Novel substituted 2, 3, 4, 9-tetrahydro-1h-pyrido [3, 4-b] indolecarboxylic acid derivatives, process for preparation thereof and therapeutic use thereof

Abstract

Disclosed herein are compounds of 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 but not both of R3 and R3'represents a-COOH group, and R3 and R3 'do not represent a hydrogen atom at the same time; r4 represents a hydrogen atom or a fluorine atom; r5 and R5'independently represent a hydrogen atom or a fluorine atom; y represents-CH2-,-CH =,-CR9 =,-O-or-NH-wherein R9 represents a fluorine atom or a (C1-C3) 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 (C1-C3) alkyl or halogen atom such as fluorine or chlorine atom, cyano, or a (C1-C3) fluoroalkyl group such as trifluoromethyl; r7 independently represents a (C1-C3) alkyl group such as a methyl group, a halogen atom such as a fluorine atom, a cyano group, or a (C1-C3) fluoroalkyl group such as a trifluoromethyl group; n is 0, 1 or 2; and R6 represents an optionally substituted (C1-C9) alkyl group, and R8 in particular represents a (C1-C6) alkyl group. Further disclosed are processes for their preparation, pharmaceutical compositions comprising them and the compounds of formula (I) for use as inhibitors and degradation agents of estrogen receptors, in particular in the treatment of ovulation dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia or inflammation. # imgabs0 #

Description

[0001] Disclosed herein are novel substituted 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indolecarboxylic acid derivatives, methods for their preparation, and their therapeutic uses, particularly as anticancer agents via selective antagonism and degradation of estrogen receptors.

[0002] Estrogen receptor (ER) belongs to the steroid / nuclear receptor superfamily that participates in regulating differentiation in eukaryotic gene expression, cell proliferation and target tissues. ER is in two forms: estrogen receptor α (ERα) and estrogen receptor β (ERβ) encoded by ESR1 and ESR2 genes, respectively. ERα and ERβ are ligand-activated transcription factors, which are activated by the hormone estrogen (the most potent estrogen produced in vivo is 17β-estradiol). In the absence of hormones, ER is mainly located in the cytosol of cells. When the hormone estrogen binds to ER, ER migrates from the cytosol of cells to the nucleus, forms a dimer, and then binds to a specific genomic sequence called an estrogen response element (ERE). DNA / ER complexes interact with co-regulators to regulate the transcription of target genes.

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

[0004] ERα is expressed in no more than 10% of normal breast epithelium, but is expressed in approximately 50%-80% of breast tumors. Such breast tumors with high levels of ERα are classified as ERα-positive breast tumors. The etiological role of estrogen in breast cancer is established, and regulation of ERα signaling remains an important approach to breast cancer treatment for most ERα-positive breast tumors. Currently, there are several strategies for inhibiting the estrogen axis in breast cancer, including: 1-Blocking estrogen synthesis through aromatase inhibitors for the treatment of early and late ERα-positive breast cancer patients; 2-Antagonizing estrogen ligand binding to ERα through tamoxifen for the treatment of ERα-positive breast cancer patients in both premenopausal and postmenopausal situations; 3-Antagonizing and downregulating ERα levels through Fulvestrant for the treatment of breast cancer in patients who have progressed despite endocrine therapy such as tamoxifen or aromatase inhibitors.

[0005] Although these endocrine therapies have greatly contributed to the reduction of breast cancer development, about more than one-third of ERα-positive patients show resistance to such existing therapies from the beginning or develop resistance over time. Several mechanisms have been described to explain resistance to such hormone therapies. For example, in the treatment with aromatase inhibitors, ERα is hypersensitive to low estrogen levels, and in tamoxifen treatment, the tamoxifen effect is switched from an antagonist effect to an agonist effect or a variety of growth factor receptor signaling pathways. ERα acquired mutations that occur after hormone therapy is initiated can also play a role in treatment failure and cancer progression. Certain mutations in ERα, particularly those identified in the ligand binding domain (LBD), lead to the ability to bind to DNA in the absence of a ligand and confer hormone independence in cells with such mutant receptors.

[0006] Most of the identified mechanisms of resistance to endocrine therapy rely on ERα-dependent activity. One of the new strategies to combat this resistance is to shut down ERα signaling by removing ERα from tumor cells using selective estrogen receptor degraders (SERDs). Clinical and preclinical data suggest that a number of resistance pathways can be circumvented by using SERDs.

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

[0008] Documents WO 2017 / 140669 and WO 2018 / 091153 disclose some substituted 6,7-dihydro-5H-benzo[7]annulene compounds and substituted N-(3-fluoropropyl)-pyrrolidine derivatives that can be used as SERDs.

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

[0010] Disclosed herein are compounds of formula (I) or pharmaceutically acceptable salts thereof:

[0011]

[0012] in:

[0013] - R1 and R2 independently represent a hydrogen atom or a deuterium atom;

[0014] -R3 represents a hydrogen atom or a -COOH group;

[0015] -R3' represents a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom, a cyano group, or a -COOH group;

[0016] -R3" represents a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom, or a cyano group;

[0017] Provided that one but not both of R3 and R3' represents -COOH, and R3 and R3' do not simultaneously represent hydrogen atoms;

[0018] -R4 represents a hydrogen atom or a fluorine atom;

[0019] - R5 and R5' independently represent a hydrogen atom or a fluorine atom;

[0020] -Y represents -CH2-, -CH=, -CR9=, -O- or -NH-, wherein R9 represents a fluorine atom or a (C1-C3) alkyl group;

[0021] - represents a single bond or a double bond;

[0022] -p is 0 or 1;

[0023] -X represents -CH=, -N= or -CR"=, wherein R" represents a (C1-C3)alkyl group or a halogen atom such as a fluorine or chlorine atom, a cyano group, or a (C1-C3)fluoroalkyl group such as a trifluoromethyl group;

[0024] - R7 independently represents a (C1-C3)alkyl group such as a methyl group, a halogen atom such as a fluorine atom, a cyano group, or a (C1-C3)fluoroalkyl group such as a trifluoromethyl group;

[0025] -n is 0, 1, or 2; and

[0026] -R6 represents a (C1-C9) alkyl group, which may be substituted by 1 to 4 substituents independently selected from the following: a halogen atom, a -cyano group, a -OR a Group, -N(R a )2 group, (C1-C9) alkyl, (C1-C9) alkoxy, (C1-C3) fluoroalkoxy, (C3-C9) cycloalkyl, (C3-C9) heterocyclic group, (C6-C9) aryl, (C5-C 10 )heteroaryl, -C(O)R b Group, -C(O)NR a Group, -SO2CH3 group, and SO2NR a Group;

[0027] -R a represents a hydrogen atom, a (C1-C6) alkyl group, a (C2-C8) alkenyl group, a propargyl group, a (C3-C6) cycloalkyl group, and a (C3-C7) heterocycloalkyl group, which may be optionally substituted by one or more substituents independently selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a cyano group, an -OH group, a methoxy group, and a -SO2CH3 group;

[0028] -R brepresents a hydrogen atom, -O((C1-C3) alkyl), (C1-C6) alkyl, (C2-C8) alkenyl, propargyl, -((C2-C6) alkene)-((C3-C6) cycloalkyl), (C3-C6) cycloalkyl, and (C3-C7) heterocycloalkyl, which may be optionally substituted by one or more substituents independently selected from the following: a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a cyano group, a -CH2F group, a -CHF2 group, a -CF3 group, a -CH2CF3 group, a -CH2CHF2 group,

[0029] -CH2CH2F group, -OH group, methoxy group, and -SO2CH3 group; and

[0030] -R8 represents a hydrogen atom, a cyano group, a (C1-C6) alkyl group, a -CH2OH group, a -CH2OCH3 group, a -CH2CH2OH group, a -C(CH3)2OH group, a -CH(OH)CH(CH3)2 group, a -C(CH3)2CH2OH group, a -CH2CH2SO2CH3 group, a -CH2OP(O)(OH)2 group, a -CH2F group, a -CHF2 group, a -CH2NH2 group, a -CH2NHSO2CH3 group, a -CH2NHCH3 group, a -CH2N(CH3)2 group, a -CF3 group, a -CH2CF3 group, a -CH2CHF2 group, a -CH(CH3)CN group, a -C(CH3)2CN group, a -CH2CN group, a -C O2H group, -COCH3 group, -CO2CH3 group, -CO2C(CH3)3 group, -COCH(OH)CH3 group, -CONH2 group, -CONHCH3 group, -CONHCH2CH3 group, -CONHCH(CH3)2 group, -CON(CH3)2 group, -C(CH3)2CONH2 group, cyclopropyl group, cyclopropylamide group, cyclobutyl group, oxetanyl group, azetidinyl group, 1-methylazetidin-3-yl)oxy group, N-methyl-N-oxetan-3-ylamino, azetidin-1-ylmethyl, benzyloxyphenyl, pyrrolidin-1-yl, pyrrolidin-1-yl-methanone group, piperazin-1-yl, morpholinomethyl, morpholino-methanone group, or morpholino group.

[0031] Disclosed herein are compounds of formula (I) or pharmaceutically acceptable salts thereof:

[0032]

[0033] in:

[0034] - R1 and R2 independently represent a hydrogen atom or a deuterium atom;

[0035] -R3 represents a hydrogen atom or a -COOH group;

[0036] -R3' represents a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom, a cyano group, or a -COOH group;

[0037] -R3" represents a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom, or a cyano group;

[0038] Provided that one but not both of R3 and R3' represents -COOH, and R3 and R3' do not simultaneously represent hydrogen atoms;

[0039] -R4 represents a hydrogen atom or a fluorine atom;

[0040] - R5 and R5' independently represent a hydrogen atom or a fluorine atom;

[0041] -Y represents -CH2-, -CH=, -CR9=, -O- or -NH-, wherein R9 represents a fluorine atom or a (C1-C3) alkyl group;

[0042] - represents a single bond or a double bond;

[0043] -p is 0 or 1;

[0044] -X represents -CH=, -N= or -CR"=, wherein R" represents a (C1-C3)alkyl group or a halogen atom such as a fluorine or chlorine atom, a cyano group, or a (C1-C3)fluoroalkyl group such as a trifluoromethyl group;

[0045] - R7 independently represents a (C1-C3)alkyl group such as a methyl group, a halogen atom such as a fluorine atom, a cyano group, or a (C1-C3)fluoroalkyl group such as a trifluoromethyl group;

[0046] -n is 0, 1, or 2; and

[0047] -R6 represents a (C1-C9) alkyl group, which may be substituted by 1 to 4 substituents independently selected from the following: a halogen atom, a -cyano group, a -OR a Group, -N(R a )2 group, (C1-C9) alkyl, (C1-C9) alkoxy, (C1-C3) fluoroalkoxy, (C3-C9) cycloalkyl, (C3-C9) heterocyclic group, (C6-C9) aryl, (C5-C 10 )heteroaryl, -C(O)R b Group, -C(O)NR a Group, -SO2CH3 group, and SO2NR a Group;

[0048] -R arepresents a hydrogen atom, a (C1-C6) alkyl group, a (C2-C8) alkenyl group, a propargyl group, a (C3-C6) cycloalkyl group, and a (C3-C7) heterocycloalkyl group, which may be optionally substituted by one or more substituents independently selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a cyano group, an -OH group, a methoxy group, and a -SO2CH3 group;

[0049] -R b represents a hydrogen atom, -O((C1-C3)alkyl), (C1-C6)alkyl, (C2-C8)alkenyl, propargyl, -((C2-C6)alkene)-((C3-C6)cycloalkyl), (C3-C6)cycloalkyl, and (C3-C7)heterocycloalkyl, which may be optionally substituted by one or more substituents independently selected from the following: a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a cyano group, a -CH2F group, a -CHF2 group, a -CF3 group, a -CH2CF3 group, a -CH2CHF2 group, a -CH2CH2F group, an -OH group, a methoxy group, and a -SO2CH3 group; and

[0050] -R8 represents a hydrogen atom, a cyano group, a (C1-C6) alkyl group, a -CH2OH group, a -CH2OCH3 group, a -CH2CH2OH group, a -C(CH3)2OH group, a -CH(OH)CH(CH3)2 group, a -C(CH3)2CH2OH group, a -CH2CH2SO2CH3 group, a -CH2OP(O)(OH)2 group, a -CH2F group, a -CHF2 group, a -CH2NH2 group, a -CH2NHSO2CH3 group, a -CH2NHCH3 group, a -CH2N(CH3)2 group, a -CF3 group, a -CH2CF3 group, a -CH2CHF2 group, a -CH(CH3)CN group, a -C(CH3)2CN group, a -CH2CN group, a -C an O2H group, a -COCH3 group, a -CO2CH3 group, a -CO2C(CH3)3 group, a -COCH(OH)CH3 group, a -CONH2 group, a -CONHCH3 group, a -CONHCH2CH3 group, a -CONHCH(CH3)2 group, a -CON(CH3)2 group, a -C(CH3)2CONH2 group, a cyclopropyl group, a cyclopropylamide group, a cyclobutyl group, an oxetanyl group, an azetidinyl group, a 1-methylazetidin-3-yl)oxy group, an N-methyl-N-oxetan-3-ylamino group, an azetidin-1-ylmethyl group, a benzyloxyphenyl group, a pyrrolidin-1-yl group, a pyrrolidin-1-yl-methanone group, a piperazin-1-yl group, a morpholinomethyl group, a morpholino-methanone group, or a morpholino group,

[0051] - provided that when p is 1, X is CH; Y is CH2; R3 is COOH; R1, R2, R3', R3", R4, R5 and R5' are H; R7 is F; n is 2; R8 is CH3, R6 does not represent 2,2-difluoropropyl, and

[0052] - Provided 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 CH3, R6 does not represent 2,2-difluoro-3-hydroxypropyl.

[0053] The compounds of formula (I) may contain one or more asymmetric carbon atoms and may therefore exist in the form of enantiomers.

[0054] The compounds of formula (I) may also exist in tautomeric forms.

[0055] The compound of formula (I) may exist in the form of a base, an acid, a zwitterion or an addition salt with an acid or a base. Accordingly, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0056] These salts may be prepared with pharmaceutically acceptable acids or bases, although salts of other acids or bases useful, for example, in the purification or isolation of compounds of formula (I) are also provided.

[0057] Among suitable salts of the compounds of formula (I), hydrochlorides may be cited.

[0058] As used herein, unless otherwise mentioned throughout this specification, the following terms have the following definitions:

[0059] - halogen atoms: fluorine, chlorine, bromine or iodine atoms, and in particular fluorine and chlorine atoms;

[0060] - Alkyl: a straight or branched saturated hydrocarbon aliphatic group, which, unless otherwise mentioned, contains 1 to 9 carbon atoms (indicated as "(C1-C9) alkyl"). By way of example, but not limited to: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl and isohexyl, etc. may be mentioned;

[0061] - Olefin group: a linear or branched unsaturated or partially unsaturated aliphatic group containing one or more conjugated or non-conjugated double bonds and, unless otherwise mentioned, containing 2 to 6 carbon atoms;

[0062] - Cycloalkyl: saturated or partially unsaturated and unsubstituted or substituted monocyclic alkyl which, unless otherwise mentioned, contains 3 to 9 carbon atoms;

[0063] - Heterocyclic group: a 3-, 4-, 5-, 6-, 7-, 8- or 9-membered ring containing at least one heteroatom independently selected from the group consisting of O, N and S, wherein the ring is saturated or unsaturated, but not aromatic. The 3- or 4-membered ring may contain 1 heteroatom selected from the group consisting of O, N and S. The 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. The 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;

[0064] - Heterocycloalkyl: saturated or partially unsaturated 3- to 7-membered cycloalkyl containing 1 to 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, in particular oxygen or nitrogen;

[0065] -Fluoroalkyl: an alkyl group as defined previously, wherein the alkyl group is substituted by at least one fluorine atom. In other words, at least one hydrogen atom of the alkyl group is replaced by a fluorine atom. By way of example, -CH2F, -CHF2, -CH2CHF2, -CH2CH2F, etc. may be mentioned. When all hydrogen atoms belonging to the alkyl group are replaced by fluorine atoms, the fluoroalkyl group may be named as a perfluoroalkyl group. By way of example, trifluoromethyl or trifluoroethyl, etc. may be mentioned;

[0066] - Alkoxy: -O-alkyl, wherein alkyl is as defined previously. By way of example, but not limited to, there may be mentioned: methoxy; ethoxy; propoxy; isopropoxy; linear butoxy, sec-butoxy or tert-butoxy; isobutoxy; pentyloxy; or hexyloxy, etc.;

[0067] -Fluoroalkoxy: -O-alkyl, wherein alkyl is as defined previously and wherein alkyl is substituted by at least one fluorine atom. In other words, at least one hydrogen atom of the alkyl is replaced by a fluorine atom. By way of example, -OCH2F, -OCHF2, -OCH2CH2F, etc. may be mentioned. When all hydrogen atoms belonging to the alkyl are replaced by fluorine atoms, the fluoroalkoxy may be named as perfluoroalkoxy. By way of example, trifluoromethoxy, etc. may be mentioned;

[0068] -Aryl: a monocyclic or bicyclic aromatic group containing 6 or 9 carbon atoms.

[0069] -Heteroaryl: A cyclic 5- to 10-membered aromatic group containing 2 to 9 carbon atoms and 1 to 3 heteroatoms such as nitrogen, oxygen or sulfur. Such nitrogen atoms may be replaced by oxygen atoms to form an -N-O bond. Such -N-O bonds may be in the form of N-oxides (-N + -O - ) in the form of

[0070] - Zwitterion means: a generally neutral molecule having both positive and negative charges and possessing both acidic and basic groups.

[0071] In another embodiment, in the compound of formula (I) as defined above, R3 represents a -COOH group. In another embodiment, in the compound of formula (I) as defined above, R3' represents a -COOH group. Thus, compounds of formula (II) and (III) are described herein:

[0072]

[0073] Among them, R1, R2, R3, R3', R3", R4, R5, R5', R6, R7, R8, Y, n and p are as defined above in formula (I).

[0074] In another embodiment, the compound of formula (I) as defined above has formula (II).

[0075] In another embodiment, in the compounds of formula (I) or (II) as defined above, R3′ and R3″ both represent a hydrogen atom.

[0076] In another embodiment, in the compound of formula (I) as defined above, R3 represents a -COOH group, and R3' and R3" both represent a hydrogen atom.

[0077] In another embodiment, in the compound of formula (I) as defined above, R3′ represents a —COOH group, and R′ and R3″ both represent a hydrogen atom.

[0078] In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, R1 and R2 are hydrogen atoms.

[0079] In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, R4 represents a hydrogen atom.

[0080] In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, R5 and R5' represent hydrogen atoms.

[0081] 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.

[0082] 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.

[0083] In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, X represents -CH=.

[0084] In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, R6 represents a (C1-C6) alkyl group, which is optionally substituted with 1 to 3 substituents independently selected from a fluorine atom, a methyl group and an -OH group.

[0085] In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, R6 represents a -CH2-CF3 group, a -CH2-CF2-CH2-OH group or a -CH2-CF2-CH3 group.

[0086] In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, R7 represents a halogen atom, and preferably a fluorine atom.

[0087] In another embodiment, in the compound of formula (I), (II) or (III) as defined above, n is 0. In another embodiment, in the compound of formula (I), (II) or (III) as defined above, n is 1. In another embodiment, in the compound of formula (I), (II) or (III) as defined above, n is 2.

[0088] 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.

[0089] In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, R8 represents (C1-C6)alkyl, and preferably represents methyl.

[0090] In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, Y represents -CH2-, -CH=, -O- or -NH-.

[0091] In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, Y represents -CH2. 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-.

[0092] In another embodiment, in the compound of formula (I), (II) or (III) as defined above, In another embodiment, Represents a double bond.

[0093] In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, p is equal to 1.

[0094] Among the compounds of formula (I), (II) or (III) described herein, the following compounds or their pharmaceutically acceptable salts, in particular their hydrochlorides, may be mentioned in particular:

[0095] -(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)

[0096] -(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)

[0097] -(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)

[0098] -(1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid, (4)

[0099] -(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)

[0100] -(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)

[0101] -(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)

[0102] -(1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid, (8)

[0103] -(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)

[0104] -(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)

[0105] -(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)

[0106] -(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)

[0107] -(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)

[0108] -(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)

[0109] -(1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid, (15).

[0110] 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.

[0111] 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.

[0112] Another embodiment is a method of inhibiting and degrading estrogen receptors, which comprises administering a therapeutically effective amount of a compound selected from the above list or a pharmaceutically acceptable salt thereof to a subject, especially a human, in need thereof.

[0113] Another embodiment is a method for treating ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hypertrophy or inflammation, comprising administering to a subject, particularly a human, in need thereof a therapeutically effective amount of a compound selected from the above list or a pharmaceutically acceptable salt thereof.

[0114] Another embodiment is a method of treating cancer, comprising administering to a subject, particularly a human, in need thereof a therapeutically effective amount of a compound selected from the above list or a pharmaceutically acceptable salt thereof.

[0115] Another embodiment is a pharmaceutical composition comprising, as an active ingredient, 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.

[0116] The compounds of formula (I), (II) or (III) can be prepared by the following methods.

[0117] Compounds of formula (I), (II) or (III) and other related compounds having different substituents are synthesized using techniques and materials described below or otherwise known to those skilled in the art. In addition, the solvents, temperatures and other reaction conditions presented below may be varied as deemed appropriate by those skilled in the art.

[0118] The following general methods for preparing compounds of formula (I), (II) or (III) optionally modified by using appropriate reagents and conditions for introducing the various moieties found in formula (I), (II) or (III) are described below.

[0119] The following abbreviations and empirical formulas are used:

[0120] AcOH Acetic acid

[0121] MeCN Acetonitrile

[0122] NH4HCO3 Ammonium acetate

[0123] NH4OAc Ammonium bicarbonate

[0124] NH4Cl Ammonium chloride

[0125] BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl)

[0126] Pd(dppf)Cl2 [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) chloride

[0127] NiCl2.dtbbpy [4,4'-Bis(1,1-dimethylethyl)-2,2'-bipyridyl] nickel(II) chloride

[0128] n-BuLi n-butyllithium

[0129] CO Carbon monoxide

[0130] CO2 Carbon dioxide

[0131] Cs2CO3 Cesium carbonate

[0132] CuCl Cuprous chloride

[0133] DCM Dichloromethane

[0134] SPhos 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl

[0135] DIPEA Diisopropylethylamine

[0136] DMF N,N-Dimethylformamide

[0137] DMSO Dimethyl sulfoxide

[0138] EtOAc Ethyl acetate

[0139] HPLC High Performance Liquid Chromatography

[0140] H2 Hydrogen

[0141] HCl

[0142] LG Leaving Group

[0143] LiOH Lithium Hydroxide

[0144] MeOH Methanol

[0145] MgSO4 Magnesium sulfate

[0146] MeMgCl Methyl magnesium chloride

[0147] Pd / C Palladium / Carbon

[0148] Pd(OH)2 Palladium Hydroxide

[0149] POCl3 Phosphorus oxychloride

[0150] PtO2 Platinum Oxide

[0151] K2CO3 Potassium carbonate

[0152] K3PO4 Potassium Phosphate

[0153] LG Leaving Group

[0154] NaHCO3 Sodium bicarbonate

[0155] NaCl Sodium chloride

[0156] NaBH3CN Sodium cyanoborohydride

[0157] Na2SO4 Sodium sulfate

[0158] NaOH Sodium hydroxide

[0159] SFC Supercritical Fluid Chromatography

[0160] tBuBrettPhos Dimethoxy-2',4',6'-tri(1-methylethyl)[1,1'-biphenyl]-2-yl]bis(1,1-dimethylethyl)phosphine

[0161] tBuBrettPhos Pd G3 [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]methanesulfonate palladium(II)

[0162] TBAF Tetra-n-butylammonium fluoride

[0163] TMAD Tetramethylazodicarbonamide

[0164] TEA Triethylamine

[0165] TFA Trifluoroacetic acid

[0166] THF Tetrahydrofuran

[0167] PPh3 Triphenylphosphine

[0168] RT Room temperature

[0169] Option 1a Parts 1 and 2 : Preparation of compounds of formula (II) - General method

[0170] Scheme 1a-Part-1 :

[0171]

[0172] Scheme 1a-Part-2 :

[0173]

[0174] According to Scheme 1a - Part 1 and Part 2, wherein R3a is a carboxylate such as -COOMe or -COOEt, R1, R2, R3, R3', R3", R4, R5, R5', R6, R7, R8, n, p, X, Y and As defined above, compound 1A can be converted to compound 1C in step 1 by treatment with compound 1B in the presence of methylmagnesium chloride (MeMgCl) and cuprous chloride (CuCl).

[0175] Compound 1C can be converted to compound 1D in step 2 by carbonylation with carbon monoxide (CO) in the presence of a palladium catalyst such as palladium acetate or [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) complexed with DCM in solution in MeOH or EtOH.

[0176] Compound 1D can be converted to compound 1E in step 3 by treatment with TFA or HCl or chlorotrimethylsilane.

[0177] Compound 1E can be converted to compound 1G in step 4 by treatment with compound 1F (R6-LG) (wherein LG is a suitable leaving group, e.g., a halogen atom such as iodine, bromine or chlorine or triflate) in the presence of a suitable base such as diisopropylethylamine (DIPEA) in a suitable solvent such as DMF.

[0178] Compound 1G can be converted to compound 1J in step 5 by treating 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 such as toluene by heating to reflux of the solvent.

[0179] Alternatively, compound 1J can be obtained by treating compound 1G with compound 1K in a Pict-Spengler cyclization reaction in the presence of an acid such as TFA or acetic acid in a suitable solvent such as toluene by heating to the reflux of the solvent in step 6, followed by a coupling reaction between the obtained compound 1L and one of the compounds 1M under coupling reaction conditions in step 7.

[0180] Compound 1J can be converted to compound II in step 8 by treatment with an aqueous solution of sodium hydroxide (NaOH) or lithium hydroxide (LiOH) in MeOH or THF. Extraction of the product can give the sodium or lithium salt of compound II. Acidification with an aqueous solution of HCl to pH 6-7 can give the neutral form of compound II. Acidification with an aqueous solution of HCl to pH 1-2 can give the hydrochloride salt of compound II. Purification using HPLC in the presence of formic acid or trifluoroacetic acid in the eluent can give the formate or trifluoroacetate salt of compound II.

[0181] When Y═CH═, compound II can be reduced by hydrogenation in step 9 with a catalyst such as Pd / C or platinum oxide (PtO 2 ) under hydrogen (H 2 ) pressure to give the corresponding saturated compound II′.

[0182] Alternatively, when Y=CH=, compound II' can be prepared in step 10 by hydrogenation of compound 1J with a catalyst such as Pd / C or platinum oxide (PtO2) under hydrogen (H2) pressure, followed by treatment with an aqueous solution of NaOH or LiOH in MeOH or THF. The extracted product can give the sodium or lithium salt of compound II'. Acidification with an aqueous solution of HCl to pH 6-7 can give the neutral form of compound II'. Acidification with an aqueous solution of HCl to pH 1-2 can give the hydrochloride salt of compound II'. Purification in the eluent using HPLC in the presence of formic acid or trifluoroacetic acid can give the formate or trifluoroacetate salt of compound II'.

[0183] Scheme 1b: Alternative method for the preparation of intermediate 1J

[0184]

[0185] According to Scheme 1b, wherein R3a is a carboxylate such as -COOMe or -COOEt, R1, R2, R3', R3", R4, R5, R5', R6, R7, R8, n, p, X, Y and As defined above, compound 1G can be converted to compound 1N in step 1 by treating with compound 1H' in a Pict-Spengler cyclization reaction in the presence of an acid such as TFA or acetic acid in a suitable solvent such as toluene by heating to reflux of the solvent.

[0186] Alternatively, compound 1N can be obtained in step 2 in a coupling reaction by treating compound 1L with one of compounds 1M' under coupling reaction conditions.

[0187] Compound 1N can be converted to compound 1O in step 3 by treatment with TFA or HCl.

[0188] Compound 10 can be converted to compound 1J in step 4 by treatment with compound 1P (wherein W is Cl, Br or I or OSO2R, where R = CH3, PhMe, CF3 or CF2CF2CF2CF3) in the presence of a base such as potassium carbonate (K2CO3) in DMF as solvent.

[0189] Scheme 1c: Alternative method for preparing intermediate 1E

[0190]

[0191] According to Scheme 1c, wherein R3a is a carboxylate such as -COOMe or -COOEt, R8 is methyl, R3' and R3" are as defined above, compound 1Q can be converted to compound 1R in step 1 under Vilsmeier-Haack reaction conditions in the presence of POCl3 and DMF.

[0192] Compound 1R can be converted to compound 1S in step 2 by treatment with nitroethane in the presence of ammonium acetate.

[0193] Compound 1S can be converted to compound 1T in step 3 by treatment with iron in the presence of an acid such as HCl.

[0194] Compound 1T can be converted to compound 1V in step 4 in a reductive amination reaction by treatment with compound 1U in the presence of NaBH3CN and acetic acid.

[0195] Compound 1E can be obtained in step 5 by hydrogenating compound 1V in the presence of a catalyst such as Pd / C or Pd(OH)2.

[0196] Scheme 1d Parts 1 and 2: General Method for Preparing Compounds of Formula (III)

[0197] Scheme 1d-Part-1 :

[0198]

[0199] Scheme 1d-Part-2 :

[0200]

[0201] According to Scheme 1d - Part 1 and Part 2, wherein R3a' is a carboxylate such as -COOMe or -COOEt, R8 is methyl and R1, R2, R3, R3', R3", R4, R5, R5', R6, R7, n, p, X, Y and As defined above, compound 1W can be converted to compound 1X in step 1 under Vilsmeier-Hack reaction conditions in the presence of POCl 3 and DMF.

[0202] Compound 1X can be converted to compound 1Y in step 2 by treatment with nitroethane in the presence of ammonium acetate (NH4OAc).

[0203] Compound 1Y can be converted to compound 1Z in step 3 by treatment with iron (Fe) in the presence of an acid such as HCl.

[0204] Compound 1Z can be converted to compound 1Aa in step 4 in a reductive amination reaction by treatment with compound 1U in the presence of NaBH3CN and acetic acid.

[0205] Compound 1Ab can be obtained in step 5 by hydrogenating compound 1Aa in the presence of a catalyst such as Pd / C or Pd(OH)2.

[0206] Compound 1Ab can be converted to compound 1Ac in step 6 by treatment with compound 1F (R6-LG) (wherein LG is a suitable leaving group, e.g., a halogen atom such as iodine, bromine or chlorine or triflate) in the presence of a suitable base such as diisopropylethylamine (DIPEA) in a suitable solvent such as DMF.

[0207] According to Scheme 1d - part 2, compound 1Ac can be converted to compound 1Ae in step 7 by treating with compound 1H in a Pict-Spengler cyclization reaction in the presence of an acid such as TFA or acetic acid in a suitable solvent such as toluene by heating to reflux of the solvent.

[0208] Alternatively, compound 1Ae can be obtained by treating compound 1Ac with compound 1K in a Pict-Spengler cyclization reaction in the presence of an acid such as TFA or acetic acid in a suitable solvent such as toluene by heating to the reflux of the solvent in step 8, followed by a coupling reaction between the obtained compound 1Ad and one of the compounds 1M under coupling reaction conditions in step 9.

[0209] Compound 1Ae can be converted to compound III in step 10 by treatment with an aqueous solution of sodium hydroxide (NaOH) or lithium hydroxide (LiOH) in MeOH or THF. Extraction of the product can give the sodium or lithium salt of compound III. Acidification with an aqueous solution of HCl to pH 6-7 can give the neutral form of compound III. Acidification with an aqueous solution of HCl to pH 1-2 can give the hydrochloride salt of compound III. Purification using HPLC in the presence of formic acid or trifluoroacetic acid in the eluent can give the formate or trifluoroacetate salt of compound III.

[0210] When Y═CH═, compound III can be reduced by hydrogenation in step 11 with a catalyst such as Pd / C or platinum oxide (PtO 2 ) under hydrogen (H 2 ) pressure to give the corresponding saturated compound III′.

[0211] Alternatively, when Y=CH=, compound III' can be prepared in step 12 by hydrogenation of compound 1Ae with a catalyst such as Pd / C or platinum oxide (PtO2) under hydrogen (H2) pressure, followed by treatment with an aqueous solution of NaOH or LiOH in MeOH or THF. The extracted product can give the sodium or lithium salt of compound III'. Acidification with an aqueous solution of HCl to pH 6-7 can give the neutral form of compound III'. Acidification with an aqueous solution of HCl to pH 1-2 can give the hydrochloride salt of compound III'. Purification in the eluent using HPLC in the presence of formic acid or trifluoroacetic acid can give the formate or trifluoroacetate salt of compound III'.

[0212] Scheme 1e: Alternative method for preparing intermediate 1Ae

[0213]

[0214] According to Scheme 1e, wherein R3a′ is a carboxylate such as —COOMe or —COOEt, R1, R2, R3, R3″, R4, R5, R5′, R6, R7, R8, n, p, X, Y and As defined above, compound 1Ac can be converted to compound 1Af in step 1 by treating with compound 1H' in a Pict-Spengler cyclization reaction in the presence of an acid such as TFA or acetic acid in a suitable solvent such as toluene by heating to reflux of the solvent.

[0215] Alternatively, compound 1Af can be obtained in step 2 in a coupling reaction by treating compound 1Ad with one of compounds 1M' under coupling reaction conditions.

[0216] Compound 1Af can be converted to compound 1Ag in step 3 by treatment with TFA or HCl.

[0217] Compound 1Ag can be converted to compound 1Ae in step 4 by treating with compound 1P (wherein W is Cl, Br or I or OSO2R, where R=CH3, PhMe, CF3 or CF2CF2CF2CF3) in the presence of a base such as potassium carbonate (K2CO3) in DMF as solvent.

[0218] Also provided herein is a process for preparing a compound of formula (II) as defined above, wherein a compound of formula 1J:

[0219]

[0220] --Among which R1, R2, R3', R3", R4, R5, R5', R6, R7, R8, n, p, X and Y are as defined above, and R3a is a carboxylate such as -COOMe or -COOEt - is converted to a compound of formula (II) in solution in methanol or THF in the presence of a hydroxide ion source such as NaOH or LiOH, optionally preceded by a step to obtain compound 1J, wherein a compound of formula 1L:

[0221]

[0222] - wherein R3', R3", R6, R7, R8, n and X are as defined above, and R3a is a carboxylate such as -COOMe or -COOEt - is subjected to a coupling step with one of the compounds 1M under coupling reaction conditions:

[0223]

[0224] wherein R1, R2, R4, R5, R5' and p are as defined above.

[0225] Also provided herein is a process for preparing a compound of formula (II) as defined above, wherein a compound of formula 1J:

[0226]

[0227] --Among which R1, R2, R3', R3", R4, R5, R5', R6, R7, R8, n, p, X and Y are as defined above, and R3a is a carboxylate such as -COOMe or -COOEt - is converted to a compound of formula (II) in the presence of a hydroxide ion source such as NaOH or LiOH in solution in methanol or THF, said step optionally being preceded by a step to obtain compound 1J, wherein a compound of formula 1G:

[0228]

[0229] -- wherein R3', R3", R6 and R8 are as defined above, and R3a is a carboxylate such as -COOMe or -COOEt -- is subjected to a Pict-Spengler cyclization reaction with compound 1H in the presence of an acid such as TFA or acetic acid in a suitable solvent such as toluene:

[0230]

[0231] Among them, R1, R2, R4, R5, R5', R7, X, Y, n and p are as defined above.

[0232] Also provided herein is a process for preparing a compound of formula (II) as defined above, wherein a compound of formula 1J:

[0233]

[0234] --Among which R1, R2, R3', R3", R4, R5, R5', R6, R7, R8, n, p, X and Y are as defined above, and R3a is a carboxylate such as -COOMe or -COOEt - is converted to a compound of formula (II) in the presence of a hydroxide ion source such as NaOH or LiOH in solution in methanol or THF, said step optionally being preceded by a step to obtain compound 1J, wherein a compound of formula 10:

[0235]

[0236] -- Among them R3', R3", R6, R7, R8, n, p, X and Y are as defined above, and R3a is a carboxylate such as -COOMe or -COOEt - is converted to compound 1J by treatment with compound 1P in the presence of a base such as potassium carbonate (K2CO3) in DMF as solvent:

[0237]

[0238] wherein W is Cl, Br or I or OSO2R, wherein R=CH3, PhMe, CF3 or CF2CF2CF2CF3, and R1, R2, R4, R5 and R5' are as defined above.

[0239] Also described herein are intermediate compounds selected from compounds of Formula 1J, 1L, 1N, 1O, or any pharmaceutically acceptable salt thereof,

[0240]

[0241]

[0242] Among them, R1, R2, R3, R3', R3", R4, R5, R5', R6, R7, R8, n, p, X and Y are as defined above, and R3a is a hydrogen atom or a carboxylate such as -COOMe or -COOEt.

[0243] Also provided herein is a process for preparing a compound of formula (III) as defined above, wherein a compound of formula 1Ae:

[0244]

[0245] --Among which R1, R2, R3, R3', R4, R5, R5', R6, R7, R8, n, p, X and Y are as defined above, and R3a' is a carboxylate such as -COOMe or -COOEt - is converted to a compound of formula (III) in solution in methanol or THF in the presence of a hydroxide ion source such as NaOH or LiOH, optionally preceded by a step to obtain compound 1Ae, wherein a compound of formula 1Ad:

[0246]

[0247] - wherein R3, R3″, R6, R7, R8, n and X are as defined above, and R3a′ is a carboxylate such as -COOMe or -COOEt - is subjected to a coupling step with one of the compounds 1M under coupling reaction conditions:

[0248]

[0249] wherein R1, R2, R4, R5, R5' and p are as defined above.

[0250] Also provided herein is a process for preparing a compound of formula (III) as defined above, wherein a compound of formula 1Ae:

[0251]

[0252] --Among which R1, R2, R3, R3', R4, R5, R5', R6, R7, R8, n, p, X and Y are as defined above, and R3a' is a carboxylate such as -COOMe or -COOEt - is converted to a compound of formula (III) in solution in methanol or THF in the presence of a hydroxide ion source such as NaOH or LiOH, optionally preceded by a step to obtain compound 1Ae, wherein a compound of formula 1Ac:

[0253]

[0254] -- wherein R3, R3″, R6 and R8 are as defined above, and R3a′ is a carboxylate such as —COOMe or —COOEt -- is subjected to a Pict-Spengler cyclization reaction with compound 1H in the presence of an acid such as TFA or acetic acid in a suitable solvent such as toluene:

[0255]

[0256] Among them, R1, R2, R4, R5, R5', R7, X, Y, n and p are as defined above.

[0257] Also provided herein is an intermediate compound selected from a compound of Formula 1Ae or any pharmaceutically acceptable salt thereof,

[0258]

[0259] wherein R3a′ is a carboxylate such as —COOMe or —COOEt, R1, R2, R3, R3″, R4, R5, R5′, R6, R7, R8, n, p, X and Y are as defined above.

[0260] In another aspect, there is also provided herein a process for the preparation of a compound of formula (I), comprising a deprotection step of a compound of formula 1J as defined above, optionally followed by a purification step.

[0261] In another aspect, there is also provided herein a process for the preparation of a compound of formula (III), comprising a deprotection step of a compound of formula 1Ae as defined above, optionally followed by a purification step.

[0262] The purification step may, for example, include an acidification step (eg with aqueous hydrochloric acid) as described in step 2 of Example 1 herein below.

[0263] At 400 and 500MHz 1 H NMR spectra were performed on Bruker Avance DRX-400 and Bruker Avance DPX-500 spectrometers, respectively, with chemical shifts (δ, in ppm) in the solvent dimethyl sulfoxide-d6 (d6-DMSO) referenced to 2.5 ppm at a temperature of 303 K. Coupling constants (J) are given in Hertz.

[0264] Liquid chromatography / mass spectrometry (LC / MS) was obtained on a UPLC Acquity Waters instrument using UV detection DAD 210-400 nm and fast Acquity UPLC CSH C18 1.7 μm, size 2.1×30 mm, mobile phase H2O+0.1% HCO2H / CH3CN+0.1% HCO2H, light scattering detector Sedere and SQD Waters mass spectrometer.

[0265] Tables 1a and 1b below contain specific compounds (names and structures) of formula (I) according to the present disclosure and their characterizations ( 1 H NMR and LC / MS / MS).

[0266] Table 1a : (the first column "Example" corresponds to the compound and example number)

[0267]

[0268]

[0269]

[0270]

[0271]

[0272] Table 1b :

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279] The following examples describe the preparation of some of the compounds of formula (I), (II) and (III) described herein. The quantities of the compounds exemplified below match those given in Tables 1a and 1b above. Unless otherwise specified, all reactions were carried out under an inert atmosphere.

[0280] In the following examples, when the origin of the starting product is not specified, it is understood that the product is a known compound.

[0281] Examples

[0282] Intermediates:

[0283] Intermediate 1a: (R)-3-(2-aminopropyl)-1H-indole-6-carboxylic acid methyl ester, hydrochloride

[0284]

[0285] Step 1: (R)-tert-butyl (1-(6-bromo-1H-indol-3-yl)propan-2-yl)carbamate

[0286]

[0287] At 0 ° C, 3M MeMgCl (14.3ml, 42.9mmol) in THF was added dropwise to a suspension of 6-bromoindole (10g, 49.5mmol) and CuCl (4.29g, 42.9mmol) in DCM (120ml). The reaction mixture was stirred for 1h at 0 ° C and then cooled to -20 ° C. At -20 ° C, a solution of (R)-4-methyl-2,2-dioxo-1,2,3-oxathiazolidine-3-tert-butyl formate (7.83g, 33.0mmol) in DCM (50ml) was added dropwise to the reaction mixture. The reaction mixture was allowed to warm to room temperature and stirred for 18h. The reaction mixture was then cooled to 0 ° C and 2M citric acid aqueous solution (330ml) was carefully added. The mixture was allowed to warm to room temperature, stirred for 10min, and then filtered on a celite pad. After decanting the filtrate, the organic phase was washed with brine (50 ml), dried over MgSO4, filtered and concentrated under reduced pressure. The obtained residue was purified by flash chromatography eluting with DCM to give 7.34 g (63%) of tert-butyl (R)-(1-(6-bromo-1H-indol-3-yl)propan-2-yl)carbamate.

[0288] LC / MS(m / z,MH+):353

[0289] Step 2: (R)-3-(2-((tert-Butyloxycarbonyl)amino)propyl)-1H-indole-6-carboxylic acid methyl ester

[0290]

[0291] In a stainless steel bomb, a mixture of (R)-tert-butyl(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]palladium(II) dichloride complex with dichloromethane (0.92 g, 1.13 mmol) in MeOH (40 ml) was heated at 100° C. under a CO atmosphere (5 bar) for 18 h. The reaction mixture was cooled to room temperature and then filtered over a pad of celite. The filtrate was concentrated under reduced pressure and the obtained residue 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 (R)-methyl 3-(2-((tert-butoxycarbonyl)amino)propyl)-1H-indole-6-carboxylate.

[0292] LC / MS(m / z,MH+):333

[0293] Step 3: (R)-3-(2-aminopropyl)-1H-indole-6-carboxylic acid methyl ester, hydrochloride

[0294]

[0295] To a solution of (R)-methyl 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 room temperature. The solution was stirred at room temperature for 18 h. The solution was concentrated under reduced pressure to give 4.8 g (crude) of (R)-methyl 3-(2-aminopropyl)-1H-indole-6-carboxylate, hydrochloride, which was used as is in the next step.

[0296] LC / MS(m / z,MH+):233

[0297] Intermediate 1b: 3-(2-aminopropyl)-1H-indole-6-carboxylic acid methyl ester, racemic mixture

[0298]

[0299] Step 1: 3-Formyl-1H-indole-6-carboxylic acid methyl ester

[0300]

[0301] At room temperature, POCl3 (1.31 g, 8.56 mmol, 795.70 μl) was added to a solution of 1H-indole-6-formic acid methyl ester (1 g, 5.71 mmol) in DMF (100 ml), and the mixture was stirred for 3 h. Water (20 ml) was slowly added to the reaction mixture, and the mixture was then heated at 120 ° C for 15 minutes. After cooling to room temperature, the precipitated solid was filtered and dried under reduced pressure to give 1 g (86%) of 3-formyl-1H-indole-6-formic acid methyl ester as a pink solid.

[0302] LC / MS(m / z,MH+):204

[0303] Step 2: (E)-3-(2-nitroprop-1-en-1-yl)-1H-indole-6-carboxylic acid methyl ester

[0304]

[0305] 3-formyl-1H-indole-6-methyl formate (1g, 4.92mmol) and NH4OAc (948mg, 12.30mmol) mixture in nitroethane (11.08g, 147.64mmol, 10.56ml) is heated to 100 DEG C for 4h. After cooling to room temperature, the reaction mixture is diluted with water (20ml) and EtOAc (40ml). After decantation, the organic phase is dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The obtained residue is purified by flash chromatography with a gradient elution of petroleum ether / EtOAc from 100 / 00 to 70 / 30, to give 728mg (57%) of (E)-3-(2-nitroprop-1-ene-1-yl)-1H-indole-6-methyl formate as a yellow solid.

[0306] LC / MS(m / z,MH+):261

[0307] Step 3: 3-(2-oxopropyl)-1H-indole-6-carboxylic acid methyl ester

[0308]

[0309] At room temperature, to (E)-3-(2-nitroprop-1-ene-1-yl)-1H-indole-6-methyl-formiate (300mg, 1.15mmol) solution in EtOH (6mL), add iron powder (644mg, 11.53mmol) and AcOH (623mg, 10.37mmol, 593 μ l), and suspension is stirred for 1.5h at 60 ℃.Then HCl aqueous solution (2M, 0.58ml) is added in reaction mixture and stirs 6h.Reaction mixture is filtered, and filtrate is concentrated under reduced pressure.The obtained residue is purified by the gradient elution of petroleum ether / EtOAc from 100 / 00 to 50 / 50 by flash chromatography, to give 3-(2-oxopropyl)-1H-indole-6-methyl-formiate of 200mg (crude product), which is used for next step as it is.

[0310] LC / MS(m / z,MH+):232

[0311] Step 4: 3-(2-((1-phenylethyl)amino)propyl)-1H-indole-6-carboxylic acid methyl ester

[0312]

[0313] AcOH was added dropwise to a solution of 1-phenylethylamine (300 mg, 2.48 mmol, 319.15 μl) in MeOH (10 ml) to adjust pH=5 to 6. Then 3-(2-oxopropyl)-1H-indole-6-methyl formate (572 mg, 2.48 mmol) and NaBH CN (156 mg, 2.48 mmol) were added in batches. The mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in DCM (20 ml) and washed with saturated NH .H O (10 ml). After decantation, the organic phase was dried over anhydrous Na SO, 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 a yellow oil.

[0314] LC / MS(m / z,MH+):337

[0315] Step 5: 3-(2-aminopropyl)-1H-indole-6-carboxylic acid methyl ester, racemic mixture

[0316]

[0317] Under N2 atmosphere, to a mixture of 3-(2-((1-phenylethyl)amino)propyl)-1H-indole-6-formic acid methyl ester (685mg, 2.04mmol) in MeOH (13ml), Pd(OH)2 / C 20% (286mg) was added, and then purged several times with H2, and then the mixture was stirred for 12h at room temperature under H2 atmosphere (3 bar). The reaction mixture was filtered through diatomaceous earth and the filter cake was washed with MeOH (2×20ml). Then, the filtrate was concentrated under reduced pressure to give 460mg (crude) of 3-(2-aminopropyl)-1H-indole-6-formic acid methyl ester, a racemic mixture, which was used as is in the next step.

[0318] LC / MS(m / z,MH+):233

[0319] Intermediate 1c: 3-(2-aminopropyl)-1H-indole-5-carboxylic acid methyl ester, racemic mixture

[0320]

[0321] Step 1: 3-Formyl-1H-indole-5-carboxylic acid methyl ester

[0322]

[0323] Step 1 of Intermediate 1c was prepared from methyl 1H-indole-5-carboxylate following a procedure similar to that of Step 1 of Intermediate 1b to give 10.4 g (90%) of methyl 3-formyl-1H-indole-5-carboxylate as a pink solid.

[0324] LC / MS(m / z,MH+):204

[0325] Step 2: (E)-3-(2-nitroprop-1-en-1-yl)-1H-indole-5-carboxylic acid methyl ester

[0326]

[0327] Step 2 of Intermediate 1c was prepared from methyl 3-formyl-1H-indole-5-carboxylate following a procedure similar to that of Step 2 of Intermediate 1b to give 18 g (crude) of methyl (E)-3-(2-nitroprop-1-en-1-yl)-1H-indole-5-carboxylate as a yellow solid.

[0328] LC / MS(m / z,MH+):261

[0329] Step 3: 3-(2-oxopropyl)-1H-indole-5-carboxylic acid methyl ester

[0330]

[0331] Step 3 of Intermediate 1c was prepared following a procedure similar to that of Step 3 of Intermediate 1b from (E)-3-(2-nitroprop-1-en-1-yl)-1H-indole-5-carboxylic acid methyl ester to give 881 mg (50%) of 3-(2-oxopropyl)-1H-indole-5-carboxylic acid methyl ester, which was used as such in the next step.

[0332] LC / MS(m / z,MH+):232

[0333] Step 4: 3-(2-((1-phenylethyl)amino)propyl)-1H-indole-5-carboxylic acid methyl ester

[0334]

[0335] Step 4 of Intermediate 1c was prepared following a procedure similar to that of Step 4 of Intermediate 1b from methyl 3-(2-oxopropyl)-1H-indole-5-carboxylate and 1-phenylethylamine to give 1.04 g (62%) of methyl 3-(2-((1-phenylethyl)amino)propyl)-1H-indole-5-carboxylate as a yellow oil.

[0336] LC / MS(m / z,MH+):337

[0337] Step 5: 3-(2-aminopropyl)-1H-indole-5-carboxylic acid methyl ester, racemic mixture

[0338]

[0339] Step 5 of Intermediate 1c was prepared from methyl 3-(2-((1-phenylethyl)amino)propyl)-1H-indole-5-carboxylate following a procedure similar to that of Step 5 of Intermediate 1b to give 660 mg (crude) of methyl 3-(2-aminopropyl)-1H-indole-5-carboxylate as a racemic mixture which was used as such in the next step.

[0340] LC / MS(m / z,MH+):233

[0341] Intermediate 2: (R)-3-(2-((2,2,2-trifluoroethyl)amino)propyl)-1H-indole-6-carboxylic acid methyl ester

[0342]

[0343] A mixture of (R)-3-(2-aminopropyl)-1H-indole-6-carboxylic acid methyl ester, 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 18 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the obtained residue was purified by flash chromatography eluting with a gradient of DCM / MeOH from 100 / 00 to 80 / 20 to give 455 mg (34%) of (R)-3-(2-((2,2,2-trifluoroethyl)amino)propyl)-1H-indole-6-carboxylic acid methyl ester.

[0344] LC / MS(m / z,MH+):315

[0345] Intermediate 3a: (R)-3-(2-((2,2-difluoropropyl)amino)propyl)-1H-indole-6-carboxylic acid methyl ester

[0346]

[0347] Intermediate 3a was prepared from (R)-3-(2-aminopropyl)-1H-indole-6-carboxylic acid methyl ester, hydrochloride (Intermediate 1a) and 2,2-difluoropropyl trifluoromethanesulfonate following a procedure similar to that of Intermediate 2 to give 620 mg (54%) of (R)-3-(2-((2,2-difluoropropyl)amino)propyl)-1H-indole-6-carboxylic acid methyl ester.

[0348] LC / MS(m / z,MH+):311

[0349] Intermediate 3b: 3-(2-((2,2-difluoropropyl)amino)propyl)-1H-indole-6-carboxylic acid methyl ester, racemic mixture

[0350]

[0351] Intermediate 3b was prepared from methyl 3-(2-aminopropyl)-1H-indole-6-carboxylate (Intermediate 1b) and 2,2-difluoropropyl trifluoromethanesulfonate following a procedure similar to that of Intermediate 2 to give 40 mg (56%) of methyl 3-(2-((2,2-difluoropropyl)amino)propyl)-1H-indole-6-carboxylate as a colorless oil, a racemic mixture.

[0352] LC / MS(m / z,MH+):311

[0353] Intermediate 3c: 3-(2-((2,2-difluoropropyl)amino)propyl)-1H-indole-5-carboxylic acid methyl ester, racemic mixture

[0354]

[0355] Intermediate 3c was prepared from methyl 3-(2-aminopropyl)-1H-indole-5-carboxylate (Intermediate 1c) and 2,2-difluoropropyl trifluoromethanesulfonate following a procedure similar to that for Intermediate 2 to give 400 mg (40%) of methyl 3-(2-((2,2-difluoropropyl)amino)propyl)-1H-indole-5-carboxylate as a racemic mixture as a yellow oil.

[0356] LC / MS(m / z,MH+):311

[0357] Intermediate 4: (R)-3-(2-((3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)amino)propyl)-1H-indole-6-carboxylic acid methyl ester

[0358]

[0359] Intermediate 4 was prepared following a procedure similar to that of Intermediate 2 from (R)-methyl 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.

[0360] LC / MS(m / z,MH+):565

[0361] Intermediate 5: (S)-2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)benzaldehyde

[0362]

[0363] To a solution of 2,6-difluoro-4-hydroxybenzaldehyde (0.88 g, 5.44 mmol) in dry THF (20 ml), (R)-1-(3-fluoropropyl)pyrrolidin-3-ol (prepared according to WO 2018091153) (1 g, 6.79 mmol), PPh3 (2.88 g, 10.9 mmol) and TMAD (1.87 g, 10.87 mmol) were added. The reaction mixture was stirred at room temperature for 48 h. Water (50 ml) and EtOAc (100 ml) were added, and the aqueous layer was then separated and extracted with EtOAc (50 ml) again. The combined organic layer was 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.

[0364] LC / MS(m / z,MH+):288

[0365] Intermediate 6: (S)-2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)benzaldehyde

[0366]

[0367] Step 1: (S)-tert-butyl (1-(3-fluoropropyl)pyrrolidin-3-yl)carbamate

[0368]

[0369] A suspension of N-[(3S)-pyrrolidin-3-yl] tert-butyl carbamate (5.00 g, 26.04 mmol), 1-fluoro-3-iodopropane (5.38 g, 28.64 mmol) and KCO (10.36 g, 74.21 mmol) in MeCN (100 ml) was stirred at 50 ° C for 18 h. After cooling to room temperature, the suspension was filtered through a celite pad and the filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc, then washed with water and saturated NaCl aqueous solution in sequence, then dried over MgSO, filtered and concentrated under reduced pressure to give 6.03 g (94%) of tert-butyl (S)-(1-(3-fluoropropyl) pyrrolidin-3-yl) carbamate.

[0370] LC / MS(m / z,MH+):247

[0371] Step 2: (S)-tert-butyl (3,5-difluoro-4-formylphenyl)(1-(3-fluoropropyl)pyrrolidin-3-yl)carbamate

[0372]

[0373] A mixture of 4-bromo-2,6-difluorobenzaldehyde (1.83 g, 8.12 mmol, 1 eq.), Cs2CO3 (5.32 g, 16.24 mmol), palladium acetate (0.038 g, 0.081 mmol), BINAP (0.101 g, 0.16 mmol) and (S)-(1-(3-fluoropropyl)pyrrolidin-3-yl)carbamic acid tert-butyl ester (2 g, 8.12 mmol) in toluene (100 ml) was stirred at 80 ° C for 96 h. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth. Water (50 ml) was added to the filtrate, the organic phase was then separated, and the aqueous phase was extracted again with EtOAc (2×20 ml). The combined organic layer was dried over MgSO4, filtered out and evaporated under reduced pressure. The residue obtained was purified by flash chromatography eluting with a gradient of heptane / EtOAc from 30 / 70 to 100 / 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.

[0374] LC / MS(m / z,MH+):387

[0375] Intermediate 7: tert-Butyl (3,5-difluoro-4-formylphenyl)(1-(3-fluoropropyl)azetidin-3-yl)carbamate

[0376]

[0377] Step 1: tert-Butyl (1-(3-fluoropropyl)azetidin-3-yl)carbamate

[0378]

[0379] 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 KCO (8.19 g, 58.7 mmol) in THF (100 ml) and water (0.21 ml, 11.7 mmol) was stirred at 70 ° C for 5 h. The crude mixture was cooled to room temperature, poured into water (100 ml) and extracted with EtOAc (200 ml). The organic layer was dried over MgSO, 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.

[0380] LC / MS(m / z,MH+):233

[0381] Step 2: tert-Butyl (1-(3-fluoropropyl)azetidin-3-yl)carbamate

[0382]

[0383] Step 2 of Intermediate 7 was prepared following a procedure similar 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 afford 2.95 g (92%) of tert-butyl (3,5-difluoro-4-formylphenyl)(1-(3-fluoropropyl)azetidin-3-yl)carbamate as an orange oil.

[0384] LC / MS(m / z,MH+):373

[0385] Step 3: 2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)benzaldehyde

[0386]

[0387] TFA (2.99 ml, 40.28 mmol) was added dropwise to a solution of tert-butyl (3,5-difluoro-4-formylphenyl)(1-(3-fluoropropyl)azetidin-3-yl)carbamate (1 g, 2.69 mmol) in DCM (30 ml) at 0 °C. The reaction mixture was stirred at room temperature for 18 h. DCM (20 ml) and 10% aqueous NaHCO3 were added to the reaction mixture. The aqueous layer was separated and extracted again with DCM (2×10 ml). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give 0.6 g (82%) of 2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)benzaldehyde.

[0388] LC / MS(m / z,MH+):273

[0389] Intermediate 8: 2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzaldehyde

[0390]

[0391] Step 1: tert-Butyl 3-(3,5-difluoro-4-bromophenoxy)azetidine-1-carboxylate

[0392]

[0393] By 4- bromo-3,5-difluorophenol (2.09g, 10mmol), Cs2CO3 (6.52g, 20mmol) and 3- iodoazetidine -1- tert-butyl formate (2.25mL, 12mmol) in DMF (17ml) mixture is heated at 100 DEG C for 3h.After cooling to room temperature, the reaction mixture is filtered, the solid is washed with EtOAc, and the filtrate is concentrated under reduced pressure.The residual oil is diluted in EtOAc and washed with water and brine.The organic phase is dried over MgSO4, filtered, and concentrated under reduced pressure.The obtained crude residue is washed with heptane and the precipitate is filtered to give 2.52g (69%) of 3- (3,5- difluoro-4- bromophenoxy) azetidine -1- tert-butyl formate as white powder.

[0394] LC / MS(m / z,MH+):364

[0395] Step 2: 3-(4-Bromo-3,5-difluoro-phenoxy)azetidine, 2,2,2-trifluoroacetic acid

[0396]

[0397] Step 2 of Intermediate 8 was prepared following a procedure similar to that of Step 3 of Intermediate 7 starting from tert-butyl 3-(3,5-difluoro-4-bromophenoxy)azetidine-1-carboxylate to afford 2 g (crude) of 3-(4-bromo-3,5-difluoro-phenoxy)azetidine, 2,2,2-trifluoroacetic acid which was used as such in the next step.

[0398] LC / MS(m / z,MH+):264

[0399] Step 3: 3-(4-Bromo-3,5-difluoro-phenoxy)-1-(3-fluoropropyl)azetidine

[0400]

[0401] By 3- (4- bromo -3,5- difluoro - phenoxy) azetidine, 2,2,2- trifluoroacetic acid (2g, crude), 1- iodo -3- fluoropropane (0.56mL, 5.49mmol), DIPEA (4.78mL, 27.5mmol) in DMF (20ml) mixture was stirred at room temperature 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 1.69g (95%) of 3- (4- bromo -3,5- difluoro - phenoxy) -1- (3- fluoropropyl) azetidine in a brown oil.

[0402] LC / MS(m / z,MH+):324

[0403] Step 4: 2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzaldehyde

[0404]

[0405] A mixture of 3-(4-bromo-3,5-difluoro-phenoxy)-1-(3-fluoropropyl)azetidine (1.5g, 4.63mmol) in THF (46ml) was cooled to -78 °C. Then, 1.6M n-BuLi (3.05ml, 4.86mmol) in hexane was added dropwise to the crude mixture and stirred at this temperature for 30 minutes. Then, at -78 °C, DMF (0.72mL, 9.26mmol) was added dropwise to the crude mixture and stirred at this temperature for 3 hours. The crude mixture was quenched with water at room temperature and stirred for 15 minutes. Then, the aqueous phase was extracted with EtOAc (50ml), dried over MgSO4, filtered out and concentrated under reduced pressure. The residue obtained was purified by flash chromatography eluting with a gradient of heptane / EtOAc from 50 / 50 to 100 / 100 to give 0.38 g (30%) of 2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzaldehyde as a yellow liquid.

[0406] LC / MS(m / z,MH+):274

[0407] Intermediate 9: (Z)-tert-butyl 3-(3,5-difluoro-4-formylbenzylidene)pyrrolidine-1-carboxylate

[0408]

[0409] Step 1: tert-Butyl 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)pyrrolidine-1-carboxylate, mixture of Z isomer and E isomer

[0410]

[0411] To a solution of 2,2,6,6-tetramethylpiperidine (5.51 ml, 32.4 mmol) in 2-methyltetrahydrofuran (50 ml) was added 1.6 M n-BuLi (20.2 ml, 32.4 mmol) in THF at -78°C (the internal temperature was kept below -65°C). The solution was stirred at -78°C for 30 minutes. Then, a solution of 4,4,5,5-tetramethyl-2-[(tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]-1,3,2-dioxaborolan (7.23 g, 27 mmol) in 2-methyltetrahydrofuran (50 ml) was added dropwise at -78°C (the internal temperature was kept below -65°C). The reaction mixture was stirred at -78°C for 30 minutes. Then, a solution of tert-butyl 3-oxopyrrolidine-1-formate (5 g, 27.0 mmol) in 2-methyltetrahydrofuran (50 ml) was added dropwise at -78 °C (the internal temperature was kept below -65 °C). The reaction mixture was allowed to slowly warm to room temperature and stirred at this temperature for 18 h. The reaction mixture was cooled to 0 °C and slowly quenched with 10% NH4Cl aqueous solution (30 ml). The aqueous layer was separated and extracted again with EtOAc (2 × 50 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 70 / 30 to give 6.23 g (75%) of tert-butyl 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)pyrrolidine-1-carboxylate, a mixture of Z and E isomers as a colorless oil.

[0412] LC / MS(m / z,MH+):310

[0413] Step 2: (Z)-tert-butyl 3-(3,5-difluoro-4-formylbenzylidene)pyrrolidine-1-carboxylate

[0414]

[0415] A mixture of tert-butyl 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)pyrrolidine-1-carboxylate, a mixture of Z and E isomers (5.10 g, 16.5 mmol), 4-bromo-2,6-difluorobenzaldehyde (3.04 g, 13.7 mmol), K3PO4 (8.75 g, 41.2 mmol), palladium acetate (0.11 g, 0.69 mmol) and SPhos (0.28 g, 0.69 mmol) in THF (15 ml) and water (1.5 ml) was heated at 40° C. for 18 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and filtered on a pad of celite. The filtrate was dried over MgSO4, filtered and concentrated under reduced pressure. The obtained residue was purified by flash chromatography eluting with a gradient of heptane / EtOAc from 90 / 10 to 70 / 30 to give 320 mg (7%) of (Z)-tert-butyl 3-(3,5-difluoro-4-formylbenzylidene)pyrrolidine-1-carboxylate and 3 g (68%) of a mixture of E and Z isomers of tert-butyl 3-(3,5-difluoro-4-formylbenzylidene)pyrrolidine-1-carboxylate.

[0416] LC / MS(m / z,MH+):324

[0417] Intermediate 10: tert-Butyl 3-(3,5-difluoro-4-formylbenzyl)azetidine-1-carboxylate

[0418]

[0419] A mixture of 4-bromo-2,6-difluorobenzaldehyde (2 g, 9.05 mmol), tert-butyl 3-(bromomethyl)azetidine-1-carboxylate (2.94 g, 11.76 mmol), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (102 mg, 0.090 mmol), NiCl2.dtbbpy (18 mg, 0.045 mmol), tris(trimethylsilyl)silane (2.25 g, 9.05 mmol, 2.79 mL) and Na2CO3 (1.92 g, 18.10 mmol) in 1,2-dimethoxyethane (80 ml) was sealed and placed under N2 atmosphere. The reaction was stirred and irradiated with a 34 W blue LED lamp (7 cm away) under a cooling fan to maintain the reaction temperature at 25°C for 14 hours. The reaction mixture was filtered, and the filtrate was washed with brine (40 ml), dried over anhydrous Na2SO4 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.

[0420] LC / MS(m / z,MH+):312

[0421] Intermediate 11: 1-(3-fluoropropyl)-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine

[0422]

[0423] Step 1: 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine, 2,2,2-trifluoroacetic acid

[0424]

[0425] TFA (2.89 ml, 38.96 mmol) was added dropwise to a solution of commercially available tert-butyl 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine-1-carboxylate (2.3 g, 7.79 mmol) in DCM (20 ml) at room temperature. The solution was stirred for 18 h. The crude oil was concentrated under reduced pressure to give 2.67 g (crude) of 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine, 2,2,2-trifluoroacetic acid, which was used as is in the next step.

[0426] LC / MS(m / z,MH+):196

[0427] Step 2: 1-(3-Fluoropropyl)-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine

[0428]

[0429] Step 2 of Intermediate 11 was prepared following a procedure similar to that of Step 3 of Intermediate 8 from 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine, 2,2,2-trifluoroacetic acid and 1-fluoro-3-iodopropane to give 1.05 g (60%) of 1-(3-fluoropropyl)-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine.

[0430] LC / MS(m / z,MH+):256

[0431] Intermediate 12: 1-(3-fluoropropyl)azetidine-3-amine

[0432]

[0433] Step 1: tert-Butyl (1-(3-fluoropropyl)azetidin-3-yl)carbamate

[0434]

[0435] 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 KCO (8.19 g, 58.7 mmol) in THF (100 ml) and water (0.21 ml, 11.7 mmol) was stirred at 70 ° C for 5 h. The crude mixture was cooled to room temperature, poured into water (100 ml) and extracted with EtOAc (200 ml). The organic layer was dried over MgSO, 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.

[0436] LC / MS(m / z,MH+):233

[0437] Step 2: 1-(3-Fluoropropyl)azetidine-3-amine

[0438]

[0439] TFA (4.34ml, 48.6mmol) is added dropwise to a solution of tert-butyl (1-(3-fluoropropyl)azetidine-3-yl)carbamate (1g, 4.305mmol) in DCM (10ml). The reaction mixture is stirred at room temperature for 16h. Then, the reaction mixture is concentrated under reduced pressure. The obtained residue is dissolved in MeOH (10ml), and Amberlyst A26 (4g) is added, and the mixture is stirred at room temperature for 64h. The reaction mixture is filtered out to remove Amberlyst A26 and washed with MeOH to give 0.5g (88%) of 1-(3-fluoropropyl)azetidine-3-amine.

[0440] LC / MS(m / z,MH+):133

[0441] Intermediate 13: (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-carboxylic acid methyl ester

[0442]

[0443] A mixture of 4-bromo-2,6-difluorobenzaldehyde (195 mg, 0.603 mmol) and (R)-3-(2-((2,2-difluoropropyl)amino)propyl)-1H-indole-6-carboxylic acid methyl ester (intermediate 3a) (170 mg, 0.55 mmol) and AcOH (0.19 ml, 3.28 mmol) in toluene (5 ml) was stirred at 110 ° C for 18 h. After cooling to room temperature, EtOAc and 10% NaHCO3 aqueous solution were added. The aqueous layer was separated and extracted again with EtOAc (2×10 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 (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-carboxylic acid methyl ester.

[0444] LC / MS(m / z,MH+):513

[0445] Intermediate 14: (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-carboxylic acid methyl ester

[0446]

[0447] A mixture of (R)-methyl 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 18 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by flash chromatography eluting with a gradient of heptane / EtOAc from 100 / 00 to 70 / 30 to give 470 mg (72%) of (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-carboxylic acid methyl ester as a light yellow powder.

[0448] LC / MS(m / z,MH+):767

[0449] Examples

[0450] Method A:

[0451] Example 1 :(1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid

[0452]

[0453] Step 1: (1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid methyl ester

[0454] and

[0455] (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 methyl ester

[0456]

[0457] Step 1 of Example 1 was prepared from (R)-3-(2-((2,2,2-trifluoroethyl)amino)propyl)-1H-indole-6-carboxylic acid methyl ester (Intermediate 2) and (S)-2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)benzaldehyde (Intermediate 5) according to a procedure similar to that of Intermediate 14. The obtained residue was purified by preparative chiral SFC (stationary phase: chiralpak IG 250×30 mm, mobile phase: CO 70% / iPrOH 30% / iPrNH 2 0.3%)) was purified to give 96 mg (52%) of (1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid methyl ester and 15 mg (8%) of (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 methyl ester.

[0458] LC / MS(m / z,MH+):584

[0459] 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

[0460]

[0461] A mixture of (1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid methyl ester (80 mg, 0.14 mmol) and LiOH monohydrate (29 mg, 0.69 mmol) in MeOH (1.2 ml) was heated at 60 °C for 48 h. After cooling to room temperature, the crude product was diluted with DCM (5 ml). 1N HCl aqueous solution 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 MgSO4, filtered and concentrated under reduced pressure. The residue was purified by HPLC (column YMC-Actus Triart Prep C18-S 150×30 mm 10 μm, flow rate 50 ml / min-central gradient from 25 / 75 to 55 / 45 MeCN / aqueous NH4HCO3 0.2% pH=7.9) to give 10 mg (13%) of (1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid as a white solid.

[0462] Example 2 :(1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid

[0463]

[0464] Example 2 was prepared according to a procedure similar to that of Step 2 of Preparative Example 1 from (1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid methyl ester (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-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid.

[0465] Example 3:(1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid

[0466]

[0467] Step 1: (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 methyl ester

[0468]

[0469] Step 1 of Example 3 was prepared following a procedure similar to that for Intermediate 14 from (R)-3-(2-((2,2-difluoropropyl)amino)propyl)-1H-indole-6-carboxylic acid methyl ester (Intermediate 3a) and (S)-2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)benzaldehyde (Intermediate 5) to give 199 mg (53%) of (1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid methyl ester.

[0470] LC / MS(m / z,MH+):580

[0471] 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

[0472]

[0473] Step 2 of Example 3 was prepared according to a procedure similar to that of Step 2 of Preparative 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-tetrahydro-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-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate.

[0474] Example 4 :(1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid

[0475]

[0476] Step 1: (1R,3R)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid methyl ester

[0477]

[0478] Step 1 of Example 4 was prepared following a procedure analogous to that of Intermediate 14 from (R)-methyl 3-(2-((3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)amino)propyl)-1H-indole-6-carboxylate (Intermediate 4) and (S)-2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)benzaldehyde (Intermediate 5) to give 680 mg (crude) of methyl (1R,3R)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate which was used as such in the next step.

[0479] LC / MS(m / z,MH+):834

[0480] Step 2: (1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid methyl ester

[0481]

[0482] 1M tetra-n-butylammonium fluoride (TBAF) in THF (1.22 ml, 1.22 mmol) was added dropwise to a solution of (1R,3R)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid methyl ester (680 mg, 0.82 mmol) in THF (5 ml) previously cooled at 0°C. The mixture was warmed to room temperature and stirred for 18 h. DCM (10 ml) and 10% aqueous NH4Cl solution were added to the reaction mixture. The aqueous layer was separated and extracted with DCM (2×5 ml). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The obtained residue was purified by flash chromatography eluting with a gradient of EtOAc / MeOH from 100 / 00 to 90 / 10 to give 154 mg (32%) of (1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid methyl ester.

[0483] LC / MS(m / z,MH+):596

[0484] Step 3: (1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid

[0485]

[0486] Step 3 of Example 4 was prepared according to a procedure similar to that of Step 2 of Preparative Example 1 from (1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid methyl ester 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)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid.

[0487] Example 5 :(1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid

[0488]

[0489] Step 1: (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 methyl ester

[0490]

[0491] Step 1 of Example 5 was prepared following a procedure similar to that for Intermediate 14 from (R)-3-(2-((2,2,2-trifluoroethyl)amino)propyl)-1H-indole-6-carboxylic acid methyl ester (Intermediate 2) and 2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)benzaldehyde (Intermediate 7) to give 71 mg (44%) of (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid methyl ester.

[0492] LC / MS(m / z,MH+):569

[0493] Step 2: (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid

[0494]

[0495] Step 2 of Example 5 was prepared according to a procedure similar to that of Step 2 of Preparative 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-pyrido[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-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate.

[0496] 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

[0497]

[0498] Step 1: (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 methyl ester

[0499]

[0500] Step 1 of Example 6 was prepared following a procedure similar to that for Intermediate 14 from (R)-3-(2-((2,2,2-trifluoroethyl)amino)propyl)-1H-indole-6-carboxylic acid methyl ester (Intermediate 2) and 2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzaldehyde (Intermediate 8) to give 84 mg (46%) of (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid methyl ester.

[0501] LC / MS(m / z,MH+):570

[0502] 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

[0503]

[0504] Step 2 of Example 6 was prepared according to a procedure similar to that of Step 2 of Preparative 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-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate.

[0505] 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

[0506]

[0507] Step 1: (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 methyl ester

[0508]

[0509] Step 1 of Example 7 was prepared following a procedure similar to that for Intermediate 13 from (R)-3-(2-((2,2-difluoropropyl)amino)propyl)-1H-indole-6-carboxylic acid methyl ester (Intermediate 3a) and 2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzaldehyde (Intermediate 8) to give 50 mg (27%) of (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid methyl ester.

[0510] LC / MS(m / z,MH+):566

[0511] 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

[0512]

[0513] Step 2 of Example 7 was prepared according to a procedure similar to that of Step 2 of Preparative 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-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate.

[0514] Example 8:(1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid

[0515]

[0516] Step 1: (1R,3R)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid methyl ester

[0517]

[0518] Step 1 of Example 8 was prepared following a procedure similar to that for Intermediate 14 from (R)-3-(2-((3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)amino)propyl)-1H-indole-6-carboxylic acid methyl ester (Intermediate 4) and 2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzaldehyde (Intermediate 8) to give 250 mg (57%) of (1R,3R)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid methyl ester.

[0519] LC / MS(m / z,MH+):820

[0520] Step 2: (1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid methyl ester

[0521]

[0522] Step 2 of Example 8 was prepared according to a procedure similar to that of Step 2 of Preparative Example 4 from methyl (1R,3R)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate to give 96 mg (53%) of methyl (1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate.

[0523] LC / MS(m / z,MH+):582

[0524] Step 3: (1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid

[0525]

[0526] Step 3 of Example 8 was prepared according to a procedure similar to that of Step 2 of Preparation 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-tetrahydro-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)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate.

[0527] Example 9 :(1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid

[0528]

[0529] Step 1: (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-carboxylic acid methyl ester

[0530]

[0531] Step 1 of Example 9 was prepared following a procedure similar to that for Intermediate 14 from (R)-3-(2-((2,2-difluoropropyl)amino)propyl)-1H-indole-6-carboxylic acid methyl ester (Intermediate 3a) and (S)-tert-butyl(3,5-difluoro-4-formylphenyl)(1-(3-fluoropropyl)pyrrolidin-3-yl)carbamate (Intermediate 6) to give 433 mg (99%) of (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-carboxylic acid methyl ester.

[0532] LC / MS(m / z,MH+):679

[0533] Step 2: (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 methyl ester

[0534]

[0535] Step 2 of Example 9 was prepared following a procedure similar 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.

[0536] LC / MS(m / z,MH+):579

[0537] 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

[0538]

[0539] Step 3 of Example 9 was prepared according to a procedure similar to that of Step 2 of Preparative 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-tetrahydro-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-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate.

[0540] Method B:

[0541] 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

[0542]

[0543] Step 1: (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-carboxylic acid methyl ester

[0544]

[0545] Step 1 of Example 10 was prepared following a procedure similar to that for Intermediate 13 from (R)-3-(2-((2,2-difluoropropyl)amino)propyl)-1H-indole-6-carboxylic acid methyl ester (Intermediate 3a) and (Z)-3-(3,5-difluoro-4-formylbenzylidene)pyrrolidine-1-carboxylic acid tert-butyl ester (Intermediate 9) to give 141 mg (42%) of (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-carboxylic acid methyl ester.

[0546] LC / MS(m / z,MH+):616

[0547] Step 2: (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-carboxylic acid methyl ester, 2,2,2-trifluoroacetic acid

[0548]

[0549] Step 2 of Example 10 was prepared according to a procedure similar 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-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate, 2,2,2-trifluoroacetic acid, which was used as is in the next step.

[0550] LC / MS(m / z,MH+):516

[0551] Step 3: (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 methyl ester

[0552]

[0553] Step 3 of Example 10 was prepared following a procedure similar 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-ylidenemethyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate.

[0554] LC / MS(m / z,MH+):576

[0555] 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

[0556]

[0557] Step 4 of Example 10 was prepared according to a procedure similar to that of Step 2 of Preparative Example 1 from (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 methyl ester 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-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid.

[0558] 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

[0559]

[0560] 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

[0561]

[0562] Step 1: Methyl 1-(4-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate, mixture of trans isomers

[0563]

[0564] Step 1 of Examples 11 and 12 was prepared following a procedure similar to that for the preparation 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-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate, a mixture of trans isomers.

[0565] LC / MS(m / z,MH+):604

[0566] Step 2: 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-carboxylic acid methyl ester, 2,2,2-trifluoroacetic acid, mixture of trans isomers

[0567]

[0568] Step 2 of Examples 11 and 12 was prepared according to a procedure similar 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-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate, a mixture of trans isomers to give 214 mg (crude) of methyl 1-(4-(azetidin-3-ylmethyl)-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate, a mixture of trans isomers, which was used as is in the next step.

[0569] LC / MS(m / z,MH+):504

[0570] Step 3: Methyl 1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate, mixture of trans isomers

[0571]

[0572] Step 3 of Examples 11 and 12 was prepared following a procedure similar 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, a 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)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate, a mixture of trans isomers.

[0573] LC / MS(m / z,MH+):560

[0574] Step 4: 1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid, mixture of trans isomers

[0575]

[0576] Step 4 of Examples 11 and 12 was prepared following a procedure similar to that of Preparative Example 1, Step 2, from 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 methyl ester, a 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-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid, a mixture of trans isomers.

[0577] 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

[0578] and

[0579] (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

[0580]

[0581] A mixture of 1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid, a mixture of trans isomers (170 mg, 0.31 mmol) was purified by SFC (column: DAICEL CHIRALPAK IC (250 mm×30 mm, 10 um); mobile phase: [0.1% NH3H2O MeOH]; B%: 30%-30%, 4.2; 40min) was separated to give 90 mg of (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid (Example 11) and 26 mg of (1S,3S)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid (Example 12).

[0582] 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

[0583]

[0584] Step 1: Methyl 1-(4-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-carboxylate, mixture of trans isomers

[0585]

[0586] Step 1 of Example 13 was prepared following a procedure similar to that for Intermediate 14 from methyl 3-(2-((2,2-difluoropropyl)amino)propyl)-1H-indole-5-carboxylate, racemic mixture (Intermediate 3c) and tert-butyl 3-(3,5-difluoro-4-formylbenzyl)azetidine-1-carboxylate (Intermediate 10) 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-carboxylate, a mixture of trans isomers.

[0587] LC / MS(m / z,MH+):604

[0588] Step 2: 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-carboxylic acid methyl ester, 2,2,2-trifluoroacetate, mixture of trans isomers

[0589]

[0590] Step 2 of Example 13 was prepared according to a procedure similar 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-tetrahydro-1H-pyrido[3,4-b]indole-6-carboxylate, a mixture of trans isomers to give 490 mg (crude) of methyl 1-(4-(azetidin-3-ylmethyl)-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-carboxylate, 2,2,2-trifluoroacetate, a mixture of trans isomers, which was used as such in the next step.

[0591] LC / MS(m / z,MH+):504

[0592] Step 3: 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 methyl ester, mixture of trans isomers

[0593]

[0594] Following a procedure similar to that for the preparation of Intermediate 6, Step 3 of Example 13 was prepared 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, a 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)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-carboxylate, a mixture of trans isomers.

[0595] LC / MS(m / z,MH+):560

[0596] 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

[0597]

[0598] Step 4 of Example 13 was prepared according to a procedure similar to that of Step 2 of Preparative 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-tetrahydro-1H-pyrido[3,4-b]indole-6-carboxylate, trans isomer mixture to give 70 mg (87%) of 1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate, trans isomer compound.

[0599] 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

[0600]

[0601] A mixture of 1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-carboxylic acid, a mixture of trans isomers (170 mg, 0.31 mmol) was purified by SFC (column: DAICEL CHIRALCEL OD (250 mm×30 mm, 10 μm); mobile phase: [0.1% NH 3 H 2 O 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-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-carboxylic acid as a yellow solid.

[0602] Method C:

[0603] 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

[0604]

[0605] Step 1: (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 methyl ester

[0606]

[0607] A mixture of 1-(3-fluoropropyl)azetidine-3-amine (Intermediate 12) (288 mg, 1.17 mmol), (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-carboxylic acid methyl ester (Intermediate 13) (120 mg, 0.23 mmol), Cs2CO3 (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 at 100° C. for 24 h. After cooling to room temperature, water (10 ml) and EtOAc (10 ml) were added. After decantation, the organic phase was dried over MgSO4, filtered off and evaporated under reduced pressure. The obtained residue was purified by flash chromatography eluting with heptane / EtOAc from 100 / 00 to 00 / 100 to give 74 mg (56%) of (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid methyl ester.

[0608] LC / MS(m / z,MH+):565

[0609] 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

[0610]

[0611] Step 2 of Example 14 was prepared according to a procedure similar to that of Step 2 of Preparative 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-tetrahydro-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-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate.

[0612] Method D:

[0613] 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

[0614]

[0615] Step 1: (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 methyl ester

[0616]

[0617] A mixture of methyl (1R,3R)-1-(4-bromo-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate (Intermediate 13) (200 mg, 0.39 mmol), K3PO4 (248 mg, 1.17 mmol), palladium acetate (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 48 h. After being cooled to room temperature, the reaction mixture is diluted with EtOAc (10ml) and water (5ml). The aqueous layer is separated and extracted with EtOAc again. The combined organic layer is dried over MgSO4, filtered and concentrated under reduced pressure. The obtained residue is purified by flash chromatography eluting with DCM / MeOH from 100 / 00 to 94 / 04 to give 75mg (34%) of (1R, 3R) -1- (2,6- difluoro -4- ((1- (3- fluoropropyl) azetidine -3- subunit) methyl) phenyl) -2- (2,2- difluoropropyl) -3- methyl -2,3,4,9- tetrahydro -1H- pyrido [3,4-b] indole -7- methyl formate.

[0618] LC / MS(m / z,MH+):562

[0619] Step 2: (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid

[0620]

[0621] Step 2 of Example 15 was prepared according to a procedure similar to that of Step 2 of Preparative Example 1 from (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 methyl ester to give 28 mg (38%) of (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid.

[0622] The compounds according to Table 1 above were subjected to pharmacological testing for determining their degradation effect on estrogen receptors.

[0623] Test: Estrogen receptor degradation activity

[0624] The test involves measuring the in vitro degradation activity of the compounds of Table 1.

[0625] Degradation activity of ERα was measured using breast cancer cells in a cellular Western blot assay as described below.

[0626] MCF7 cells (ATCC) were seeded in red phenol-free MEMα medium (Invitrogen) containing 5% charcoal dextran-treated FBS at a concentration of 10,000 cells / 30 μL / well in 384-well microplates (collagen coated). The next day, 9 points of each compound were added to the cells in a final concentration ranging from 0.3-0.0000018 μM (Table 2) or 0.1 μM of Fulvestrant (used as a positive control) in 2.5 μL cells: 1:5 dilutions were added to the cells. 4 hours after compound addition, cells were fixed by adding 25 μL of formalin (5% formalin with a final concentration of 0.1% triton) for 10 minutes at room temperature, and then washed twice with PBS. Then, 50 μL of LI-COR blocking buffer containing 0.1% Triton was added to the plate for 30 minutes at room temperature. LI-COR blocking buffer was removed and cells were incubated overnight in a cold room with 50 μL of anti-ER rabbit monoclonal antibody (Thermo scientific MA1-39540) diluted 1:1000 in LI-COR blocking buffer containing 0.1% tween-20. Wells treated with blocking buffer but without antibody were used as background controls. The 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 Alexa488 (1:1000) and Syto-64a DNA dye (2 μM final concentration). The cells were then washed 3 times in PBS and scanned in an ACUMEN detector (TTP-Labtech). The integrated intensity of green and red fluorescence was measured to determine the levels of ERα and DNA, respectively.

[0627] In this test, the degradation activity of estrogen receptor is determined by the concentration that degrades 50% of the estrogen receptor (or IC 50 ) is given in nM.

[0628] The % reduction in ERa levels was determined as follows: % inhibition = 100*(1 - (sample-fulvestrant:DMSO-fulvestrant)).

[0629] The following Table 2 shows the estrogen receptor degradation activity results of the compounds of Table 1 tested at 0.3 μM, and demonstrates that the compounds have significant degradation activity on the estrogen receptor.

[0630] Table 2:

[0631]

[0632] Therefore, it is obvious that the tested compounds have degradation activity on estrogen receptors, with IC50 less than 1 μM and degradation levels greater than 50%. Therefore, the compounds of formula (I), (II) or (III) can be used to prepare drugs, especially drugs as degraders of estrogen receptors.

[0633] Therefore, also provided herein is a medicament comprising a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof.

[0634] Also provided herein is a compound of formula (I), (II) or (III) as defined above, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0635] Also provided herein are compounds of formula (I), (II) or (III) as defined above, or pharmaceutically acceptable salts thereof, for use in therapy, particularly as inhibitors and degraders of estrogen receptors.

[0636] Also provided herein is a compound of formula (I), (II) or (III) as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hypertrophy or inflammation.

[0637] A particular aspect is a compound of formula (I), (II) or (III) as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

[0638] In embodiments, the cancer is a hormone-dependent cancer.

[0639] In another embodiment, the cancer is an estrogen receptor dependent cancer, in particular the cancer is an estrogen receptor alpha dependent cancer.

[0640] In another embodiment, the cancer is selected from breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, cervical cancer, and lung cancer, or metastases thereof.

[0641] In another embodiment, the metastasis is a brain metastasis.

[0642] In another embodiment, the cancer is breast cancer. In particular, the breast cancer is estrogen receptor positive breast cancer (ERα positive breast cancer).

[0643] In another embodiment, the cancer is resistant to anti-hormone therapy.

[0644] In further embodiments, the compounds of Formula (I), (II) or (III) are used as single agents or in combination with other agents such as CDK4 / 6, mTOR or PI3K inhibitors.

[0645] According to another aspect, there is provided herein a method of treating the above indicated pathological conditions, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof. In embodiments of this method of treatment, the subject is a human.

[0646] Also provided herein is the use of a compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament useful for the treatment of any of the above indicated pathological conditions, more particularly useful for the treatment of cancer.

[0647] Also provided herein are pharmaceutical compositions comprising a compound of formula (I), (II) or (III) as an active ingredient. 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 at least one pharmaceutically acceptable excipient.

[0648] The excipients are selected from the customary excipients known to those skilled in the art, depending on the desired pharmaceutical form and the method of administration.

[0649] In pharmaceutical compositions for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of the above formula (I), (II) or (III) or its base, acid, zwitterion or salt thereof can be administered to animals and humans in a unit administration form, as a mixture with conventional pharmaceutical excipients for the treatment of the above disorders or diseases.

[0650] Suitable unit administration forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular and intranasal administration forms, forms for inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration, rectal administration forms and implants. For topical application, the compounds of formula (I), (II) or (III) can be used in creams, gels, ointments or lotions.

[0651] As an example, a unit administration form of a compound of formula (I), (II) or (III) in the form of a tablet may comprise the following components:

[0652]

[0653] There may be specific cases where higher or lower doses are appropriate. According to routine practice, the appropriate dose for each patient is determined by the physician according to the mode of administration and the weight and response of the patient.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: in: - R1 and R2 independently represent a hydrogen atom or a deuterium atom; -R3 represents a hydrogen atom or a -COOH group; -R3' represents a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom, a cyano group, or a -COOH group; -R3" represents a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom, or a cyano group; Provided that one but not both of R3 and R3' represents a -COOH group and R3 and R3' do not simultaneously represent hydrogen atoms; -R4 represents a hydrogen atom or a fluorine atom; - R5 and R5' independently represent a hydrogen atom or a fluorine atom; -Y represents -CH2-, -CH=, -CR9=, -O- or -NH-, wherein R9 represents a fluorine atom or a (C1-C3) alkyl group; - represents a single or double bond; -p is 0 or 1; -X represents -CH=, -N= or -CR"=, wherein R" represents a (C1-C3)alkyl group or a halogen atom such as a fluorine or chlorine atom, a cyano group, or a (C1-C3)fluoroalkyl group such as a trifluoromethyl group; - R7 independently represents a (C1-C3)alkyl group such as a methyl group, a halogen atom such as a fluorine atom, a cyano group, or a (C1-C3)fluoroalkyl group such as a trifluoromethyl group; -n is 0, 1, or 2; and -R6 represents a (C1-C9) alkyl group, which may be substituted by 1 to 4 substituents independently selected from the following: a halogen atom, a -cyano group, a -OR a Group, -N(R a )2 group, (C1-C9) alkyl, (C1-C9) alkoxy, (C1-C3) fluoroalkoxy, (C3-C9) cycloalkyl, (C3-C9) heterocyclic group, (C6-C9) aryl, (C5-C 10 )heteroaryl, -C(O)R b Group, -C(O)NR a Group, -SO2CH3 group, and SO2NR a Group; -R a represents a hydrogen atom, a (C1-C6) alkyl group, a (C2-C8) alkenyl group, a propargyl group, a (C3-C6) cycloalkyl group, and a (C3-C7) heterocycloalkyl group, which may be optionally substituted by one or more substituents independently selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a cyano group, an -OH group, a methoxy group, and a -SO2CH3 group; -R b represents a hydrogen atom, -O((C1-C3)alkyl), (C1-C6)alkyl, (C2-C8)alkenyl, propargyl, -((C2-C6)alkene)-((C3-C6)cycloalkyl), (C3-C6)cycloalkyl, and (C3-C7)heterocycloalkyl, which may be optionally substituted by one or more substituents independently selected from the following: a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a cyano group, a -CH2F group, a -CHF2 group, a -CF3 group, a -CH2CF3 group, a -CH2CHF2 group, a -CH2CH2F group, an -OH group, a methoxy group, and a -SO2CH3 group; and -R8 represents a hydrogen atom, a cyano group, a (C1-C6) alkyl group, a -CH2OH group, a -CH2OCH3 group, a -CH2CH2OH group, a -C(CH3)2OH group, a -CH(OH)CH(CH3)2 group, a -C(CH3)2CH2OH group, a -CH2CH2SO2CH3 group, a -CH2OP(O)(OH)2 group, a -CH2F group, a -CHF2 group, a -CH2NH2 group, a -CH2NHSO2CH3 group, a -CH2NHCH3 group, a -CH2N(CH3)2 group, a -CF3 group, a -CH2CF3 group, a -CH2CHF2 group, a -CH(CH3)CN group, a -C(CH3)2CN group, a -CH2CN group, a -C O2H group, -COCH3 group, -CO2CH3 group, -CO2C(CH3)3 group, -COCH(OH)CH3 group, -CONH2 group, -CONHCH3 group, -CONHCH2CH3 group, -CONHCH(CH3)2 group, -CON(CH3)2 group, -C(CH3)2CONH2 group, cyclopropyl group, cyclopropylamide group, cyclobutyl group, oxetanyl group, azetidinyl group, 1-methylazetidin-3-yl)oxy group, N-methyl-N-oxetan-3-ylamino, azetidin-1-ylmethyl, benzyloxyphenyl, pyrrolidin-1-yl, pyrrolidin-1-yl-methanone group, piperazin-1-yl, morpholinomethyl, morpholino-methanone group, or morpholino group.

2. The compound of formula (I) according to claim 1, wherein - when p is 1, X is -CH=; Y is -CH2-; R3 is -COOH; R1, R2, R3', R3", R4, R5 and R5' are H; R7 is F; n is 2; R8 is -CH3, R6 does not represent 2,2-difluoropropyl, and -When p is 0, X is -CH=; Y is -NH-; R3 is -COOH; R1, R2, R3', R3", R4, R5 and R5' are H; R7 is F; n is 2; R8 is -CH3, R6 does not represent 2,2-difluoro-3-hydroxypropyl.

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: The compound has formula (II) or (III): Among them, R1, R2, R3, R3', R3", R4, R5, R5', R6, R7, R8, Y, n and p are as described in claim 1.

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

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

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

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

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

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

10. A compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, characterized in that: R6 represents a (C1-C6) alkyl group, which is optionally substituted by 1 to 3 substituents independently selected from the following: a fluorine atom, a methyl group or a -OH group.

11. A compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, characterized in that: R6 represents a -CH2-CF3 group, a -CH2-CF2-CH2-OH group or a -CH2-CF2-CH3 group.

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

13. A compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, characterized in that: R8 represents a (C1-C6) alkyl group, and preferably represents a methyl group.

14. A compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein: Y represents -CH2-, -CH=, -O- or -NH-.

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

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

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

18. A method for preparing a compound of formula (II) according to any one of claims 2 to 17, wherein The compound of formula 1J: --Among which R1, R2, R3', R3", R4, R5, R5', R6, R7, R8, n, p, X and Y are any one of claims 1 to 16, and R3a is a carboxylate such as -COOMe or -COOEt-- is converted to a compound of formula (II) in the presence of a hydroxide ion source such as NaOH or LiOH in solution in methanol or THF, said step optionally being preceded by a step to obtain compound 1J, wherein a compound of formula 1L: -- wherein R3', R3", R6, R7, R8, n and X are any one of claims 1 to 16, and R3a is a carboxylate such as -COOMe or -COOEt--subjected to a coupling step with one of the compounds 1M: wherein R1, R2, R4, R5, R5′ and p are any one of claims 1 to 16.

19. A method for preparing a compound of formula (II) according to any one of claims 2 to 17, wherein The compound of formula 1J: --Among which R1, R2, R3', R3", R4, R5, R5', R6, R7, R8, n, p, X and Y are any one of claims 1 to 16, and R3a is a carboxylate such as -COOMe or -COOEt-- is converted to a compound of formula (II) in the presence of a hydroxide ion source such as NaOH or LiOH in solution in methanol or THF, said step optionally being preceded by a step to obtain compound 1J, wherein a compound of formula 1G: -- wherein R3', R3", R6 and R8 are any one of claims 1 to 16, and R3a is a carboxylate such as -COOMe or -COOEt -- is subjected to a Pict-Spengler cyclization reaction with compound 1H in the presence of an acid such as TFA or acetic acid in a suitable solvent such as toluene: Among them, R1, R2, R4, R5, R5', R7, X, Y, n and p are any one of claims 1 to 16.

20. A method for preparing a compound of formula (II) according to any one of claims 2 to 17, wherein The compound of formula 1J: --Among which R1, R2, R3', R3", R4, R5, R5', R6, R7, R8, n, p, X and Y are any one of claims 1 to 16, and R3a is a carboxylate such as -COOMe or -COOEt-- is converted to a compound of formula (II) in the presence of a hydroxide ion source such as NaOH or LiOH in solution in methanol or THF, said step optionally being preceded by a step to obtain compound 1J, wherein a compound of formula 10: -- Among them R3', R3", R6, R7, R8, n, p, X and Y are any one of claims 1 to 16, and R3a is a carboxylate such as -COOMe or -COOEt - in the presence of a base such as potassium carbonate (K2CO3) in DMF as solvent, is converted to compound 1J by treatment with compound 1P: wherein W is Cl, Br or I or OSO2R, wherein R═CH3, PhMe, CF3 or CF2CF2CF2CF3, and R1, R2, R4, R5 and R5′ are any one of claims 1 to 16.

21. A method for preparing a compound of formula (III) according to any one of claims 3 to 17, wherein a compound of formula 1Ae: --Among which R1, R2, R3, R3', R4, R5, R5', R6, R7, R8, n, p, X and Y are any one of claims 1 to 16, and R3a' is a carboxylate such as -COOMe or -COOEt-- is converted to a compound of formula (III) in the presence of a hydroxide ion source such as NaOH or LiOH in solution in methanol or THF, said step optionally being preceded by a step to obtain compound 1Ae, wherein a compound of formula 1Ad: -- wherein R3, R3″, R6, R7, R8, n and X are any one of claims 1 to 16, and R3a′ is a carboxylate such as —COOMe or —COOEt -- is subjected to a coupling step with one of the compounds 1M under coupling reaction conditions: wherein R1, R2, R4, R5, R5′ and p are any one of claims 1 to 16.

22. A method for preparing a compound of formula (III) according to any one of claims 3 to 17, wherein The compound of formula 1Ae: --Among which R1, R2, R3, R3', R4, R5, R5', R6, R7, R8, n, p, X and Y are any one of claims 1 to 16, and R3a' is a carboxylate such as -COOMe or -COOEt-- is converted to a compound of formula (III) in the presence of a hydroxide ion source such as NaOH or LiOH in solution in methanol or THF, said step optionally being preceded by a step to obtain compound 1Ae, wherein a compound of formula 1Ac: -- wherein R3, R3″, R6 and R8 are any one of claims 1 to 16, and R3a′ is a carboxylate such as —COOMe or —COOEt -- is subjected to a Pict-Spengler cyclization reaction with compound 1H in the presence of an acid such as TFA or acetic acid in a suitable solvent such as toluene: Among them, R1, R2, R4, R5, R5', R7, X, Y, n and p are any one of claims 1 to 16.

23. A compound of formula 1Ae or any pharmaceutically acceptable salt thereof: wherein R3a′ is a carboxylate such as —COOMe or —COOEt, R1, R2, R3, R3″, R4, R5, R5′, R6, R7, R8, n, p, X and Y are any one of claims 1 to 16.

24. A drug, characterized in that The medicament comprises a compound of formula (I), (II) or (III) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof.

25. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises a compound of formula (I), (II) or (III) according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

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

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

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

Images