NOVEL SUBSTITUTED 2,3,4,9-TETRAHYDRO-1H-PYRIDO[3,4-B]INDOLE CARBOXYLIC ACID DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND THERAPEUTIC USES THEREOF Disclosed herein are novel substituted 2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole carboxylic acid, the processes for their preparation, as well as the therapeutic uses thereof, in particular as anticancer agents via selective antagonism and degradation of estrogen receptors. The Estrogen Receptors (ER) belong to the steroid/nuclear receptor superfamily involved in the regulation of eukaryotic gene expression, cellular proliferation and differentiation in target tissues. ERs are in two forms: the estrogen receptor alpha (ERα) and the estrogen receptor beta (ERβ) respectively encoded by the ESR1 and the ESR2 genes. ERα and ERβ are ligand-activated transcription factors which are activated by the hormone estrogen (the most potent estrogen produced in the body is 17β-estradiol). In the absence of hormone, ERs are largely located in the cytosol of the cell. When the hormone estrogen binds to ERs, ERs migrate from the cytosol to the nucleus of the cell, form dimers and then bind to specific genomic sequences called Estrogen Response Elements (ERE). The DNA/ER complex interacts with co-regulators to modulate the transcription of target genes. ERα is mainly expressed in reproductive tissues such as uterus, ovary, breast, bone and white adipose tissue. Abnormal ERα signaling leads to development of a variety of diseases, such as cancers, metabolic and cardiovascular diseases, neurodegenerative diseases, inflammation diseases and osteoporosis. ERα is expressed in not more than 10% of normal breast epithelium but approximately 50-80% of breast tumors. Such breast tumors with high level of ERα are classified as ERα-positive breast tumors. The etiological role of estrogen in breast cancer is well established and modulation of ERα signaling remains the mainstay of breast cancer treatment for the majority ERα-positive breast tumors. Currently, several strategies for inhibiting the estrogen axis in breast cancer exist, including: 1- blocking estrogen synthesis by aromatase inhibitors that are used to treat early and advanced ERα-positive breast cancer patients; 2- antagonizing estrogen ligand binding to ERα by tamoxifen which is used to treat ERα-positive breast cancer patients in both pre- and post- menopausal setting; 3- antagonizing and downregulating ERα levels by fulvestrant, which is used to treat breast cancer in patients that have progressed despite endocrine therapies such as tamoxifen or aromatase inhibitors. Although these endocrine therapies have contributed enormously to reduction in breast cancer development, about more than one-third of ERα-positive patients display de- novo resistance or develop resistance over time to such existing therapies. Several mechanisms have been described to explain resistance to such hormone therapies. For example, hypersensitivity of ERα to low estrogen level in treatment with aromatase inhibitors, the switch of tamoxifen effects from antagonist to agonist effects in tamoxifen treatments or multiple growth factor receptor signaling pathways. Acquired mutations in ERα occurring after initiation of hormone therapies may also play a role in treatment failure and cancer progression. Certain mutations in ERα, particularly those identified in the Ligand Binding Domain (LBD), result in the ability to bind to DNA in the absence of ligand and confer hormone independence in cells harboring such mutant receptors. Most of the endocrine therapy resistance mechanisms identified rely on ERα- dependent activity. One of the new strategies to counterforce such resistance is to shut down the ERα signaling by removing ERα from the tumor cells using Selective Estrogen Receptors Degraders (SERDs). Clinical and preclinical data showed that a significant number of the resistance pathways can be circumvented by the use of SERDs. There is still a need to provide SERDs with good degradation efficacy. Documents WO2017/140669 and WO2018/091153 disclose some substituted 6,7-dihydro-5H-benzo[7]annulene compounds and substituted N-(3-fluoropropyl)- pyrrolidine derivatives useful as SERDs. The inventors have now found novel compounds able to selectively antagonize and degrade the estrogen receptors (SERDs compounds), for use in cancer treatment. Disclosed herein are compounds of the formula (I), or pharmaceutically acceptable salts thereof:

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; with the proviso that one of R3 and R3’, but not both, represents a -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 -CH ₂ -, -CH=, -CR9=, -O- or -NH-, wherein R9 represents a fluorine atom or a (C ₁ -C ₃ )alkyl group; - represents a single bond or a double bond; - p is 0 or 1; - X represents -CH=, -N= or -CR”=, wherein R” represents a (C ₁ -C ₃ )alkyl group or a halogen atom, such as a fluorine or a chlorine atom, a cyano group, or a (C ₁ -C ₃ )fluoroalkyl group, such as a trifluoromethyl; - R7 independently represents a (C ₁ -C ₃ )alkyl group, such as a methyl group, a halogen atom, such as a fluorine atom, a cyano group, or a (C ₁ -C ₃ )fluoroalkyl group, such as a trifluoromethyl; - n is 0, 1 or 2; and - R6 represents a (C ₁ -C ₉ )alkyl group, said (C ₁ -C ₉ )alkyl group being optionally substituted with 1 to 4 substituents independently selected from: a halogen atom, a -cyano group, a -ORa group, a -N(Ra)2 group, a (C ₁ -C ₉ )alkyl group, a (C ₁ -C ₉ )alkoxy group, a (C ₁ -C ₃ )fluoroalkoxy group, a (C ₃ -C ₉ )cycloalkyl group, a (C ₃ -C ₉ )heterocycle group, a (C ₆ -C ₉ )aryl group, a (C ₅ -C ₁₀ )heteroaryl group, a -C(O)R _b group, a -C(O)NR _a group, a -SO ₂ CH ₃ group, and a SO ₂ NRa group; - Ra represents a hydrogen atom, a (C ₁ -C ₆ )alkyl group, a (C ₂ -C ₈ )alkenyl group, a propargyl group, a (C ₃ -C ₆ )cycloalkyl group, and a (C ₃ -C ₇ )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 -OH group, a methoxy group, and a -SO ₂ CH ₃ group; - Rb represents a hydrogen atom, a -O((C ₁ -C ₃ )alkyl) group, a (C ₁ -C ₆ )alkyl group, a (C ₂ -C ₈ )alkenyl group, a propargyl group, a -((C ₂ -C ₆ )alkene)-((C ₃ -C ₆ )cycloalkyl) group, a (C ₃ -C ₆ )cycloalkyl group, and a (C ₃ -C ₇ )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 -CH ₂ F group, a -CHF ₂ group, a -CF ₃ group, a -CH ₂ CF ₃ group, a -CH ₂ CHF ₂ group, a -CH ₂ CH ₂ F group, a -OH group, a methoxy group, and a -SO ₂ CH ₃ group; and - R8 represents a hydrogen atom, a cyano group, a (C ₁ -C ₆ )alkyl group, a -CH ₂ OH group, a -CH ₂ OCH ₃ group, a -CH ₂ CH ₂ OH group, a -C(CH ₃ ) ₂ OH group, a -CH(OH)CH(CH ₃ ) ₂ group, a -C(CH ₃ ) ₂ CH ₂ OH group, a -CH ₂ CH ₂ SO ₂ CH ₃ group, a -CH ₂ OP(O)(OH)2 group, a -CH ₂ F group, a -CHF ₂ group, a -CH ₂ NH2 group, a -CH ₂ NHSO ₂ CH ₃ group, a -CH ₂ NHCH ₃ group, a -CH ₂ N(CH ₃ )2 group, a -CF ₃ group, a -CH ₂ CF ₃ group, a -CH ₂ CHF ₂ group, a -CH(CH ₃ )CN group, a -C(CH ₃ ) ₂ CN group, a -CH ₂ CN group, a -CO ₂ H group, a -COCH ₃ group, a -CO ₂ CH ₃ group, a -CO ₂ C(CH ₃ )3 group, a -COCH(OH)CH ₃ group, a -CONH ₂ group, a -CONHCH ₃ group, a -CONHCH ₂ CH ₃ group, a -CONHCH(CH ₃ ) ₂ group, a -CON(CH ₃ ) ₂ group, a -C(CH ₃ )2CONH ₂ group, a cyclopropyl group, a cyclopropylamide group, a cyclobutyl group, an oxetanyl group, an azetidinyl group, a 1-methylazetidin-3- yl)oxy group, a N-methyl-N-oxetan-3-ylamino group, an azetidin-1-ylmethyl group, a benzyloxyphenyl group, a pyrrolidin-1-yl group, a pyrrolidin-l-yl-methanone group, a piperazin-l-yl group, a morpholinomethyl group, a morpholino-methanone group, or a morpholino group. Disclosed herein are compounds of the formula (I), or pharmaceutically acceptable salts thereof: 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; with the proviso that one of R3 and R3’, but not both, represents a -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 -CH ₂ -, -CH=, -CR9=, -O- or -NH-, wherein R9 represents a fluorine atom or a (C ₁ -C ₃ )alkyl group; - represents a single bond or a double bond; - p is 0 or 1; - X represents -CH=, -N= or -CR”=, wherein R” represents a (C ₁ -C ₃ )alkyl group or a halogen atom, such as a fluorine or a chlorine atom, a cyano group, or a (C ₁ -C ₃ )fluoroalkyl group, such as a trifluoromethyl; - R7 independently represents a (C ₁ -C ₃ )alkyl group, such as a methyl group, a halogen atom, such as a fluorine atom, a cyano group, or a (C ₁ -C ₃ )fluoroalkyl group, such as a trifluoromethyl; - n is 0, 1 or 2; and - R6 represents a (C ₁ -C ₉ )alkyl group, said (C ₁ -C ₉ )alkyl group being optionally substituted with 1 to 4 substituents independently selected from: a halogen atom, a -cyano group, a -OR _a group, a -N(R _a ) ₂ group, a (C ₁ -C ₉ )alkyl group, a (C ₁ -C ₉ )alkoxy group, a (C ₁ -C ₃ )fluoroalkoxy group, a (C ₃ -C ₉ )cycloalkyl group, a (C ₃ -C ₉ )heterocycle group, a (C ₆ -C ₉ )aryl group, a (C ₅ -C ₁₀ )heteroaryl group, a -C(O)R _b group, a -C(O)NR _a group, a -SO ₂ CH ₃ group, and a SO ₂ NR _a group; - R _a represents a hydrogen atom, a (C ₁ -C ₆ )alkyl group, a (C ₂ -C ₈ )alkenyl group, a propargyl group, a (C ₃ -C ₆ )cycloalkyl group, and a (C ₃ -C ₇ )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 -OH group, a methoxy group, and a -SO ₂ CH ₃ group; - R _b represents a hydrogen atom, a -O((C ₁ -C ₃ )alkyl) group, a (C ₁ -C ₆ )alkyl group, a (C ₂ -C ₈ )alkenyl group, a propargyl group, a -((C ₂ -C ₆ )alkene)-((C ₃ -C ₆ )cycloalkyl) group, a (C ₃ -C ₆ )cycloalkyl group, and a (C ₃ -C ₇ )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 -CH ₂ F group, a -CHF ₂ group, a -CF ₃ group, a -CH ₂ CF ₃ group, a -CH ₂ CHF ₂ group, a -CH ₂ CH ₂ F group, a -OH group, a methoxy group, and a -SO ₂ CH ₃ group; and - R8 represents a hydrogen atom, a cyano group, a (C ₁ -C ₆ )alkyl group, a -CH ₂ OH group, a -CH ₂ OCH ₃ group, a -CH ₂ CH ₂ OH group, a -C(CH ₃ )2OH group, a -CH(OH)CH(CH ₃ ) ₂ group, a -C(CH ₃ ) ₂ CH ₂ OH group, a -CH ₂ CH ₂ SO ₂ CH ₃ group, a -CH ₂ OP(O)(OH) ₂ group, a -CH ₂ F group, a -CHF ₂ group, a -CH ₂ NH ₂ group, a -CH ₂ NHSO ₂ CH ₃ group, a -CH ₂ NHCH ₃ group, a -CH ₂ N(CH ₃ ) ₂ group, a -CF ₃ group, a -CH ₂ CF ₃ group, a -CH ₂ CHF ₂ group, a -CH(CH ₃ )CN group, a -C(CH ₃ )2CN group, a -CH ₂ CN group, a -CO ₂ H group, a -COCH ₃ group, a -CO ₂ CH ₃ group, a -CO ₂ C(CH ₃ ) ₃ group, a -COCH(OH)CH ₃ group, a -CONH ₂ group, a -CONHCH ₃ group, a -CONHCH ₂ CH ₃ group, a -CONHCH(CH ₃ ) ₂ group, a -CON(CH ₃ ) ₂ group, a -C(CH ₃ ) ₂ CONH ₂ group, a cyclopropyl group, a cyclopropylamide group, a cyclobutyl group, an oxetanyl group, an azetidinyl group, a 1-methylazetidin-3- yl)oxy group, a N-methyl-N-oxetan-3-ylamino group, an azetidin-1-ylmethyl group, a benzyloxyphenyl group, a pyrrolidin-1-yl group, a pyrrolidin-l-yl-methanone group, a piperazin-l-yl group, a morpholinomethyl group, a morpholino-methanone group, or a morpholino group, - with the proviso that when 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 ; then R6 does not represent a 2,2-difluoropropyl group, and - with the proviso that 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 CH ₃ ; then R6 does not represent a 2,2-difluoro-3-hydroxypropyl group. The compounds of formula (I) can contain one or more asymmetric carbon atoms. They may therefore exist in the form of enantiomers. The compounds of formula (I) may be present as well under tautomer forms. The compounds of formula (I) may exist in the form of bases, acids, zwitterion or of addition salts with acids or bases. Hence, herein are provided compounds of formula (I) or pharmaceutically acceptable salts thereof. These salts may be prepared with pharmaceutically acceptable acids or bases, although the salts of other acids or bases useful, for example, for purifying or isolating the compounds of formula (I) are also provided. Among suitable salts of the compounds of formula (I), hydrochloride may be cited. As used herein, the terms below have the following definitions unless otherwise mentioned throughout the instant specification: - a halogen atom: a fluorine, a chlorine, a bromine or an iodine atom, and in particular a fluorine and a chlorine atom; - an alkyl group: a linear or branched saturated hydrocarbon-based aliphatic group comprising, unless otherwise mentioned, from 1 to 9 carbon atoms (noted “(C ₁ -C ₉ ) alkyl”). By way of examples, mention may be made of, but not limited to: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl and isohexyl groups, and the like; - an alkene group: a linear or branched unsatured or partially unsaturated aliphatic group containing conjugated or non-conjugated double bond(s), comprising, unless otherwise mentioned, from 2 to 6 carbon atoms; - a cycloalkyl group: a monocyclic alkyl group comprising, unless otherwise mentioned, from 3 to 9 carbon atoms, saturated or partially unsaturated and unsubstituted or substituted; - a heterocycle 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 where the ring is saturated or unsaturated, but not aromatic. A 3 or 4 membered ring may contain 1 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; - a heterocycloalkyl group: a 3 to 7-membered cycloalkyl group, saturated or partially unsaturated, comprising 1 to 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, in particular being oxygen or nitrogen; - a fluoroalkyl group: an alkyl group as previously defined where the alkyl group is substituted with at least one fluorine atom. In other terms, at least one hydrogen atom of the alkyl group is replaced by a fluorine atom. By way of example, mention may be made of -CH ₂ F, -CHF ₂ , -CH ₂ CHF ₂ , -CH ₂ CH ₂ F and the like. When all the hydrogen atoms belonging to the alkyl group are replaced by fluorine atoms, the fluoroalkyl group can be named perfluoroalkyl group. By way of example, mention may be made of trifluoromethyl group or trifluoroethyl group and the like; - an alkoxy group: an -O-alkyl group where the alkyl group is as previously defined. By way of examples, mention may be made of, but not limited to: methoxy, ethoxy, propoxy, isopropoxy, linear, secondary or tertiary butoxy, isobutoxy, pentoxy or hexoxy groups, and the like; - a fluoroalkoxy group: an -O-alkyl group where the alkyl group is as previously defined and where the alkyl group is substituted with at least one fluorine atom. In other terms, at least one hydrogen atom of the alkyl group is replaced by a fluorine atom. By way of example, mention may be made of -OCH ₂ F, -OCHF ₂ , -OCH ₂ CH ₂ F and the like. When all the hydrogen atoms belonging to the alkyl group are replaced by fluorine atoms, the fluoroalkoxy group can be named perfluoroalkoxy group. By way of example, mention may be made of trifluoromethoxy group and the like; - an aryl group : a monocyclic or bicyclic aromatic group containing 6 or 9 carbon atoms. - a heteroaryl group: a cyclic 5 to 10-membered aromatic group containing between 2 and 9 carbon atoms and containing between 1 and 3 heteroatoms, such as nitrogen, oxygen or sulfur. Such nitrogen atom may be substituted with an oxygen atom in order to form a -N-O bond. Such -N-O bond can be in a form of a N-oxide (-N ⁺ -O-); - a zwitterion means: a globally neutral molecule with a positive and a negative electrical charge and having an acidic group and a basic group. 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’ represents a -COOH group. Accordingly, herein are described compounds of formula (II) and (III): wherein R1, R2, R3, R3’, R3”, R4, R5, R5’, R6, R7, R8, , Y, n and p are as defined in formula (I) hereabove. In another embodiment, the compounds of formula (I) as defined above are of formula (II). In another embodiment, in the compounds of formula (I) or (II) as defined above, R3’ and R3” both represent a hydrogen atom. 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. 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. In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, R1 and R2 are a hydrogen atom. In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, R4 represents a hydrogen atom. In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, R5 and R5’ represent a hydrogen atom. In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, p is 0. In another embodiment, in the compounds of formula (I) as defined above, p is 1. In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, X represents -CR”=, wherein R” represents a halogen atom, preferably a fluorine atom. In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, X represents -CH=. In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, R6 represents a (C ₁ -C ₆ )alkyl group, said (C ₁ -C ₆ )alkyl group being optionally substituted with 1 to 3 substituents independently selected from a fluorine atom, a methyl group and a -OH group. In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, R6 represents a -CH ₂ -CF ₃ group, a -CH ₂ -CF ₂ -CH ₂ -OH group or a -CH ₂ -CF ₂ -CH ₃ group. In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, R7 is a halogen atom, and preferably a fluorine atom. In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, n is 0. In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, n is 1. In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, n is 2. 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. In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, R8 represents a (C ₁ -C ₆ )alkyl group, and preferably represents a methyl group. In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, Y represents -CH ₂ -, -CH=, -O- or -NH-. In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, Y represents -CH ₂ . In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, Y represents -CH=. In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, Y represents -O-. In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, Y represents -NH-. In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, represents a single bond. In another embodiment, represents a double bond. In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, p is equal to 1. Among the compounds of formula (I), (II) or (III) described herein, mention may be made in particular of the following compounds or a pharmaceutically acceptable salt thereof, in particular hydrochloride salt thereof: - (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-te trahydro-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-tetr ahydro-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-yli dene)methyl)phenyl)- 2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido [3,4-b]indole-7- carboxylic acid, (15). Another embodiment is a compound selected from the above list, or a pharmaceutically acceptable salt thereof, for use in therapy, especially as an inhibitor and degrader of estrogen receptors. Another embodiment is a compound selected from the above list, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, especially breast cancer. Another embodiment is a method of inhibiting and degrading estrogen receptors, comprising administering to a subject in need thereof, in particular a human, a therapeutically effective amount of a compound selected from the above list, or a pharmaceutically acceptable salt thereof. Another embodiment is a method of treating ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hypertrophy or inflammation, comprising administering to a subject in need thereof, in particular a human, a therapeutically effective amount of a compound selected from the above list, or a pharmaceutically acceptable salt thereof. Another embodiment is a method of treating cancer, comprising administering to a subject in need thereof, in particular a human, a therapeutically effective amount of a compound selected from the above list, or a pharmaceutically acceptable salt thereof. Another embodiment is a pharmaceutical composition comprising as active principle an effective dose of a compound selected from the above list, or a pharmaceutically acceptable salt thereof, and also at least one pharmaceutically acceptable excipient. The compounds of the formula (I), (II) or (III) can be prepared by the following processes. The compounds of the formula (I), (II) or (III) and other related compounds having different substituents are synthesized using techniques and materials described below or otherwise known by the skilled person in the art. In addition, solvents, temperatures and other reaction conditions presented below may vary as deemed appropriate to the skilled person in the art. General below methods for the preparation of 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 the formula (I), (II) or (III) are described below. The following abbreviations and empirical formulae are used: AcOH Acetic acid MeCN Acetonitrile NH ₄ HCO ₃ Ammonium acetate NH ₄ OAc Ammonium bicarbonate NH4Cl Ammonium chloride BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) Pd(dppf)Cl ₂ [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II ) NiCl ₂ .dtbbpy [4,4′-Bis(1,1-dimethylethyl)-2,2′-bipyridine] nickel (II) dichloride n-BuLi n-Butyllithium CO Carbon monoxide CO ₂ Carbon dioxide Cs ₂ CO ₃ 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 LG Leaving group LiOH Lithium hydroxide MeOH Methanol MgSO ₄ Magnesium sulfate MeMgCl Methyl magnesium chloride Pd/C Palladium on carbon Pd(OH) ₂ Palladium hydroxide POCl3 Phosphorus oxychloride PtO ₂ Platinum oxide K ₂ CO ₃ Potassium carbonate K ₃ PO ₄ Potassium phosphate LG Leaving group NaHCO ₃ Sodium bicarbonate NaCl Sodium chloride NaBH ₃ CN Sodium cayanoborohydride Na ₂ SO ₄ 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 tBuBrettPhos Pd G ₃ [(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 PPh ₃ Triphenylphosphine RT Room temperature SCHEME 1a Parts 1 and 2: Preparation of compounds of the formula (II) – General process SCHEME 1a – Part - 1:

According to SCHEME 1a – Part 1 and Part 2, in which R3a is a carboxylic ester such as -COOMe or -COOEt, R1, R2, R3, R3’, R3’’, R4, R5, R5’, R6, R7, R8, n, p, X, Y and are defined as described above, compound 1A can be converted in STEP 1 to compound 1C by treatment with compound 1B in the presence of methylmagnesium chloride (MeMgCl) and copper chloride (CuCl). Compound 1C can be converted in STEP 2 to compound 1D by carbonylation with carbon monoxide (CO), in solution in MeOH or EtOH, in the presence of a palladium catalyst, for example palladium acetate or [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (Pd(dppf)Cl ₂ ), complex with DCM. Compound 1D can be converted in STEP 3 to compound 1E by treatment with TFA or HCl or chlorotrimethylsilane. Compound 1E can be converted in STEP 4 to compound 1G by treatment with compound 1F (R6-LG), wherein 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. Compound 1G can be converted in STEP 5 to compound 1J by treatment with compound 1H in a Pictet-Spengler cyclization reaction in the presence of an acid, such as TFA or acetic acid, in a suitable solvent, for example toluene by heating up to reflux of solvent. Alternatively, compound 1J can be obtained by treatment of compound 1G with compound 1K in STEP 6 in a Pictet-Spengler cyclization reaction in the presence of an acid, such as TFA or acetic acid, in a suitable solvent, for example toluene, by heating up to reflux of solvent, followed by a coupling reaction in STEP 7 between obtained compound 1L and one of compounds 1M under coupling reaction conditions. Compound 1J can be converted in STEP 8 to compound II by treatment with an aqueous solution of sodium hydroxide (NaOH) or lithium hydroxide (LiOH) in MeOH or THF. Extraction of the product could give the sodium or lithium salt of compound II. The acidification with an aqueous solution of HCl to pH 6-7 could give the neutral form of compound II. The acidification with an aqueous solution of HCl to pH 1-2 could give the hydrochloride salt of compound II. The purification using HPLC in presence of formic acid or trifluoroacetic acid in the eluent could give the formate or trifluoroacetate salt of compound II. When Y = CH=, compound II may be reduced by hydrogenation in STEP 9 with a catalyst, such as Pd/C or platinum oxide (PtO2) under hydrogen (H2) pressure to give the corresponding saturated compound II’. Alternatively, when Y = CH=, compound II’ could be prepared in STEP 10 by hydrogenation of compound 1J with a catalyst, such as Pd/C or platinum oxide (PtO ₂ ) under hydrogen (H ₂ ) pressure followed by the treatment with an aqueous solution of NaOH or LiOH in MeOH or THF. Extraction of the product could give the sodium or lithium salt of compound II’. The acidification with an aqueous solution of HCl to pH 6-7 could give the neutral form of compound II’. The acidification with an aqueous solution of HCl to pH 1-2 could give the hydrochloride salt of compound II’. The purification using HPLC in presence of formic acid or trifluoroacetic acid in the eluent could give the formate or trifluoroacetate salt of compound II’. SCHEME 1b: Alternative process to prepare Intermediate 1J According to SCHEME 1b, in which R3a is a carboxylic ester such as -COOMe or -COOEt, R1, R2, R3’, R3’’, R4, R5, R5’, R6, R7, R8, n, p, X, Y and are defined as described above, compound 1G can be converted in STEP 1 to compound 1N by treatment with compound 1H’ in a Pictet-Spengler cyclization reaction in the presence of an acid, such as TFA or acetic acid, in a suitable solvent, for example toluene, by heating up to reflux of solvent. Alternatively, compound 1N can be obtained, in STEP 2, in a coupling reaction, by treatment of compound 1L with one of compounds 1M’ under coupling reaction conditions. Compound 1N can be converted in STEP 3 to compound 1O by treatment with TFA or HCl. Compound 1O can be converted in STEP 4 to compound 1J by the treatment with compound 1P, wherein W is Cl, Br or I or OSO ₂ R with R = CH ₃ , PhMe, CF ₃ or CF ₂ CF ₂ CF ₂ CF ₃ in the presence of a base such as potassium carbonate (K ₂ CO ₃ ) in DMF as a solvent. SCHEME 1c: Alternative process to prepare Intermediate 1E According to SCHEME 1c, in which R3a is a carboxylic ester such as -COOMe or -COOEt, R8 is a methyl group, R3’ and R3’’ are defined as described above, compound 1Q can be converted in STEP 1 to compound 1R in Vilsmeier-Haack reaction conditions in the presence of POCl ₃ and DMF. Compound 1R can be converted in STEP 2 to compound 1S by treatment with nitroethane in the presence of ammonium acetate. Compound 1S can be converted in STEP 3 to compound 1T by treatment with iron in the presence of an acid such as HCl. Compound 1T can be converted in STEP 4 to compound 1V in reductive amination reaction by treatment with compound 1U in the presence of NaBH3CN and acetic acid. Compound 1E can be obtained in STEP 5 by hydrogenation of compound 1V in the presence of a catalyst such as Pd/C or Pd(OH)2. SCHEME 1d Parts 1 and 2: General process to prepare compounds of the formula (III) SCHEME 1d – Part - 1: SCHEME 1d – Part - 2: According to SCHEME 1d – Part 1 and Part 2, in which R3a’ is a carboxylic 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 are defined as above, compound 1W can be converted in STEP 1 to compound 1X in Vilsmeier-Haack reaction conditions in the presence of POCl ₃ and DMF. Compound 1X can be converted in STEP 2 to compound 1Y by treatment with nitroethane in the presence of ammonium acetate (NH4OAc). Compound 1Y can be converted in STEP 3 to compound 1Z by treatment with iron (Fe) in the presence of an acid such as HCl. Compound 1Z can be converted in STEP 4 to compound 1Aa in reductive amination reaction by treatment with compound 1U in the presence of NaBH3CN and acetic acid. Compound 1Ab can be obtained in STEP 5 by hydrogenation of compound 1Aa in the presence of a catalyst such as Pd/C or Pd(OH) ₂ . Compound 1Ab can be converted in STEP 6 to compound 1Ac by treatment with compound 1F (R6-LG), wherein 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. According to SCHEME 1d –Part 2, compound 1Ac can be converted in STEP 7 to compound 1Ae by treatment with compound 1H in a Pictet-Spengler cyclization reaction in the presence of an acid, such as TFA or acetic acid, in a suitable solvent, for example toluene by heating up to reflux of solvent. Alternatively, compound 1Ae can be obtained by treatment of compound 1Ac with compound 1K in STEP 8 in a Pictet-Spengler cyclization reaction in the presence of an acid, such as TFA or acetic acid, in a suitable solvent, for example toluene, by heating up to reflux of solvent, followed by a coupling reaction in STEP 9 between obtained compound 1Ad and one of compounds 1M under coupling reaction conditions. Compound 1Ae can be converted in STEP 10 to compound III by treatment with an aqueous solution of sodium hydroxide (NaOH) or lithium hydroxide (LiOH) in MeOH or THF. Extraction of the product could give the sodium or lithium salt of compound III. The acidification with an aqueous solution of HCl to pH 6-7 could give the neutral form of compound III. The acidification with an aqueous solution of HCl to pH 1-2 could give the hydrochloride salt of compound III. The purification using HPLC in presence of formic acid or trifluoroacetic acid in the eluent could give the formate or trifluoroacetate salt of compound III. When Y = CH=, compound III may be reduced by hydrogenation in STEP 11 with a catalyst, such as Pd/C or platinum oxide (PtO2) under hydrogen (H2) pressure to give the corresponding saturated compound III’. Alternatively, when Y = CH=, compound III’ could be prepared in STEP 12 by hydrogenation of compound 1Ae with a catalyst, such as Pd/C or platinum oxide (PtO ₂ ) under hydrogen (H2) pressure followed by the treatment with an aqueous solution of NaOH or LiOH in MeOH or THF. Extraction of the product could give the sodium or lithium salt of compound III’. The acidification with an aqueous solution of HCl to pH 6-7 could give the neutral form of compound III’. The acidification with an aqueous solution of HCl to pH 1-2 could give the hydrochloride salt of compound III’. The purification using HPLC in presence of formic acid or trifluoroacetic acid in the eluent could give the formate or trifluoroacetate salt of compound III’. SCHEME 1e: Alternative process to prepare Intermediate 1Ae

According to SCHEME 1e, in which R3a’ is a carboxylic ester such as -COOMe or -COOEt, R1, R2, R3, R3’’, R4, R5, R5’, R6, R7, R8, n, p, X, Y and are defined as described above, compound 1Ac can be converted in STEP 1 to compound 1Af by treatment with compound 1H’ in a Pictet-Spengler cyclization reaction in the presence of an acid, such as TFA or acetic acid, in a suitable solvent, for example toluene, by heating up to reflux of solvent. Alternatively, compound 1Af can be obtained, in STEP 2, in a coupling reaction, by treatment of compound 1Ad with one of compounds 1M’ under coupling reaction conditions. Compound 1Af can be converted in STEP 3 to compound 1Ag by treatment with TFA or HCl. Compound 1Ag can be converted in STEP 4 to compound 1Ae by the treatment with compound 1P, wherein W is Cl, Br or I or OSO ₂ R with R = CH ₃ , PhMe, CF ₃ or CF ₂ CF ₂ CF ₂ CF ₃ in the presence of a base such as potassium carbonate (K ₂ CO ₃ ) in DMF as a solvent. Herein is also provided a process for preparing a compound of formula (II) as defined above, wherein a compound of formula 1J: wherein R1, R2, R3’, R3’’, R4, R5, R5’, R6, R7, R8, n, p, X and Y are defined as described above and R3a is a carboxylic ester such as -COOMe or -COOEt, is converted to compound of formula (II), in presence of a source of hydroxide ions, such as NaOH or LiOH in solution in methanol or THF, said step being optionally preceded by a step of obtaining compound 1J, wherein a compound of formula 1L:

wherein R3’, R3’’, R6, R7, R8, n and X are defined as described above and R3a is a carboxylic ester such as -COOMe or -COOEt, is subjected to a coupling step with one of compounds 1M under coupling reaction conditions: wherein R1, R2, R4, R5, R5’ and p are as defined above. Herein is also provided a process for preparing a compound of formula (II) as defined above, wherein a compound of formula 1J: wherein R1, R2, R3’, R3’’, R4, R5, R5’, R6, R7, R8, , n, p, X and Y are defined as described above and R3a is a carboxylic ester such as -COOMe or -COOEt, is converted to compound of formula (II), in presence of a source of hydroxide ions, such as NaOH or LiOH in solution in methanol or THF, said step being optionally preceded by a step of obtaining compound 1J, wherein a compound of formula 1G: wherein R3’, R3’’, R6 and R8 are defined as described above and R3a is a carboxylic ester such as -COOMe or -COOEt, is subjected to a Pictet-Spengler cyclization reaction in the presence of an acid, such as TFA or acetic acid, in a suitable solvent, for example toluene, with compound 1H: wherein R1, R2, R4, R5, R5’, R7, X, Y, , n and p are as defined above. Herein is also provided a process for preparing a compound of formula (II) as defined above, wherein a compound of formula 1J: wherein R1, R2, R3’, R3’’, R4, R5, R5’, R6, R7, R8, , n, p, X and Y are defined as described above and R3a is carboxylic ester such as -COOMe or -COOEt is converted to compound of formula (II), in presence of a source of hydroxide ions, such as NaOH or LiOH in solution in methanol or THF, said step being optionally preceded by a step of obtaining compound 1J, wherein a compound of formula 1O: wherein R3’, R3’’, R6, R7, R8, , n, p, X and Y are defined as described above and R3a is a carboxylic ester such as -COOMe or -COOEt, is converted to compound 1J, in presence of a base, such as potassium carbonate (K2CO3) in DMF as a solvent, by the treatment with compound 1P: wherein W is Cl, Br or I or OSO ₂ R with R = CH ₃ , PhMe,CF ₃ or CF ₂ CF ₂ CF ₂ CF ₃ and R1, R2, R4, R5 and R5’ are as defined above. Herein are also described the intermediate compounds selected from compounds of formula 1J, 1L, 1N, 1O, or any of its pharmaceutically acceptable salt,

wherein R1, R2, R3, R3’, R3’’, R4, R5, R5’, R6, R7, R8, n, p, , X and Y are defined above and R3a is a hydrogen atom or carboxylic ester such as -COOMe or -COOEt. Herein is also provided a process for preparing a compound of formula (III) as defined above, wherein a compound of formula 1Ae: e wherein R1, R2, R3, R3’’, R4, R5, R5’, R6, R7, R8, n, p, X and Y are defined as described above and R3a’ is carboxylic ester such as -COOMe or -COOEt is converted to compound of formula (III), in presence of a source of hydroxide ions, such as NaOH or LiOH in solution in methanol or THF, said step being optionally preceded by a step of obtaining compound 1Ae, wherein a compound of formula 1Ad:

wherein R3, R3’’, R6, R7, R8, n and X are defined as described above and R3a’ is as a carboxylic ester such as -COOMe or -COOEt, is subjected to a coupling step with one of compounds 1M under coupling reaction conditions: wherein R1, R2, R4, R5, R5’ and p are as defined above. Herein is also provided a process for preparing a compound of formula (III) as defined above, wherein a compound of formula 1Ae: wherein R1, R2, R3, R3’’, R4, R5, R5’, R6, R7, R8, , n, p, X and Y are defined as described above and R3a’ is a carboxylic ester such as -COOMe or -COOEt is converted to compound of formula (III), in presence of a source of hydroxide ions, such as NaOH or LiOH in solution in methanol or THF, said step being optionally preceded by a step of obtaining compound 1Ae, wherein a compound of formula 1Ac: wherein R3, R3’’, R6 and R8 are defined as described above and R3a’ is a carboxylic ester such as -COOMe or -COOEt, is subjected to a Pictet-Spengler cyclization reaction in the presence of an acid, such as TFA or acetic acid, in a suitable solvent, for example toluene, with compound 1H: wherein R1, R2, R4, R5, R5’, R7, X, Y, , n and p are as defined above. Herein are also provided the intermediate compounds selected from compounds of formula 1Ae, or any of its pharmaceutically acceptable salt, wherein R3a’ is a carboxylic ester such as -COOMe or -COOEt, R1, R2, R3, R3’’, R4, R5, R5’, R6, R7, R8, n, p, , X and Y are defined above. In another aspect, herein is also provided a process for the preparation of a compound of formula (I), comprising a deprotection step of a compound of formula 1J as defined above, optionally followed by a purification step. In another aspect, herein is also provided a process for the preparation of a compound of formula (III), comprising a deprotection step of a compound of formula 1Ae as defined above, optionally followed by a purification step. Said purification steps may for example consist, as illustrated in step 2 of example 1 herein after, in an acidification step, for example with an aqueous solution of hydrochloric acid. The ¹ H NMR Spectra at 400 and 500 MHz were performed on a Bruker Avance DRX-400 and Bruker Avance DPX-500 spectrometer, respectively, with the chemical shifts (δ in ppm) in the solvent dimethyl sulfoxide-d6 (d6-DMSO) referenced at 2.5 ppm at a temperature of 303 K. Coupling constants (J) are given in Hertz. The liquid chromatography/mass spectra (LC/MS) were obtained on a UPLC Acquity Waters instrument, light scattering detector Sedere and SQD Waters mass spectrometer using UV detection DAD 210-400 nm and flash Acquity UPLC CSH C181.7 µm, dimension 2.1x30 mm, mobile phase H ₂ O + 0.1% HCO ₂ H / CH ₃ CN + 0.1% HCO ₂ H. The following tables 1a and 1b comprises respectively specific compounds of formula (I) (name and structure) in accordance with the present disclosure as well their characterization ( ¹ H NMR and liquid chromatography/mass). Table 1a: (the first column “Ex” corresponds to the compound and example number)

Table 1b: The examples which follow describe the preparation of some compounds of formula (I), (II) and (III) described herein. The numbers of the compounds exemplified below match those given in the Tables 1a and 1b above. All reactions are performed under inert atmosphere, unless otherwise stated. In the following examples, when the source of the starting products is not specified, it should be understood that said products are known compounds. Examples Intermediates: Intermediate 1a: Methyl (R)-3-(2-aminopropyl)-1H-indole-6-carboxylate, hydrochloride Step 1: Tert-butyl (R)-(1-(6-bromo-1H-indol-3-yl)propan-2-yl)carbamate 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 was added dropwise MeMgCl 3 M in THF (14.3 ml, 42.9 mmol). The reaction mixture was stirred at 0 °C for 1h 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 dropwise added into the reaction mixture at -20 °C. The reaction mixture was allowed to warm to RT and stirred for 18 h. The reaction mixture was then cooled to 0 °C and a 2 M aqueous solution of citric acid (330 ml) was carefully added. The mixture was allowed to warm to RT, stirred for 10 min then filtered on a pad of celite. After decantation of the filtrate, the organic phase was washed with brine (50 ml), dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The residue obtained 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 Step 2: Methyl (R)-3-(2-((tert-butoxycarbonyl)amino)propyl)-1H-indole-6-car boxylate In a stainless steel bomb, 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 eq) and [1,1’- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.92 g, 1.13 mmol) in MeOH (40 ml) was heated at 100 °C under CO atmosphere (5 bars) for 18h. The reaction mixture was cooled to RT then filtered on a pad of celite. The filtrate was concentrated under reduced pressure and the residue obtained was purified by flash chromatography eluting with a gradient of DCM/MeOH from 100/00 to 98/02 to give 1.85 g (98%) of methyl (R)-3-(2-((tert-butoxycarbonyl)amino)propyl)-1H-indole-6-car boxylate. LC/MS (m/z, MH+): 333 Step 3: Methyl (R)-3-(2-aminopropyl)-1H-indole-6-carboxylate, hydrochloride 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 slowly added chlorotrimethylsilane (23 ml, 177 mmol) at RT. The solution was stirred for 18h at RT. The solution was concentrated under reduced pressure to give 4.8 g (crude) of methyl (R)-3-(2-aminopropyl)- 1H-indole-6-carboxylate, hydrochloride used as such in the next step. LC/MS (m/z, MH+): 233 Intermediate 1b: Methyl 3-(2-aminopropyl)-1H-indole-6-carboxylate, racemic mixture Step 1: Methyl 3-formyl-1H-indole-6-carboxylate To a solution of methyl 1H-indole-6-carboxylate (1 g, 5.71 mmol) in DMF (100 ml) at RT was added POCl ₃ (1.31 g, 8.56 mmol, 795.70 µl) and the mixture was stirred for 3h. Water (20 ml) was slowly added into the reaction mixture and then, the mixture was heated at 120°C for 15 minutes. After cooling to RT, the solid precipitated was filtered and dried under reduced pressure to give 1 g (86%) of methyl 3-formyl-1H-indole-6-carboxylate as a pink solid. LC/MS (m/z, MH+): 204 Step 2: Methyl (E)-3-(2-nitroprop-1-en-1-yl)-1H-indole-6-carboxylate A mixture of methyl 3-formyl-1H-indole-6-carboxylate (1 g, 4.92 mmol) and NH4OAc (948 mg, 12.30 mmol) in nitroethane (11.08 g, 147.64 mmol, 10.56 ml) was heated to 100°C for 4h. After cooling to RT, the reaction mixture was diluted with water (20 ml) and EtOAc (40 ml). After decantation, the organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by flash chromatography eluting with a gradient of petroleum ether/ EtOAc from 100/00 to 70/30 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 Step 3: Methyl 3-(2-oxopropyl)-1H-indole-6-carboxylate 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) was added iron powder (644 mg, 11.53 mmol) and AcOH (623 mg, 10.37 mmol, 593 µl) at RT and the suspension was stirred at 60°C for 1.5h. Then aqueous HCl (2 M, 0.58 ml) was added into the reaction mixture and stirred for 6h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by flash chromatography eluting with a gradient of petroleum ether/EtOAc from 100/00 to 50/50 to give 200 mg (crude) of methyl 3-(2-oxopropyl)-1H- indole-6-carboxylate used as such in the next step. LC/MS (m/z, MH+): 232 Step 4: Methyl 3-(2-((1-phenylethyl)amino)propyl)-1H-indole-6-carboxylate To a solution of 1-phenylethanamine (300 mg, 2.48 mmol, 319.15 µl) in MeOH (10 ml) was dropwise added AcOH to adjust pH=5~6. Then methyl 3-(2-oxopropyl)-1H-indole-6- carboxylate (572 mg, 2.48 mmol) and NaBH3CN (156 mg, 2.48 mmol) were portionwise added. The mixture was stirred at RT for 16h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in DCM (20 ml) and washed with saturted NH ₃ .H ₂ O (10 ml). After decantation, the organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by flash chromatography eluting with a gradient of petroleum ether/ EtOAc from 100/00 to 00/100 to give 786 mg (94%) of methyl 3-(2-((1-phenylethyl)amino)propyl)-1H-indole-6- carboxylate as yellow oil. LC/MS (m/z, MH+): 337 Step 5: Methyl 3-(2-aminopropyl)-1H-indole-6-carboxylate, racemic mixture To a mixture of methyl 3-(2-((1-phenylethyl)amino)propyl)-1H-indole-6-carboxylate (685 mg, 2.04 mmol) in MeOH (13 ml) was added Pd(OH) ₂ /C 20% (286 mg) under N ₂ atmosphere and then purged with H2 for several times, and then the mixture was stirred at RT for 12h under H ₂ atmosphere (3 bars). The reaction mixture was filtered through celite and the filter cake was washed with MeOH (2x20 ml). Then the filtrate was concentrated under reduced pressure to give 460 mg (crude) of methyl 3-(2-aminopropyl)-1H-indole-6-carboxylate, racemic mixture used as such in the next step. LC/MS (m/z, MH+): 233 Intermediate 1c: Methyl 3-(2-aminopropyl)-1H-indole-5-carboxylate, racemic mixture Step 1: Methyl 3-formyl-1H-indole-5-carboxylate Step 1 of Intermediate 1c was prepared following a similar procedure to that of step 1 of Intermediate 1b from methyl 1H-indole-5-carboxylate to give 10.4 g (90%) of methyl 3- formyl-1H-indole-5-carboxylate as a pink solid. LC/MS (m/z, MH+): 204 Step 2: Methyl (E)-3-(2-nitroprop-1-en-1-yl)-1H-indole-5-carboxylate Step 2 of Intermediate 1c was prepared following a similar procedure to that of step 2 of Intermediate 1b from methyl 3-formyl-1H-indole-5-carboxylate to give 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 Step 3: Methyl 3-(2-oxopropyl)-1H-indole-5-carboxylate Step 3 of Intermediate 1c was prepared following a similar procedure to that of step 3 of Intermediate 1b from methyl (E)-3-(2-nitroprop-1-en-1-yl)-1H-indole-5-carboxylate to give 881 mg (50%) of methyl 3-(2-oxopropyl)-1H-indole-5-carboxylate used as such in the next step. LC/MS (m/z, MH+): 232 Step 4: Methyl 3-(2-((1-phenylethyl)amino)propyl)-1H-indole-5-carboxylate Step 4 of Intermediate 1c was prepared following a similar procedure to that of step 4 of Intermediate 1b from methyl 3-(2-oxopropyl)-1H-indole-5-carboxylate and 1- phenylethanamine to give 1.04 g (62%) of methyl 3-(2-((1-phenylethyl)amino)propyl)-1H- indole-5-carboxylate as yellow oil. LC/MS (m/z, MH+): 337 Step 5: Methyl 3-(2-aminopropyl)-1H-indole-5-carboxylate, racemic mixture Step 5 of Intermediate 1c was prepared following a similar procedure to that of step 5 of Intermediate 1b from methyl 3-(2-((1-phenylethyl)amino)propyl)-1H-indole-5-carboxylate to give 660 mg (crude) of methyl 3-(2-aminopropyl)-1H-indole-5-carboxylate, racemic mixture used as such in the next step. LC/MS (m/z, MH+): 233 Intermediate 2: Methyl (R)-3-(2-((2,2,2-trifluoroethyl)amino)propyl)-1H-indole-6- carboxylate A mixture of methyl (R)-3-(2-aminopropyl)-1H-indole-6-carboxylate, hydrochloride (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 18h. After cooling down to RT, the reaction mixture was concentrated under reduced pressure and the residue obtained was purified by flash chromatography eluting with a gradient of DCM/MeOH from 100/00 to 80/20 to give 455 mg (34%) of methyl (R)-3-(2- ((2,2,2-trifluoroethyl)amino)propyl)-1H-indole-6-carboxylate . LC/MS (m/z, MH+): 315 Intermediate 3a: Methyl (R)-3-(2-((2,2-difluoropropyl)amino)propyl)-1H-indole-6- carboxylate Intermediate 3a was prepared following a similar procedure to that of Intermediate 2 from methyl (R)-3-(2-aminopropyl)-1H-indole-6-carboxylate, hydrochloride (Intermediate 1a) and 2,2-difluoropropyl trifluoromethanesulfonate to give 620 mg (54%) of methyl (R)-3- (2-((2,2-difluoropropyl)amino)propyl)-1H-indole-6-carboxylat e. LC/MS (m/z, MH+): 311 Intermediate 3b: Methyl 3-(2-((2,2-difluoropropyl)amino)propyl)-1H-indole-6- carboxylate, racemic mixture Intermediate 3b was prepared following a similar procedure to that of Intermediate 2 from methyl 3-(2-aminopropyl)-1H-indole-6-carboxylate (Intermediate 1b) and 2,2- difluoropropyl trifluoromethanesulfonate to give 40 mg (56%) of methyl 3-(2-((2,2- difluoropropyl)amino)propyl)-1H-indole-6-carboxylate, racemic mixture as colorless oil. LC/MS (m/z, MH+): 311

Intermediate 3c: Methyl 3-(2-((2,2-difluoropropyl)amino)propyl)-1H-indole-5- carboxylate, racemic mixture Intermediate 3c was prepared following a similar procedure to that of Intermediate 2 from methyl 3-(2-aminopropyl)-1H-indole-5-carboxylate (Intermediate 1c) and 2,2- difluoropropyl trifluoromethanesulfonate to give 400 mg (40%) of methyl 3-(2-((2,2- difluoropropyl)amino)propyl)-1H-indole-5-carboxylate, racemic mixture as yellow oil. LC/MS (m/z, MH+): 311 Intermediate 4: Methyl (R)-3-(2-((3-((tert-butyldiphenylsilyl)oxy)-2,2- difluoropropyl)amino)propyl)-1H-indole-6-carboxylate Intermediate 4 was prepared following a similar procedure to that of Intermediate 2 from methyl (R)-3-(2-aminopropyl)-1H-indole-6-carboxylate, hydrochloride (Intermediate 1a) and 3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl trifluoromethanesulfonate to give 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 Intermediate 5: (S)-2,6-Difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)b enzaldehyde To a solution of 2,6-difluoro-4-hydroxybenzaldehyde (0.88 g, 5.44 mmol) in dry THF (20 ml), were added (R)-1-(3-fluoropropyl)pyrrolidin-3-ol (prepared according to WO2018091153) (1 g, 6.79 mmol), PPh ₃ (2.88 g, 10.9 mmol) and TMAD (1.87 g, 10.87 mmol). The reaction mixture was stirred at RT for 48h. Water (50 ml) and EtOAc (100 ml) were added, then aqueous layer was 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 DCM/MeOH from 100/00 to 80/20 to give 660 mg (36%) of (S)-2,6-difluoro-4-((1-(3- fluoropropyl)pyrrolidin-3-yl)oxy)benzaldehyde. LC/MS (m/z, MH+): 288 Intermediate 6: (S)-2,6-Difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3- yl)amino)benzaldehyde Step 1: Tert-butyl (S)-(1-(3-fluoropropyl)pyrrolidin-3-yl)carbamate 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 K ₂ CO ₃ (10.36 g, 74.21 mmol) in MeCN (100 ml) was stirred for 18h at 50 °C. After cooling down to RT, the suspension was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was solubilized in EtOAc then successively washed with water and a saturated aqueous solution of NaCl, then dried over MgSO ₄ , 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 Step 2: Tert-butyl (S)-(3,5-difluoro-4-formylphenyl)(1-(3-fluoropropyl)pyrrolid in-3- yl)carbamate A mixture of 4-bromo-2,6-difluorobenzaldehyde (1.83 g, 8.12 mmol, 1 eq), 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 during 96h at 80 °C. After cooling to RT, the reaction mixture was filtered through celite. Water (50 ml) was added to the filtrate, then, the organic phase was separated, and the aqueous phase was extracted again with EtOAc (2x20ml). The combined organic layers were dried over MgSO4, filtered off and evaporated under reduced pressure. The residue obtained was purified by flash chromatography eluting with a gradient of heptane/EtOAc from 30/70 to 00/100 to give 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 Intermediate 7: Tert-butyl (3,5-difluoro-4-formylphenyl)(1-(3-fluoropropyl)azetidin-3- yl)carbamate Step 1: Tert-butyl (1-(3-fluoropropyl)azetidin-3-yl)carbamate 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 K ₂ CO ₃ (8.19 g, 58.7 mmol) in THF (100 ml) and water (0.21 ml, 11.7 mmol) was stirred at 70 °C for 5h. The crude mixture was cooled to RT, poured into water (100 ml) and extracted with EtOAc (200 ml). The organic layer was dried over MgSO ₄ , 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 Step 2: Tert-butyl (1-(3-fluoropropyl)azetidin-3-yl)carbamate Step 2 of Intermediate 7 was prepared following a similar procedure to that of Step 2 of Intermediate 6 from tert-butyl (1-(3-fluoropropyl)azetidin-3-yl)carbamate and 4-bromo-2,6- difluorobenzaldehyde to give 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 Step 3: 2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)benza ldehyde TFA (2.99 ml, 40.28 mmol) was dropwise added 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 RT for 18h. DCM (20 ml) and a 10% aqueous solution of NaHCO3 were added to the reaction mixture. The aqueous layer was separated and extracted again with DCM (2x10 ml). The combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure to give 0.6 g (82 %) of 2,6- difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)benzaldeh yde. LC/MS (m/z, MH+): 273

Intermediate 8: 2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzald ehyde Step 1: Tert-butyl 3-(3,5-difluoro-4-bromophenoxy)azetidine-1-carboxylate A mixture of 4-bromo-3,5-difluorophenol (2.09 g, 10 mmol), Cs ₂ CO ₃ (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 3h. After cooling down to RT, the reaction mixture was filtered, the solid was washed with EtOAc, and the filtrate was concentrated under reduced pressure. The residual oil was diluted in EtOAc and washed with water and brine. The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue obtained 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

Step 2: 3-(4-Bromo-3,5-difluoro-phenoxy)azetidine, 2,2,2-trifluoroacetic acid Step 2 of Intermediate 8 was was prepared following a similar procedure to that of Step 3 of Intermediate 7 starting from tert-butyl 3-(3,5-difluoro-4-bromophenoxy)azetidine-1- carboxylate to give 2 g (crude) of 3-(4-bromo-3,5-difluoro-phenoxy)azetidine, 2,2,2- trifluoroacetic acid used as such in the next step. LC/MS (m/z, MH+): 264 Step 3: 3-(4-Bromo-3,5-difluoro-phenoxy)-1-(3-fluoropropyl)azetidine A mixture of 3-(4-bromo-3,5-difluoro-phenoxy)azetidine, 2,2,2-trifluoroacetic acid (2 g, crude), 1-iodo-3-fluoropropane (0.56 mL, 5.49 mmol), DIPEA (4.78 mL, 27.5 mmol) in DMF (20 ml) was stirred at RT for 16h. The crude mixture was poured into water and extracted with EtOAc. The organic phase was dried over MgSO4, 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-difluoro-phenoxy)-1-(3- fluoropropyl)azetidine as a brown-yellow oil. LC/MS (m/z, MH+): 324 Step 4: 2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzald ehyde A mixture of 3-(4-bromo-3,5-difluoro-phenoxy)-1-(3-fluoropropyl)azetidine (1.5 g, 4.63 mmol) in THF (46 ml) was cooled to -78°C. Then, n-BuLi 1.6M in hexane (3.05 ml, 4.86 mmol) was dropwise added to the crude mixture and stirred at this temperature for 30 minutes. Then, DMF (0.72 mL, 9.26 mmol) was dropwise added to the crude mixture at - 78°C and stirred at this temperature for 3 hours. The crude mixture was quenched with water at RT and stirred for 15 minutes. Then, the aqueous phase was extracted with EtOAc (50 ml), dried over MgSO ₄ , filtered off and concentrated under reduced pressure. The residue obtained was purified by flash chromatography eluting with a gradient of Heptane/EtOAc from 50/50 to 00/100 to give 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 Intermediate 9: Tert-butyl (Z)-3-(3,5-difluoro-4-formylbenzylidene)pyrrolidine-1- carboxylate Step 1: Tert-butyl 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)py rrolidine- 1-carboxylate, mixture of Z and E isomers

To a solution of 2,2,6,6-tetramethylpiperidine (5.51 ml, 32.4 mmol) in 2- methyltetrahydrofuran (50 ml) at -78 °C was dropwise added n-BuLi 1.6 M in THF (20.2 ml, 32.4 mmol) (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 dropwise added (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 dropwise added at -78°C (internal temperature maintained below -65 °C). The reaction mixture was allowed to slowly warm to RT and stirred at this temperature for 18 h. The reaction mixture was cooled to 0 °C and slowly quenched with a 10% aqueous solution of NH4Cl (30 ml). The aqueous layer was separated and extracted again with EtOAc (2x50 ml). The combined organic layers were dried over MgSO4, filtered and, concentrated under reduced pressure. The residue obtained was purified by flash chromatography eluting with a gradient of gradient heptane/EtOAc from 90/10 to 70/30 to give 6.23 g (75%) of tert-butyl 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)py rrolidine-1-carboxylate, mixture of Z and E isomers as a colorless oil. LC/MS (m/z, MH+): 310

Step 2: Tert-butyl (Z)-3-(3,5-difluoro-4-formylbenzylidene)pyrrolidine-1-carbox ylate A mixture of tert-butyl 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)methylene)pyrrolidine-1-carboxylate, mixture of Z and E isomers (5.10 g, 16.5 mmol), 4- bromo-2,6-difluorobenzaldehyde (3.04 g, 13.7 mmol), K3PO4 (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 18h. After cooling down to RT, the reaction mixture was diluted with EtOAc and filtered on a pad of celite. The filtrate was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by flash chromatography eluting with a gradient of heptane/EtOAc from 90/10 to 70/30 to give 320 mg (7%) of tert-butyl (Z)-3-(3,5-difluoro-4-formylbenzylidene)pyrrolidine-1-carbox ylate 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 Intermediate 10: Tert-butyl 3-(3,5-difluoro-4-formylbenzyl)azetidine-1-carboxylate 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(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (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 N ₂ atmosphere. The reaction was stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25°C for 14 hrs. The reaction mixture was filtered, and the filtrate was washed with brine (40 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of petroleum ether/EtOAc from 100/00 to 75/25 to give 1.6 g (57%) of tert-butyl 3-(3,5-difluoro-4-formylbenzyl)azetidine- 1-carboxylate. LC/MS (m/z, MH+): 312 Intermediate 11: 1-(3-Fluoropropyl)-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborola n-2- yl)methylene)azetidine Step 1: 3-((4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)az etidine, 2,2,2- trifluoroacetic acid TFA (2.89 ml, 38.96 mmol) was dropwise added at RT to a solution of commercially available tert-butyl 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)az etidine-1- carboxylate (2.3 g, 7.79 mmol) in DCM (20 ml). The solution was stirred for 18h. 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 used as such in the next step. LC/MS (m/z, MH+): 196 Step 2: 1-(3-Fluoropropyl)-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborola n-2- yl)methylene)azetidine Step 2 of Intermediate 11 was prepared following a similar procedure to that of step 3 of Intermediate 8 from 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)az etidine, 2,2,2-trifluoroacetic acid and 1-fluoro-3-iodopropane to give 1.05 g (60%) of 1-(3- fluoropropyl)-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y l)methylene)azetidine. LC/MS (m/z, MH+): 256 Intermediate 12: 1-(3-Fluoropropyl)azetidin-3-amine Step 1: Tert-butyl (1-(3-fluoropropyl)azetidin-3-yl)carbamate 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 K ₂ CO ₃ (8.19 g, 58.7 mmol) in THF (100 ml) and water (0.21 ml, 11.7 mmol) was stirred at 70 °C for 5h. The crude mixture was cooled to RT, poured into water (100 ml) and extracted with EtOAc (200 ml). The organic layer was dried over MgSO ₄ , 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 Step 2: 1-(3-Fluoropropyl)azetidin-3-amine TFA (4.34 ml, 48.6 mmol) was dropwise added 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 RT for 16h. Then, the reaction mixture was concentrated under reduced pressure. The residue obtained was dissolved in MeOH (10 ml) and Amberlyst A26 (4 g) was added, and the mixture was stirred at RT for 64h. The reaction mixture was filtered off 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 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-carboxy late 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-carboxylat e (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 18h. After cooling down to RT, EtOAc and a 10 % aqueous solution of NaHCO3 were added. The aqueous layer was separated and extracted again with EtOAc (2 x 10 ml). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by flash chromatography eluting with a gradient of heptane/EtOAc from 90/10 to 50/50 to give 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 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 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) and 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 18h. After cooling down to RT, the reaction mixture was concentrated under reduced pressure. The residue obtained was purified by flash chromatography eluting with a gradient of heptane/EtOAc from 100/00 to 70/30 to give 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 light-yellow powder. LC/MS (m/z, MH+): 767 Examples 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-tet rahydro-1H-pyrido[3,4- b]indole-7-carboxylic acid 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-tet rahydro-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 Step 1 of Example 1 was prepared following a similar procedure to that of Intermediate 14 from methyl (R)-3-(2-((2,2,2-trifluoroethyl)amino)propyl)-1H-indole-6-ca rboxylate (Intermediate 2) and (S)-2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3- yl)amino)benzaldehyde (Intermediate 5). The residue obtained was purified by preparative chiral SFC (Stationary phase: chiralpak IG 250x30mm, Mobile phase: CO ₂ 70% / iPrOH 30%/ iPrNH20.3%) to give 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-t rifluoroethyl)-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)pheny l)-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 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

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-tet rahydro-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 48h. After cooling down to RT, the crude was diluted with DCM (5 ml). A 1N aqueous solution of HCl was added until pH 3-4, the aqueous layer was separated and extracted again with DCM (5 ml). The combined organic layers were dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by HPLC (Column YMC –Actus Triart Prep C18-S 150x30mm 10µm, flow rate 50ml/min- Focused gradient of MeCN/aq.NH ₄ HCO ₃ 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-tet rahydro-1H-pyrido[3,4- b]indole-7-carboxylic acid as a white solid. 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-tet rahydro-1H-pyrido[3,4- b]indole-7-carboxylic acid Example 2 was prepared following a similar procedure to that of Step 2 of Example 1 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) to give 5 mg (43%) of (1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-2-(2,2-difluoroprop yl)-3-methyl-2,3,4,9- tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid. 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-tetra hydro-1H-pyrido[3,4- b]indole-7-carboxylic acid 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-tetra hydro-1H-pyrido[3,4- b]indole-7-carboxylate Step 1 of Example 3 was prepared following a similar procedure to that of Intermediate 14 from methyl (R)-3-(2-((2,2-difluoropropyl)amino)propyl)-1H-indole-6-carb oxylate (Intermediate 3a) and (S)-2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3- yl)amino)benzaldehyde (Intermediate 5) to give 199 mg (53%) of methyl (1R,3R)-1-(2,6- difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)pheny l)-2-(2,2-difluoropropyl)-3- methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxyla te. LC/MS (m/z, MH+): 580 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 Step 2 of Example 3 was prepared following a similar procedure to that of Step 2 of Example 1 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-tetra hydro-1H-pyrido[3,4- b]indole-7-carboxylate to give 52 mg (27%) of (1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-2-(2,2-difluoroprop yl)-3-methyl-2,3,4,9- tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid. 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-te trahydro-1H-pyrido[3,4- b]indole-7-carboxylic acid Step 1: Methyl (1R,3R)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoroprop yl)-1-(2,6- difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)pheny l)-3-methyl-2,3,4,9- tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate

Step 1 of Example 4 was prepared following a similar procedure to that of Intermediate 14 from methyl (R)-3-(2-((3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoroprop yl)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-difluoroprop yl)-1-(2,6-difluoro- 4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-meth yl-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indole-7-carboxylate used as such in the next step. LC/MS (m/z, MH+): 834 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-te trahydro-1H-pyrido[3,4- b]indole-7-carboxylate Tetra-n-butylammonium fluoride (TBAF) 1M in THF (1.22 ml, 1.22 mmol) was dropwise added to a previously cooled at 0 °C 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-te trahydro-1H-pyrido[3,4- b]indole-7-carboxylate (680 mg, 0.82 mmol) in THF (5 ml). The mixture was raised to RT and stirred for 18h. DCM (10 ml) and a 10% aqueous solution of NH ₄ Cl were added to the reaction mixture. The aqueous layer was separated and extracted with DCM (2x5 ml). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by flash chromatography eluting with a gradient of EtOAc/MeOH from 100/00 to 90/10 to give 154 mg (32%) of methyl (1R,3R)-2-(2,2- difluoro-3-hydroxypropyl)-1-(2,6-difluoro-4-(((S)-1-(3-fluor opropyl)pyrrolidin-3- yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]i ndole-7-carboxylate. LC/MS (m/z, MH+): 596 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-te trahydro-1H-pyrido[3,4- b]indole-7-carboxylic acid Step 3 of Example 4 was prepared following a similar procedure to that of Step 2 of Example 1 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-te trahydro-1H-pyrido[3,4- b]indole-7-carboxylate to give 52 mg (35%) of (1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)- 1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)ox y)phenyl)-3-methyl-2,3,4,9- tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid. Example 5: 1R,3R)-1-(2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)a mino)phenyl)-3- methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido [3,4-b]indole-7-carboxylic acid

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-t etrahydro-1H-pyrido[3,4- b]indole-7-carboxylate Step 1 of Example 5 was prepared following a similar procedure to that of Intermediate 14 from methyl (R)-3-(2-((2,2,2-trifluoroethyl)amino)propyl)-1H-indole-6-ca rboxylate (Intermediate 2) and 2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)benza ldehyde (Intermediate 7) to give 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-t rifluoroethyl)-2,3,4,9- tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate. LC/MS (m/z, MH+): 569 Step 2: 1R,3R)-1-(2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)a mino)phenyl)-3- methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido [3,4-b]indole-7-carboxylic acid

Step 2 of Example 5 was prepared following a similar procedure to that of Step 2 of Example 1 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-pyri do[3,4-b]indole-7-carboxylate to give 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-t etrahydro-1H-pyrido[3,4- b]indole-7-carboxylic acid. 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 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-pyri do[3,4-b]indole-7-carboxylate Step 1 of Example 6 was prepared following a similar procedure to that of Intermediate 14 from methyl (R)-3-(2-((2,2,2-trifluoroethyl)amino)propyl)-1H-indole-6-ca rboxylate (Intermediate 2) and 2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzald ehyde (Intermediate 8) to give 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-tri fluoroethyl)-2,3,4,9- tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate. LC/MS (m/z, MH+): 570 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 Step 2 of Example 6 was prepared following a similar procedure to that of Step 2 of Example 1 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 to give 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-tet rahydro-1H-pyrido[3,4- b]indole-7-carboxylic acid. 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

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 Step 1 of Example 7 was prepared following a similar procedure to that of Intermediate 13 from methyl (R)-3-(2-((2,2-difluoropropyl)amino)propyl)-1H-indole-6-carb oxylate (Intermediate 3a) and 2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzald ehyde (Intermediate 8) to give 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 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 Step 2 of Example 7 was prepared following a similar procedure to that of Step 2 of Example 1 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 to give 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-tetra hydro-1H-pyrido[3,4- b]indole-7-carboxylic acid. 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-tetr ahydro-1H-pyrido[3,4- b]indole-7-carboxylic acid Step 1: Methyl (1R,3R)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoroprop yl)-1-(2,6- difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-m ethyl-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indole-7-carboxylate Step 1 of Example 8 was prepared following a similar procedure to that of Intermediate 14 from methyl (R)-3-(2-((3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoroprop yl)amino)propyl)- 1H-indole-6-carboxylate (Intermediate 4) and 2,6-difluoro-4-((1-(3-fluoropropyl)azetidin- 3-yl)oxy)benzaldehyde (Intermediate 8) to give 250 mg (57%) of methyl (1R,3R)-2-(3- ((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-1-(2,6-di fluoro-4-((1-(3- fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetr ahydro-1H-pyrido[3,4- b]indole-7-carboxylate. LC/MS (m/z, MH+): 820 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-tetr ahydro-1H-pyrido[3,4- b]indole-7-carboxylate Step 2 of Example 8 was prepared following a similar procedure to that of Step 2 of Example 4 from methyl (1R,3R)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoroprop yl)-1-(2,6- difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-m ethyl-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indole-7-carboxylate to give 96 mg (53%) of methyl (1R,3R)-2-(2,2-difluoro- 3-hydroxypropyl)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azeti din-3-yl)oxy)phenyl)-3- methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxyla te. LC/MS (m/z, MH+): 582 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-tetr ahydro-1H-pyrido[3,4- b]indole-7-carboxylic acid Step 3 of Example 8 was prepared following a similar procedure to that of Step 2 of Example 1 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-tetr ahydro-1H-pyrido[3,4- b]indole-7-carboxylate to give 23 mg (50%) of (1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)- 1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phen yl)-3-methyl-2,3,4,9- tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid. 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-tet rahydro-1H-pyrido[3,4- b]indole-7-carboxylic acid Step 1: Methyl (1R,3R)-1-(4-((tert-butoxycarbonyl)((S)-1-(3-fluoropropyl)py rrolidin-3- yl)amino)-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methy l-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indole-7-carboxylate Step 1 of Example 9 was prepared following a similar procedure to that of Intermediate 14 from methyl (R)-3-(2-((2,2-difluoropropyl)amino)propyl)-1H-indole-6-carb oxylate (Intermediate 3a) and tert-butyl (S)-(3,5-difluoro-4-formylphenyl)(1-(3- fluoropropyl)pyrrolidin-3-yl)carbamate (Intermediate 6) to give 433 mg (99%) of methyl (1R,3R)-1-(4-((tert-butoxycarbonyl)((S)-1-(3-fluoropropyl)py rrolidin-3-yl)amino)-2,6- difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetr ahydro-1H-pyrido[3,4- b]indole-7-carboxylate. LC/MS (m/z, MH+): 679 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-tet rahydro-1H-pyrido[3,4- b]indole-7-carboxylate Step 2 of Example 9 was prepared following a similar procedure to that of 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 give 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 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 Step 3 of Example 9 was prepared following a similar procedure to that of Step 2 of Example 1 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-tet rahydro-1H-pyrido[3,4- b]indole-7-carboxylate to give 52 mg (27%) of (1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3- fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-2-(2,2-difluoropr opyl)-3-methyl-2,3,4,9- tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid. 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 Step 1: Methyl (1R,3R)-1-(4-((Z)-(1-(tert-butoxycarbonyl)pyrrolidin-3-ylide ne)methyl)- 2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9- tetrahydro-1H-pyrido[3,4- b]indole-7-carboxylate Step 1 of Example 10 was prepared following a similar procedure to that of Intermediate 13 from methyl (R)-3-(2-((2,2-difluoropropyl)amino)propyl)-1H-indole-6-carb oxylate (Intermediate 3a) and tert-butyl (Z)-3-(3,5-difluoro-4-formylbenzylidene)pyrrolidine-1- carboxylate (Intermediate 9) to give 141 mg (42 %) of methyl (1R,3R)-1-(4-((Z)-(1-(tert- butoxycarbonyl)pyrrolidin-3-ylidene)methyl)-2,6-difluorophen yl)-2-(2,2-difluoropropyl)- 3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxy late. LC/MS (m/z, MH+): 616 Step 2: Methyl (1R,3R)-1-(2,6-difluoro-4-((Z)-pyrrolidin-3-ylidenemethyl)ph enyl)-2-(2,2- difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b] indole-7-carboxylate, 2,2,2- trifluoroacetic acid Step 2 of Example 10 was prepared following a similar procedure to that of Step 3 of Intermediate 7 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 to give 167 mg (crude) of methyl (1R,3R)-1-(2,6- difluoro-4-((Z)-pyrrolidin-3-ylidenemethyl)phenyl)-2-(2,2-di fluoropropyl)-3-methyl- 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate, 2,2,2-trifluoroacetic acid used as such in the next step. LC/MS (m/z, MH+): 516 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 Step 3 of Example 10 was prepared following a similar procedure to that of 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 give 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 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 Step 4 of Example 10 was prepared following a similar procedure to that of Step 2 of Example 1 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 to give 5 mg (10%) of (1R,3R)-1-(2,6-difluoro-4-((Z)-(1-(3- fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-2-(2,2-difl uoropropyl)-3-methyl-2,3,4,9- tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid. 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 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 Step 1: Methyl 1-(4-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)-2,6-difl uorophenyl)-2- (2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3 ,4-b]indole-7-carboxylate, mixture of trans isomers Step 1 of Examples 11 and 12 was prepared following a similar procedure to that of Intermediate 13 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) to give 210 mg (47 %) of methyl 1- (4-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)-2,6-difluo rophenyl)-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 Step 2: Methyl 1-(4-(azetidin-3-ylmethyl)-2,6-difluorophenyl)-2-(2,2-difluo ropropyl)-3- methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxyla te, 2,2,2-trifluoroacetic acid, mixture of trans isomers Step 2 of Examples 11 and 12 was prepared following a similar procedure to that of Step 3 of Intermediate 7 from methyl 1-(4-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)-2,6- difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetr ahydro-1H-pyrido[3,4- b]indole-7-carboxylate, mixture of trans isomers to give 214 mg (crude) of methyl 1-(4- (azetidin-3-ylmethyl)-2,6-difluorophenyl)-2-(2,2-difluoropro pyl)-3-methyl-2,3,4,9- tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate, 2,2,2-trifluoroacetic acid, mixture of trans isomers used as such in the next step. LC/MS (m/z, MH+): 504 Step 3: Methyl 1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)p henyl)-2-(2,2- difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b] indole-7-carboxylate, mixture of trans isomers Step 3 of Examples 11 and 12 was prepared following a similar procedure to that of 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, mixture of trans isomers and 1-fluoro-3-iodopropane to give 90 mg (44%) of methyl 1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)p henyl)-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+): 560 Step 4: 1-(2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)p henyl)-2-(2,2- difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b] indole-7-carboxylic acid, mixture of trans isomers Step 4 of Examples 11 and 12 was prepared following a similar procedure to that of Step 2 of Example 1 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-te trahydro-1H-pyrido[3,4- b]indole-7-carboxylate, mixture of trans isomers to give 150 mg (41%) of 1-(2,6-difluoro- 4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-(2,2-di fluoropropyl)-3-methyl- 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid, mixture of trans isomers. 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 The mixture 1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)p henyl)-2-(2,2- difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b] indole-7-carboxylic acid, mixture of trans isomers (170 mg, 0.31 mmol) was separated by SFC (column: DAICEL CHIRALPAK IC (250 mmx30 mm, 10 um); mobile phase: [0.1% NH ₃ H ₂ O MeOH]; B%: 30%-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-difluoropro pyl)-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)phe nyl)-2-(2,2-difluoropropyl)-3- methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxyli c acid (Example 12). 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 Step 1: Methyl 1-(4-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)-2,6-difl uorophenyl)-2- (2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3 ,4-b]indole-6-carboxylate, mixture of trans isomers Step 1 of Example 13 was prepared following a similar procedure to that of Intermediate 14 from methyl 3-(2-((2,2-difluoropropyl)amino)propyl)-1H-indole-5-carboxyl ate, racemic mixture (Intermediate 3c) and tert-butyl 3-(3,5-difluoro-4-formylbenzyl)azetidine-1- carboxylate (Intermediate 10) to give 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-carboxyla te, mixture of trans isomers. LC/MS (m/z, MH+): 604 Step 2: Methyl 1-(4-(azetidin-3-ylmethyl)-2,6-difluorophenyl)-2-(2,2-difluo ropropyl)-3- methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-carboxyla te, 2,2,2-trifluoroacetate, mixture of trans isomers Step 2 of Example 13 was prepared following a similar procedure to that of Step 3 of Intermediate 7 from methyl 1-(4-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)-2,6- difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetr ahydro-1H-pyrido[3,4- b]indole-6-carboxylate, mixture of trans isomers to give 490 mg (crude) of methyl 1-(4- (azetidin-3-ylmethyl)-2,6-difluorophenyl)-2-(2,2-difluoropro pyl)-3-methyl-2,3,4,9- tetrahydro-1H-pyrido[3,4-b]indole-6-carboxylate, 2,2,2-trifluoroacetate, mixture of trans isomers used as such in the next step. LC/MS (m/z, MH+): 504 Step 3: Methyl 1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)p henyl)-2-(2,2- difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b] indole-6-carboxylate, mixture of trans isomers Step 3 of Example 13 was prepared following a similar procedure to that of 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- trifluoroacetate, mixture of trans isomers and 1-fluoro-3-iodopropane to give 120 mg (23%) of methyl 1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)p henyl)-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+): 560 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 Step 4 of Examples 13 was prepared following a similar procedure to that of Step 2 of Example 1 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-te trahydro-1H-pyrido[3,4- b]indole-6-carboxylate, mixture of trans isomers to give 70 mg (87%) of 1-(2,6-difluoro-4- ((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-(2,2-difl uoropropyl)-3-methyl-2,3,4,9- tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid, mixture of trans isomers. 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

The mixture 1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)p henyl)-2-(2,2- difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b] indole-6-carboxylic acid, mixture of trans isomers (170 mg, 0.31 mmol) was separated by SFC(column: DAICEL CHIRALCEL OD (250 mmx30 mm, 10 µm); mobile phase: [0.1% NH3H2O MeOH]; B%: 35%-35%, 4.0 min; 30 min) to give 30 mg of (1R,3R)-1-(2,6-difluoro-4-((1-(3- fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-(2,2-difluoropro pyl)-3-methyl-2,3,4,9- tetrahydro-1H-pyrido[3,4-b]indole-6-carboxylic acid as a yellow solid. 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 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-tet rahydro-1H-pyrido[3,4- b]indole-7-carboxylate

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), Cs ₂ CO ₃ (762 mg, 2.34 mmol), t-BuBrettPhos (11 mg, 0.023 mmol) and t-BuBrettPhos Pd G3 (10 mg, 0.012 mmol) in dioxane (1.8 ml) was stirred for 24 h at 100 °C. After cooling to RT, addition of water (10 ml) and EtOAc (10 ml). After decantation, the organic phase was dried over MgSO4, filtered off and evaporated under reduced pressure. The residue obtained was purified by flash chromatography elution with heptane/EtOAc from 100/00 to 00/100 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-difluoroprop yl)-3-methyl-2,3,4,9- tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate. LC/MS (m/z, MH+): 565 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 Step 2 of Example 14 was prepared following a similar procedure to that of Step 2 of Example 1 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-tet rahydro-1H-pyrido[3,4- b]indole-7-carboxylate to give 13 mg (17%) of (1R,3R)-1-(2,6-difluoro-4-((1-(3- fluoropropyl)azetidin-3-yl)amino)phenyl)-2-(2,2-difluoroprop yl)-3-methyl-2,3,4,9- tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid. 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 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 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-carboxyla te (Intermediate 13) (200 mg, 0.39 mmol), K ₃ PO ₄ (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 H2O (0.04 ml) was heated at 40 °C for 48h. After cooling down to RT, 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 MgSO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by flash chromatography elution with DCM/MeOH from 100/00 to 94/04 to give 75 mg (34 %) of methyl (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yli dene)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 Step 2: (1R,3R)-1-(2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-yli dene)methyl)phenyl)- 2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido [3,4-b]indole-7-carboxylic acid Step 2 of Example 15 was prepared following a similar procedure to that of Step 2 of Example 1 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-tet rahydro-1H-pyrido[3,4- b]indole-7-carboxylate to give 28 mg (38%) of (1R,3R)-1-(2,6-difluoro-4-((1-(3- fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-2-(2,2-difluo ropropyl)-3-methyl-2,3,4,9- tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid. The compounds according to table 1 above were subjected to pharmacological tests for determining their degradation effects on estrogen receptors. Test: Estrogen receptor degradation activity Said test involves measuring the in vitro degradation activity of the compounds of the table 1. The measurements of the degradation activities were made using a breast cancer cell ERα in cell western assay as described hereunder. MCF7 cells (ATCC) were seeded in 384 wells microplate (collagen coated) at a concentration of 10000 cells/ 30 µL per well in red phenol free MEM alpha medium (invitrogen) containing 5% charcoal dextran striped FBS. The following day, 9 points serial 1:5 dilution of each compound was added to the cells in 2.5µL at final concentrations ranging from 0.3-0.0000018 µM (in table 2), or 0.1 µM for fulvestrant (using as positive control). At 4 hours post compound addition the cells were fixed by adding 25 µL of formalin (final concentration 5% formalin containing 0.1% triton) for 10 minutes at RT and then washed twice with PBS. Then, 50 µL of LI-COR blocking buffer containing 0.1% Triton was added to plate for 30 minutes at RT. LI-COR blocking buffer was removed and cells were incubated overnight at cold room with 50 µL anti-ER rabbit monoclonal antibody (Thermo scientific MA1-39540) diluted at 1:1000 in LI-COR blocking buffer containing 0.1% tween-20. Wells which were treated with blocking buffer but no antibody were used as background control. Wells were washed twice with PBS (0.1% tween-20) and incubated at 37 °C for 60 minutes 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). Cells were then washed 3 times in PBS and scanned in ACUMEN explorer (TTP-Labtech). Integrated intensities in the green fluorescence and red fluorescence were measured to determine the levels of ERα and DNA respectively. The degradation activity with respect to estrogen receptors in this test is given by the concentration which degrades 50% of the estrogen receptor (or IC ₅₀ ) in nM. The % of ERα levels decrease were determined as follows: % inhibition = 100 * (1- (sample – fulvestrant: DMSO - fulvestrant)). The Table 2 below indicates the estrogen receptor degradation activity results for the compounds of table 1 tested at 0.3 µM, and demonstrates that said compounds have a significant degradation activity on estrogen receptors. Table 2:

It is therefore apparent that the tested compounds have degradation activities for estrogen receptors, with IC50 less than 1 µM and with degradation levels greater than 50%. The compounds of formula (I), (II) and (III) can therefore be used for preparing medicaments, especially medicaments which are degraders of estrogen receptors. Accordingly, also provided herein are medicaments which comprise a compound of the formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof. Herein are also provided the compounds of formula (I), (II) or (III) defined above, or pharmaceutically acceptable salts thereof, for use as medicines. Herein are also provided the compounds of formula (I), (II) or (III) defined above, or pharmaceutically acceptable salt thereof, for use in therapy, especially as inhibitors and degraders of estrogen receptors. Herein are also provided the compounds of formula (I), (II) or (III) defined above, or a pharmaceutically acceptable salts thereof, for use in the treatment of ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hypertrophy or inflammation. A particular aspect is a compound of formula (I), (II) or (III) defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer. In an embodiment, the cancer is a hormone dependent cancer. In another embodiment, the cancer is an estrogen receptor dependent cancer, particularly the cancer is an estrogen receptor α dependent cancer. In another embodiment, the cancer is selected from breast, ovarian, endometrial, prostate, uterine, cervical and lung cancer, or a metastasis thereof. In another embodiment, the metastasis is a cerebral metastasis. In another embodiment, the cancer is breast cancer. Particularly, the breast cancer is an estrogen receptor positive breast cancer (ERα positive breast cancer). In another embodiment, the cancer is resistant to anti-hormonal treatment. In a further embodiment, the compound of formula (I), (II) or (III) is as used as single agent or in combination with other agents such as CDK4/6, mTOR or PI3K inhibitors. According to another aspect, herein is provided a method of treating the pathological conditions indicated above, 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 an embodiment of this method of treatment, the subject is a human. Herein is also provided the use of a compound of the formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful in treating any of the pathological conditions indicated above, more particularly useful in treating cancer. Herein are also provided the pharmaceutical compositions comprising as active principle a compound of formula (I), (II) or (III). These pharmaceutical compositions comprise an effective dose of at least one compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, and also at least one pharmaceutically acceptable excipient. The said excipients are selected, in accordance with the pharmaceutical form and method of administration desired, from the customary excipients, which are known to a person skilled in the art. In the pharmaceutical compositions for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intra-tracheal, intranasal, transdermal or rectal administration, the active principle of formula (I), (II) or (III) above, or its base, acid, zwitterion or salt thereof, may be administered in a unit administration form, in a mixture with conventional pharmaceutical excipients, to animals and to human beings for the treatment of the above disorders or diseases. The unit administration forms appropriate include oral forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intra-tracheal, intra-ocular and intra-nasal administration forms, forms for inhalative, topical, transdermal, subcutaneous, intra-muscular or intravenous administration, rectal administration forms and implants. For topical application it is possible to use the compounds of formula (I), (II) or (III) in creams, gels, ointments or lotions. As an example, a unit administration form of a compound of formula (I), (II) or (III) in tablet form may comprise the following components: Compound of formula (I) 50.0 mg Mannitol 223.75 mg Sodium croscarmellose 6.0 mg Corn starch 15.0 mg Hydroxypropylmethylcellulose 2.25 mg Magnesium stearate 3.0 mg There may be particular cases in which higher or lower dosages are appropriate. According to usual practice, the dosage that is appropriate for each patient is determined by the doctor according to the mode of administration and the weight and response of the said patient.