4, R5, R5', R6, R7, R8, [ka] , n, p, X and Y are defined as above and R3a is a carboxylic acid ester such as -COOMe or -COOEt) is converted to a compound of formula (II) in the presence of a hydroxide ion source such as NaOH or LiOH in methanol or THF solution, said step being optionally preceded by a step to obtain compound 1J, wherein compound 1O is [ka] (In the formula, R3', R3'', R6, R7, R8, [ka] , n, p, X and Y are defined as above, and R3a is a sodium carboxylate such as -COOMe or -COOEt, in the presence of a base such as potassium carbonate (K2CO3) in DMF as a solvent, to give compound 1P: [ka] where W is Cl, Br, or I, or OSO2R (R = CH3, PhMe, CF3, or CF2CF2CF2CF3), and R1, R2, R4, R5, and R5' are as defined above, to give compound 1J.

[0086] Also provided herein is an intermediate compound selected from any of the compounds of formula 1J, 1L, 1N, 1O, or a pharmaceutically acceptable salt thereof. [ka] [ka] (In the formula, R1, R2, R3, R3', R3'', R4, R5, R5', R6, R7, R8, n, p, [ka] , X and Y are defined above, and R3a is a hydrogen atom or a carboxylic acid ester such as -COOMe or -COOEt).

[0087] Also provided herein is a process for preparing a compound of formula (III) as defined above, wherein the compound of formula 1Ae: [ka] (In the formula, R1, R2, R3, R3'', R4, R5, R5', R6, R7, R8, [ka] wherein n, p, X and Y are as defined above and R3a is a carboxylic acid ester such as -COOMe or -COOEt) is converted to a compound of formula (III) in the presence of a hydroxide ion source such as NaOH or LiOH in methanol or THF solution, said step being optionally preceded by a step to obtain a compound 1Ae, wherein a compound of formula 1Ad: [ka] wherein R, R′, R, R, R, n, and X are defined as above, and R is a carboxylic acid ester such as —COOMe or —COOEt, can be converted under coupling reaction conditions to compound 1M: [ka] wherein R1, R2, R4, R5, R5' and p are as defined above.

[0088] Also provided herein is a process for preparing a compound of formula (III) as defined above, wherein the compound of formula 1Ae: [ka] (In the formula, R1, R2, R3, R3'', R4, R5, R5', R6, R7, R8, [ka] , n, p, X and Y are defined as above, and R3a' is a carboxylic acid ester such as -COOMe or -COOEt) is converted to a compound of formula (III) in the presence of a hydroxide ion source such as NaOH or LiOH in methanol or THF solution, said step being optionally preceded by a step to obtain a compound 1Ae, wherein a compound of formula 1Ac: [ka] wherein R, R'', R and R are defined as above, and R is a carboxylic acid ester such as -COOMe or -COOEt, can be converted to compound 1H: [ka] (In the formula, R1, R2, R4, R5, R5', R7, X, Y, [ka] , n and p are as defined above).

[0089] Also provided herein is an intermediate compound selected from any of the compounds of formula 1Ae, or a pharmaceutically acceptable salt thereof. [ka] (Wherein R3a is a carboxylic acid ester such as -COOMe or -COOEt, and R1, R2, R3, R3″, R4, R5, R5′, R6, R7, R8, n, p, [ka] , X and Y are defined above).

[0090] In another aspect, there is also provided herein a process for the preparation of a compound of formula (I), comprising a deprotection step of a compound of formula 1J as defined above, followed optionally by a purification step.

[0091] In another aspect, there is also provided herein a process for the preparation of a compound of formula (III), comprising a deprotection step of a compound of formula 1Ae as defined above, followed optionally by a purification step.

[0092] Said purification step may consist of an acidification step, for example with an aqueous solution of hydrochloric acid, as shown, for example, in step 2 of Example 1 hereinafter.

[0093] 400 and 500MHz 1 H NMR spectra were performed on a Bruker Avance DRX-400 and a Bruker Avance DPX-500 spectrometer, respectively, with chemical shifts (δ in ppm) in the solvent dimethylsulfoxide-d6 (d6-DMSO) referenced at 2.5 ppm at a temperature of 303 K. Coupling constants (J) are given in Hertz.

[0094] Liquid chromatography / mass spectra (LC / MS) were obtained on a UPLC Acquity Waters instrument using UV detection DAD 210-400 nm and flash Acquity UPLC CSH C18 1.7 μm, dimensions 2.1x30 mm, mobile phase H2O+0.1% HC02H / CH3CN+0.1% HC02H, light scattering detector Sedere and SQD Waters mass spectrometer.

[0095] Tables 1a and 1b below respectively list specific compounds (names and structures) of formula (I) according to the present disclosure along with their characteristics ( 1 1 H NMR and liquid chromatography / mass).

[0096] [Table 1]

[0097] [Table 2]

[0098] [Table 3]

[0099] [Table 4]

[0100] [Table 5]

[0101] [Table 6]

[0102] [Table 7]

[0103] [Table 8]

[0104] The following examples describe the preparation of some compounds of formula (I), (II), and (III) described herein. The number of compounds exemplified below corresponds to those given in Tables 1a and 1b above. All reactions are carried out under an inert atmosphere unless otherwise specified.

[0105] In the following examples, unless the source of a starting product is specified, it is to be understood that said product is a known compound. [Example]

[0106] Intermediates: Intermediate 1a: Methyl (R)-3-(2-aminopropyl)-1H-indole-6-carboxylate, hydrochloride [ka] Step 1: tert-Butyl (R)-(1-(6-bromo-1H-indol-3-yl)propan-2-yl)carbamate [ka] To a suspension of 6-bromoindole (10 g, 49.5 mmol) and CuCl (4.29 g, 42.9 mmol) in DCM (120 ml) at 0°C, MeMgCl 3M in THF (14.3 ml, 42.9 mmol) was added dropwise. The reaction mixture was stirred at 0°C for 1 hour and then cooled to -20°C. A solution of (R)-4-methyl-2,2-dioxo-1,2,3-oxathiazolidine-3-carboxylic acid tert-butyl ester (7.83 g, 33.0 mmol) in DCM (50 ml) was added dropwise to the reaction mixture at -20°C. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours, then cooled to 0°C, and 2 M aqueous citric acid (330 ml) was carefully added. The mixture was allowed to warm to room temperature, stirred for 10 minutes, and then filtered through a pad of Celite. After decantation of the filtrate, the organic phase was washed with brine (50 ml), dried over MgSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with DCM to give 7.34 g (63%) of tert-butyl (R)-(1-(6-bromo-1H-indol-3-yl)propan-2-yl)carbamate. LC / MS(m / z, MH+):353.

[0107] Step 2: Methyl (R)-3-(2-((tert-butoxycarbonyl)amino)propyl)-1H-indole-6-carboxylate [ka] A mixture of tert-butyl (R)-(1-(6-bromo-1H-indol-3-yl)propan-2-yl)carbamate (2 g, 5.66 mmol), TEA (2.36 mL, 17.0 mmol, 3 equiv.), and a complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (0.92 g, 1.13 mmol) in methanol (40 mL) was heated at 100°C under a CO atmosphere (5 bar) for 18 h. The reaction mixture was cooled to room temperature and then filtered through a pad of Celite. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with a gradient of 100 / 00 to 98 / 02 DCM / MeOH to afford 1.85 g (98%) of methyl (R)-3-(2-((tert-butoxycarbonyl)amino)propyl)-1H-indole-6-carboxylate. LC / MS(m / z, MH+): 333

[0108] Step 3: Methyl (R)-3-(2-aminopropyl)-1H-indole-6-carboxylate, hydrochloride [ka] To a solution of methyl (R)-3-(2-((tert-butoxycarbonyl)amino)propyl)-1H-indole-6-carboxylate (5.9 g, 17.7 mmol) in DCM (350 ml) was added chlorotrimethylsilane (23 ml, 177 mmol) slowly at room temperature. The solution was stirred at room temperature for 18 hours. The solution was concentrated under reduced pressure to give 4.8 g (crude) of methyl (R)-3-(2-aminopropyl)-1H-indole-6-carboxylate, hydrochloride salt, which was used directly in the next step. LC / MS(m / z, MH+): 233

[0109] Intermediate 1b: Methyl 3-(2-aminopropyl)-1H-indole-6-carboxylate, racemic mixture [ka] Step 1: Methyl 3-formyl-1H-indole-6-carboxylate [ka] To a solution of methyl 1H-indole-6-carboxylate (1 g, 5.71 mmol) in DMF (100 ml) at room temperature, POCl (1.31 g, 8.56 mmol, 795.70 μl) was added, and the mixture was stirred for 3 h. Water (20 ml) was slowly added to the reaction mixture, and then the mixture was heated at 120 °C for 15 min. After cooling to room temperature, the precipitated solid was filtered and dried under reduced pressure to give 1 g (86%) of methyl 3-formyl-1H-indole-6-carboxylate as a pale pink solid. LC / MS(m / z, MH+):204

[0110] Step 2: Methyl (E)-3-(2-nitroprop-1-en-1-yl)-1H-indole-6-carboxylate [ka] A mixture of methyl 3-formyl-1H-indole-6-carboxylate (1 g, 4.92 mmol) and NHOAc (948 mg, 12.30 mmol) in nitroethane (11.08 g, 147.64 mmol, 10.56 ml) was heated at 100 °C for 4 h. After cooling to room temperature, the reaction mixture was diluted with water (20 ml) and ethyl acetate (40 ml). After decantation, the organic phase was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of 100 / 00 to 70 / 30 petroleum ether / ethyl acetate to give 728 mg (57%) of methyl (E)-3-(2-nitroprop-1-en-1-yl)-1H-indole-6-carboxylate as a yellow solid. LC / MS(m / z, MH+):261

[0111] Step 3: Methyl 3-(2-oxopropyl)-1H-indole-6-carboxylate [ka] To a solution of methyl (E)-3-(2-nitroprop-1-en-1-yl)-1H-indole-6-carboxylate (300 mg, 1.15 mmol) in EtOH (6 mL), iron powder (644 mg, 11.53 mmol) and AcOH (623 mg, 10.37 mmol, 593 μL) were added at room temperature, and the suspension was stirred at 60° C. for 1.5 h. Aqueous HCl (2 M, 0.58 mL) was then added to the reaction mixture, and the mixture was stirred for 6 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of 100 / 00 to 50 / 50 petroleum ether / ethyl acetate to give 200 mg (crude) of methyl 3-(2-oxopropyl)-1H-indole-6-carboxylate, which was used directly in the next step. LC / MS(m / z, MH+): 232

[0112] Step 4: Methyl 3-(2-((1-phenylethyl)amino)propyl)-1H-indole-6-carboxylate [ka] A solution of 1-phenylethanamine (300 mg, 2.48 mmol, 319.15 μl) in MeOH (10 ml) was adjusted to pH 5-6 by dropwise addition of AcOH. Then, methyl 3-(2-oxopropyl)-1H-indole-6-carboxylate (572 mg, 2.48 mmol) and NaBHCN (156 mg, 2.48 mmol) were added portionwise. The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in DCM (20 ml) and washed with saturated NH.H.O (10 ml). After decantation, the organic phase was dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of 100 / 00 to 00 / 100 petroleum ether / ethyl acetate to afford 786 mg (94%) of methyl 3-(2-((1-phenylethyl)amino)propyl)-1H-indole-6-carboxylate as a yellow oil. LC / MS(m / z, MH+): 337

[0113] Step 5: Methyl 3-(2-aminopropyl)-1H-indole-6-carboxylate, racemic mixture [ka] To a mixture of methyl 3-(2-((1-phenylethyl)amino)propyl)-1H-indole-6-carboxylate (685 mg, 2.04 mmol) in MeOH (13 ml) under N atmosphere was added 20% (286 mg) of Pd(OH) / C, which was then purged with H several times, and the mixture was then stirred under H atmosphere (3 bar) at room temperature for 12 h. The reaction mixture was filtered through Celite, and the filter cake was washed with MeOH (2 x 20 ml). The filtrate was then concentrated under reduced pressure to give 460 mg (crude) of methyl 3-(2-aminopropyl)-1H-indole-6-carboxylate, racemic mixture, which was used directly in the next step. LC / MS(m / z, MH+): 233

[0114] Intermediate 1c: Methyl 3-(2-aminopropyl)-1H-indole-5-carboxylate, racemic mixture [ka] Step 1: Methyl 3-formyl-1H-indole-5-carboxylate [ka] Step 1 of intermediate 1c was prepared from methyl 1H-indole-5-carboxylate following a procedure similar to step 1 of intermediate 1b to afford 10.4 g (90%) of methyl 3-formyl-1H-indole-5-carboxylate as a pale pink solid. LC / MS(m / z, MH+):204

[0115] Step 2: Methyl (E)-3-(2-nitroprop-1-en-1-yl)-1H-indole-5-carboxylate [ka] Step 2 of intermediate 1c was prepared from methyl 3-formyl-1H-indole-5-carboxylate following a procedure similar to step 2 of intermediate 1b to afford 18 g (crude) of methyl (E)-3-(2-nitroprop-1-en-1-yl)-1H-indole-5-carboxylate as a yellow solid. LC / MS(m / z, MH+):261

[0116] Step 3: Methyl 3-(2-oxopropyl)-1H-indole-5-carboxylate [ka] Step 3 of intermediate 1c was prepared from methyl (E)-3-(2-nitroprop-1-en-1-yl)-1H-indole-5-carboxylate following a procedure similar to step 3 of intermediate 1b to afford 881 mg (50%) of methyl 3-(2-oxopropyl)-1H-indole-5-carboxylate, which was used directly in the next step. LC / MS(m / z, MH+): 232

[0117] Step 4: Methyl 3-(2-((1-phenylethyl)amino)propyl)-1H-indole-5-carboxylate [ka] Step 4 of intermediate 1c was prepared from methyl 3-(2-oxopropyl)-1H-indole-5-carboxylate and 1-phenylethanamine following a procedure similar to step 4 of intermediate 1b to afford 1.04 g (62%) of methyl 3-(2-((1-phenylethyl)amino)propyl)-1H-indole-5-carboxylate as a yellow oil. LC / MS(m / z, MH+): 337

[0118] Step 5: Methyl 3-(2-aminopropyl)-1H-indole-5-carboxylate, racemic mixture [ka] Step 5 of intermediate 1c was prepared from methyl 3-(2-((1-phenylethyl)amino)propyl)-1H-indole-5-carboxylate following a procedure similar to step 5 of intermediate 1b to afford 660 mg (crude) of methyl 3-(2-aminopropyl)-1H-indole-5-carboxylate, racemic mixture, which was used directly in the next step. LC / MS(m / z, MH+): 233

[0119] Intermediate 2: Methyl (R)-3-(2-((2,2,2-trifluoroethyl)amino)propyl)-1H-indole-6-carboxylate [ka] A mixture of methyl (R)-3-(2-aminopropyl)-1H-indole-6-carboxylate, hydrochloride salt (Intermediate 1a) (976 mg, 4.20 mmol), DIPEA (1.40 ml, 8.40 mmol), and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.10 g, 4.62 mmol) in dioxane (20 ml) was heated at 65° C. for 18 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by flash chromatography eluting with a gradient of 100 / 00 to 80 / 20 DCM / MeOH to afford 455 mg (34%) of methyl (R)-3-(2-((2,2,2-trifluoroethyl)amino)propyl)-1H-indole-6-carboxylate. LC / MS(m / z, MH+): 315

[0120] Intermediate 3a: Methyl (R)-3-(2-((2,2-difluoropropyl)amino)propyl)-1H-indole-6-carboxylate [ka] Intermediate 3a was prepared from methyl (R)-3-(2-aminopropyl)-1H-indole-6-carboxylate, hydrochloride salt (Intermediate 1a) and 2,2-difluoropropyl trifluoromethanesulfonate following a similar procedure as for Intermediate 2 to afford 620 mg (54%) of methyl (R)-3-(2-((2,2-difluoropropyl)amino)propyl)-1H-indole-6-carboxylate. LC / MS(m / z, MH+): 311

[0121] Intermediate 3b: methyl 3-(2-((2,2-difluoropropyl)amino)propyl)-1H-indole-6-carboxylate, racemic mixture [ka] Intermediate 3b was prepared from methyl 3-(2-aminopropyl)-1H-indole-6-carboxylate (Intermediate 1b) and 2,2-difluoropropyltrifluoromethanesulfonate following a similar procedure as for Intermediate 2 to afford 40 mg (56%) of methyl 3-(2-((2,2-difluoropropyl)amino)propyl)-1H-indole-6-carboxylate, a racemic mixture, as a colorless oil. LC / MS(m / z, MH+): 311

[0122] Intermediate 3c: methyl 3-(2-((2,2-difluoropropyl)amino)propyl)-1H-indole-5-carboxylate, racemic mixture [ka] Intermediate 3c was prepared from methyl 3-(2-aminopropyl)-1H-indole-5-carboxylate (Intermediate 1c) and 2,2-difluoropropyltrifluoromethanesulfonate following a similar procedure as for Intermediate 2 to afford 400 mg (40%) of methyl 3-(2-((2,2-difluoropropyl)amino)propyl)-1H-indole-5-carboxylate, a racemic mixture, as a yellow oil. LC / MS(m / z, MH+): 311

[0123] Intermediate 4: Methyl (R)-3-(2-((3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)amino)propyl)-1H-indole-6-carboxylate [ka] Intermediate 4 was prepared from methyl (R)-3-(2-aminopropyl)-1H-indole-6-carboxylate, hydrochloride salt (Intermediate 1a) and 3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl trifluoromethanesulfonate following a similar procedure as for Intermediate 2 to afford 930 mg (64%) of methyl (R)-3-(2-((3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)amino)propyl)-1H-indole-6-carboxylate. LC / MS(m / z, MH+):565

[0124] Intermediate 5(S)-2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)benzaldehyde [ka] To a solution of 2,6-difluoro-4-hydroxybenzaldehyde (0.88 g, 5.44 mmol) in dry THF (20 mL) was added (R)-1-(3-fluoropropyl)pyrrolidin-3-ol (prepared according to WO 2018091153) (1 g, 6.79 mmol), PPh3 (2.88 g, 10.9 mmol), and TMAD (1.87 g, 10.87 mmol). The reaction mixture was stirred at room temperature for 48 hours. Water (50 mL) and EtOAc (100 mL) were added, and the aqueous layer was then separated and extracted again with EtOAc (50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of 100 / 00 to 80 / 20 DCM / MeOH to afford 660 mg (36%) of (S)-2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)benzaldehyde. LC / MS(m / z, MH+):288

[0125] Intermediate 6(S)-2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)benzaldehyde [ka] Step 1: tert-butyl (S)-(1-(3-fluoropropyl)pyrrolidin-3-yl)carbamate [ka] A suspension of tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate (5.00 g, 26.04 mmol), 1-fluoro-3-iodopropane (5.38 g, 28.64 mmol), and K2CO3 (10.36 g, 74.21 mmol) in MeCN (100 ml) was stirred at 50 °C for 18 h. After cooling to room temperature, the suspension was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc, washed successively with water and a saturated aqueous solution of NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure to give 6.03 g (94%) of tert-butyl (S)-(1-(3-fluoropropyl)pyrrolidin-3-yl)carbamate. LC / MS(m / z, MH+): 247

[0126] Step 2: tert-butyl (S)-(3,5-difluoro-4-formylphenyl)(1-(3-fluoropropyl)pyrrolidin-3-yl)carbamate [ka] A mixture of 4-bromo-2,6-difluorobenzaldehyde (1.83 g, 8.12 mmol, 1 equiv.), Cs2CO3 (5.32 g, 16.24 mmol), palladium diacetate (0.038 g, 0.081 mmol), BINAP (0.101 g, 0.16 mmol), and tert-butyl (S)-(1-(3-fluoropropyl)pyrrolidin-3-yl)carbamate (2 g, 8.12 mmol) in toluene (100 ml) was stirred at 80 °C for 96 h. After cooling to room temperature, the reaction mixture was filtered through Celite. Water (50 ml) was added to the filtrate, and the organic phase was then separated. The aqueous phase was extracted again with EtOAc (2 × 20 ml). The combined organic phases were dried over MgSO4, filtered, and evaporated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of 30 / 70 to 00 / 100 heptane / ethyl acetate to afford 760 mg (24%) of tert-butyl (S)-(3,5-difluoro-4-formylphenyl)(1-(3-fluoropropyl)pyrrolidin-3-yl)carbamate as a yellow oil. LC / MS(m / z, MH+): 387

[0127] Intermediate 7: tert-butyl (3,5-difluoro-4-formylphenyl)(1-(3-fluoropropyl)azetidin-3-yl)carbamate [ka] Step 1: tert-butyl (1-(3-fluoropropyl)azetidin-3-yl)carbamate [ka] A suspension of tert-butyl N-(azetidin-3-yl)carbamate hydrochloride (5 g, 23.5 mmol), 1-fluoro-3-iodopropane (4.86 g, 25.8 mmol), and K2CO3 (8.19 g, 58.7 mmol) in THF (100 mL) and water (0.21 mL, 11.7 mmol) was stirred at 70 °C for 5 h. The crude mixture was cooled to room temperature, poured into water (100 mL), and extracted with EtOAc (200 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give 5.37 g (98%) of tert-butyl (1-(3-fluoropropyl)azetidin-3-yl)carbamate as a white powder. LC / MS(m / z, MH+): 233

[0128] Step 2: tert-butyl (1-(3-fluoropropyl)azetidin-3-yl)carbamate [ka] Step 2 of intermediate 7 was prepared from tert-butyl (1-(3-fluoropropyl)azetidin-3-yl)carbamate and 4-bromo-2,6-difluorobenzaldehyde following a procedure similar to step 2 of intermediate 6 to afford 2.95 g (92%) of tert-butyl (3,5-difluoro-4-formylphenyl)(1-(3-fluoropropyl)azetidin-3-yl)carbamate as an orange oil. LC / MS(m / z, MH+): 373

[0129] Step 3: 2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)benzaldehyde [ka] TFA (2.99 ml, 40.28 mmol) was added dropwise to a solution of tert-butyl (3,5-difluoro-4-formylphenyl)(1-(3-fluoropropyl)azetidin-3-yl)carbamate (1 g, 2.69 mmol) in DCM (30 ml) at 0° C. The reaction mixture was stirred at room temperature for 18 hours. DCM (20 ml) and 10% aqueous NaHCO3 were added to the reaction mixture. The aqueous layer was separated and extracted again with DCM (2 × 10 ml). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give 0.6 g (82%) of 2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)benzaldehyde. LC / MS(m / z, MH+): 273

[0130] Intermediate 8: 2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzaldehyde [ka] Step 1: tert-Butyl 3-(3,5-difluoro-4-bromophenoxy)azetidine-1-carboxylate [ka] A mixture of 4-bromo-3,5-difluorophenol (2.09 g, 10 mmol), CsCO (6.52 g, 20 mmol), and tert-butyl 3-iodoazetidine-1-carboxylate (2.25 mL, 12 mmol) in DMF (17 mL) was heated at 100° C. for 3 h. After cooling to room temperature, the reaction mixture was filtered, the solid was washed with EtOAc, and the filtrate was concentrated under reduced pressure. The residual oil was diluted with EtOAc and washed with water and brine. The organic phase was dried over MgSO, filtered, and concentrated under reduced pressure. The resulting crude residue was washed with heptane, and the precipitate was filtered to give 2.52 g (69%) of tert-butyl 3-(3,5-difluoro-4-bromophenoxy)azetidine-1-carboxylate as a white powder. LC / MS(m / z, MH+): 364

[0131] Step 2: 3-(4-bromo-3,5-difluorophenoxy)azetidine, 2,2,2-trifluoroacetic acid [ka] Step 2 of intermediate 8 was prepared following a similar procedure as step 3 of intermediate 7 starting from tert-butyl 3-(3,5-difluoro-4-bromophenoxy)azetidine-1-carboxylate to afford 2 g (crude) of 3-(4-bromo-3,5-difluorophenoxy)azetidine, 2,2,2-trifluoroacetic acid, which was used directly in the next step. LC / MS(m / z, MH+):264

[0132] Step 3: 3-(4-bromo-3,5-difluorophenoxy)-1-(3-fluoropropyl)azetidine [ka] A mixture of 3-(4-bromo-3,5-difluorophenoxy)azetidine, 2,2,2-trifluoroacetic acid (2 g, crude), 1-iodo-3-fluoropropane (0.56 mL, 5.49 mmol), and DIPEA (4.78 mL, 27.5 mmol) in DMF (20 mL) was stirred at room temperature for 16 hours. The crude mixture was poured into water and extracted with EtOAc. The organic phase was dried over MgSO, filtered, and concentrated under reduced pressure. The resulting oil was dissolved in heptane and concentrated under reduced pressure to give 1.69 g (95%) of 3-(4-bromo-3,5-difluorophenoxy)-1-(3-fluoropropyl)azetidine as a tan oil. LC / MS(m / z, MH+): 324

[0133] Step 4: 2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzaldehyde [ka] A mixture of 3-(4-bromo-3,5-difluorophenoxy)-1-(3-fluoropropyl)azetidine (1.5 g, 4.63 mmol) in THF (46 ml) was cooled to −78° C. Then, n-BuLi 1.6 M in hexane (3.05 ml, 4.86 mmol) was added dropwise to the crude mixture and stirred at this temperature for 30 minutes. DMF (0.72 mL, 9.26 mmol) was then added dropwise to the crude mixture at −78° C. and stirred at this temperature for 3 hours. The crude mixture was quenched with water at room temperature and stirred for 15 minutes. The aqueous phase was then extracted with EtOAc (50 ml), dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of 50 / 50 to 00 / 100 heptane / ethyl acetate to afford 0.38 g (30%) of 2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzaldehyde as a yellow liquid. LC / MS(m / z, MH+):274

[0134] Intermediate 9: tert-butyl (Z)-3-(3,5-difluoro-4-formylbenzylidene)pyrrolidine-1-carboxylate [ka] Step 1: tert-Butyl 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)pyrrolidine-1-carboxylate, mixture of Z and E isomers [ka] To a solution of 2,2,6,6-tetramethylpiperidine (5.51 ml, 32.4 mmol) in 2-methyltetrahydrofuran (50 ml) at −78° C., 1.6 M n-BuLi in THF (20.2 ml, 32.4 mmol) was added dropwise (internal temperature maintained below −65° C.). The solution was stirred at −78° C. for 30 minutes. Then, at −78° C., a solution of 4,4,5,5-tetramethyl-2-[(tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]-1,3,2-dioxaborolane (7.23 g, 27 mmol) in 2-methyltetrahydrofuran (50 ml) was added dropwise (internal temperature maintained below −65° C.). The reaction mixture was stirred at −78° C. for 30 minutes. Then, a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (5 g, 27.0 mmol) in 2-methyltetrahydrofuran (50 ml) was added dropwise at −78° C. (internal temperature maintained below −65° C.). The reaction mixture was slowly warmed to room temperature and stirred at this temperature for 18 hours. The reaction mixture was cooled to 0° C. and slowly quenched with 10% aqueous NH4Cl (30 ml). The aqueous layer was separated and re-extracted with EtOAc (2×50 ml). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of 90 / 10 to 70 / 30 heptane / ethyl acetate to afford 6.23 g (75%) of tert-butyl 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)pyrrolidine-1-carboxylate, a mixture of Z and E isomers, as a colorless oil. LC / MS (m / z, MH+): 310

[0135] Step 2: tert-Butyl (Z)-3-(3,5-difluoro-4-formylbenzylidene)pyrrolidine-1-carboxylate [ka] A mixture of tert-butyl 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)pyrrolidine-1-carboxylate, a mixture of Z and E isomers (5.10 g, 16.5 mmol), 4-bromo-2,6-difluorobenzaldehyde (3.04 g, 13.7 mmol), KPO (8.75 g, 41.2 mmol), palladium diacetate (0.11 g, 0.69 mmol), and SPhos (0.28 g, 0.69 mmol) in THF (15 ml) and water (1.5 ml) was heated at 40 °C for 18 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and filtered through a pad of Celite. The filtrate was dried over MgSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of 90 / 10 to 70 / 30 heptane / ethyl acetate to afford 320 mg (7%) of tert-butyl (Z)-3-(3,5-difluoro-4-formylbenzylidene)pyrrolidine-1-carboxylate and 3 g (68%) of a mixture of E and Z isomers of tert-butyl 3-(3,5-difluoro-4-formylbenzylidene)pyrrolidine-1-carboxylate. LC / MS(m / z, MH+): 324

[0136] Intermediate 10: tert-butyl 3-(3,5-difluoro-4-formylbenzyl)azetidine-1-carboxylate [ka] A mixture of 4-bromo-2,6-difluorobenzaldehyde (2 g, 9.05 mmol), tert-butyl 3-(bromomethyl)azetidine-1-carboxylate (2.94 g, 11.76 mmol), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (102 mg, 0.090 mmol), NiCl2.dtbbpy (18 mg, 0.045 mmol), tris(trimethylsilyl)silane (2.25 g, 9.05 mmol, 2.79 mL), and Na2CO3 (1.92 g, 18.10 mmol) in 1,2-dimethoxyethane (80 mL) was sealed and placed under a N2 atmosphere. The reaction was stirred and irradiated with a 34 W blue LED lamp (7 cm distance) for 14 h while maintaining the reaction temperature at 25 °C with a cooling fan. The reaction mixture was filtered, and the filtrate was washed with brine (40 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of 100 / 00 to 75 / 25 petroleum ether / ethyl acetate to give 1.6 g (57%) of tert-butyl 3-(3,5-difluoro-4-formylbenzyl)azetidine-1-carboxylate. LC / MS(m / z, MH+): 312

[0137] Intermediate 11: 1-(3-fluoropropyl)-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine [ka] Step 1: 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine, 2,2,2-trifluoroacetic acid [ka] At room temperature, TFA (2.89 ml, 38.96 mmol) was added dropwise to a solution of commercially available tert-butyl 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine-1-carboxylate (2.3 g, 7.79 mmol) in DCM (20 ml). The solution was stirred for 18 hours. The crude oil was concentrated under reduced pressure to give 2.67 g (crude) of 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine, 2,2,2-trifluoroacetic acid, which was used directly in the next step. LC / MS(m / z, MH+): 196

[0138] Step 2: 1-(3-fluoropropyl)-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine [ka] Step 2 of intermediate 11 was prepared from 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine, 2,2,2-trifluoroacetic acid and 1-fluoro-3-iodopropane according to a procedure similar to step 3 of intermediate 8 to afford 1.05 g (60%) of 1-(3-fluoropropyl)-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine. LC / MS(m / z, MH+): 256

[0139] Intermediate 12: 1-(3-fluoropropyl)azetidin-3-amine [ka] Step 1: tert-butyl (1-(3-fluoropropyl)azetidin-3-yl)carbamate [ka] A suspension of tert-butyl N-(azetidin-3-yl)carbamate hydrochloride (5 g, 23.5 mmol), 1-fluoro-3-iodopropane (4.86 g, 25.8 mmol), and K2CO3 (8.19 g, 58.7 mmol) in THF (100 mL) and water (0.21 mL, 11.7 mmol) was stirred at 70 °C for 5 h. The crude mixture was cooled to room temperature, poured into water (100 mL), and extracted with EtOAc (200 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give 5.37 g (98%) of tert-butyl (1-(3-fluoropropyl)azetidin-3-yl)carbamate as a white powder. LC / MS(m / z, MH+): 233

[0140] Step 2: 1-(3-fluoropropyl)azetidin-3-amine [ka] TFA (4.34 ml, 48.6 mmol) was added dropwise to a solution of tert-butyl (1-(3-fluoropropyl)azetidin-3-yl)carbamate (1 g, 4.305 mmol) in DCM (10 ml). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then concentrated under reduced pressure. The resulting residue was dissolved in MeOH (10 ml), Amberlyst A26 (4 g) was added, and the mixture was stirred at room temperature for 64 hours. The reaction mixture was filtered to remove Amberlyst A26 and washed with MeOH to give 0.5 g (88%) of 1-(3-fluoropropyl)azetidin-3-amine. LC / MS(m / z, MH+): 133

[0141] Intermediate 13: Methyl (1R,3R)-1-(4-bromo-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate [ka] A mixture of 4-bromo-2,6-difluorobenzaldehyde (195 mg, 0.603 mmol) and methyl (R)-3-(2-((2,2-difluoropropyl)amino)propyl)-1H-indole-6-carboxylate (Intermediate 3a) (170 mg, 0.55 mmol) and AcOH (0.19 ml, 3.28 mmol) in toluene (5 ml) was stirred at 110 °C for 18 h. After cooling to room temperature, EtOAc and 10% aqueous NaHCO were added. The aqueous layer was separated and extracted again with EtOAc (2 × 10 ml). The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of 90 / 10 to 50 / 50 heptane / ethyl acetate to afford 141 mg (42%) of methyl (1R,3R)-1-(4-bromo-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate. LC / MS(m / z, MH+):513

[0142] Intermediate 14: Methyl (1R,3R)-1-(4-bromo-2,6-difluorophenyl)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate [ka] A mixture of methyl (R)-3-(2-((3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)amino)propyl)-1H-indole-6-carboxylate (Intermediate 4) (480 mg, 0.85 mmol), 4-bromo-2,6-difluorobenzaldehyde (189 mg, 0.85 mmol) and TFA (63 μl, 0.85 mmol) in toluene (5 ml) was heated at 110° C. for 18 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of 100 / 00 to 70 / 30 heptane / ethyl acetate to afford 470 mg (72%) of methyl (1R,3R)-1-(4-bromo-2,6-difluorophenyl)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate as a pale yellow powder. LC / MS(m / z, MH+):767

[0143] Example Method A: Example 1: (1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid [ka] Step 1: Methyl (1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate and Methyl (1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate [ka] Step 1 of Example 1 was prepared from methyl (R)-3-(2-((2,2,2-trifluoroethyl)amino)propyl)-1H-indole-6-carboxylate (Intermediate 2) and (S)-2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)benzaldehyde (Intermediate 5) following the same procedure as for Intermediate 14. The resulting residue was purified by preparative chiral SFC (stationary phase: chiralpak IG 250 × 30 mm, mobile phase: CO 70% / iPrOH). Purification with 30% / iPrNH20.3% afforded 96 mg (52%) of methyl (1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate and 15 mg (8%) of methyl (1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate. LC / MS(m / z, MH+):584

[0144] Step 2: (1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid [ka] A mixture of methyl (1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate (80 mg, 0.14 mmol) and LiOH monohydrate (29 mg, 0.69 mmol) in MeOH (1.2 mL) was heated at 60° C. for 48 h. After cooling to room temperature, the crude product was diluted with DCM (5 mL). A 1N aqueous solution of HCl was added to pH 3-4, and the aqueous layer was separated and extracted again with DCM (5 mL). The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by HPLC (column YMC-Actus Triart Prep C18-S 150 × 30 mm 10 μm, flow rate 50 ml / min, focused gradient of MeCN / aq. NH4HCO3 0.2% pH = 7.9 from 25 / 75 to 55 / 45) to give 10 mg (13%) of (1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid as a white solid.

[0145] Example 2: (1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid [ka] Example 2 was prepared from methyl (1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate (Step 1 of Example 1) following a procedure similar to Step 2 of Example 1 to afford 5 mg (43%) of (1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid.

[0146] Example 3: (1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid [ka] Step 1: Methyl (1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate [ka] Step 1 of Example 3 was prepared from methyl (R)-3-(2-((2,2-difluoropropyl)amino)propyl)-1H-indole-6-carboxylate (Intermediate 3a) and (S)-2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)benzaldehyde (Intermediate 5) following a procedure similar to Intermediate 14 to afford 199 mg (53%) methyl (1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate. LC / MS (m / z, MH+): 580

[0147] Step 2: (1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid [ka] Step 2 of Example 3 was prepared from methyl (1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate according to a procedure similar to Step 2 of Example 1 to afford 52 mg (27%) of (1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid.

[0148] Example 4: (1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid [ka] Step 1: Methyl (1R,3R)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate [ka] Step 1 of Example 4 was prepared in a similar procedure to Intermediate 14 from methyl (R)-3-(2-((3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)amino)propyl)-1H-indole-6-carboxylate (Intermediate 4) and (S)-2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)benzaldehyde (Intermediate 5) to give 680 mg (crude) of methyl (1R,3R)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate was obtained and used directly in the next step. LC / MS(m / z, MH+):834

[0149] Step 2: Methyl (1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate [ka] Tetra-n-butylammonium fluoride (TBAF) 1M in THF (1.22 mL, 1.22 mmol) was added dropwise to a solution of methyl (1R,3R)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate (680 mg, 0.82 mmol) in THF (5 mL) precooled to 0°C. The mixture was allowed to warm to room temperature and stirred for 18 hours. DCM (10 mL) and 10% aqueous NH4Cl were added to the reaction mixture. The aqueous layer was separated and extracted with DCM (2 × 5 mL). The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of 100 / 00 to 90 / 10 ethyl acetate / methanol to afford 154 mg (32%) of methyl (1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate. LC / MS(m / z, MH+):596

[0150] Step 3: (1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid [ka] Step 3 of Example 4 was prepared from methyl (1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate according to a procedure similar to Step 2 of Example 1 to afford 52 mg (35%) of (1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid.

[0151] Example 5: (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid [ka] Step 1: Methyl (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate [ka] Step 1 of Example 5 was prepared from methyl (R)-3-(2-((2,2,2-trifluoroethyl)amino)propyl)-1H-indole-6-carboxylate (Intermediate 2) and 2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)benzaldehyde (Intermediate 7) following a procedure similar to Intermediate 14 to afford 71 mg (44%) of methyl (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate. LC / MS(m / z, MH+):569

[0152] Step 2: (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid [ka] Step 2 of Example 5 was prepared from methyl (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate according to a procedure similar to Step 2 of Example 1 to afford 5 mg (7%) of (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid.

[0153] Example 6: (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid [ka] Step 1: Methyl (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate [ka] Step 1 of Example 6 was prepared from methyl (R)-3-(2-((2,2,2-trifluoroethyl)amino)propyl)-1H-indole-6-carboxylate (Intermediate 2) and 2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzaldehyde (Intermediate 8) following a procedure similar to Intermediate 14 to afford 84 mg (46%) of methyl (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate. LC / MS(m / z, MH+): 570

[0154] Step 2: (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid [ka] Step 2 of Example 6 was prepared from methyl (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate according to a procedure similar to Step 2 of Example 1 to afford 12 mg (6%) of 1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid.

[0155] Example 7: (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid [ka] Step 1: Methyl (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate [ka] Step 1 of Example 7 was prepared from methyl (R)-3-(2-((2,2-difluoropropyl)amino)propyl)-1H-indole-6-carboxylate (Intermediate 3a) and 2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzaldehyde (Intermediate 8) following a procedure similar to Intermediate 13 to afford 50 mg (27%) of methyl (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate. LC / MS(m / z, MH+):566

[0156] Step 2: (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid [ka] Step 2 of Example 7 was prepared from methyl (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate according to a procedure similar to Step 2 of Example 1 to afford 8 mg (17%) of (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid.

[0157] Example 8: (1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid [ka] Step 1: Methyl (1R,3R)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate [ka] Step 1 of Example 8 was prepared in a similar procedure to Intermediate 14 from methyl (R)-3-(2-((3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)amino)propyl)-1H-indole-6-carboxylate (Intermediate 4) and 2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzaldehyde (Intermediate 8) to afford 250 mg (57%) of methyl (1R,3R)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate. LC / MS(m / z, MH+):820

[0158] Step 2: Methyl (1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate [ka] Step 2 of Example 8 was prepared in a manner similar to Step 2 of Example 4 from methyl (1R,3R)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate to afford 96 mg (53%) of methyl (1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate. LC / MS(m / z, MH+):582

[0159] Step 3: (1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid [ka] Step 3 of Example 8 was prepared from methyl (1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate according to a procedure similar to Step 2 of Example 1 to afford 23 mg (50%) of (1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid.

[0160] Example 9: (1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid [ka] Step 1: Methyl (1R,3R)-1-(4-((tert-butoxycarbonyl)((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate [ka] Step 1 of Example 9 was prepared from methyl (R)-3-(2-((2,2-difluoropropyl)amino)propyl)-1H-indole-6-carboxylate (Intermediate 3a) and tert-butyl (S)-(3,5-difluoro-4-formylphenyl)(1-(3-fluoropropyl)pyrrolidin-3-yl)carbamate (Intermediate 6) following a procedure similar to Intermediate 14 to afford 433 mg (99%) of methyl (1R,3R)-1-(4-((tert-butoxycarbonyl)((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate. LC / MS(m / z, MH+):679

[0161] Step 2: Methyl (1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate [ka] Step 2 of Example 9 was prepared in a similar procedure to Step 3 of Intermediate 7 from methyl (1R,3R)-1-(4-((tert-butoxycarbonyl)((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate to afford 133 mg (36%) of methyl (1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate. LC / MS(m / z, MH+):579

[0162] Step 3: (1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid [ka] Step 3 of Example 9 was prepared from methyl (1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate according to a procedure similar to Step 2 of Example 1 to afford 52 mg (27%) of (1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid.

[0163] Method B: Example 10: (1R,3R)-1-(2,6-difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid [ka] Step 1: Methyl (1R,3R)-1-(4-((Z)-(1-(tert-butoxycarbonyl)pyrrolidin-3-ylidene)methyl)-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate [ka] Step 1 of Example 10 was prepared from methyl (R)-3-(2-((2,2-difluoropropyl)amino)propyl)-1H-indole-6-carboxylate (Intermediate 3a) and tert-butyl (Z)-3-(3,5-difluoro-4-formylbenzylidene)pyrrolidine-1-carboxylate (Intermediate 9) following a procedure similar to Intermediate 13 to afford 141 mg (42%) of methyl (1R,3R)-1-(4-((Z)-(1-(tert-butoxycarbonyl)pyrrolidin-3-ylidene)methyl)-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate. LC / MS(m / z, MH+):616

[0164] Step 2: Methyl (1R,3R)-1-(2,6-difluoro-4-((Z)-pyrrolidin-3-ylidenemethyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate, 2,2,2-trifluoroacetic acid [ka] Step 2 of Example 10 was prepared from methyl (1R,3R)-1-(4-((Z)-(1-(tert-butoxycarbonyl)pyrrolidin-3-ylidene)methyl)-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate according to a procedure similar to Step 3 of Intermediate 7 to afford 167 mg (crude) of methyl (1R,3R)-1-(2,6-difluoro-4-((Z)-pyrrolidin-3-ylidenemethyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate, 2,2,2-trifluoroacetic acid, which was used directly in the next step. LC / MS(m / z, MH+):516

[0165] Step 3: Methyl (1R,3R)-1-(2,6-difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate [ka] Step 3 of Example 10 was prepared according to a procedure similar to Step 1 of Intermediate 6 from methyl (1R,3R)-1-(2,6-difluoro-4-((Z)-pyrrolidin-3-ylidenemethyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate, 2,2,2-trifluoroacetic acid, and 1-fluoro-3-iodopropane to afford 50 mg (27%) of methyl (1R,3R)-1-(2,6-difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate. LC / MS(m / z, MH+):576

[0166] Step 4: (1R,3R)-1-(2,6-difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid [ka] Step 4 of Example 10 was prepared from methyl (1R,3R)-1-(2,6-difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate according to a procedure similar to Step 2 of Example 1 to provide 5 mg (10%) of (1R,3R)-1-(2,6-difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid.

[0167] Example 11: (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid [ka]

[0168] Example 12: (1S,3S)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid [ka] Step 1: Methyl 1-(4-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate, mixture of trans isomers [ka] Step 1 of Examples 11 and 12 was prepared from methyl 3-(2-((2,2-difluoropropyl)amino)propyl)-1H-indole-6-carboxylate, racemic mixture (Intermediate 3b) and tert-butyl 3-(3,5-difluoro-4-formylbenzyl)azetidine-1-carboxylate (Intermediate 10) following a procedure similar to Intermediate 13 to afford 210 mg (47%) of methyl 1-(4-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate, mixture of trans isomers. LC / MS(m / z, MH+):604

[0169] Step 2: Methyl 1-(4-(azetidin-3-ylmethyl)-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate, 2,2,2-trifluoroacetic acid, mixture of trans isomers [ka] Step 2 of Examples 11 and 12 was prepared from methyl 1-(4-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate, a mixture of trans isomers, following a procedure similar to Step 3 of Intermediate 7 to yield 214 mg (crude) of methyl 1-(4-(azetidin-3-ylmethyl)-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate, 2,2,2-trifluoroacetic acid, a mixture of trans isomers, which was used directly in the next step. LC / MS(m / z, MH+):504

[0170] Step 3: Methyl 1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate, mixture of trans isomers [ka] Step 3 of Examples 11 and 12 was prepared according to a procedure similar to Step 1 of Intermediate 6 from methyl 1-(4-(azetidin-3-ylmethyl)-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate, 2,2,2-trifluoroacetic acid, a mixture of trans isomers, and 1-fluoro-3-iodopropane to afford 90 mg (44%) of methyl 1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate, a mixture of trans isomers. LC / MS (m / z, MH+): 560

[0171] Step 4: 1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid, mixture of trans isomers [ka] Step 4 of Examples 11 and 12 was prepared from methyl 1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate, a mixture of trans isomers, following a procedure similar to Step 2 of Example 1 to afford 150 mg (41%) of 1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid, a mixture of trans isomers.

[0172] Step 5: (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid and (1S,3S)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid [ka] 1-(2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid, a mixture of trans isomers (170 mg, 0.31 mmol) was purified by SFC (column: DAICEL CHIRALPAK IC (250 mm x 30 mm, 10 μm); mobile phase: [0.1% NH3H2O MeOH]; B%: 30% to 30%, 4.2; 40 min) to give 90 mg of (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid (Example 11) and 26 mg of (1S,3S)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid (Example 12).

[0173] Example 13: (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-carboxylic acid [ka] Step 1: Methyl 1-(4-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-carboxylate, mixture of trans isomers [ka] Step 1 of Example 13 was prepared from methyl 3-(2-((2,2-difluoropropyl)amino)propyl)-1H-indole-5-carboxylate, racemic mixture (Intermediate 3c) and tert-butyl 3-(3,5-difluoro-4-formylbenzyl)azetidine-1-carboxylate (Intermediate 10) following a procedure similar to Intermediate 14 to afford 750 mg (84%) of methyl 1-(4-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-carboxylate, mixture of trans isomers. LC / MS(m / z, MH+):604

[0174] Step 2: Methyl 1-(4-(azetidin-3-ylmethyl)-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-carboxylate, 2,2,2-trifluoroacetic acid, mixture of trans isomers [ka] Step 2 of Example 13 was prepared from methyl 1-(4-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-carboxylate, mixture of trans isomers according to a procedure similar to Step 3 of Intermediate 7 to yield 490 mg (crude) of methyl 1-(4-(azetidin-3-ylmethyl)-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-carboxylate, 2,2,2-trifluoroacetic acid, mixture of trans isomers, which was used directly in the next step. LC / MS(m / z, MH+):504

[0175] Step 3: Methyl 1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-carboxylate, mixture of trans isomers [ka] Step 3 of Example 13 was prepared according to a procedure similar to Step 1 of Intermediate 6 from methyl 1-(4-(azetidin-3-ylmethyl)-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-carboxylate, 2,2,2-trifluoroacetic acid, a mixture of trans isomers, and 1-fluoro-3-iodopropane to afford 120 mg (23%) of methyl 1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-carboxylate, a mixture of trans isomers. LC / MS (m / z, MH+): 560

[0176] Step 4: (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid [ka] Step 4 of Example 13 was prepared from methyl 1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-carboxylate, a mixture of trans isomers, following a procedure similar to Step 2 of Example 1 to afford 70 mg (87%) of 1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid, a mixture of trans isomers.

[0177] Step 5: (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-carboxylic acid [ka] 1-(2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-carboxylic acid, a mixture of trans isomers (170 mg, 0.31 mmol) was purified by SFC (column: DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 μm); mobile phase: [0.1% NH3H2O MeOH]; B%: 35% to 35%, 4.0 min; 30 min) to afford 30 mg of (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-carboxylic acid as a yellow solid.

[0178] Method C: Example 14: (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid [ka] Step 1: Methyl (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate [ka] A mixture of 1-(3-fluoropropyl)azetidin-3-amine (Intermediate 12) (288 mg, 1.17 mmol), methyl (1R,3R)-1-(4-bromo-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate (Intermediate 13) (120 mg, 0.23 mmol), CsCO (762 mg, 2.34 mmol), t-BuBrettPhos (11 mg, 0.023 mmol), and t-BuBrettPhos Pd G (10 mg, 0.012 mmol) in dioxane (1.8 mL) was stirred at 100° C. for 24 hours. After cooling to room temperature, water (10 mL) and ethyl acetate (10 mL) were added. After decantation, the organic phase was dried over MgSO, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with 100 / 00 to 00 / 100 heptane / ethyl acetate to give 74 mg (56%) of methyl (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate. LC / MS(m / z, MH+):565

[0179] Step 2: (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid [ka] Step 2 of Example 14 was prepared from methyl (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate according to a procedure similar to Step 2 of Example 1 to afford 13 mg (17%) of (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid.

[0180] Method D: Example 15: (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid [ka] Step 1: Methyl (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate [ka] A mixture of methyl (1R,3R)-1-(4-bromo-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate (Intermediate 13) (200 mg, 0.39 mmol), KPO (248 mg, 1.17 mmol), palladium diacetate (9 mg, 0.039 mmol), SPhos (6 mg, 0.039 mmol) and 1-(3-fluoropropyl)-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine (Intermediate 11) (199 mg, 0.78 mmol) in THF (0.4 mL) and HO (0.04 mL) was heated at 40 °C for 48 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc (10 mL) and water (5 mL). The aqueous layer was separated and extracted again with EtOAc. The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with DCM / MeOH 100 / 00 to 94 / 04 to give 75 mg (34%) of methyl (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate. LC / MS(m / z, MH+):562

[0181] Step 2: (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid [ka] Step 2 of Example 15 was prepared from methyl (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate according to a procedure similar to Step 2 of Example 1 to afford 28 mg (38%) of (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid.

[0182] The compounds listed in Table 1 above were subjected to pharmacological testing to determine their disruptive effects on the estrogen receptor.

[0183] Test: Estrogen receptor degrading activity Said test is directed to determining the in vitro degradation activity of the compounds of Table 1.

[0184] Measurement of degradation activity was done using breast cancer cell ERα in a cell Western assay as described below.

[0185] MCF7 cells (ATCC) were seeded in 384-well microplates (collagen-coated) at a concentration of 10,000 cells per well in phenol red-free MEM alpha medium (Invitrogen) containing 5% charcoal dextran-striped FBS. The following day, nine serial 1:5 dilutions of each compound were added to the cells in 2.5 μL, ranging from 0.3 to 0.0000018 μM (Table 2), or fulvestrant (used as a positive control) at a final concentration of 0.1 μM. Four hours after compound addition, cells were fixed by adding 25 μL of formalin (final concentration 5% formalin containing 0.1% Triton) for 10 minutes at room temperature, followed by two washes with PBS. Next, 50 μL of LI-COR blocking buffer containing 0.1% Triton was added to the plate for 30 minutes at room temperature. The LI-COR blocking buffer was removed, and the cells were incubated overnight in the cold with 50 μL of anti-ER rabbit monoclonal antibody (Thermo Scientific MA1-39540) diluted 1:1000 in LI-COR blocking buffer containing 0.1% Tween-20. Wells treated with blocking buffer but without antibody served as background controls. The wells were washed twice with PBS (0.1% Tween-20) and incubated for 60 minutes at 37°C in LI-COR (0.1% Tween-20) containing goat anti-rabbit antibody Alexa 488 (1:1000) and Syto-64 a DNA dye (2 μM final concentration). The cells were then washed three times with PBS and scanned in an ACUMEN explorer (TTP-Labtech). The integrated intensity of green and red fluorescence was measured to determine the levels of ERα and DNA, respectively.

[0186] The degradative activity of the estrogen receptor in this test is expressed as the concentration (or IC ) required to degrade 50% of the estrogen receptor in nM. 50 ) is given by

[0187] The % reduction in ERα levels was determined as follows: % inhibition = 100 * (1 - (sample - fulvestrant: DMSO - fulvestrant)).

[0188] Table 2 below shows the estrogen receptor degrading activity results for the compounds of Table 1 tested at 0.3 μM, demonstrating that the compounds have significant degrading activity against the estrogen receptor.

[0189] [Table 9]

[0190] Therefore, it is clear that the tested compounds have degradation activity on estrogen receptors with IC50 less than 1 μM and degradation levels greater than 50%. Therefore, the compounds of formulas (I), (II) and (III) can be used to prepare pharmaceuticals, particularly pharmaceuticals that are degraders of estrogen receptors.

[0191] Accordingly, also provided herein are medicaments comprising compounds of formula (I), (II) and (III), or pharmaceutically acceptable salts thereof.

[0192] There is also provided herein a compound of formula (I), (II) and (III), or a pharmaceutically acceptable salt thereof, as defined above for use as a pharmaceutical.

[0193] Also provided herein are compounds of formula (I), (II) and (III), or pharmaceutically acceptable salts thereof, as defined above, for use in therapy, in particular as inhibitors and degraders of estrogen receptors.

[0194] Also provided herein are compounds of formula (I), (II) and (III), or pharmaceutically acceptable salts thereof, as defined above, for use in the treatment of ovulatory dysfunction, cancer, endometriosis, osteoporosis, prostatic hyperplasia or inflammation.

[0195] A particular embodiment is a compound of formula (I), (II) and (III), or a pharmaceutically acceptable salt thereof, as defined above, for use in the treatment of cancer.

[0196] In some embodiments, the cancer is a hormone-dependent cancer.

[0197] In another embodiment, the cancer is an estrogen receptor dependent cancer, in particular, the cancer is an estrogen receptor alpha dependent cancer.

[0198] In another embodiment, the cancer is selected from breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, cervical cancer and lung cancer, or metastases thereof.

[0199] In another embodiment, the metastasis is a cerebral metastasis.

[0200] In another embodiment, the cancer is breast cancer. In particular, the breast cancer is estrogen receptor positive breast cancer (ERα positive breast cancer).

[0201] In another embodiment, the cancer is resistant to anti-hormonal therapy.

[0202] In further embodiments, compounds of Formulae (I), (II) and (III) are used as single agents or in combination with other agents, such as CDK4 / 6, mTOR or PI3K inhibitors.

[0203] According to another aspect, provided herein is a method of treating the above-noted pathological conditions, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof. In one embodiment of this method of treatment, the subject is a human.

[0204] Also provided herein is the use of a compound of formula (I), (II) and (III), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful in treating any of the pathological conditions set out above, more particularly useful in treating cancer.

[0205] Also provided herein are pharmaceutical compositions comprising the compounds of Formulas (I), (II), and (III) as an active ingredient. These pharmaceutical compositions also comprise an effective dose of at least one compound of Formulas (I), (II), and (III) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0206] Said excipients are chosen according to the desired pharmaceutical form and method of administration from the usual excipients known to those skilled in the art.

[0207] In pharmaceutical compositions for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active ingredients of formulas (I), (II) and (III) above, or bases, acids, zwitterions or salts thereof, in admixture with conventional pharmaceutical excipients, can be administered to animals and humans in unit dosage forms for the treatment of the above disorders or diseases.

[0208] Suitable unit dosage forms include oral forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular and intranasal dosage forms, forms for inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration, rectal dosage forms and implants. For topical application, it is possible to use the compounds of formula (I), (II) and (III) in creams, gels, ointments or lotions.

[0209] As an example, a unit dosage form of the compounds of formula (I), (II) and (III) in tablet form may contain the following ingredients: Compound of formula (I) 50.0 mg Mannitol 223.75mg Croscarmellose sodium 6.0mg Cornstarch 15.0mg Hydroxypropyl methylcellulose 2.25mg Magnesium stearate 3.0mg.

[0210] There may be specific cases in which higher or lower dosages are appropriate. According to normal practice, the dosage appropriate for each patient is determined by the physician according to the mode of administration and the weight and response of said patient.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: 【Chemical 1】 (In the formula, R1 and R2 independently represent a hydrogen atom or a deuterium atom; R3 represents a hydrogen atom or a —COOH group; R3' represents a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom, a cyano group, or a -COOH group; R3″ represents a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom, or a cyano group; provided that either R3 or R3' represents a -COOH group, but not both of them represent -COOH groups, and R3 and R3' do not simultaneously represent a hydrogen atom; R4 represents a hydrogen atom or a fluorine atom; R5 and R5' independently represent a hydrogen atom or a fluorine atom; - Y is -CH ２ represents -, -CH=, -CR9=, -O- or -NH-, wherein R9 is a fluorine atom or (C １ -C ３ ) represents an alkyl group; － 【Chemistry 2】 represents a single or double bond; p is 0 or 1; X is -CH=, -N= or -CR"= (wherein R" is a group selected from the group consisting of (C １ -C ３ ) alkyl group or a halogen atom such as a fluorine atom or a chlorine atom, a cyano group, or a trifluoromethyl group, etc. １ -C ３ ) represents a fluoroalkyl group; R7 independently represents a (C １ -C ３ ) alkyl group, halogen atom such as fluorine atom, cyano group, or trifluoromethyl １ -C ３ ) represents a fluoroalkyl group; n is 0, 1 or 2; and - R6 is (C １ -C ９ ) alkyl group, １ -C ９ ) The alkyl group is not a halogen atom, a -cyano group, or an -OR ａ group, -N(R ａ ) ２ Group, (C １ -C ９ ) alkyl group, (C １ -C ９ ) an alkoxy group, (C １ -C ３ ) a fluoroalkoxy group, (C ３ -C ９ ) a cycloalkyl group, (C ３ -C ９ ) heterocyclic group, (C ６ -C ９ ) an aryl group, (C ５ -C １０ ) heteroaryl group, —C(O)R ｂ group, -C(O)NR ａ group, —SO ２ CH ３ group, and SO ２ NR ａ optionally substituted with 1 to 4 substituents independently selected from the group -R ａ is a hydrogen atom, (C １ -C ６ ) alkyl group, (C ２ -C ８ ) alkenyl group, propargyl group, (C ３ -C ６ ) cycloalkyl groups, and (C ３ -C ７ ) represents a heterocycloalkyl group, and is selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a cyano group, an —OH group, a methoxy group, and —SO ２ CH ３ optionally substituted with one or more substituents independently selected from the group; -R ｂ is a hydrogen atom, -O((C １ -C ３ ) alkyl) group, (C １ -C ６ ) alkyl group, (C ２ -C ８ ) alkenyl group, propargyl group, -((C ２ -C ６ ) alkene)-((C ３ -C ６ ) cycloalkyl) group, (C ３ -C ６ ) cycloalkyl groups, and (C ３ -C ７ ) heterocycloalkyl group, and is selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a cyano group, and —CH ２ F group, -CHF ２ group, -CF ３ group, -CH ２ CF ３ group, -CH ２ CF ２ group, -CH ２ CH ２ F group, —OH group, methoxy group, and —SO ２ CH ３ optionally substituted with one or more substituents independently selected from the group - R8は, hydrogen atom, シアノ group, (C １ -C ６ )アルキルbase、-CH ２ OH group, -CH ２ OCH ３ -CH ２ CH ２ OH group, -C(CH ３ ) ２ OH base, -CH (OH) CH (CH ３ ) ２ -C(CH ３ ) ２ CH ２ OH group, -CH ２ CH ２ SO ２ CH ３ Base, -CH ２ OP(O)(OH) ２ Base, -CH ２ F group, -CHF ２ -CH ２ NH ２ , -CH ２ NHS ２ CH ３ Base, -CH ２ NHC ３ Base, -CH ２ N (CH ３ ) ２ Base, -CF ３ Base, -CH ２ CF ３ Base, -CH ２ CF ２ -CH(CH ３ ) CN base, -C (CH ３ ) ２ CN group, -CH ２ CN group, -CO ２ H group, -COCH ３ Base, -CO ２ CH ３ Base, -CO ２ C (CH ３ ) ３ Base, -COCH(OH)CH ３ Base, -CONH ２ -CONHCH ３ -CONHCH ２ CH ３ -CONHCH (CH ３ ) ２ group, -CON(CH ３ ) ２ group, -C(CH ３ ) ２ CONH ２ group, cyclopropyl group, cyclopropylamido group, cyclobutyl group, oxetanyl group, azetidinyl group, 1-methylazetidin-3-yloxy group, N-methyl-N-oxetan-3-ylamino group, azetidin-1-ylmethyl group, benzyloxyphenyl group, pyrrolidin-1-yl group, pyrrolidin-1-ylmethanone group, piperazin-1-yl group, morpholinomethyl group, morpholinomethanone group, or morpholino group).

2. p is 1, X is -CH=; Y is -CH ２ -; R3 is -COOH; R1, R2, R3', R3'', R4, R5 and R5' are H; R7 is F; n is 2; R8 is -CH ３ R6 does not represent a 2,2-difluoropropyl group; - p is 0, X is -CH=; Y is -NH-; R3 is -COOH; R1, R2, R3', R3'', R4, R5 and R5' are H; R7 is F; n is 2; R8 is -CH ３ 2. A compound of formula (I) according to claim 1, wherein: R6 does not represent a 2,2-difluoro-3-hydroxypropyl group.

3. Formula (II) or (III): 【Chemistry 3】 (In the formula, R1, R2, R3, R3', R3'', R4, R5, R5', R6, R7, R8, 【Chemistry 4】 3. A compound of formula (I) according to claim 1 or 2, characterized in that: Y, n and p are as defined in claim 1), or a pharmaceutically acceptable salt thereof.

4. A compound of formula (I) according to any one of claims 1 to 3, characterized in that it is of formula (II), or a pharmaceutically acceptable salt thereof.

5. A compound of formula (I) or (II) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, characterized in that R3' and R3" represent a hydrogen atom.

6. A compound of formula (I), (II) or (III) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, characterized in that R1 and R2 are hydrogen atoms.

7. A compound of formula (I), (II) or (III) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, characterized in that R4 represents a hydrogen atom.

8. A compound of formula (I), (II) or (III) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, characterized in that R5 and R5' represent a hydrogen atom.

9. A compound of formula (I), (II) or (III) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, characterized in that X represents -CR"=, wherein R" represents a halogen atom, preferably a fluorine atom.

10. R6 (C １ -C ６ ) alkyl group, １ -C ６ 10. The compound of formula (I), (II) or (III) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein the alkyl group is optionally substituted with 1 to 3 substituents independently selected from a fluorine atom, a methyl group and an -OH group.

11. R6 is —CH ２ -CF ３ group, -CH ２ -CF ２ -CH ２ -OH group or -CH ２ -CF ２ -CH ３ 11. A compound of formula (I), (II) or (III) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, characterized in that it represents a group.

12. A compound of formula (I), (II) or (III) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, characterized in that R7 represents a fluorine atom and n is 1 or 2.

13. R8 (C １ -C ６ 13. A compound of formula (I), (II) or (III) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, characterized in that: 1) represents an alkyl group, preferably a methyl group.

14. Y is -CH ２ A compound of formula (I), (II) or (III) according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, characterized in that it represents -, -CH=, -O- or -NH-.

15. 【Chemical 5】 A compound of formula (I), (II) or (III) according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, characterized in that: represents a single bond.

16. A compound of formula (I), (II) or (III) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, characterized in that p is 1.

17. The compound is the following compound: (1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid, (1) (1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid, (2) (1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid, (3) (1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid, (4) (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid, (5) (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid, (6) (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid, (7) (1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid, (8) (1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid, (9) (1R,3R)-1-(2,6-difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid, (10) (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid, (11) (1S,3S)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid, (12) (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-carboxylic acid, (13) (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid, (14) (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid, (15) 17. A compound of formula (I), (II) or (III) according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, in particular the hydrochloride thereof, characterized in that it is selected from:

18. Compound of Formula 1J: 【Chemistry 6】 (In the formula, R1, R2, R3', R3'', R4, R5, R5', R6, R7, R8, 【Chemistry 7】 wherein n, p, X and Y are as defined in any one of claims 1 to 16 and R3a is a carboxylic acid ester such as -COOMe or -COOEt) is converted to a compound of formula (II) in the presence of a hydroxide ion source such as NaOH or LiOH in methanol or THF solution, said step being optionally preceded by a step to obtain compound 1J, to obtain a compound of formula 1L: 【Chemistry 8】 wherein R3′, R3′″, R6, R7, R8, n and X are as defined in any one of claims 1 to 16, and R3a is a carboxylic acid ester such as —COOOMe or —COOEt, to give compound 1M: 【Chemistry 9】 wherein R1, R2, R4, R5, R5' and p are as defined in any of claims 1 to 16.

19. Compound of Formula 1J: 【Chemistry 10】 (In the formula, R1, R2, R3', R3'', R4, R5, R5', R6, R7, R8, 【Chemistry 11】 , n, p, X and Y are as defined in any one of claims 1 to 16, and R3a is a carboxylic acid ester such as -COOMe or -COOEt) is converted to a compound of formula (II) in the presence of a hydroxide ion source such as NaOH or LiOH in methanol or THF solution, said step being optionally preceded by a step to obtain compound 1J, to give a compound of formula 1G: 【Chemistry 12】 wherein R3, R3″, R6 and R8 are as defined in any one of claims 1 to 16 and R3a is a carboxylic acid ester such as —COOMe or —COOEt, can be converted to compound 1H: 【Chemistry 13】 (In the formula, R1, R2, R4, R5, R5', R7, X, Y, 【Chemistry 14】 18. A process for preparing a compound of formula (II) according to any one of claims 2 to 17, wherein the compound is subjected to a Pictet-Spengler cyclization reaction with 2-(2-methyl-2-phenylpropanol), wherein n, n and p are as defined in any one of claims 1 to 16.

20. Compound of Formula 1J: 【Chemistry 15】 (In the formula, R1, R2, R3', R3'', R4, R5, R5', R6, R7, R8, 【Chemistry 16】 , n, p, X and Y are as defined in any one of claims 1 to 16, and R3a is a carboxylic acid ester such as -COOMe or -COOEt) is converted to a compound of formula (II) in the presence of a hydroxide ion source such as NaOH or LiOH in methanol or THF solution, said step being optionally preceded by a step to obtain compound 1J, to give a compound of formula 1O: 【Chemistry 17】 (In the formula, R3', R3'', R6, R7, R8, 【Chemistry 18】 , n, p, X and Y are as defined in any one of claims 1 to 16, and R3a is a sodium carboxylate such as -COOMe or -COOEt) is reacted with potassium carbonate (K ２ CO ３ ), compound 1P: 【Chemistry 19】 (Wherein W is Cl, Br, or I, or OSO ２ R (R = CH ３ , PhMe, CF ３ or CF ２ CF ２ CF ２ CF ３ 18. A process for preparing a compound of formula (II) according to any one of claims 2 to 17, wherein R1, R2, R4, R5 and R5' are as defined in any one of claims 1 to 16, to be converted to compound 1J by treating

21. Compound of Formula 1Ae: 【Chemistry 20】 (In the formula, R1, R2, R3, R3'', R4, R5, R5', R6, R7, R8, 【Chemical Formula 21】 wherein n, p, X and Y are as defined in any one of claims 1 to 16 and R3a is a carboxylic acid ester such as -COOMe or -COOEt, is converted to a compound of formula (III) in the presence of a hydroxide ion source such as NaOH or LiOH in methanol or THF solution, said step being optionally preceded by a step to obtain compound 1Ae, to give a compound of formula 1Ad: 【Chemical formula 22】 wherein R3, R3″, R6, R7, R8, n and X are as defined in any one of claims 1 to 16, and R3a′ is a carboxylic acid ester such as —COOOMe or —COOEt, can be converted under coupling reaction conditions to compound 1M: 【Chemical 23】 wherein R1, R2, R4, R5, R5' and p are as defined in any one of claims 1 to 16.

22. Compound of Formula 1Ae: 【Chemistry 24】 (In the formula, R1, R2, R3, R3'', R4, R5, R5', R6, R7, R8, 【Chemistry 25】 , n, p, X and Y are as defined in any one of claims 1 to 16, and R3a' is a carboxylic acid ester such as -COOMe or -COOEt) is converted to a compound of formula (III) in the presence of a hydroxide ion source such as NaOH or LiOH in methanol or THF solution, said step being optionally preceded by a step to obtain compound 1Ae, to give a compound of formula 1Ac: 【Chemical 26】 wherein R3, R3″, R6 and R8 are as defined in any one of claims 1 to 16 and R3a′ is a carboxylic acid ester such as —COOMe or —COOEt, can be converted to compound 1H: 【Chemical 27】 (In the formula, R1, R2, R4, R5, R5', R7, X, Y, 【Chemical 28】 18. A process for preparing a compound of formula (III) according to any one of claims 3 to 17, wherein the compound is subjected to a Pictet-Spengler cyclization reaction with 2-( ...3-(2-(2-(2-(2-(2-(2-(2-(2-(2-(3-(2-(2-(2-(2-(2-(2-(

23. A compound of formula 1Ae, or any of its pharmaceutically acceptable salts: 【Chemical 29】 (Wherein R3a' is a carboxylic acid ester such as -COOMe or -COOEt, and R1, R2, R3, R3'', R4, R5, R5', R6, R7, R8, n, p, 【Chemistry 30】 , X and Y are as defined in any of claims 1 to 16).

24. A medicament comprising a compound of formula (I), (II) or (III) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof.

25. 18. A pharmaceutical composition comprising a compound of formula (I), (II) or (III) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

26. 18. A compound of formula (I), (II) or (III) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, for use as an inhibitor and degrader of estrogen receptors.

27. 18. A compound of formula (I), (II) or (III) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, for use in the treatment of ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia or inflammation.

28. 28. A compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, for use according to claim 27, for use in the treatment of cancer.

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