Estrogen receptor modulators

Abstract

The compounds of formula (I) are estrogen receptor alpha modulators, and the variables in formula (I) are described in this disclosure. Such compounds, as well as pharma- ceutically acceptable salts and compositions thereof, are useful for treating diseases or conditions that are estrogen receptor alpha dependent and / or estrogen receptor alpha mediated, including conditions characterized by excessive cell proliferation, such as cancer. TIFF2024502270000103.tif52153

Description

[Technical field]

[0001] INCORPORATION BY REFERENCE OF PRIORITY APPLICATION This application claims priority to U.S. Provisional Application No. 63 / 130,123, filed December 23, 2020, U.S. Provisional Application No. 63 / 164,095, filed March 22, 2021, and U.S. Provisional Application No. 63 / 265,052, filed December 7, 2021. The disclosures of each of the foregoing applications are incorporated herein by reference in their entirety.

[0002] background This application relates to compounds that are estrogen receptor alpha modulators and methods of using them to treat conditions characterized by excessive cell proliferation, such as cancer. [Background technology]

[0003] Many cancer cells express estrogen receptors (ER) and have growth characteristics regulated by estrogen. Many breast cancer drug therapies have been developed that target ER. In many cases, the drugs are selective estrogen receptor modulators (SERMs) or selective estrogen receptor degraders (SERDs) that have agonistic and / or antagonistic effects on ER. For example, fulvestrant is a drug used for the treatment of metastatic breast cancer. It has an antagonistic effect on ERα and is considered a SERD. Fulvestrant has the following chemical structure:

[0004] [ka]

[0005] Many other SERMs and SERDs are also known, see, for example, U.S. Patent No. 5,399,633. However, there remains a long-felt need for well-tolerated, orally administered SERDs or SERMs that have estrogen-regulated growth characteristics and are useful in the study and treatment of proliferative diseases such as breast cancer, particularly breast cancer with brain metastases. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Publication No. 2017 / 172957 [Patent Document 2] International Publication No. 2016 / 097072 Summary of the Invention

[0007] Various embodiments provide compounds of formula (I) having the following structure: or a pharma- ceutically acceptable salt thereof:

[0008] [ka]

[0009] During the ceremony, each X 1 , X 2 , X 3 and X 4 are independently N or CR 2 and Y is a bond, alkenyl (C 1~6 Alkenyl or C 1~3 alkenyl, etc.), -O(CR 3 R 4 ) m - or -NH(CR 5 R 6 ) n - and R 1 is H, F, OH, CN, alkyl (C 1~6 Alkyl or C 1~3 Alkyl, haloalkyl (C 1~6 Haloalkyl or C1~3 haloalkyl, etc.), alkoxy (C 1~6 Alkoxy or C 1~3 alkoxy, amide, or hydroxyalkyl (C 1~6 Hydroxyalkyl or C 1~3 hydroxyalkyl, etc. Each R 2 , R 3 , R 4 , R 5 and R 6 are independently H, halogen (such as F, Cl, or Br), alkoxy (C 1~6 Alkoxy or C 1~3 Alkoxy, etc.), or alkyl (C 1~6 Alkyl or C 1~3 alkyl, etc.), R 7 is H or a halogen (such as F, Cl or Br), m and n are each 0, 1, or 2; A is halogen, CN, OH, alkyl (C 1~6 Alkyl or C 1~3 Alkyl, alkenyl (C 1~6 Alkenyl or C 1~3 alkenyl, etc.), alkynyl (C 1~6 Alkynyl or C 1~3 alkynyl, etc.), cycloalkyl (C 3~6 cycloalkyl, haloalkyl (C 1~6 Haloalkyl or C 1~3 haloalkyl, haloalkylamino (C 1~6 Haloalkylamino or C 1~3 haloalkylamino, haloalkoxy (C 1~6 Haloalkoxy or C 1~3 haloalkoxy, etc.), hydroxyalkyl (C 1~6 Hydroxyalkyl or C 1~3 hydroxyalkyl, etc.), or cyanoalkyl (C 1~6 Cyanoalkyl or C 1~3 and heterocyclyl (such as azetidinyl or pyrrolidinyl) optionally substituted with one or more substituents selected from aryl, aryloxy ...

[0010] Various embodiments provide a pharmaceutical composition comprising an effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, diluent, excipient, or combination thereof.

[0011] Various embodiments provide a method of treatment, comprising: Identifying a subject in need of treatment for an estrogen receptor alpha-dependent and / or estrogen receptor alpha-mediated disease or condition; and administering to the subject an effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof.

[0012] These and other embodiments are described in more detail below. [Brief description of the drawings]

[0013] [Figure 1] 1 shows a general reaction scheme for preparing compounds of formula (I). [Diagram 2] 1 shows the chemical structures of AZD-9833 and GDC-9545. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] definition Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. All patents, applications, published applications, and other publications referenced herein are incorporated by reference in their entirety unless otherwise stated. In the event that there are a plurality of definitions for a term herein, the definition in this section prevails unless otherwise stated.

[0015] Whenever a group is described as being "optionally substituted," the group can be unsubstituted or substituted with one or more of the indicated substituents. Similarly, when a group is described as being "unsubstituted or substituted," if substituted, the substituents may be selected from one or more of the indicated substituents. If no substituents are specified, it means that the specified "optionally substituted" or "substituted" group may be substituted with one or more groups individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), cycloalkyl(alkyl), heteroaryl(alkyl), heterocyclyl(alkyl), hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, nitro, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, amino, monosubstituted amino, and disubstituted amino.

[0016] As used herein, "C" refers to a set of integers where "a" and "b" are integers. a ~C b " refers to the number of carbon atoms in the group. The designated group can contain from "a" to "b" carbon atoms, inclusive. Thus, for example, a "C1-C4 alkyl" group refers to all alkyl groups having from 1 to 4 carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-. When "a" and "b" are not specified, the broadest ranges described by these definitions are intended to be assumed.

[0017] When two "R" groups are described as being "together," the R groups and the atom to which they are attached can form a cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclic ring. For example, and without limitation, NRa R b R in the group a and R b When are shown to be "together", it is meant that they are covalently linked to each other to form a ring.

[0018] [ka]

[0019] As used herein, the term "alkyl" refers to a fully saturated aliphatic hydrocarbon group. The alkyl moiety may be branched or straight chain. Examples of branched chain alkyl groups are: Examples of linear alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and the like. An alkyl group may have 1-30 carbon atoms (wherever it appears in this specification, a numerical range such as "1-30" refers to each integer within the given range, e.g., "1-30 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 30 carbon atoms, but this definition also extends to the occurrence of the term "alkyl" where no numerical range is specified). An alkyl group may also be a medium-sized alkyl group having 1-12 carbon atoms. An alkyl group may also be a lower alkyl group having 1-6 carbon atoms. An alkyl group may be substituted or unsubstituted. For example, a "haloalkyl" is an alkyl group in which one or more hydrogen atoms are replaced with one or more halogen atoms. Similarly, a "hydroxyalkyl" group is an alkyl group in which one or more hydrogen atoms are replaced with one or more hydroxy groups. Similarly, a "cyanoalkyl" group is an alkyl group in which one or more hydrogen atoms are replaced with one or more cyano groups.

[0020] As used herein, the term "alkenyl" refers to a monovalent straight or branched chain radical of 2 to 20 carbon atoms containing a carbon double bond, including, but not limited to, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, etc. Alkenyl groups can be unsubstituted or substituted.

[0021] As used herein, the term "alkynyl" refers to a monovalent straight or branched chain radical of 2 to 20 carbon atoms containing a carbon triple bond, including, but not limited to, 1-propynyl, 1-butynyl, 2-butynyl, etc. Alkynyl groups can be unsubstituted or substituted.

[0022] As used herein, "cycloalkyl" refers to a monocyclic or polycyclic hydrocarbon ring system that is fully saturated (no double or triple bonds). When composed of two or more rings, the rings may be joined together in a fused, bridged, or spiro fashion. As used herein, the term "fused" refers to two rings that share one bond with two atoms. As used herein, the term "bridged cycloalkyl" refers to a compound in which a cycloalkyl contains a linkage of one or more atoms connecting non-adjacent atoms. As used herein, the term "spiro" refers to two rings that share one atom, where the two rings are not joined by a bridge. Cycloalkyl groups can contain 3-30 atoms in the ring, 3-20 atoms in the ring, 3-10 atoms in the ring, 3-8 atoms in the ring, or 3-6 atoms in the ring. Cycloalkyl groups can be unsubstituted or substituted. Exemplary mono-cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of fused cycloalkyl groups are decahydronaphthalenyl, dodecahydro-1H-phenalenyl, and tetradecahydroanthracenyl; examples of bridged cycloalkyl groups are bicyclo[1.1.1]pentyl, adamantanyl, and norbornanyl; examples of spirocycloalkyl groups include spiro[3.3]heptane and spiro[4.5]decane.

[0023] As used herein, "cycloalkenyl" refers to a monocyclic or polycyclic hydrocarbon ring system containing one or more double bonds in at least one ring, provided that if more than one is present, the double bonds cannot form a completely delocalized pi-electron system throughout all rings (otherwise the group is an "aryl" as defined herein). Cycloalkenyl groups can contain 3 to 10 atoms in a ring or 3 to 8 atoms in a ring. When composed of more than one ring, the rings may be joined together in a fused, bridged, or spiro fashion. A cycloalkenyl group can be unsubstituted or substituted.

[0024] As used herein, "cycloalkynyl" refers to a monocyclic or polycyclic hydrocarbon ring system containing one or more triple bonds in at least one ring. If more than one triple bond is present, the triple bonds cannot form a completely delocalized pi-electron system throughout all rings. Cycloalkynyl groups can contain 6-10 atoms in a ring or 6-8 atoms in a ring. When composed of more than one ring, the rings may be fused, bridged, or joined together in a spiro fashion. Cycloalkynyl groups may be unsubstituted or substituted.

[0025] As used herein, "aryl" refers to a carbocyclic (all carbon) monocyclic or polycyclic aromatic ring system (including fused ring systems in which two carbon rings share a chemical bond) having a completely delocalized pi-electron system throughout all rings. The number of carbon atoms in an aryl group can vary. For example, an aryl group can be any of C6 to C7. 14 Aryl groups, C6-C 10 It may be an aryl group or a C6 aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. The aryl group may be substituted or unsubstituted.

[0026] As used herein, "heteroaryl" refers to a monocyclic or polycyclic aromatic ring system (a ring system having a fully delocalized π-electron system) containing one or more heteroatoms (e.g., 1, 2, or 3 heteroatoms), i.e., elements other than carbon, including, but not limited to, nitrogen, oxygen, and sulfur. The number of atoms in the ring of a heteroaryl group can vary. For example, a heteroaryl group can contain 4 to 14 atoms in the ring, 5 to 10 atoms in the ring, or 5 to 6 atoms in the ring. Furthermore, the term "heteroaryl" includes fused ring systems in which two rings share at least one chemical bond, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, and triazine. Heteroaryl groups can be substituted or unsubstituted.

[0027] As used herein, "heterocyclyl" or "heteroalicyclyl" refers to 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, and up to 18-membered monocyclic, bicyclic, and tricyclic ring systems in which carbon atoms and 1-5 heteroatoms together constitute the ring system. Heterocycles may optionally contain one or more unsaturated bonds positioned such that a fully delocalized pi-electron system does not occur throughout all rings. Heteroatoms are elements other than carbon, including but not limited to oxygen, sulfur, and nitrogen. Heterocycles may further contain one or more carbonyl or thiocarbonyl functional groups, to be defined as including oxo and thio systems, such as lactams, lactones, cyclic imides, cyclic thioimides, and cyclic carbamates. When composed of two or more rings, the rings may be fused, bridged, or joined together in a spiro fashion. As used herein, the term "fused" refers to two rings sharing one bond with two atoms. As used herein, the term "bridged heterocyclyl" or "bridged heteroalicyclyl" refers to a compound in which a heterocyclyl or heteroalicyclyl contains a linkage of one or more atoms connecting non-adjacent atoms. As used herein, the term "spiro" refers to two rings sharing one atom, where the two rings are not joined by a bridge. Heterocyclyl and heteroalicyclyl groups can contain 3-30 atoms in the ring, 3-20 atoms in the ring, 3-10 atoms in the ring, 3-8 atoms in the ring, or 3-6 atoms in the ring. In addition, any nitrogen in the heteroalicyclyl ring may be quaternized. Heterocyclyl or heteroalicyclyl groups may be substituted or unsubstituted. Examples of such "heterocyclyl" or "heteroalicyclyl" groups include 1,3-dioxine, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiine, 1,3-oxathiolane, 1,3-dithiole, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoline, imidazolidine, isopropyl alcohol ... These include, but are not limited to, soxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine N-oxide, piperidine, piperazine, pyrrolidine, azepane, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone, and their benzo-fused analogs (e.g., benzimidazolidinone, tetrahydroquinoline, and / or 3,4-methylenedioxyphenyl). Examples of spiroheterocyclyl groups include 2-azaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2-oxaspiro[3.4]octane, and 2-azaspiro[3.4]octane.

[0028] As used herein, "aralkyl" and "aryl(alkyl)" refer to an aryl group connected as a substituent through a lower alkylene group. The lower alkylene and aryl groups of an aralkyl may be substituted or unsubstituted. Examples include, but are not limited to, benzyl, 2-phenylalkyl, 3-phenylalkyl, and naphthylalkyl.

[0029] As used herein, "heteroaralkyl" and "heteroaryl(alkyl)" refer to a heteroaryl group connected as a substituent through a lower alkylene group. The lower alkylene and heteroaryl groups of a heteroaralkyl may be substituted or unsubstituted. Examples include, but are not limited to, 2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, and imidazolylalkyl, and benzo-fused analogs thereof.

[0030] "Heteroalicyclyl(alkyl)" and "heterocyclyl(alkyl)" refer to a heterocyclic or heteroalicyclic group connected as a substituent through a lower alkylene group. The lower alkylene and heterocyclyl of (heteroalicyclyl)alkyl may be substituted or unsubstituted. Examples include, but are not limited to, tetrahydro-2H-pyran-4-yl(methyl), piperidin-4-yl(ethyl), piperidin-4-yl(propyl), tetrahydro-2H-thiopyran-4-yl(methyl), and 1,3-thiazinane-4-yl(methyl).

[0031] As used herein, a "lower alkylene group" is a straight-chain -CH- linking group that forms bonds to connect molecular fragments through their terminal carbon atoms. Examples include methylene (-CH-), ethylene (-CHCH-), propylene (-CHCH-), and propylene (-CHCH-). Lower alkylene groups include, but are not limited to, cycloalkyl groups such as, for example,

[0032] [ka]

[0033] ) by replacing one or more hydrogens on a lower alkylene group, and / or by replacing both hydrogens on the same carbon.

[0034] As used herein, the term "hydroxy" refers to an --OH group.

[0035] As used herein, "alkoxy" refers to the formula -OR, where R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl) as defined herein. A non-limiting list of alkoxy is methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy, and benzoxy. Alkoxy may be substituted or unsubstituted.

[0036] As used herein, "acyl" refers to hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), and heterocyclyl(alkyl) connected as a substituent through a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl, and acryl. Acyl may be substituted or unsubstituted.

[0037] A "cyano" group refers to a "-CN" group.

[0038] As used herein, the term "halogen atom" or "halogen" means any one of the radiostable atoms in column 7 of the Periodic Table of the Elements, such as fluorine, chlorine, bromine, and iodine.

[0039] A "thiocarbonyl" group refers to a "-C(=S)R" group, where R can be the same as defined for O-carboxy. Thiocarbonyl can be substituted or unsubstituted.

[0040] The "O-carbamyl" group is defined as "-OC(=O)N(R A R B )" group, where R A and R B may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). O-carbamyl may be substituted or unsubstituted.

[0041] The "N-carbamyl" group is ROC(=O)N(R A )-" group, where R and R A may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). N-carbamyl may be substituted or unsubstituted.

[0042] The "O-thiocarbamyl" group is defined as "-OC(=S)-N(R A R B )" group, where R A and R Bmay be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). O-thiocarbamyl may be substituted or unsubstituted.

[0043] The "N-thiocarbamyl" group is ROC(=S)N(R A )-" group, where R and R A may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). N-thiocarbamyl may be substituted or unsubstituted.

[0044] A "C-amide" group is defined as -C(=O)N(R A R B )" group, where R A and R B may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). C-amides may be substituted or unsubstituted.

[0045] The "N-amide" group is defined as "RC(=O)N(R A )-" group, where R and R A may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). N-amides may be substituted or unsubstituted.

[0046] The "S-sulfonamide" group is "-SO2N(R A R B )" group, where R A and R B may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). S-sulfonamides may be substituted or unsubstituted.

[0047] The "N-sulfonamide" group is A )-" group, where R and R A may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). N-sulfonamides may be substituted or unsubstituted.

[0048] An "O-carboxy" group refers to an "RC(=O)O-" group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. O-carboxy can be substituted or unsubstituted.

[0049] The terms "ester" and "C-carboxy" refer to the group "-C(=O)OR", where R can be the same as defined for O-carboxy. Ester and C-carboxy can be substituted or unsubstituted.

[0050] A "nitro" group refers to a "-NO2" group.

[0051] A "sulfenyl" group refers to a "-SR" group, where R is hydrogen, alkyl, alkenyl, Sulfenyl may be substituted or unsubstituted.

[0052] A "sulfinyl" group refers to a "-S(=O)-R" group, where R can be the same as defined for sulfenyl. Sulfinyl can be substituted or unsubstituted.

[0053] A "sulfonyl" group refers to a "SO2R" group, where R may be the same as defined for sulfenyl. The sulfonyl may be substituted or unsubstituted.

[0054] As used herein, "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms are replaced by halogen (e.g., mono-haloalkyl, di-haloalkyl, and tri-haloalkyl). Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl, and 2-fluoroisobutyl. Haloalkyl can be substituted or unsubstituted.

[0055] As used herein, "haloalkoxy" refers to an alkoxy group in which one or more of the hydrogen atoms are replaced by halogen (e.g., mono-haloalkoxy, di-haloalkoxy, and tri-haloalkoxy). Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy, and 2-fluoroisobutoxy. Haloalkoxy can be substituted or unsubstituted.

[0056] As used herein, the term "amino" refers to the group --NH.

[0057] A "monosubstituted amino" group refers to an "-NHR" group, where R can be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. A monosubstituted amino can be substituted or unsubstituted. Examples of monosubstituted amino groups include, but are not limited to, -NH(methyl), -NH(phenyl), and the like.

[0058] A "disubstituted amino" group is defined as "-NR A R B " group, where R A and R B may be independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl) as defined herein. Disubstituted amino may be substituted or unsubstituted. Examples of disubstituted amino groups include, but are not limited to, -N(methyl)2, -N(phenyl)(methyl), -N(ethyl)(methyl), and the like.

[0059] When the number of substituents is not specified (e.g., haloalkyl), one or more substituents may be present. For example, "haloalkyl" may include one or more of the same or different halogens. As another example, "C1-C3 alkoxyphenyl" may include one or more of the same or different alkoxy groups containing 1, 2, or 3 atoms.

[0060] As used herein, a radical refers to a species that is covalently bonded to another species. "Radical" refers to a species that has a single unpaired electron such that it can be broken down into any desired form. Thus, in this context, a radical is not necessarily a free radical. Rather, a radical refers to a specific portion of a larger molecule. The term "radical" may be used interchangeably with the term "group."

[0061] As used herein, a chemical group or unit is denoted by an asterisk ( * ), the asterisk indicates the point of attachment of the group or unit to another structure.

[0062] As used herein, a "linking group" is a chemical group depicted as having multiple open valences for connecting to two or more other groups. For example, a linking group of the general formula -(CH) n Lower alkylene groups such as - (where n is in the range of 1 to 10) are examples of linking groups described elsewhere herein as connecting molecular fragments through their terminal carbon atoms. Other examples of linking groups include -(CH2) n O-, -(CH2) n NH-, -(CH2) n N(C1-C6 alkyl)- and -(CH2) n S-, where each n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. Those skilled in the art will recognize that n is -(CH2) n It will be appreciated that for some linking groups, such as -O-, the linking group is simply -O-. Those of skill in the art will also appreciate that a reference to an asymmetric linking group herein is understood to refer to all orientations of that group (unless otherwise indicated). For example, -(CH2) n A reference to O- is -(CH2) n O- and -O-(CH2) n - will be understood as a reference to both

[0063] The term "pharmaceutical acceptable salt" refers to a salt of a compound that does not cause significant irritation to the organism to which it is administered and does not abolish the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with an inorganic acid, such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid (such as 2,3-dihydroxypropyl dihydrogen phosphate). Pharmaceutical salts can also be obtained by reacting a compound with an organic acid, such as an aliphatic or aromatic carboxylic or sulfonic acid, such as formic acid, acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, benzoic acid, salicylic acid, 2-oxopentanedioic acid, or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt, for example, an ammonium salt, an alkali metal salt, for example, sodium, potassium, or lithium salt, an alkaline earth metal salt, for example, calcium or magnesium salt, a carbonate salt, a bicarbonate salt, a salt with an organic base, for example, dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamines, cyclohexylamine, triethanolamine, ethylenediamine, and amino acids such as arginine and lysine. With respect to the compound of formula (I), one skilled in the art will appreciate that when a salt is formed by protonation of a nitrogen-based group (e.g., NH2), the nitrogen-based group may be associated with a positive charge (e.g., NH2 becomes NH3). + ions), the positive charge can be a negatively charged counterion (Cl - Understand that balance can be achieved by

[0064] In any compound described herein having one or more chiral centers, unless the absolute stereochemistry is explicitly indicated, it is understood that each center may be independently in the R or S configuration, or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixtures, diastereomerically pure compounds, diastereomerically enriched compounds, or stereoisomeric mixtures. In addition, in any compound described herein having one or more double bonds that generate geometric isomers that can be defined as E or Z, it is understood that each double bond may be independently E or Z, or a mixture thereof. Similarly, it is understood that in any compound described, all tautomeric forms are also intended to be included.

[0065] Where the compounds disclosed herein have unfilled valences, it is understood that the valences are filled with hydrogen or an isotope thereof, such as hydrogen-1 (protium) and hydrogen-2 (deuterium).

[0066] It is understood that the compounds described herein may be isotopically labeled. Substitution with an isotope such as deuterium may provide certain therapeutic advantages due to greater metabolic stability, such as, for example, increased in vivo half-life or reduced required dosage. Each chemical element represented in a compound structure may include any isotope of that element. For example, in a compound structure, a hydrogen atom may be expressly disclosed or understood as being present in the compound. At any position of a compound where a hydrogen atom may be present, the hydrogen atom may be any isotope of hydrogen, including, but not limited to, hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference to a compound herein encompasses all possible isotopic forms, unless the context clearly indicates otherwise.

[0067] It is understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, which include different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates, and hydrates. In some embodiments, the compounds described herein exist in solvated forms with pharma- ceutically acceptable solvents such as water, ethanol, etc. In other embodiments, the compounds described herein exist in nonsolvated forms. Solvates contain either stoichiometric or nonstoichiometric amounts of solvent, and may be formed during the crystallization process with pharma-ceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein can exist in nonsolvated as well as solvated forms. In general, solvated forms are considered equivalent to nonsolvated forms for the purposes of the compounds and methods provided herein.

[0068] When a range of values ​​is provided, it is understood that the upper and lower limits, as well as every intervening value between the upper and lower limits of that range, are encompassed within an embodiment.

[0069] Terms and phrases used in this application, and variations thereof, particularly in the appended claims, should be construed as open-ended rather than limiting, unless expressly stated otherwise. As an example above, the term "including" should be construed to mean "including without limitation," "including but not limited to," and the like. As used herein, the term "comprising" is synonymous with "including," "containing," or "featuring," and is inclusive or open-ended, and does not exclude additional unrecited elements or method steps. The term "having" should be construed as "having at least." The term "including" should be construed as "including, but not limited to." The term "example" is used to provide illustrative examples rather than an exhaustive or exclusive list of the items under discussion. The use of terms such as "preferably," "preferred," "desired," or "desirable," and words of similar import, should not be understood as implying that a particular feature is critical, essential, or even important to the structure or function, but rather is intended merely to highlight alternative or additional features that may or may not be utilized in a particular embodiment. Additionally, the term "comprising" is to be construed as synonymous with the phrases "having at least" or "including at least." When used in the context of a process, the term "comprising" means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound, composition, or device, the term "comprising" means that the compound, composition, or device includes at least the recited features or components, but may also include additional features or components. Similarly, a group of items joined by the conjunction "and" should not be construed as requiring every single one of the items to be present in the group, but rather as "and / or," unless the context clearly indicates otherwise. Similarly, a group of items joined by the conjunction "or" should not be construed as requiring mutual exclusivity within the group, but rather as "and / or," unless the context clearly indicates otherwise.

[0070] With respect to the use of substantially any plural and / or singular term herein, those skilled in the art can convert from plural to singular and / or from singular to plural as appropriate depending on the context and / or application. Various singular / plural permutations may be expressly stated herein for clarity. The indefinite article "a" or "an" does not exclude a plurality. The mere fact that certain means are recited in mutually different dependent claims does not indicate that a combination of these means cannot be used to advantage. Any reference signs in the claims should not be interpreted as limiting the scope thereof.

[0071] compound Some embodiments disclosed herein relate to a compound of formula (I), or a pharma- ceutically acceptable salt thereof.

[0072] [ka]

[0073] In various embodiments, the compounds of formula (I) are useful for ameliorating, treating, and / or diagnosing diseases or conditions that are estrogen receptor dependent and / or estrogen receptor mediated. In one embodiment, the disease is cancer. In one embodiment, the cancer is metastatic cancer. In one embodiment, the cancer is breast cancer. In one embodiment, the breast cancer is metastatic breast cancer that has metastasized to at least one organ selected from the brain, liver, bone, and lung. In one embodiment, the metastatic breast cancer is breast cancer that has metastasized to the brain. In one embodiment, the compounds of formula (I) are selective estrogen receptor modulators (SERMs). In one embodiment, the compounds of formula (I) are selective estrogen receptor degraders (SERDs). Further details regarding various uses and methods of treatment are described elsewhere herein.

[0074] In various embodiments, the variable X in formula (I) 1 , X 2 , X 3 and X4 are each independently N or CR 2 In one embodiment, X 1 is N and X 2 , X 3 and X 4 are CR 2 In one embodiment, X 2 is N and X 1 , X 3 and X 4 are CR 2 In one embodiment, X 1 and X 2 are N and X 3 and X 4 are CR 2 In one embodiment, X 1 and X 3 are N and X 2 and X 4 are CR 2 It is.

[0075] In various embodiments, the variable Y in formula (I) is a bond, alkenyl (C 1~6 Alkenyl or C 1~3 alkenyl, etc.), -O(CR 3 R 4 ) m - or -NH(CR 5 R 6 ) n In one embodiment, Y is a bond. In one embodiment, Y is alkenyl. For example, in one embodiment, Y is C 1~6 Alkenyl (e.g., C 1~3 In one embodiment, Y is -O(CR 3 R 4 ) m -, where m is 0, 1 or 2. In one embodiment, Y is -NH(CR 5 R 6 ) n -, where n is 0, 1 or 2.

[0076] In various embodiments, the variable R 1 is H, F, OH, CN, alkyl (C1~6 Alkyl or C 1~3 Alkyl, haloalkyl (C 1~6 Haloalkyl or C 1~3 haloalkyl, etc.), alkoxy (C 1~6 Alkoxy or C 1~3 alkoxy, amide, or hydroxyalkyl (C 1~6 Hydroxyalkyl or C 1~3 In one embodiment, R 1 is H. In one embodiment, R 1 is F. In one embodiment, R 1 is OH. In one embodiment, R 1 is CN. In one embodiment, R 1 is an alkyl (C 1~6 Alkyl or C 1~3 In one embodiment, R 1 is haloalkyl (C 1~6 Haloalkyl or C 1~3 haloalkyl, etc. In one embodiment, R 1 is an alkoxy (C 1~6 Alkoxy or C 1~3 In one embodiment, R 1 is an amide. In one embodiment, R 1 is hydroxyalkyl (C 1~6 Hydroxyalkyl or C 1~3 hydroxyalkyl, etc.

[0077] In various embodiments, the variable R 2 , R 3 , R 4 , R 5 and R 6 are each independently H, halogen (such as F, Cl, or Br), alkoxy (C 1~6 Alkoxy or C 1~3 Alkoxy, etc.), or alkyl (C 1~6 Alkyl or C 1~3 In one embodiment, R 2 is H. In one embodiment, R2 is a halogen (such as F, Cl, or Br). In one embodiment, R 2 is alkoxy. For example, in one embodiment, R 2 is C 1~6 Alkoxy (e.g., C 1~3 In one embodiment, R 2 is an alkyl (C 1~6 Alkyl or C 1~3 In one embodiment, R 3 and R 4 At least one of R 3 is a halogen (such as F, Cl, or Br), and R 4 is H. In one embodiment, R 3 is an alkyl (C 1~6 Alkyl or C 1~3 alkyl, etc.), and R 4 is H. In one embodiment, R 5 and R 6 At least one of R 5 is a halogen (such as F, Cl, or Br), and R 6 is H. In one embodiment, R 5 is an alkyl (C 1~6 Alkyl or C 1~3 alkyl, etc.), and R 6 is H. In one embodiment, R 7 is H. In another embodiment, R 7 is a halogen (such as F, Cl, or Br).

[0078] In various embodiments, the variable A in formula (I) is selected from halogen, CN, OH, alkyl (C 1~6 Alkyl or C 1~3 Alkyl, alkenyl (C 1~6 Alkenyl or C 1~3 alkenyl, etc.), alkynyl (C 1~6 Alkynyl or C 1~3 alkynyl, etc.), cycloalkyl (C 3~6 Cycloalkyl, e.g., cyclopropyl), haloalkyl (C1~6 Haloalkyl or C 1~3 haloalkyl, haloalkylamino (C 1~6 Haloalkylamino or C 1~3 haloalkylamino, haloalkoxy (C 1~6 Haloalkoxy or C 1~3 haloalkoxy, etc.), hydroxyalkyl (C 1~6 Hydroxyalkyl or C 1~3 hydroxyalkyl, etc.), or cyanoalkyl (C 1~6 Cyanoalkyl or C 1~3 In one embodiment, A is an unsubstituted 3-6 membered N-containing heterocyclyl (e.g., azetidinyl or pyrrolidinyl), optionally substituted with one or more substituents selected from aryl, aryloxy ...

[0079] In various embodiments, the variable A in formula (I) is F, CN, C 1~3 Alkyl, C 3~6 Cycloalkyl, C 1~3 Fluoroalkyl, C 1~3 Fluoroalkylamino, C 1~3 Fluoroalkoxy, C 1~3 Hydroxyalkyl or C 1~3 A is a 3-6 membered N-containing heterocyclyl (such as azetidinyl or pyrrolidinyl) substituted with cyanoalkyl. In one embodiment, A is substituted with F. For example, in one embodiment, A is azetidinyl substituted with F or pyrrolidinyl substituted with F. In one embodiment, A is substituted with CN. For example, in one embodiment, A is azetidinyl substituted with CN or pyrrolidinyl substituted with CN. In one embodiment, A is C 1~3 For example, in one embodiment, A is substituted with C 1~3 Alkyl-substituted azetidinyl or C 1~3 In one embodiment, A is pyrrolidinyl substituted with alkyl. 3~6For example, in one embodiment, A is substituted with C 3~6 In one embodiment, A is azetidinyl substituted with cycloalkyl (such as cyclopropyl). 1~3 For example, in one embodiment, A is substituted with C 1~3 Fluoroalkyl-substituted azetidinyl or C 1~3 In one embodiment, A is pyrrolidinyl substituted with fluoroalkyl. 1~3 For example, in one embodiment, A is substituted with C 1~3 In one embodiment, A is azetidinyl substituted with fluoroalkylamino. 1~3 For example, in one embodiment, A is substituted with C 1~3 In one embodiment, A is azetidinyl substituted with fluoroalkoxy. 1~3 For example, in one embodiment, A is substituted with C 1~3 Hydroxyalkyl-substituted azetidinyl or C 1~3 In one embodiment, A is pyrrolidinyl substituted with hydroxyalkyl. 1~3 For example, in one embodiment, A is substituted with C 1~3 Azetidinyl or C substituted with cyanoalkyl 1~3 It is pyrrolidinyl substituted with cyanoalkyl.

[0080] In various embodiments, the compound of formula (I) is a compound described in Table 1 herein.

[0081] Method of preparation Compounds of formula (I), or pharma- ceutically acceptable salts thereof, can be made in a variety of ways by those skilled in the art using known techniques guided by the detailed teachings provided herein. For example, in one embodiment, compounds of formula (I) are prepared according to the general reaction scheme summarized in Figure 1 and described in the Examples below. The variables in the general chemical structure shown in Figure 1 are as described elsewhere herein with respect to formula (I).

[0082] Methods of Use and Treatment As described herein, one or more compounds of formula (I), or pharma- ceutically acceptable salts thereof, or pharmaceutical compositions described herein, can be used to inhibit cell growth. In one embodiment, the cells are identified as having an estrogen receptor that mediates the growth properties of the cells. The growth of the cells can be inhibited by contacting the cells with an effective amount of at least one of the compounds described herein, or pharma- ceutically acceptable salts thereof, or pharmaceutical compositions described elsewhere herein. Such contacting of one or more compounds, or pharma- ceutically acceptable salts thereof, can be performed in a variety of ways and locations, including, but not limited to, away from the living subject (e.g., in a laboratory and / or diagnostic and / or analytical facility) or in close proximity to the living subject (e.g., on an internal or external part of an animal, e.g., a human). For example, one embodiment provides a method of treating a subject comprising identifying a subject in need of treatment for a disease or condition that is estrogen receptor dependent and / or estrogen receptor mediated, such as cancer, and administering to the subject an effective amount of one or more compounds of formula (I), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as described elsewhere herein. Another embodiment provides the use of one or more compounds of formula (I), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition (as described elsewhere herein) in the manufacture of a medicament for the treatment of a disease or condition that is estrogen receptor alpha dependent and / or estrogen receptor alpha mediated, such as cancer.

[0083] Non-limiting examples of diseases or conditions that are estrogen receptor alpha dependent and / or estrogen receptor alpha dependent and / or estrogen alpha receptor mediated and thus suitable for treatment using the compounds, compositions, and methods described herein include breast cancer and gynecological cancer. For example, such diseases or conditions may include one or more of the following cancers: breast cancer, endometrial cancer, ovarian cancer, and cervical cancer. One embodiment provides for the use of one or more compounds of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition (described elsewhere herein) in the treatment (or in the manufacture of a medicament for the treatment) of breast cancer and gynecological cancer, including, for example, one or more of the following: breast cancer, endometrial cancer, ovarian cancer, and cervical cancer. In various embodiments, the compound, pharmaceutically acceptable salt, or pharmaceutical composition is for use in a method of treatment (or in the manufacture of a medicament for the treatment) of metastatic cancer, such as metastatic breast cancer. In various embodiments of such methods and uses of treatment, the metastatic breast cancer is breast cancer that has metastasized to at least one organ selected from the brain, liver, bone, and lung. In one embodiment, the metastatic breast cancer is breast cancer that has metastasized to the brain. In one embodiment, the metastatic breast cancer is breast cancer that has metastasized to the liver. In one embodiment, the metastatic breast cancer is breast cancer that has metastasized to the bone. In one embodiment, the metastatic breast cancer is breast cancer that has metastasized to the lung.

[0084] As described herein, the compounds of formula (I), or pharma- ceutically acceptable salts thereof, or pharmaceutical compositions described elsewhere herein, may be administered to such subjects by a variety of methods. In any of the uses or methods described herein, administration may be by a variety of routes known to those skilled in the art, including, but not limited to, oral, intravenous, intramuscular, topical, subcutaneous, systemic, and / or intraperitoneal administration to a subject in need thereof.

[0085] As used herein, the terms "treat," "treating," "treatment," "therapeutic," and "therapy" do not necessarily mean a complete cure or elimination of an estrogen receptor-dependent and / or estrogen receptor-mediated disease or condition. Any alleviation, to any extent, of any undesirable signs or symptoms of a disease or condition may be considered treatment and / or therapy. Additionally, treatment may include actions that may worsen a subject's overall feeling of health or appearance.

[0086] The terms "therapeutically effective amount" and "effective amount" are used to indicate the amount of an active compound or pharmaceutical agent that induces the biological or medical response described. For example, a therapeutically effective amount of a compound, salt, or composition may be the amount required to prevent, reduce, or ameliorate the symptoms of an estrogen receptor-dependent and / or estrogen receptor-mediated disease or condition, or to prolong the survival of the subject being treated. This response may occur in a tissue, system, animal, or human, and includes the alleviation of signs or symptoms of the estrogen receptor-dependent and / or estrogen receptor-mediated disease or condition being treated. Determination of an effective amount is well within the capabilities of one of ordinary skill in the art in light of the disclosure provided herein. The therapeutically effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal being treated, such as a human, and the physical characteristics of the particular animal under consideration. Dosage may be adjusted to achieve the desired effect, depending on factors such as body weight, diet, concurrent medication, and other factors that one of ordinary skill in the medical arts would recognize.

[0087] The amount of the compound of formula (I) or its pharmaceutically acceptable salt required for use in treatment will vary depending on the particular compound or salt selected, the route of administration, the nature and / or symptoms of the estrogen receptor-dependent and / or estrogen receptor-mediated disease or condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the attending physician or clinician. In the case of administration of a pharmaceutically acceptable salt, the dosage may be calculated as a free base. As will be understood by those skilled in the art, in certain circumstances, it may be necessary to administer the compounds disclosed herein in amounts that exceed or even far exceed the dosage ranges described herein in order to effectively and aggressively treat particularly aggressive estrogen receptor-dependent and / or estrogen receptor-mediated diseases or conditions.

[0088] Generally, however, suitable doses will often be within the range of about 0.05 mg / kg to about 10 mg / kg. For example, suitable doses may be within the range of about 0.10 mg / kg to about 7.5 mg / kg of body weight per day, for example, about 0.15 mg / kg to about 5.0 mg / kg of the recipient's body weight per day, about 0.2 mg / kg to 4.0 mg / kg of the recipient's body weight per day. The compound may be administered in unit dosage form, for example, containing 1 to 500 mg, 10 to 100 mg, or 5 to 50 mg of active ingredient per unit dosage form.

[0089] The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more partial doses per day. The partial dose itself may be further divided, for example, into several discrete loosely spaced administrations.

[0090] As will be readily apparent to those skilled in the art, the useful in vivo dosage and the specific method of administration will vary depending on the age, weight, severity of the affliction, and mammalian species being treated, the specific compound being used, and the specific application for which these compounds are used.Determination of effective dosage levels, i.e., the dosage levels required to achieve the desired results, can be achieved by those skilled in the art using routine methods, such as human clinical trials, in vivo studies, and in vitro studies.For example, the useful dosage of the compound of formula (I), or its pharma-ceutically acceptable salt, can be determined by comparing their in vitro activity and in vivo activity in animal models.Such comparisons can be made by comparison with established drugs, such as fulvestrant.

[0091] Dosage and interval may be adjusted individually to provide plasma concentrations sufficient for the active moiety to maintain a modulatory effect or minimal effective concentration (MEC). The MEC varies from compound to compound but may be estimated from in vivo and / or in vitro data. The dosage required to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays may be used to determine plasma concentrations. Dosage intervals may also be determined using the MEC value. Compositions should be administered using a regimen that maintains plasma concentrations above the MEC for 10-90% of the time, preferably 30-90%, and most preferably 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.

[0092] It should be noted that the attending physician will know how and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunction. Conversely, the attending physician will also know to adjust treatment to higher levels if the clinical response is not adequate (precluding toxicity). The size of the dose administered in the management of the disease of interest will vary with the severity of the estrogen receptor-dependent and / or estrogen receptor-mediated disease or condition being treated as well as the route of administration. The severity of the estrogen receptor-dependent and / or estrogen receptor-mediated disease or condition may be evaluated, for example, in part, by standard prognostic evaluation methods. Furthermore, the dose and perhaps the number of doses will also vary with the age, weight, and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.

[0093] The compounds, salts, and compositions disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a particular compound or a subset of compounds sharing a certain chemical moiety can be established by evaluating in vitro toxicity on cell lines, such as mammalian cell lines, preferably human cell lines. The results of such studies often predict toxicity in animals, such as mammals, or especially humans. Alternatively, the toxicity of a particular compound in an animal model, such as mice, rats, rabbits, dogs, or monkeys, can be determined using known methods. The efficacy of a particular compound can be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine efficacy, a person skilled in the art can be guided by the state of the art in selecting the appropriate model, dose, route of administration, and / or regimen.

[0094] Pharmaceutical Compositions Some embodiments described herein relate to pharmaceutical compositions that can include an effective amount of one or more compounds described herein (e.g., a compound of Formula (I), or a pharma- ceutically acceptable salt thereof) and a pharma- ceutically acceptable carrier, diluent, excipient, or combination thereof.

[0095] The term "pharmaceutical composition" refers to a mixture of one or more compounds and / or salts disclosed herein with other chemical components, such as diluents or carriers. Pharmaceutical compositions facilitate the administration of a compound to an organism. Pharmaceutical compositions can also be obtained by reacting a compound with an inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutical compositions are generally tailored to the specific intended route of administration.

[0096] The term "physiologically acceptable" defines a carrier, diluent, or excipient that does not neutralize the biological activity and properties of the compound or cause substantial damage or injury to the animal to which the composition is intended to be delivered.

[0097] As used herein, a "carrier" refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, but not limited to, dimethyl sulfoxide (dimethyl sulfoxide), Dimethyl sulfoxide (DMSO) is a commonly used carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.

[0098] As used herein, "diluent" refers to an ingredient in a pharmaceutical composition that has no apparent pharmacological activity, but may be pharma- ceutically necessary or desirable. For example, a diluent may be used to bulk a potent drug whose mass is too small for manufacture and / or administration. It may also be a liquid for dissolving a drug to be administered by injection, ingestion, or inhalation. A common form of diluent in the art is a buffered aqueous solution, such as, but not limited to, phosphate buffered saline, which mimics the pH and isotonicity of human blood.

[0099] As used herein, "excipient" refers to an essentially inert substance added to a pharmaceutical composition to provide the composition with, but not limited to, bulk, consistency, stability, binding ability, lubrication, disintegration ability, etc. For example, stabilizers such as antioxidants and metal chelators are excipients. In one embodiment, the pharmaceutical composition contains antioxidants and / or metal chelators. A "diluent" is a type of excipient.

[0100] The pharmaceutical compositions described herein can be administered to human patients by themselves or in pharmaceutical compositions in which they are mixed with other active ingredients, such as in combination therapy, or with carriers, diluents, excipients, or combinations thereof.The appropriate formulation depends on the route of administration selected.Techniques for formulation and administration of the compounds described herein are known to those skilled in the art.

[0101] The pharmaceutical compositions disclosed herein can be prepared in a manner known per se, for example, by conventional mixing, dissolving, granulating, dragee-making, elutriating, emulsifying, encapsulating, entrapping or tabletting processes. In addition, the active ingredient is contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharma-ceutically compatible counterions.

[0102] Multiple techniques of administering the compounds, salts, and / or compositions exist in the art, including, but are not limited to, oral, rectal, intrapulmonary, topical, aerosol, injection, infusion, and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injection, intrathecal, direct intraventricular, intraperitoneal, intranasal, and intraocular injection.

[0103] The compounds, salts, and / or compositions may also be administered in a local rather than systemic manner, for example, by injecting or implanting the compound directly into the affected area, often as a depot or sustained release formulation. Additionally, the compounds can be administered in targeted drug delivery systems, for example, in liposomes coated with tissue-specific antibodies. The liposomes will be targeted to and taken up selectively by the organ. For example, intranasal or intrapulmonary delivery may be desired to target respiratory diseases or conditions.

[0104] The composition may be provided in a pack or dispenser device, which may contain one or more unit dosage forms containing the active ingredient, if desired. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied by a notice associated with the container, in a format prescribed by a governmental agency regulating the manufacture, use, or sale of drugs, which notice reflects the approval by the agency of the drug form for human or animal administration. Such notice may, for example, be a label approved by the U.S. Food and Drug Administration for prescription drugs, or an approved product insert. The composition may comprise the compounds and / or salts described herein, formulated in a compatible pharmaceutical carrier, and may also be prepared, placed in a suitable container, and labeled for the treatment of the indicated condition. EXAMPLES

[0105] Further embodiments, which are not intended to limit the scope of the claims in any way, are described in more detail in the examples below.

[0106] compound The compounds of formula (I) shown in Table 1 can be prepared in a variety of ways using techniques known to those skilled in the art, guided by the detailed teachings provided herein. For example, the compounds of formula (I) shown in Table 1 can be prepared according to the general reaction scheme shown in Figure 1, as described in the following general procedures. Those skilled in the art will appreciate that formula (I) and many of the structures shown in Table 1 are depicted as not stereospecific and / or having unsatisfied valences, and are therefore open to isotopic and / or stereochemical variants, including racemates, diastereomers, enantiomers, and / or deuterated forms, which may be readily prepared by following the advice provided herein. It will be understood that the compound may be prepared in any suitable manner.

[0107] General steps: Step 1: Intermediate A was prepared according to the procedure described in US Pat. No. 6,399,663. The Pictet-Spengler reaction was carried out in a similar manner as described in US Pat. No. 6,399,663. Briefly, intermediate A and aldehyde B in toluene were mixed with various amounts of acid. The reaction was stirred at various temperatures from 90° C. to 130° C. for 3 to 12 hours.

[0108] Step 2: The second step was carried out by Pd or Cu catalyzed Ullmann, Buchwald reaction, or by Mitsunobu or alkylation reaction as described in US Pat. No. 5,399,633.

[0109] [Table 1]

[0110] [Table 2]

[0111] [Table 3]

[0112] [Table 4]

[0113] [Table 5]

[0114] [Table 6]

[0115] [Table 7]

[0116] [Table 8]

[0117] [Table 9]

[0118] [Table 10]

[0119] Intermediate 1 tert-Butyl (1-(3-fluoropropyl)azetidin-3-yl)carbamate

[0120] [ka]

[0121] Step 1: 5M aqueous NaOH (3.5 mL, 17.43 mmol) was added to an ice-cold stirred solution of tert-butyl azetidin-3-yl carbamate (1 g, 5.81 mmol) in THF (10 mL) followed by 1-fluoro-3-iodopropane (1.20 g, 6.39 mmol) at 0° C. The reaction mixture was then stirred at room temperature (RT) for 16 h. After completion of the reaction, it was diluted with water (50 mL) and extracted into 10% MeOH in DCM (3×50 mL). The organic layer was collected, dried over Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography to give 809 mg (3.48 mmol, 60%) of tert-butyl (1-(3-fluoropropyl)azetidin-3-yl)carbamate. 1 H NMR(400MHz,DMSO-d6)δ7.27(d,J=7.2Hz,1H),4.48(t,J=6.0Hz,1H),4.36(t,J=6.0Hz,1H),4.01-3.99(q ,1H),3.45(t,J=6.8Hz,2H),2.72(t,J=6.8Hz,2H),2.40(t,J=6.8Hz,2H),1.66-1.56(m,2H),1.37(s,9H).

[0122] Step 2: To a stirred solution of tert-butyl (1-(3-fluoropropyl)azetidin-3-yl)carbamate (809 mg, 3.48 mmol) in DCM (6 mL) was added TFA (3 mL) at 0° C. Then the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, it was evaporated and then dissolved in 10% MeOH in DCM. Then K2CO3 (4.8 g, 34.8 mmol) was added at 0° C., stirred for 20 min and then filtered. The filtrate was concentrated to give 322 mg (2.44 mmol, 70%) of 1-(3-fluoropropyl)azetidin-3-amine. 1 H NMR(400MHz,DMSO-d6)δ4.48(t,J=6.0Hz,1H),4.36(t,J=6.0Hz,1H),3.47-3.43(m, 2H),3.34-3.31(q,1H),2.50-2.46(m,3H),2.38(t,J=5.6Hz,2H),1.65-1.55(m,2H).

[0123] Example 1 N-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)-1-(3-fluoropropyl)azetidin-3-amine (Compound 1)

[0124] [ka]

[0125] Step 1. To a stirred solution of (R)-N-(1-(1H-indol-3-yl)propan-2-yl)bicyclo[1.1.1]pentan-1-amine (1 g, 4.16 mmol) in toluene (10 mL), 4-bromo-2,6-difluorobenzaldehyde (1.01 g, 4.58 mmol) was added followed by AcOH (0.36 mL, 6.24 mmol) and stirred at 80 °C for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to give semi-pure crude. The crude product thus obtained was purified by silica gel column chromatography eluting with 10-15% EtOAc in petroleum ether to give (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(4-bromo-2,6-difluorophenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (700 mg, 1.57 mmol, 38% yield). MS (ESI) m / z 443.1 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ10.52(s,1H),7.41-7.37(t,J=8.8Hz,3H),7.17(d,J=8.0Hz,1H),7.01-6.91(m,2H),5.29(s,1H),4.03-4. 01(m,1H),2.96-2.92(m,1H),2.58-2.54(m,1H),2.25(s,1H),1.77(d,J=9.2Hz,3H),1.57(d,J=9.2Hz,3H),1.07(d,J=6.4Hz,3H).

[0126] Step 2. To a stirred solution of (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(4-bromo-2,6-difluorophenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (500 mg, 1.12 mmol) in 1,4-dioxane (10 mL), 1-(3-fluoropropyl)azetidin-3-amine (223.6 mg, 1.69 mmol) and NaOt-Bu (188.2 mg, 1.96 mmol) were added and the reaction mixture was degassed under argon for 30 min. Then, Brettphos-3rd generation precatalyst (30.45 mg, 0.03 mmol) was added and the reaction mixture was degassed again for 30 min. Then, it was heated at 110 °C for 16 h. After completion of the reaction, it was cooled to room temperature and filtered through a bed of celite. The filtrate was diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by RP preparative HPLC to give N-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)-1-(3-fluoropropyl)azetidin-3-amine (158 mg, 0.31 mmol, 28% yield) (compound 1). MS (ESI) m / z 495.2 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),7.34(d,J=7.6Hz,1H),7.17(d,J=8.0Hz,1H),6.97-6.89(m,2H), 6.62(d,J=6.8Hz,1H),6.09(d,J=12.0Hz,2H)5.14(s,1H),4.50(t,J=6Hz,1H),4.38(t,J=6.4Hz,1H),3. 94-3.90(m,1H),3.63-3.55(m,3H),2.90(dd,J=14.8,3.6Hz,1H),2.72(t,J=6.0Hz,2H),2.50-2.49(m,1 H),2.45(t,J=7.2Hz,2H),2.22(s,1H),1.76(d,J=8.8Hz,3H),1.69-1.57(m,5H),1.04(d,J=6.4Hz,3H).

[0127] Example 2 6-((1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-N-(1-(3-fluoropropyl)azetidin-3-yl)pyridin-3-amine (compound 2)

[0128] [ka]

[0129] Step 1: To a stirred solution of (R)-N-(1-(1H-indol-3-yl)propan-2-yl)bicyclo[1.1.1]pentan-1-amine (500 mg, 2.07 mmol) in toluene (10 mL), 5-bromopicolinaldehyde (424.5 mg, 2.28 mmol) was added followed by AcOH (0.18 mL, 3.10 mmol) and the resulting mixture was stirred at 90° C. for 16 h. After completion of the reaction, it was cooled to room temperature. The reaction mixture was diluted with water (50 mL) and extracted into EtOAc (2×50 mL). The combined organic layers were collected, dried over Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography to give 400 mg (0.98 mmol, 47%) of (1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(5-bromopyridin-2-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole. MS(ESI) m / z 408.40[M+H] + ; 1 H NMR(400MHz,CDCl3)δ8.56(d,J=2.0Hz,1H),7.98(s,1H),7.69-7.66(dd,J=8.4,2.4H z,1H),7.49-7.47(m,2H),7.24-7.22(m,1H),7.12-7.05(m,2H),5.07(s,1H),3.67-3. 69(m,1H),3.51(d,J=6.0Hz,1H),3.12-3.06(dd,J=8.4,2.0Hz,1H),2.66(d,J=7.6Hz, 1H),2.28(s,1H),1.81(d,J=8.4Hz,3H),1.63(d,J=7.6Hz,3H),1.18(d,J=6.4Hz,3H).

[0130] Step 2: To a solution of (1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(5-bromopyridin-2-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (400 mg, 0.98 mmol) in 1,4-dioxane (10 mL), 1-(3-fluoropropyl)azetidin-3-amine (194 mg, 1.47 mmol), NaOt-Bu (188.2 mg, 1.96 mmol) were added and the reaction mixture was degassed under argon for 30 min. Then, Brettphos-3rd generation precatalyst (44.39 mg, 0.05 mmol) was added and the reaction mixture was degassed again for 30 min. Then, it was heated to 110 °C for 16 h. After completion of the reaction, it was cooled to room temperature and filtered through a bed of celite. The filtrate was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were collected, dried over Na2SO4, filtered and evaporated. The crude product was purified by RP preparative HPLC to give 112.8 mg (0.24 mmol, 25%) of 6-((1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-N-(1-(3-fluoropropyl)azetidin-3-yl)pyridin-3-amine (compound 2). MS (ESI) m / z 460.57 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ10.16(s,1H),7.82(d,J=2.4Hz,1H),7.35(d,J=7.2Hz,1H),7.17(d,J=7.6Hz,1H),6.97-6 .88(m,3H),6.80-6.77(dd,J=8.4,2.4Hz,1H),6.19(d,J=7.2Hz,1H),4.86(s,1H),4.50(t,J=6.0Hz,1H),4.39(t,J =6.0Hz,1H),3.97-3.92(m,1H),3.68(br,2H),3.52(br,1H),2.96-2.92(dd,J=7.2,2.0Hz,1H),2.75(q,2H),2.61 -2.44(m,3H),2.20(s,1H),1.73(d,J=8.4Hz,3H),1.71-1.61(m,2H),1.50(d,J=7.2Hz,3H),1.08(d,J=7.6Hz,3H).

[0131] Example 3 (1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(5-((1-(3-fluoropropyl)azetidin-3-yl)oxy)pyridin-2-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (compound 3)

[0132] [ka]

[0133] Step 1: To a stirred solution of (R)-N-(1-(1H-indol-3-yl)propan-2-yl)bicyclo[1.1.1]pentan-1-amine (1 gm, 4.16 mmol) in toluene (10 mL), 5-hydroxypicolinaldehyde (561.38 mg, 4.56 mmol) was added followed by AcOH (0.36 mL, 6.24 mmol) and the resulting reaction mixture was stirred at 80° C. for 16 hours. After completion of the reaction, it was cooled to room temperature. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were collected, dried over Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography to give 220 mg (0.63 mmol, 15%) of 6-((1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-3-ol. MS(ESI) m / z 345.42[M+H] + ; 1 H NMR(400MHz,CDCl3)δ7.50-7.48(m,1H),7.25-7.15(m,3H),7.10-7.05(m,2H),6.74(d,J=8.4Hz,2H),4.82(s,1H),3.67-3.63(m, 1H),3.49(s,1H),3.14-3.09(m,1H),2.62-2.58(m,1H),2.21(s,1H),1.83-1.76(m,3H),1.59-1.57(m,5H),1.22(d,J=3.6Hz,3H).

[0134] Step 2: To a solution of 6-((1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-3-ol (220 mg, 0.63 mmol) in DMF (4 mL), tert-butyl 3-iodoazetidine-1-carboxylate (216.35 mg, 0.76 mmol), Cs2CO3 (307.89 mg, 0.94 mmol) were added at room temperature. Then it was heated to 100 °C for 3 h. After the reaction was completed, it was cooled to room temperature. The mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were collected, dried over Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography to give 155 mg (0.31 mmol, 49%) of tert-butyl 3-((6-((1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-3-yl)oxy)azetidine-1-carboxylate. MS(ESI) m / z 501.55[M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.2(s,1H),8.14(d,J=2.4Hz,1H),7.38(d,J=7.6Hz,1H),7.24-7.1 8(m,3H),6.99-6.90(m,2H),5.74(s,1H),5.05-4.97(m,2H),4.30(s,2H),4.19-4.15(m,1H) ,3.82-3.78(m,3H),3.27-3.16(m,2H),2.99-2.94(m,2H),2.61-2.58(m,2H),2.21(s,1H),1 .72(d,J=8.8Hz,3H),1.51(d,J=9.2Hz,3H),1.38(s,9H),1.21(s,2H),1.11(d,J=3.6Hz,3H).

[0135] Step 3: To a solution of tert-butyl 3-((6-((1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-3-yl)oxy)azetidine-1-carboxylate (155 mg, 0.31 mmol) in 1,4-dioxane (2 mL) was added 4M HCl in 1,4-dioxane (2 ml) at 0° C. Then it was stirred at room temperature for 16 hours. After completion of the reaction, it was directly evaporated. The crude product was triturated with diethyl ether to give 200 mg (0.49 mmol, quantitative yield) of (1S,3R)-1-(5-(azetidin-3-yloxy)pyridin-2-yl)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole. MS (ESI) m / z 403.79 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.7(s,1H),9.78-9.61(m,2H),8.31(d,J=2.4Hz,1H),7.86(s,1H),7.55 (d,J=6.8Hz,1H),7.48(d,J=7.6Hz,1H),7.25(d,J=8Hz,1H),7.09(t,J=7.2Hz,1H),7.01(t,J=7.2 Hz,1H),5.96(s,1H),5.21(m,1H),4.47(m,2H),4.24(s,2H),3.56(s,2H),3.40-3.30(m,3H),2.8 7(d,J=15.6Hz,1H),2.21-2.07(m,4H),1.81(s,3H),1.47(d,J=5.6Hz,3H),1.09(t,J=6.8Hz,3H).

[0136] Step 4: To a solution of (1S,3R)-1-(5-(azetidin-3-yloxy)pyridin-2-yl)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (200 mg, 0.49 mmol) in DMF (3 mL) was added 1-fluoro-3-iodopropane (103.25 mg, 0.54 mmol) and K2CO3 (203 mg, 1.49 mmol) at room temperature. The reaction mixture was stirred at 70 °C for 16 h. After completion of the reaction, it was cooled to room temperature. The reaction was diluted with water (5 mL) and extracted with EtOAc (2 x 15 mL). The combined organic layers were collected, dried over Na2SO4, filtered and evaporated. The crude product was purified by RP preparative HPLC to give 62 mg (0.13 mmol, 27%) of (1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(5-((1-(3-fluoropropyl)azetidin-3-yl)oxy)pyridin-2-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (compound 3). MS (ESI) m / z 461.42 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.2(s,1H),8.14(d,J=2.4Hz,1H),7.37(d,J=7.6Hz,1H),7. 21-7.15(m,3H),6.98-6.89(m,2H),4.96(s,1H),4.83(m,1H),4.50(t,J=6Hz,1H),4.3 9(t,J=6Hz,1H),3.72-3.73(m,2H),3.57-3.54(m,1H),2.97-2.93(m,3H),2.61-2.56 (m,3H),2.21(s,1H),1.73-1.52(m,5H),1.51(d,J=9.2Hz,3H),1.30(d,J=9.2Hz,3H).

[0137] Example 4 3-(3-((6-((1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-3-yl)amino)azetidin-1-yl)propanenitrile (compound 4)

[0138] [ka]

[0139] Step 1: (R)-N-(1-(1H-indole-3-yl)) in toluene (50 mL) To a stirred solution of 5-bromopicolinaldehyde (3.75 g, 22.84 mmol) followed by AcOH (1.8 mL, 16.24 mmol) was added. The resulting mixture was stirred at 80° C. for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography eluting with 10-20% ethyl acetate in petroleum ether to give (1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(5-bromopyridin-2-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (4.3 g, 10.53 mmol, 50%). MS(ESI) m / z 408.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.3 (s, 1H), 8.67 (d, J = 2Hz, 1H), 7.92-7.89 (dd, J = 6.8, 2.4Hz, 1H). 7.38(d,J=7.2Hz,1H),7.29(d,J=8.4Hz,1H),7.15(d,J=8.0Hz,1H),6.98-6.92(m,2H),4.98(s,1H),4.01-3.96 (m,1H),3.58-3.59(m,1H),3.16(d,J=5.6Hz,2H),3.02-2.97(dd,J=14Hz,1H),2.63-2.57(m,1H),2.23(s,1H). 1.74(d,J=8.4Hz,3H), 1.51(d,J=9.2Hz,3H), 1.01(d,J=6.4Hz,3H).

[0140] Step 2: To a solution of (1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(5-bromopyridin-2-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (4.3 g, 10.53 mmol) in dioxane (45 mL), add NaO t Bu (4.0 g, 41.62 mmol), Boc azetidine (1.82 g, 10.59 mmol), Brettphos-3rd generation precatalyst (289.3 mg, 0.31 mmol) were added and the reaction mixture was degassed with argon for 15 min. The reaction mixture was heated at 110° C. for 16 h. After the reaction was completed, it was cooled to room temperature. The reaction was filtered through a celite pad. The filtrate was collected, dried over Na2SO4, filtered and evaporated to give tert-butyl 3-((6-((1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-3-yl)amino)azetidine-1-carboxylate (1.1 g, 2.20 mmol, 20%). MS(ESI)m / z500.54[M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.17(s,1H),7.82(d,J=2.4Hz,1H),7.36(d,J=7.6Hz,1H),7.18(d,J=7 .6Hz,1H),6.97-6.88(m,3H),6.80-6.78(dd,J=2.8,8.8Hz,1H),6.41(d,J=5.6Hz,1H),4.88(s,1 H),4.16-4.02(m,3H),3.61-3.54(m,3H),2.93(dd,J=4.0,6.8Hz,1H),2.48(dd,J=4.0,6.8Hz,1H ),2.20(s,1H),1.73(d,J=8.4Hz,3H),1.52(d,J=9.2Hz,3H),1.48(s,9H),1.50(d,J=6.8Hz,3H).

[0141] Step 3: To a stirred solution of tert-butyl 3-((6-((1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-3-yl)amino)azetidine-1-carboxylate (1.1 g, 2.20 mmol) in dioxane (10 mL) was added 4M HCl in dioxane (15 ml, 5.56 mmol) dropwise at 0° C. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was evaporated and washed with diethyl ether (25 mL) followed by pentane (25 mL) to give N-(azetidin-3-yl)-6-((1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-3-amine (1.5 g, 3.44 mmol, quantitative yield). MS (ESI) m / z 400.30 [M+H] + .

[0142] Step 4: To a stirred solution of 3-(3-((6-((1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-3-yl)amino)azetidin-1-yl)propanenitrile (0.45 g, 1.12 mmol) in DMF (10 mL) was added 3-iodopropanenitrile (0.22 g, 1.23 mmol) followed by DIPEA (1.9 g, 13.92 mmol). The resulting reaction mixture was then stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was diluted with cold water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by RP preparative HPLC to give 3-(3-((6-((1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-3-yl)amino)azetidin-1-yl)propanenitrile (compound 4) (133.2 mg, 0.29 mmol, 22%). MS(ESI) m / z 453.85 [M+H]+ , 1 H NMR(400MHz,DMSO-d6)δ10.34(s,1H),7.82(d,J=2.4Hz,1H),7.35(d,J=7.6Hz,1H),7.17(d,J=7.6Hz ,1H),6.97-6.88(m,3H),6.81-6.78(dd,J=2.4,7.6Hz,1H),6.21(d,J=6.8Hz,1H),4.86(s,1H),4.01- 3.96(m,1H),3.67-3.7(m,2H),3.57-3.53(m,1H),2.96-2.92(dd,J=4,6.8Hz,1H),2.85-2.81(m,2H) ,2.63-2.54(m,5H),2.20(s,1H),1.72(d,J=8.4Hz,3H),1.52(d,J=9.2Hz,3H),1.09(d,J=6.8Hz,3H).

[0143] Intermediate 2 1-(3-fluoropropyl)pyrrolidin-3-ol

[0144] [ka]

[0145] To a stirred solution of pyrrolidin-3-ol (5.0 g, 57.39 mmol) in acetonitrile (50 mL) was added potassium carbonate (23.8 g, 172.17 mmol) followed by 1-fluoro-3-iodopropane (9.7 g, 68.86 mmol) and the resulting reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography eluting with 40-45% EtOAc in petroleum ether to give 1-(3-fluoropropyl)pyrrolidin-3-ol (3.8 g, 25.81 mmol, 52% yield). 1H NMR(400MHz,DMSO-d6)δ4.66-4.64(m,1H),4.53(t,J=6Hz,1H),4.41(t,J=6.0Hz,1H),4.19-4.16(m,1H),2.71-2.67(m, 1H),2.54-2.50(m,1H),2.47-2.41(m,3H),2.29-2.26(m,1H),1.99-1.94(m,1H),1.83-1.73(m,2H),1.54-1.52(m,1H).

[0146] Example 5 (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-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 (compound 5) Example 6 (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(2,6-difluoro-4-(((R)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (compound 6)

[0147] [ka]

[0148] Step 1: To a stirred solution of (R)-N-(1-(1H-indol-3-yl)propan-2-yl)bicyclo[1.1.1]pentan-1-amine (1 g, 4.16 mmol) in toluene (10 mL), 2,6-difluoro-4-hydroxybenzaldehyde (1.01 g, 4.58 mmol) was added followed by AcOH (0.36 mL, 6.24 mmol) and the resulting reaction mixture was stirred at 80° C. for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to give semi-pure crude. The crude product thus obtained was purified by silica gel column chromatography eluting with 10-15% EtOAc in petroleum ether to give 4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenol (1.0 g, 2.63 mmol, 63% yield). MS(ESI) m / z 381.41 [M+H] + ; 1 H NMR(400MHz,CDCl3)δ7.49(s,2H),7.26-7.09(m,3H),6.27(d,J=10.0Hz,1H),5.34(s,1H),3.73(br,s,1H),3.48(s,1H),3.13- 3.08(m,1H),2.65-2.59(m,1H),2.26(s,1H),1.87(d,J=8.8Hz,3H),1.68(d,J=9.2Hz,3H),1.26(s,1H),1.18(d,J=6.4Hz,3H).

[0149] Step 2: To a solution of 4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenol (1.2 g, 3.15 mmol) in toluene (12 mL), 1-(3-fluoropropyl)pyrrolidin-3-ol (557.08 mg, 3.78 mmol), tri-n-butylphosphine (1.27 g, 6.31 mmol) and diisopropyl azodicarboxylate (1.24 mL, 6.31 mmol) were added at 0° C. The resulting reaction mixture was then heated to 130° C. and stirred under microwave irradiation for 2 h. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered through a bed of Celite. The filtrate was diluted with water (15 mL) and extracted with EtOAc (2×15 mL). The combined organic layers were collected, dried over Na2SO4, filtered and evaporated. The crude product was purified by RP preparative HPLC to give (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (240 mg, 0.47 mmol, 15%). MS (ESI) m / z 510.46 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.52(s,1H),7.36(d,J=7.6Hz,1H),7.17(d,J=8.0Hz,1H),6.9 9-6.90(m,2H),6.59(d,J=11.2Hz,2H),5.23(s,1H),4.88(s,1H),4.55-4.51(m,1H),4. 43-4.4(m,1H),3.59-3.58(m,1H),2.94-2.90(m,1H),2.83-2.80(m,1H),2.70-2.60(m, 3H),2.38-2.24(m,3H),1.85-1.75(m,6H),1.57(d,J=9.2Hz,3H),1.07(d,J=6.8Hz,3H).

[0150] Step 3: (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (240 mg, 0.47 mmol) was purified by chiral SFC to give peak 1 (compound 5, 80 mg) and peak 2 (compound 6, 75 mg). Compound 5: MS (ESI) m / z 510.56 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.47(s,1H),7.36(d,J=7.6Hz,1H),7.18(d,J=8Hz,1H),6.90-6. 99(m,2H),6.59(d,J=11.2Hz,2H),5.23(s,1H),4.86(s,1H),4.55-4.52(m,1H),4.40-4.43 (m,1H),3.60(s,1H),2.90-2.94(m,1H),2.83-2.80(m,1H),2.79-2.67(m,3H),2.49-2.47( m,2H),2.42-2.24(m,3H),1.85-1.78(m,6H),1.75(d,J=7.6Hz,3H),1.07(d,J=6.4Hz,3H). Compound 6:MS(ESI)m / z510.56[M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.47(s,1H),7.38(d,J=7.6Hz,1H),7.17(d,J=7.6Hz,1H),6.90-6 .99(m,2H),6.59(d,J=11.2Hz,2H),5.23(s,1H),4.88(s,1H),4.52-4.55(m,1H),4.40-4.4 3(m,1H), 3.59(s,1H), 2.91-2.96(m,1H), 2.84-2.82(m,1H), 2.71-2.82(m,2H), 2.50-2.48(m,3H), 2.40-2.25(m,3H), 1.87-1.72(m,6H), 1.58(d,J=9.4Hz,3H), 1.07(d,J=6.4Hz,3H). Absolute stereochemistry was arbitrarily assigned to compounds 5 and 6.

[0151] Example 7 (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(4-(((R)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (compound 7) Example 8 (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (compound 8)

[0152] [ka]

[0153] Compounds 7 and 8 were prepared following procedures similar to those described above for Examples 5 and 6. Compound 7: MS (ESI) m / z 474.58 [M+H] + ;1H NMR(400MHz,DMSO-d6)δ10.29(s,1H),7.42(d,J=7.6Hz,1H),7.21(d,J=8.4Hz,3H),7.0 4-6.95(m,2H),6.82(d,J=8.4Hz,2H),4.87(s,1H),4.84(s,1H),4.54-4.40(dt,J1=12Hz ,J2=5.6Hz,2H),3.58-3.45(m,1H),3.01-2.91(m,2H),2.72-2.60(m,3H),2.52-2.48(m, 3H),2.28-2.21(m,2H),1.87-1.73(m,6H),1.56(d,J=9.2Hz,3H),1.10(d,J=6.8Hz,3H). Compound 8:MS(ESI)m / z474.58[M+H] + ; 1H NMR(400MHz,DMSO-d6)δ10.3(s,1H),7.37(d,J=7.6Hz,1H),7.18(t,J=8.4Hz,3H ),6.99-6.90(m,2H),6.79(d,J=8.4Hz,2H),4.87(s,1H),4.81(s,1H),4.54-4.40 (m,2H),3.45-3.31(m,1H),2.98-2.91(m,2H),2.72-2.60(m,3H),2.52-2.48(m,3 H),2.20(s,2H),1.83-1.71(m,6H),1.59(d,J=9.2Hz,3H),1.10(d,J=6.8Hz,3H). Absolute stereochemistry was arbitrarily assigned to compounds 7 and 8.

[0154] Example 9 (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(6-(((R)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)pyridin-3-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (compound 9) Example 10 (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(6-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)pyridin-3-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (compound 10)

[0155] [ka]

[0156] Compounds 9 and 10 were prepared according to procedures similar to those described for Examples 5 and 6. Compound 9: MS (ESI) m / z 475.49 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ10.31(s,1H),8.09(s,1H),7.49(d,J=8.4Hz,1H),7.38(d,J=7.6Hz ,1H),7.19(d,J=7.6Hz,1H),7.00-6.90(m,2H),6.69(d,J=8.4Hz,1H),5.35(s,1H),4.91(s, 1H),4.53-4.39(m,2H),3.51-3.49(m,1H),2.94-2.82(m,2H),2.70-2.55(m,3H),2.50-2.41 (m,3H),2.27-2.23(m,2H),1.84-1.73(m,6H),1.58(d,J=9.2Hz,3H),1.01(d,J=6.4Hz,3H). Compound 10:MS(ESI)m / z475.49[M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.31(s,1H),8.09(s,1H),7.49(d,J=8.4Hz,1H),7.38(d,J=7.6Hz ,1H),7.19(d,J=7.6Hz,1H),7.00-6.90(m,2H),6.69(d,J=8.4Hz,1H),5.35(s,1H),4.91(s , 1H), 4.53-4.39(m, 2H), 3.51-3.48(m, 1H), 2.94-2.82(m, 2H), 2.70-2.55(m, 3H), 2.50-2.41(m, 3H), 2.27-2.23(m, 2H), 1.85-1.73(m, 6H), 1.58-1.55(m, 3H), 1.01(d, J = 6.4 Hz, 3H). Absolute stereochemistry was arbitrarily assigned to compounds 9 and 10.

[0157] Example 11 1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(5-(((R)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (compound 11) Example 12 (1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(5-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (compound 12)

[0158] [ka]

[0159] Compounds 11 and 12 were prepared according to procedures similar to those described for Examples 5 and 6. Compound 11: MS (ESI) m / z 475.49 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.31(s,1H),8.17(d,J=2Hz,1H),7.37(d,J=7.6Hz,1H), 7.24-7.17(m,3H),6.98-6.89(m,2H),4.95(s,1H),4.90(s,1H),4.53-4.39(m,2H) ),3.51-3.49(m,1H),2.94-2.82(m,2H),2.70-2.55(m,3H),2.50-2.41(m,3H),2. 27-2.23(m,2H),1.84-1.73(m,6H),1.58(d,J=9.2Hz,3H),1.01(d,J=6.4Hz,3H). Compound 12:MS(ESI)m / z475.45[M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.31(s,1H),8.17(d,J=2Hz,1H),7.37(d,J=7.6Hz,1H), 7.24-7.17(m,3H),6.98-6.89(m,2H),4.95(s,1H),4.90(s,1H),4.54-4.39(m,2H ), 3.51-3.49 (m, 1H), 2.94-2.82 (m, 2H), 2.70-2.55 (m, 3H), 2.50-2.41 (m, 3H), 2.27-2.23 (m, 2H), 1.84-1.73 (m, 6H), 1.58 (d, J = 9.2 Hz, 3H), 1.01 (d, J = 6.4 Hz, 3H). Absolute stereochemistry was arbitrarily assigned to compounds 11 and 12.

[0160] Example 13 6-((1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-5-fluoro-N-(1-(3-fluoropropyl)azetidin-3-yl)pyridin-3-amine (compound 13)

[0161] [ka]

[0162] Compound 13 was prepared according to a procedure similar to that described for Example 1. MS (ESI) m / z 478.39 [M+H] + ; 1 H NMR(400MHz,DMSO-d6),δ10.35(s,1H),7.61(s,1H),7.36(d,J=7.6Hz,1H),7.16(d,J=8.0Hz,1H),6.98- 6.89(m,2H),6.68(dd,J=12.8Hz,2Hz,1H),6.60(d,J=6.8Hz,1H),5.2(s,1H),4.51(t,J=6Hz,1H),4.39(t ,J=6Hz,1H),3.95-3.97(m,1H),3.63(t,J=6.8Hz,2H),3.52-3.54(m,1H),2.72-2.79(m,3H),2.59-2.57 (m,1H),2.46-2.44(m,2H),2.23(s,1H),1.75(d,J=8.4Hz,3H),1.69-1.60(m,5H),1.13(d,J=7.2Hz,3H). 19 F NMR(400MHz,DMSO-d6)δ-124.52(d,J=12.0Hz,1F)-217.68-218.07(m,1F).

[0163] Example 14 (1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-yl)oxy)pyridin-2-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (compound 14)

[0164] [ka]

[0165] Compound 14 was prepared according to a procedure similar to that described for Example 3. MS (ESI) m / z 479.45 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δ10.4(s,1H),7.95(d,J=2.0Hz,1H),7.38(d,J=7.6Hz,1H),7.29-7.26(dd,J=12. 0,2.4Hz,1H),7.17(d,J=7.6Hz,1H),6.90-7.00(m,2H),5.31(s,1H),4.86(q,1H),4.50(t,J=6.0Hz,1H) ,4.39(t,J=6.0Hz,1H),3.72-3.73(m,2H),3.57-3.54(m,1H),2.97-2.93(m,2H),2.61-2.56(dd,J=7.6, 1.6Hz,1H),2.52-2.49(m,3H),2.25(s,1H),1.78-1.70(d,J=9.6Hz,3H),1.69-1.61(m,5H),1.14(d,3H).

[0166] Example 15 N-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3-fluorophenyl)-1-(3-fluoropropyl)azetidin-3-amine (compound 15)

[0167] [ka]

[0168] Compound 15 was prepared according to a procedure similar to that described for Example 1. MS (ESI) m / z 477.4 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.35(s,1H),7.40(d,J=15.2Hz,1H),7.22(d,J=19.6Hz,1H),7. 032-6.9(m,2H),6.62(t,J=8.8Hz,1H),6.30-6.15(m,3H)5.14(s,1H),4.50(t,J=6Hz,1H) ,4.38(t,J=6Hz,1H),3.93-3.86(m,1H),3.62(s,1H),3.47-3.44(m,1H),2.89-2.84(m,1H ),2.73-2.67(m,2H),2.45(s,2H),2.21(s,1H),1.75-1.59(m,8H),1.23(d,J=6.4Hz,3H), 19 F NMR(400MHz,DMSO-d6)δ-118.73(s,1F),-217.62-218.01(m,1F).

[0169] Example 16 5-((1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-N-(1-(3-fluoropropyl)azetidin-3-yl)pyrazin-2-amine (compound 16)

[0170] [ka]

[0171] Compound 16 was prepared according to a procedure similar to that described for Example 1. MS(ESI) m / z 461.08 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ10.03(s,1H),7.83(d,J=14.8Hz,2H),7.38(t,J=7.6Hz, 2H),7.18(d,J=8Hz,1H),6.99-6.89(m,2H),4.9(s,1H),4.51-4.37(m,2H),4.31- 4.29(m,1H),3.59-3.32(m,3H),2.90-2.81(m,1H),2.79-2.75(m,2H),2.58-2.54 (m,1H),2.44-2.5(m,2H),2.23(s,1H),1.75-1.55(m,8H),1.11(d,J=6.4Hz,3H), 19 F NMR (400MHz, DMSO-d6) δ-218.32-217.93 (m, 1F).

[0172] Intermediate 3A, 3B (S)-(3-((1-(1H-indol-3-yl)propan-2-yl)amino)bicyclo[1.1.1]pentan-1-yl)methanol (R)-(3-((1-(1H-indol-3-yl)propan-2-yl)amino)bicyclo[1.1.1]pentan-1-yl)methanol

[0173] [ka]

[0174] Step 1: To a stirred solution of 1-(1H-indol-3-yl)propan-2-one (6 g, 34.68 mmol) in MeOH (50 mL), (3-aminobicyclo[1.1.1]pentan-1-yl)methanol (1.01 g, 4.58 mmol) was added followed by AcOH (4.35 mL, 69.36 mmol). The reaction mixture was stirred at room temperature for 3 h. Then NaCNBH3 (1.01 g, 4.58 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to give semi-pure crude. The crude product thus obtained was purified by silica gel column chromatography eluting with 10-15% EtOAc in petroleum ether to give (3-((1-(1H-indol-3-yl)propan-2-yl)amino)bicyclo[1.1.1]pentan-1-yl)methanol (5 g 18.5 mmol, 53% yield). MS(ESI) m / z 271.67[M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.88(s,1H),7.48(d,J=7.2Hz,1H),7.31(d,J=4.0Hz, 1H),7.10(d,J=2.0Hz,1H),7.04(t,J=16.4Hz,1H),6.94(t,J=15.8Hz,1H),4.3 8(t,J=5.6Hz,1H),4.04(q,1H),3.41(d,J=8.0Hz,1H),2.98-2.95(m,1H),2.84 -2.79(dd,J=14.0,5.2Hz,1H),2.55(m,1H),1.61(m,5H),0.94(d,J=6.4Hz,3H).

[0175] Step 2: (3-((1-(1H-indol-3-yl)propan-2-yl)amino)bicyclo[1.1.1]pentan-1-yl)methanol (3, racemic) (5 g, 18.55 mmol,) was purified by chiral SFC to give (S)-(3-((1-(1H-indol-3-yl)propan-2-yl)amino)bicyclo[1.1.1]pentan-1-yl)methanol (Intermediate 3A, Peak-1) (2 g, 9.25 mmol, 33% yield) and (R)-(3-((1-(1H-indol-3-yl)propan-2-yl)amino)bicyclo[1.1.1]pentan-1-yl)methanol (Intermediate 3B, Peak-2) (2.05 g, 9.27 mmol, 34% yield). Intermediate 3A:MS(ESI)m / z271.67[M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.77(s,1H),7.48(d,J=7.6Hz,1H),7.32(d,J=8.0Hz,1H),7.1 0(d,J=2.0Hz,1H),7.04(t,J=7.6Hz,1H),6.98(t,J=8.4Hz,1H),4.38(t,J=5.6Hz,1H), 4.04(q,1H),3.44(d,J=5.2Hz,2H),3.17(d,J=5.2Hz,2H),2.98-2.94(m,1H),2.84-2.7 9(dd,J=14.0,5.2Hz,1H),2.55(m,1H),2.04(br,1H)1.62(m,6H),0.94(d,J=6.4Hz,3H). Intermediate 3B:MS(ESI)m / z271.67[M+H] + ; 1H NMR(400MHz,DMSO-d6)δ10.78(s,1H),7.48(d,J=7.6Hz,1H),7.31(d,J=8.0Hz,1H),7.1 0(d,J=2.0Hz,1H),7.04(t,J=7.6Hz,1H),6.98(t,J=8.4Hz,1H),4.38(t,J=5.6Hz,1H), 4.04 (q, 1H), 3.41 (d, J = 5.2 Hz, 2H), 3.17 (d, J = 5.2 Hz, 2H), 2.98-2.95 (m, 1H), 2.84-2.79 (dd, J = 14.0, 5.2 Hz, 1H), 2.55 (m, 1H), 2.04 (br, 1H) 1.61 (m, 6H), 0.94 (d, J = 6.4 Hz, 3H). Absolute stereochemistry was arbitrarily assigned to intermediate 3A and intermediate 3B.

[0176] Example 17 (3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentan-1-yl)methanol (compound 17)

[0177] [ka]

[0178] Step 1: To a stirred solution of 1-(1H-indol-3-yl)propan-2-one (1) (6 g, 34.68 mmol) in MeOH (60 mL), (3-aminobicyclo[1.1.1]pentan-1-yl)methanol (2) (3.95 g, 34.64 mmol) was added followed by AcOH (4.35 mL, 69.36 mmol) and the reaction mixture was stirred at room temperature for 3 h. Then NaCNBH3 (4.35 g, 69.22 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to give semi-pure crude. The crude product thus obtained was purified by silica gel column chromatography eluting with 10-15% MeOH in DCM to give (3-((1-(1H-indol-3-yl)propan-2-yl)amino)bicyclo[1.1.1]pentan-1-yl)methanol (3) (5 g, 18.5 mmol, 53% yield). MS (ESI) m / z 271.67 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ10.88(s,1H),7.48(d,J=7.2Hz,1H),7.31(d,J=4.0Hz, 1H),7.10(d,J=2.0Hz,1H),7.04(t,J=16.4Hz,1H),6.94(t,J=15.8Hz,1H),4.3 8(t,J=5.6Hz,1H),4.04(q,1H),3.41(d,J=8.0Hz,1H),2.98-2.95(m,1H),2.84 -2.79(dd,J=14.0,5.2Hz,1H),2.55(m,1H),1.61(m,5H),0.94(d,J=6.4Hz,3H).

[0179] Step 2: (3-((1-(1H-indol-3-yl)propan-2-yl)amino)bicyclo[1.1.1]pentan-1-yl)methanol (3, racemic) (5 g, 18.55 mmol,) was purified by chiral SFC to give (S)-(3-((1-(1H-indol-3-yl)propan-2-yl)amino)bicyclo[1.1.1]pentan-1-yl)methanol (4 peak-1) (2 g, 9.25 mmol, 33% yield) and (R)-(3-((1-(1H-indol-3-yl)propan-2-yl)amino)bicyclo[1.1.1]pentan-1-yl)methanol (4 peak-2) (2.05 g, 9.27 mmol, 34% yield). 4 Peak-1: MS(ESI) m / z 269.43[MH] - ; 1 H NMR(400MHz,DMSO-d6)δ10.77(s,1H),7.48(d,J=7.6Hz,1H),7.32(d,J=8.0Hz,1H),7.1 0(d,J=2.0Hz,1H),7.04(t,J=7.6Hz,1H),6.98(t,J=8.4Hz,1H),4.38(t,J=5.6Hz,1H), 4.04(q,1H),3.44(d,J=5.2Hz,2H),3.17(d,J=5.2Hz,2H),2.98-2.94(m,1H),2.84-2.7 9(dd,J=14.0,5.2Hz,1H),2.55(m,1H),2.04(br,1H)1.62(m,6H),0.94(d,J=6.4Hz,3H). 4 peak-2:MS(ESI)m / z 269.38[MH] - ; 1H NMR(400MHz,DMSO-d6)δ10.78(s,1H),7.48(d,J=7.6Hz,1H),7.31(d,J=8.0Hz,1H),7.1 0(d,J=2.0Hz,1H),7.04(t,J=7.6Hz,1H),6.98(t,J=8.4Hz,1H),4.38(t,J=5.6Hz,1H), 4.04 (q, 1H), 3.41 (d, J = 5.2 Hz, 2H), 3.17 (d, J = 5.2 Hz, 2H), 2.98-2.95 (m, 1H), 2.84-2.79 (dd, J = 14.0, 5.2 Hz, 1H), 2.55 (m, 1H), 2.04 (br, 1H) 1.61 (m, 6H), 0.94 (d, J = 6.4 Hz, 3H). Absolute stereochemistry was arbitrarily assigned to intermediate 4 peak-1 and intermediate 4 peak-2.

[0180] Step 3: To a stirred solution of (3-((1-(1H-indol-3-yl)propan-2-yl)amino)bicyclo[1.1.1]pentan-1-yl)methanol (4peak-2) (2 g, 18.55 mmol) in 20 mL of toluene, 4-bromo-2,6-difluorobenzaldehyde (5) (2.05 g, 9.36 mmol) was added followed by AcOH (0.7 mL, 12.24 mmol). The reaction mixture was stirred at 80° C. for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to give semi-pure crude. The crude product thus obtained was purified by silica gel column chromatography eluting with 10-15% EtOAc in petroleum ether to give (3-((1R,3R)-1-(4-bromo-2,6-difluorophenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentan-1-yl)methanol (6 peak-2) (500 mg, 1.05 mmol, 14.28% yield). MS (ESI) m / z 473.34 [M+1] - ; 1H NMR(400MHz,DMSO-d6)δ10.51(s,1H),7.41-7.37(m,3H),7.17(d,J=8.0Hz,1H),7.01-6.91(m,2H),5.28(s,1H),4.38(t,J=5.4Hz,1H), 3.63(m,1H),3.38(d,J=6.4Hz,2H),2.98-2.92(dd,J=6.4,2.4Hz,1H),2.56-2.53(m,3H),1.63(d,J=9.2Hz,3H),1.23(d,J=8.8Hz,3H).

[0181] Step 4: To a stirred solution of (3-((1R,3R)-1-(4-bromo-2,6-difluorophenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentan-1-yl)methanol (6peak-2) (500 mg, 1.05 mmol) in 1,4-dioxane (10 mL) was added 1-(3-fluoropropyl)azetidin-3-amine (7) (223.6 mg, 1.69 mmol) and NaOt-Bu (188.2 mg, 1.96 mmol) and the reaction mixture was degassed under argon for 30 min. Then Brettphos-3rd generation precatalyst (30.45 mg, 0.03 mmol) was added and the reaction mixture was degassed again for 30 min. Then it was heated at 110 °C for 16 h. After completion of the reaction, it was cooled to room temperature and filtered through a bed of celite. The filtrate was diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by RP preparative HPLC to give (3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentan-1-yl)methanol (compound 17) (61 mg, 0.11 mmol, 10% yield). MS (ESI) m / z 525.33 [MH] + ; 1H NMR(400MHz,DMSO-d6)δ10.38(s,1H),7.34(d,J=7.6Hz,1H),7.17(d,J=7.6Hz,1H),6.98-6 .90(m,2H),6.74(br,1H),6.12(d,J=12.4Hz,1H),5.13(s,1H),4.54(t,J=5.4Hz,1H),4.49- 4.37(m,2H),3.95(q,1H),3.64-3.57(br,4H),3.35-3.31(m,2H),2.94-2.89(dd,J=6.4,2. 4Hz,1H),1.75(br,2H),1.60(d,J=8.8Hz,3H),1.44(d,J=8.8Hz,3H),1.06(d,J=8.8Hz,3H).

[0182] Example 18 (3-((1S,3S)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentan-1-yl)methanol (compound 18)

[0183] [ka]

[0184] Compound 18 was prepared following a procedure similar to that described for Example 17, using intermediate 4 peak-1 in step 3. Compound 18: MS (ESI) m / z 525.33 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ10.38(s,1H),7.34(d,J=7.6Hz,1H),7.17(d,J=7.6Hz,1H),6.98-6 .90(m,2H),6.74(br,1H),6.12(d,J=12.4Hz,1H),5.13(s,1H),4.54(t,J=5.4Hz,1H),4.49- 4.37 (m, 2H), 3.95 (q, 1H), 3.64-3.57 (br, 4H), 3.35-3.31 (m, 2H), 2.94-2.89 (dd, J = 6.4, 2.4 Hz, 1H), 1.75 (br, 2H), 1.60 (d, J = 8.8 Hz, 3H), 1.44 (d, J = 8.8 Hz, 3H), 1.06 (d, J = 8.8 Hz, 3H). Absolute stereochemistry was arbitrarily assigned to compounds 17 and 18.

[0185] Intermediate 4 (S)-1-(3-fluoropropyl)pyrrolidin-3-amine

[0186] [ka]

[0187] Step 1: To a stirred solution of tert-butyl (S)-pyrrolidin-3-ylcarbamate (2 g, 10.73 mmol) in ACN (20.0 mL) was added K2CO3 (4.44 g, 32.19 mmol) and 1-fluoro-3-iodopropane (2.42 g, 12.87 mmol) at RT. The reaction mixture was heated to 50 °C for 16 h. After completion of the reaction, it was diluted with water (50 mL) and extracted with 10% MeOH in DCM (3 x 50 mL). The organic layer was collected, dried over Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography. Purification by column chromatography gave 1.6 g (6.49 mmol, 61%) of tert-butyl (S)-(1-(3-fluoropropyl)pyrrolidin-3-yl)carbamate. 1H NMR(400MHz,DMSO-d6)δ6.95(d,J=6.0Hz,1H),4.53(t,J=6.0Hz,1H),4.41(t,J=6.0Hz,1H),3.89-3.91(m,1H),2.75 -2.69(m,1H),2.50-2.46(m,2H),2.27(s,1H),2.03-1.98(m,1H),1.83-1.74(m,2H),1.58-1.55(m,1H),1.45(s,9H).

[0188] Step 2: To a stirred solution of tert-butyl (S)-(1-(3-fluoropropyl)pyrrolidin-3-yl)carbamate (1.6 g, 6.49 mmol) in DCM (16 mL) was added TFA (4 mL) at 0° C. The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, it was evaporated and then the residue was dissolved in 10% MeOH in DCM. K2CO3 (8.95 g, 64.9 mmol) was then added at 0° C., the mixture was stirred for 50 min and then filtered. The filtrate was concentrated to give 900 mg (6.15 mmol, 95%) of (S)-1-(3-fluoropropyl)pyrrolidin-3-amine. 1 H NMR(400MHz,DMSO-d6)δ4.52(t,J=6.0Hz,1H),4.40(t,J=6.0Hz,1H),3.32-3.29(m,1H),2.65-2.6 1(m,1H),2.52-2.37(m,4H),2.07(m,1H),1.98-1.95(m,1H)1.83-1.73(m,2H),1.36-1.34(m,1H).

[0189] Example 19 (S)-N-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine (compound 19)

[0190] [ka]

[0191] Step 1A: To a stirred solution of tert-butyl (S)-pyrrolidin-3-ylcarbamate (2 g, 10.73 mmol) in ACN (20.0 mL) was added K2CO3 (4.44 g, 32.19 mmol) and 1-fluoro-3-iodopropane (2.42 g, 12.87 mmol) at RT. The reaction mixture was heated to 50° C. for 16 h. After completion of the reaction, it was diluted with water (50 mL) and extracted with 10% MeOH in DCM (3×50 mL). The organic layer was collected, dried over Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography to give 1.6 g (6.49 mmol, 61%) of tert-butyl (S)-(1-(3-fluoropropyl)pyrrolidin-3-yl)carbamate (3a). 1 H NMR(400MHz,DMSO-d6)δ6.95(d,J=6.0Hz,1H),4.53(t,J=6.0Hz,1H),4.41(t,J=6.0Hz,1H),3.89-3.91(m,1H),2.75 -2.69(m,1H),2.50-2.46(m,2H),2.27(s,1H),2.03-1.98(m,1H),1.83-1.74(m,2H),1.58-1.55(m,1H),1.45(s,9H).

[0192] Step 2A: To a stirred solution of tert-butyl (S)-(1-(3-fluoropropyl)pyrrolidin-3-yl)carbamate (3a) (1.6 g, 6.49 mmol) in DCM (16 mL) was added TFA (4 mL) at 0° C. The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, it was evaporated and then dissolved in 10% MeOH in DCM. K2CO3 (8.95 g, 64.9 mmol) was then added at 0° C., the mixture was stirred for 50 min and then filtered. The filtrate was concentrated to give 900 mg (6.15 mmol, 95%) of (S)-1-(3-fluoropropyl)pyrrolidin-3-amine (3). 1H NMR(400MHz,DMSO-d6)δ4.52(t,J=6.0Hz,1H),4.40(t,J=6.0Hz,1H),3.32-3.29(m,1H),2.65-2.6 1(m,1H),2.52-2.37(m,4H),2.07(m,1H),1.98-1.95(m,1H)1.83-1.73(m,2H),1.36-1.34(m,1H).

[0193] Step 1: To a stirred solution of (R)-N-(1-(1H-indol-3-yl)propan-2-yl)bicyclo[1.1.1]pentan-1-amine (400 mg, 1.66 mmol) in toluene (8 mL), 4-bromo-2,6-difluorobenzaldehyde (1) (424.5 mg, 1.83 mmol) was added followed by AcOH (0.14 mL, 2.49 mmol). The reaction mixture was stirred at 90° C. for 16 h. After completion of the reaction, it was cooled to room temperature. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were collected, dried over Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography to give 310 mg (0.69 mmol, 47%) of (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(4-bromo-2,6-difluorophenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (2). MS(ESI) m / z 443.36[M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ10.52(s,1H),7.41-7.37(m,3H),7.17(d,J=8.0Hz,1H),7.01-6.92(m,2H),5.29(s,1H),3.59-3.62(m,1H),2. 92-2.97(m,1H),2.50-2.58(m,1H),2.23-2.25(d,J=17.6Hz,1H),1.78(d,J=9.2Hz,3H),1.57(d,J=9.2Hz,3H),1.07(d,J=6.4Hz,3H).

[0194] Step 2: To a solution of (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(4-bromo-2,6-difluorophenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (2) (310 mg, 0.69 mmol) in 1,4-dioxane (8 mL) was added (S)-1-(3-fluoropropyl)pyrrolidin-3-amine (3) (113 mg, 0.76 mmol), NaOt-Bu (133 mg, 1.38 mmol). The reaction mixture was degassed under argon for 30 min. Then, Brettphos-3rd generation precatalyst (18.75 mg, 0.02 mmol) was added and the reaction mixture was degassed again for 30 min. It was then heated to 110 °C for 16 h. After completion of the reaction, it was cooled to room temperature and filtered through a bed of Celite. The filtrate was diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were collected, dried over Na2SO4, filtered and evaporated. The crude product was purified by RP preparative HPLC to give 62 mg (0.12 mmol, 23%) of (S)-N-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine (compound 19). MS (ESI) m / z 508.97[M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ10.42(s,1H),7.34(d,J=7.2Hz,1H),7.17(d,J=7.6Hz,1H),6.89-6.98( m,2H),6.32(d,J=6.4Hz,1H),6.12(d,J=12Hz,2H),5.14(s,1H),4.54(t,J=6Hz,1H),4.42(t,J= 6Hz,1H),3.83(m,1H),3.57(s,1H),2.89-2.90(m,1H),2.75-2.77(m,1H),2.61-2.50(m,1H),2. 44-2.32(m,5H),2.23-2.34(m,2H),1.76-1.84(m,5H),1.52-1.60(m,4H),1.06(d,J=6.4Hz,3H).

[0195] Example 20 5-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-N-((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)pyridin-2-amine (compound 20)

[0196] [ka]

[0197] Compound 20 was prepared according to a procedure similar to that described for Example 1. MS (ESI) m / z 474.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.3(s,1H),7.88(d,J=1.6Hz,1H),7.36(d,J=7.6Hz,1H),7.19-7.13(m,2H) ),6.98-6.89(m,2H),6.53(d,J=6.8Hz,1H),6.38(d,J=8.8Hz,1H),4.82(s,1H),4.53(t,J=6Hz,1H), 4.42(t,J=6Hz,1H),4.25(s,1H),3.51-3.47(m,1H),2.95-2.90(m,1H),2.77(m,1H),2.59-2.50(m,1 H),2.45-2.22(m,5H),2.16(s,2H),1.83-1.73(m,5H),1.59(d,J=9.2Hz,4H),1.09(d,J=6.4Hz,3H).

[0198] Example 21 5-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-N-(1-(3-fluoropropyl)azetidin-3-yl)pyridin-2-amine (compound 21)

[0199] [ka]

[0200] Compound 21 was prepared according to a procedure similar to that described for Example 1. MS (ESI) m / z 460.59 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.42(s,1H),7.90(d,J=1.25Hz,1H),7.36(d,J=7.6Hz,1H),7.18-7.15(dd,J= 8.4,2.8Hz,2H),6.96-6.91(m,2H),6.84(d,J=6.8Hz,1H),6.36(d,J=8.4Hz,1H),4.82(s,1H),4.52(t,J =6.0Hz,1H),4.39-4.34(m,2H),3.58(t,J=6.8Hz,2H),3.32(m,1H),2.92-2.90(dd,J=8.4,2.4Hz,1H), 2.74(q,2H),2.56-2.42(m,3H),2.22(s,1H),1.75(d,J=8.4Hz,3H),1.66(m,5H),1.07(d,J=6.4Hz,3H).

[0201] Example 22 4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluoro-N-(2-(pyrrolidin-1-yl)ethyl)aniline (compound 22)

[0202] [ka]

[0203] Compound 22 was prepared according to a procedure similar to that described for Example 1. MS (ESI) m / z 477.26 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),7.34(d,J=7.6Hz,1H),7.17(d,J=8.0Hz,1H),6 .97-6.89(m,2H),6.16(d,J=12.4Hz,2H),6.08(t,J=5.2Hz,1H),5.14(s,1H),3.60-3. 56(m,1H),3.17-3.07(m,2H),2.93-2.88(m,1H),2.56(t,J=13.2Hz,2H),2.50-2.46(m ,5H),2.25(s,1H),1.77(d,J=8.8Hz,3H),),1.68-1.58(m,7H),1.06(d,J=6.4Hz,3H).

[0204] Example 23 (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-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 (compound 23)

[0205] [ka]

[0206] Compound 23 was prepared according to the procedure described for Example 3. MS (ESI) m / z 496.61 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.40(s,1H),7.37(d,J=7.6Hz,1H),7.17(d,J=8.0Hz,1H),7.00-6. 90(m,2H),6.62(d,J=10.8Hz,1H),5.25(s,1H),4.98(q,1H),4.56(t,J=6.0Hz,1H),4.44(t, J=6.0Hz,1H),3.61-3.57(m,2H),2.97-2.94(dd,J=7.6,1.6Hz,1H),2.57-2.49(m,1H),2.24 (s,1H),1.82(br,2H),1.78-1.70(d,J=9.6Hz,3H),1.59-1.56(m,3H),1.07(d,J=6.8Hz,3H).

[0207] Example 24 (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (compound 24)

[0208] [ka]

[0209] Step 1: To a solution of 4-hydroxybenzaldehyde (1) (5.0 g, 40.983 mmol) in ACN (50 mL) was added 1,2-dibromoethane (2) (77.1 g, 409.83 mmol) and K2CO3 (11.3 g, 81.96 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 16 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was cooled to room temperature. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with EtOAc (2 x 75 mL). The combined organic layers were collected, dried over Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography eluting with 8-7% EA / PE to give 4-(2-bromoethoxy)benzaldehyde (3) (2.2 g, 17.90 mmol, 44%). MS(ESI)m / z231.04[M+H] + ; 1 H NMR(400MHz, CDCl3) δ9.90(s,1H),7.86-7.84(dd,J=7.6,1.6Hz,2H),7.02(d,J=8.8Hz,2H),4.38(t,J=4.4Hz,2H),3.67(t,J=4.4Hz,2H).

[0210] Step 2: To a stirred solution of 4-(2-bromoethoxy)benzaldehyde (3) (500 mg, 2.183 mmol) in toluene (10 mL) was added AcOH (0.22 mL, 3.275 mmol) followed by (R)-N-(1-(1H-indol-3-yl)propan-2-yl)bicyclo[1.1.1]pentan-1-amine (786 mg, 3.275 mmol). The reaction mixture was stirred at 80° C. for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with saturated aqueous NaHCO3 followed by brine solution, dried over Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography eluting with 10-15% EA to give (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(4-(2-bromoethoxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (4) (180 mg, 398 mmol, 18%). MS (ESI) m / z 497.08 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ7.45(d,J=7.6Hz,1H),7.34-6.92(m,6H),6.84(d,J=8.4Hz,1H),5.23(s,1H),4.80(s,1H) ),4.24(br,2H),3.66(br,3H),3.11(dd,1H),2.60(dd,1H),2.21(s,1H),1.76(d,2H),1.56(d,3H),1.22(m,6H).

[0211] Step 3: To a solution of (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(4-(2-bromoethoxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (4) (180 mg, 0.4 mmol) in ACN (3 mL), 2,2,2-trifluoro-1-(3-(fluoromethyl)-1 4 (azetidin-1-yl)ethan-1-one (5) (111 mg, 0.6 mmol) and K2CO3 (110 mg, 0.8 mmol) were added at room temperature. The reaction mixture was stirred for 80℃ The mixture was stirred at rt for 2 h. After completion of the reaction, it was cooled to room temperature. The reaction was diluted with water (5 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were collected, dried over Na2SO4, filtered and evaporated. The crude product was purified by RP preparative HPLC to give (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (compound 24) (10.9 mg, 23.72 mmol, 6%). MS (ESI) m / z 458.3 [M+H] - ; 1 H NMR(400MHz,DMSO-d6)δ10.26(s,1H),7.37(d,J=7.6Hz,1H),7.19-7.17(m,3H),6.99-6.9(m,2H),6.81(d,J=8.4Hz,2H),4.86(s,1H),4.55 (d,J=4.4Hz,1H),4.43(d,J=4.0Hz,1H),3.87(t,J=5.6Hz,2H),3.47(q,1H),3.58(br,2H),3.04(t,J=7.6Hz,2H),2.81(dd,J=7.6,1.6Hz,1 H),2.73(t,J=8.4Hz,3H),2.55(m,1H),2.20(s,1H),1.73(d,J=9.6Hz,3H),1.57(d,J=9.2Hz,3H),1.10(d,J=6.4Hz,3H).

[0212] Example 25 (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(2-fluoro-4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (compound 25)

[0213] [ka]

[0214] Step 1: To a stirred solution of 2-fluoro-4-hydroxybenzaldehyde (2.0 g, 14.27 mmol) in acetonitrile (20 mL) was added potassium carbonate (3.93 g, 28.54 mmol) followed by 1,2-dibromoethane (12.31 ml, 14.22 mmol) and the resulting reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography eluting with 40-45% EtOAc in petroleum ether to give 4-(2-bromoethoxy)-2-fluorobenzaldehyde (3) (2.9 g, 11.73 mmol, yield = 82%). MS (ESI) m / z 247.05 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δ10.22(s,1H),7.84(t,J=16.8Hz,1H),6.81-6.78(m,1H),6.68-6.48(m,1H),4.35(t,J=12.4Hz,2H),3.66(t,J=12.4Hz,2H).

[0215] Step 2: To a stirred solution of (R)-N-(1-(1H-indol-3-yl)propan-2-yl)bicyclo[1.1.1]pentan-1-amine (500 mg, 2.08 mmol) in toluene (5 mL), 4-(2-bromoethoxy)-2-fluorobenzaldehyde (3) (462.56 mg, 1.87 mmol) was added followed by AcOH (0.8 mL, 3.12 mmol). The reaction mixture was stirred at 80° C. for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was diluted with water (100 mL) and extracted into EtOAc (2×100 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography eluting with 5-7% MeOH in DCM to give (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(4-(2-bromoethoxy)-2-fluorophenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (4) (350 mg, 0.74 mmol, yield = 37%). MS (ESI) m / z 469.18 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ7.49(d,J=7.2Hz,1H),7.39(s,1H),7.21-7.15(m,2H ),7.12-7.07(m,2H),6.67-6.63(m,1H),6.58-6.55(m,1H),5.29(s,1H),4.2 7-4.23(m,2H),3.66-3.60(m,3H),3.11-3.06(m,1H),2.64-2.60(m,1H),1.8 5(s,1H),1.81(d,J=9.2Hz,3H),1.64(d,J=9.2Hz,3H),1.17(d,J=6.8Hz,3H).

[0216] Step 3: To a stirred solution of (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(4-(2-bromoethoxy)-2-fluorophenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (300 mg, 0.63 mmol) in acetonitrile (5 mL) was added potassium carbonate (176.39 mg, 1.27 mmol) followed by 3-(fluoromethyl)azetidine (175.89 mg, 0.94 mmol). The resulting reaction mixture was stirred at 80° C. for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were collected, dried over Na2SO4, filtered and evaporated. The crude product was purified by RP preparative HPLC to give 16 mg (0.033 mmol, yield = 7%) of (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(2-fluoro-4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (compound 25). MS (ESI) m / z 476.27 [MH] - ; 1 H NMR(400MHz,DMSO-d6)δ10.38(s,1H),7.39(d,J=7.6Hz,1H),7.18(d,J=8Hz,1H),7.00-6.91(m,2H) ),6.86-6.77(m,2H),6.61-6.58(m,1H),5.22(s,1H),4.55(d,J=6.4Hz,1H),4.43(d,J=6Hz,1H),3 .89(t,J=12Hz,2H),3.47-3.43(m,1H),3.31-3.28(m,3H),3.00-2.87(m,3H),2.74-2.66(m,3H),2 .61-2.50(m,1H),2.22(s,1H),1.75(d,J=9.2Hz,3H),1.63(d,J=9.2Hz,3H),1.12(d,J=6.8Hz,3H).

[0217] Example 26 (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(2,6-difluoro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (compound 26)

[0218] [ka]

[0219] Step 1: To a stirred solution of (R)-N-(1-(1H-indol-3-yl)propan-2-yl)bicyclo[1.1.1]pentan-1-amine (500 mg, 2.07 mmol) in toluene (10 mL) was added 2,6-difluoro-4-hydroxybenzaldehyde. The resulting reaction mixture was stirred at 80 °C for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted with EtOAc (2 × 40 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to obtain semi-pure crude. The thus obtained crude product was purified by silica gel column chromatography eluting with 10-15% EtOAc in petroleum ether to obtain 4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenol (2) (330 mg, 0.86 mmol, 42% yield). MS(ESI)m / z381.68[M+1] + ; 1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),10.26(s,1H),7.35(d,J=7.6Hz,1H),7.16(d,J=6.8Hz,1H),6.99-6.90(m,2H),6.38(d,J=11.2Hz,2H) ),5.22(s,1H),3.62(br,1H),2.88(dd,1H),2.51(m,1H),2.23(s,1H),1.75(d,J=8.0Hz,3H),1.58(d,J=8.0Hz,3H),1.08(d,J=8.4Hz,3H).

[0220] Step 2: To a solution of 4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenol (2) (330 mg, 0.86 mmol) in toluene (5 mL), 2-(pyrrolidin-1-yl)ethan-1-ol (3) (420 mg, 0.95 mmol), tri-n-butylphosphine (347.99 mg, 1.72 mmol) and diisopropyl azodicarboxylate (0.34 mL, 1.72 mmol) were added at 0° C. The resulting reaction mixture was then heated to 130° C. under microwave irradiation for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered through a bed of celite. The filtrate was diluted with water (15 mL) and extracted with EtOAc (2×15 mL). The combined organic layers were collected, dried over Na2SO4, filtered and evaporated. The crude product was purified by RP preparative HPLC to give (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(2,6-difluoro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (compound 26) (60.4 mg, 0.12 mmol, 14.58%). MS (ESI) m / z 477.90 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ10.52(s,1H),7.36(d,J=7.6Hz,1H),7.17(d,J=8.0Hz,1H), 6.99-6.90(m,2H),6.59(d,J=11.2Hz,2H),5.23(s,1H),4.07(t,J=6.0Hz,2H),3.58( q,1H),2.92(dd,J=11.4,2.8Hz,1H),2.77(t,J=6.8Hz,2H),2.67-2.49(m.5H),2.24( s,1H),1.78-1.76(d,3H),1.68(m,4H),1.57(d,J=8.8Hz,3H),1.07(d,J=6.8Hz,3H).

[0221] Example 27 (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(6-(2-(3-fluoropyrrolidin-1-yl)ethoxy)pyridin-3-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (compound 27)

[0222] [ka]

[0223] Step 1: To a stirred solution of (R)-N-(1-(1H-indol-3-yl)propan-2-yl)bicyclo[1.1.1]pentan-1-amine (5 g, 20.82 mmol) in toluene (50 mL), 6-hydroxynicotinaldehyde (1) (2.81 g, 18.68 mmol) was added followed by AcOH (1.8 mL, 16.24 mmol). The reaction mixture was stirred at 80° C. for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography eluting with 5-7% MeOH in DCM to give 5-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-2-ol (2) (2.5 g, 13.8 mmol, 35%). MS (ESI) m / z 346.40 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ11.47(s,1H),10.42(s,1H),7.37(d,J=7.6Hz,1H),7.24-7.20(m,3H),6.24(d,J=9.6Hz,1H),5.74(s,1H),4.7 2(s,1H),4.15-4.11(m,1H),3.17(d,J=5.2Hz,4H),2.27(s,1H),1.79(t,J=15.6Hz,3H),1.68(d,J=9.2Hz,3H),1.08(d,J=6.4Hz,3H).

[0224] Step 2: To a stirred solution of 5-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-2-ol (2) (500 mg, 1.44 mmol) in toluene (5 mL), 2-(3-fluoropyrrolidin-1-yl)ethan-1-ol (3) (319.1 mg, 2.17 mmol) was added, followed by DIAD (0.28 ml, 1.13 mmol) and P(n-Bu)3 (0.35 ml, 1.13 mmol). The resulting reaction mixture was then heated under microwave irradiation at 130° C. for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered through a bed of celite. The filtrate was diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by RP preparative HPLC to give (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(6-(2-(3-fluoropyrrolidin-1-yl)ethoxy)pyridin-3-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (compound 27) (16 mg, 0.034 mmol, 3%). MS (ESI) m / z 459.36 [MH] - ; 1 H NMR(400MHz,DMSO-d6)δ10.35(s,1H),8.11(d,J=2Hz,1H),7.50-7.48(m,1H),7.6(d,J=7.6Hz) ,1H),7.18(d,J=8Hz,1H),7.00-6.90(m,2H),6.71(d,J=8.4Hz,1H),5.38-5.10(m,1H),4.91( s,1H),4.33(t,J=11.6Hz,1H),3.52(s,1H),2.99-2.80(m,5H),2.79-2.61(m,2H),2.37(d,J= 7.2Hz,1H),2.23(s,1H),1.76-1.73(m,4H),1.57(t,J=9.6Hz,3H),1.23(s,1H),1.10(d,J=6. 8Hz,3H).

[0225] Intermediate 5 2-(3-fluoropyrrolidin-1-yl)ethan-1-amine

[0226] [ka]

[0227] Step 1: To a solution of 3-fluoropyrrolidine (1A) (300 mg, 3.36 mmol) in DMF (5 mL) was added K2CO3 (929 mg, 6.73 mmol) and tert-butyl (2-bromoethyl)carbamate (2A) (905 mg, 4.04 mmol) at room temperature. The reaction mixture was stirred at 50 °C for 16 h. After completion of the reaction, it was cooled to room temperature. The reaction was diluted with water (10 mL) and extracted with 10% MeOH in DCM (2 x 20 mL). The combined organic layers were collected, dried over Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography eluting with 5-6% MeOH in DCM to give 250 mg (0.60 mmol, 32%) of tert-butyl (2-(3-fluoropyrrolidin-1-yl)ethyl)carbamate (3A). MS(ESI)m / z233.23[M+H] + , 1 H NMR(400MHz,DMSO-d6)δ6.69(s,1H),5.23(t,J=6.8Hz,1H),5.09(t,J=7.2Hz,1H),3.04-2.99(q,4H),2.8 6-2.77(m,4H),2.64-2.43(m,6H),2.33-2.16(q,2H),2.18-2.04(m,2H),1.88-1.76(m,2H),1.37(s,9H).

[0228] Step 2: To a solution of tert-butyl (2-(3-fluoropyrrolidin-1-yl)ethyl)carbamate (3A) (250 mg, 1.07 mmol) in dioxane (4 mL) cooled to 0° C., 4M HCl in 1,4-dioxane (4 ml) was added. The reaction mixture was then stirred at room temperature for 3 h. After completion of the reaction, it was evaporated. The residue was dissolved in 10% MeOH in DCM. K2CO3 (740 mg, 5.36 mmol) was then added at 0° C., the mixture was stirred for 20 min, and then filtered. The filtrate was evaporated to give 2-(3-fluoropyrrolidin-1-yl)ethan-1-amine (Intermediate 5) (110 mg, 0.82 mmol, 77%). MS (ESI) m / z 133.06 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ8.35-8.26(d,J=8.0Hz,4H),5.38(s,1H),5.25(s,1H),4.12(br,2H),3.31-2.67(br,13H),2.20-1.91(br,4H).

[0229] Example 28 5-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-N-(2-(3-fluoropyrrolidin-1-yl)ethyl)pyridin-2-amine (compound 28)

[0230] [ka]

[0231] Step 1: To a stirred solution of (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(6-bromo-5-fluoropyridin-3-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (500 mg, 2.07 mmol) in toluene (5 mL), 6-bromonicotinaldehyde (1) (425 mg, 2.28 mmol) was added followed by AcOH (0.17 mL, 3.11 mmol). The reaction mixture was stirred at 80° C. for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to give semi-pure crude. The crude product thus obtained was purified by silica gel column chromatography eluting with 3-6% EtOAc in petroleum ether to give (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(6-bromopyridin-3-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (2) (320 mg, 0.98 mmol, 38% yield). MS (ESI) m / z 408.21 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ10.41(s,1H),8.41(d,J=2.0Hz,1H),7.60-7.54(m,2H),7.40(d,J=7 .6Hz,1H),7.19(d,J=8.0Hz,1H),6.98(t,J=7.6Hz,1H),6.94(d,J=8.0Hz,1H),5.75(s,1H), 4.99(s,1H),3.54-3.52(q,1H),3.01-2.96(dd,J=15.2,8.0Hz,1H),2.62-2.57(dd,J=14.8, 7.6Hz,1H),2.24(s,1H),1.76(d,J=9.6Hz,3H),1.57(d,J=9.2Hz,3H),1.10(d,J=6.8Hz,3H).

[0232] Step 2: To a stirred solution of (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(6-bromopyridin-3-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (2) (150 mg, 0.36 mmol) in 1,4-dioxane (8 mL) was added 2-(3-fluoropyrrolidin-1-yl)ethan-1-amine (intermediate 5) (53 mg, 0.40 mmol) and NaOt-Bu (70.6 mg, 0.73 mmol). The reaction mixture was degassed under argon for 30 min. Then Brettphos-3rd generation precatalyst (9.9 mg, 0.011 mmol) was added and the reaction mixture was degassed again for 30 min. It was then heated at 110° C. for 16 h. After completion of the reaction, it was cooled to room temperature and filtered through a bed of celite. The filtrate was diluted with water (20 mL) and extracted with 10% MeOH in DCM (2×20 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by RP preparative HPLC to give 5-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-N-(2-(3-fluoropyrrolidin-1-yl)ethyl)pyridin-2-amine (compound 28) (20.1 mg, 0.043 mmol, 12% yield). MS (ESI) m / z 460.54 [MH] + ; 1 H NMR(400MHz,DMSO-d6)δ10.29(s,1H),7.90(d,J=2.0Hz,1H),7.36(d,J=7.6Hz,1H),7.18(d,J=7.6Hz ,1H),7.16-7.13(dd,J=8.4,2.4Hz,1H),6.98-6.89(m,2H),6.38(d,J=8.4Hz,1H),6.34(t,J=5.6Hz,1 H),5.38 and 5.11(t,1H),4.76(s,1H),3.56-3.48(br,1H),3.38(m,2H),2.98-2.76(m,2H),2.56-2.48 (m,4H),2.36(q,1H),2.22(s,1H),1.77(d,J=8.4Hz,3H),1.61(d,J=7.6Hz,3H),1.09(d,J=6.4Hz,3H)

[0233] Example 29 5-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-N-(2-(3-(fluoromethyl)pyrrolidin-1-yl)ethyl)pyridin-2-amine (compound 29)

[0234] [ka]

[0235] Compound 29 was prepared according to a procedure similar to that described for Example 1. MS (ESI) m / z 474.43 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.38(s,1H),7.89(d,J=2.4Hz,1H),7.36(d,J=7.6Hz,1H),7.19-7.13(m,2H),6 .98-6.89(m,2H),6.38(d,J=8.4Hz,1H),6.31(d,J=5.2Hz,1H),4.36(s,1H),4.38(d,J=6.8Hz,1H),4.26 (d,J=6.4Hz,1H),3.54(t,J=7.4Hz,1H),3.37-3.32(q,2H),2.94-2.85(dd,J=12.8,2.8Hz,1H),2.64-2. 48(m,7H),2.35(t,1H),2.22(s,1H),1.78(d,J=8.8Hz,3H),1.64(d,J=8.4Hz,3H),1.08(d,J=8.8Hz,3H).

[0236] Example 30 5-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-N-(1-propylazetidin-3-yl)pyridin-2-amine (compound 30)

[0237] [ka]

[0238] To a solution of (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(6-bromopyridin-3-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (1) (80 mg, 0.195 mmol) in 1,4-dioxane (1 mL) was added 1-propylazetidin-3-amine (2) (33.5 mg, 0.29 mmol) and NaO t Bu (37.7 mg, 0.39 mmol) was added. The reaction mixture was degassed under argon for 30 min. Then, Brettphos-3 pre-3rd generation catalyst (8.9 mg, 0.009 mmol) was added and the reaction mixture was degassed again for 30 min. It was then heated to 90° C. under microwave irradiation for 1 h. After completion of the reaction, it was cooled to room temperature and filtered through a bed of celite. The filtrate was diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were collected, dried over anhydrous Na2SO4, filtered and evaporated to give the crude product, which was purified by RP preparative HPLC to give 5-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-N-(1-propylazetidin-3-yl)pyridin-2-amine (compound 30) (10.5 mg, 12%). MS(ESI) m / z 442.40 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ10.28(s,1H),7.89(d,J=1.6Hz,1H),7.36(d,J=7.6Hz,1H),7.19-7.15(m,2H),6.98-6 .89(m,2H),6.81(d,J=7.2Hz,1H),6.35(d,J=8.4Hz,1H),4.76(s,1H),4.38-4.29(q,1H),3.57-3.47(m,2H),2 .95-2.90(dd,J=4.4Hz,4.4Hz,1H),2.73-2.66(m,3H),2.56-2.42(m,3H),2.32(t,J=6.8Hz,2H),2.22(s,1H), 1.74(d,J=9.2Hz,3H),1.58(d,J=9.2Hz,3H),1.30-1.23(m,2H),1.08(d,J=6.4Hz,3H),0.82(t,J=7.6Hz,3H).

[0239] Example 31 N-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-propylazetidin-3-amine (compound 31)

[0240] [ka]

[0241] Step 1: To a stirred solution of (R)-N-(1-(1H-indol-3-yl)propan-2-yl)bicyclo[1.1.1]pentan-1-amine (0.5 g, 2.07 mmol) in toluene (10 mL), 4-bromobenzaldehyde (1) (322 mg, 2.28 mmol) was added followed by AcOH (0.18 mL, 3.1 mmol). The reaction mixture was stirred at 80° C. for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography eluting with 2% MeOH in DCM to give (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(4-bromophenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (2) (233 mg, 0.64 mmol, 31%). MS (ESI) m / z 407.3 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ10.53(s,1H),7.84(d,J=1.6Hz,1H),7.48(d,J=8.4Hz,2H) ,7.38(d,J=7.6Hz,1H),7.28(d,J=8.0Hz,2H),7.19(d,J=8.0Hz,1H),6.99-6.91(m, 2H),4.91(s,1H),3.46(q,1H),2.92-2.71(dd,J=8.8,2.8Hz,1H),2.61-2.50(m,1H ),2.22(s,1H),1.77(d,J=9.2Hz,3H),1.55(d,J=9.2Hz,3H),1.11(d,J=6.8Hz,3H).

[0242] Step 2: To a solution of (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(4-bromophenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (2) (0.47 g, 1.29 mmol) in DMA (5 mL) was added tert-butyl 3-aminoazetidine-1-carboxylate (3) (438 mg, 1.55 mmol) and NaOt-Bu (188.2 mg, 1.96 mmol). The reaction mixture was degassed under argon for 30 min. Then, Brettphos-3rd generation precatalyst (30.45 mg, 0.03 mmol) was added and the reaction mixture was degassed again for 30 min. Then, it was heated at 110 °C under microwave irradiation for 1 h. After completion of the reaction, it was cooled to room temperature and filtered through a bed of celite. The filtrate was diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product thus obtained was purified by silica gel column chromatography eluting with 10-15% EtOAc in petroleum ether to give tert-butyl 3-((4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)amino)azetidine-1-carboxylate (4) (343 mg, 0.66 mmol, 51%). MS (ESI) m / z 500.56 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ10.3(s,1H),7.92(d,J=1.6Hz,1H),7.36(d,J=7.6Hz,1H),7.23-7.19(dd,J=8.0,2 .0Hz,2H),7.18(d,J=7.6Hz,1H),6.99-6.90(m,2H),6.38(d,J=8.4Hz,1H),4.78(s,1H),4.48(m,1H),4.26 -4.06(m,2H),3.67(br,2H),3.50(br,1H),3.18(d,J=6.8Hz,1H),2.98-2.89(dd,J=8.4,2.4Hz,1H),2.58- 2.51(m,1H),2.22(s,1H),1.77(d,J=5.6Hz,3H),1.58(d,J=9.6Hz,3H),1.39(s,9H),1.22(d,J=6.8Hz,3H).

[0243] Step 3: To a solution of tert-butyl 3-((4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)amino)azetidine-1-carboxylate (4) (340 mg, 0.65 mmol) in DCM (2 mL) cooled to 0° C., TFA (2 ml) was added dropwise. The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, it was directly evaporated. It was then triturated with diethyl ether to give 260 mg (0.57 mmol, quantitative yield) of N-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)azetidin-3-amine (5). MS (ESI) m / z 399.35 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ10.96(br,1H),10.37(br,1H),7.49(br,2H),7.34(br,2H),7.18-6.98(br,4H),6.67-6.58(br,2H),5.70(br,1H),4.36(br,1H), 4.25(br,1H),3.38(q,3H),2.98-2.72(br,2H),2.55(m,2H),2.37(brs,4H), 1.77(br,2H),1.45(br,4H),1.28(br,3H),1.22-1.03(br,5H),0.84(m,1H).

[0244] Step 4: To a solution of N-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)azetidin-3-amine (5) (260 mg, 0.57 mmol) in DMF (3 mL) was added 1-iodopropane (6) (94.4 mg, 0.68 mmol), TEA (236 mg, 1.71 mmol) at room temperature. The reaction mixture was stirred at RT for 16 h. After completion of the reaction, the reaction was diluted with water (5 mL) and extracted with EtOAc (2×15 mL). The combined organic layers were collected, dried over Na2SO4, filtered and evaporated. The crude product was purified by RP preparative HPLC to give 70.4 mg (0.15 mmol, 25%) of N-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-propylazetidin-3-amine (compound 31). MS (ESI) m / z 441.08 [M+H] - , 1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),7.35(d,J=7.6Hz,1H),7.18(d,J=8.0Hz,1H),6.96(d,J=8.4Hz,2H),6.94-6 .89(m,2H),6.42(d,J=8.4,Hz,2H),5.90(d,J=6.8Hz,1H),4.76(s,1H),3.88(q,1H),3.61(m,2H),3.49-3.41(br,1 H),2.92-2.83(dd,J=6.8,2.0Hz,1H),2.68(m,2H),2.58-2.49(m,1H),2.37(d,J=8.8Hz,2H),2.28(s,1H),1.76-1 .71(d,J=9.6Hz,3H),1.58-1.53(d,J=8.8Hz,3H),1.31-1.24(m,3H),1.21(d,J=9.2Hz,3H),0.83(t,J=7.6Hz,3H).

[0245] Example 32 3-((1S,3S)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentane-1-carboxamide (compound 32) Example 33 3-((1S,3S)-1-(2,6-difluoro-4-(((R)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentane-1-carboxamide (compound 33)

[0246] [ka]

[0247] Step 1A: To a stirred solution of pyrrolidin-3-ol (1a) (20 g, 229.56 mmol) in CH3CN (200 mL) was added 1-fluoro-3-iodopropane (2a) ( Addition of K2CO3 (51.8 g, 275.48 mmol) followed by K2CO3 (95 g, 688.68 mmol). The reaction was stirred at 50 °C for 16 h. After completion, the reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted with 10% MeOH / DCM (3 x 150 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated to give 1-(3-fluoropropyl)pyrrolidin-3-ol (3a) (10 g, 29% yield). 1 H NMR(400MHz,DMSO-d6)δ4.64(s,1H),4.52(t,J=8Hz,1H),4.40(t,J=6.0Hz,1H),4.16-4.15(m,1H),2.65(m,1H),2.51(t,J=7 .6Hz,1H),2.45-2.36(m,3H),2.28-2.25(dd,J1=7.2Hz,J2=3.36Hz,1H),1.98-1.93(m,1H),1.82-1.72(m,2H),1.51(bs,1H).

[0248] Step 2A: To a stirred solution of 1-(3-fluoropropyl)pyrrolidin-3-ol (3a) (10 g, 67.94 mmol) in THF (100 mL) was added imidazole (6.94 g, 101.94 mmol) and TPP (19.60 g, 74.73 mmol), followed by iodine (18.97 g, 74.73 mmol). The reaction was stirred at room temperature for 16 h. After completion, the reaction mixture was quenched with saturated sodium thiosulfate (20 mL) and extracted with EtOAc (3×70 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated to give a crude residue. The crude was further purified by silica gel column chromatography (eluted with 10-20% EtOAc in petroleum ether) to give 1-(3-fluoropropyl)-3-iodopyrrolidine (4a) (5 g, 28% yield). MS(ESI)m / z258.09[M+1] + ; 1H NMR(400MHz,CDCl3)δ4.56(t,J=6Hz,1H),4.59(t,J=6Hz,1H),4.29-4.25(m,1H),3.18(q,1H) ),2.93(m,1H),2.70-2.60(m,4H),2.53-2.48(m,1H),2.30-2.26(m,1H),1.93-1.83(m,2H).

[0249] Step 3A: To a stirred solution of 1-(3-fluoropropyl)-3-iodopyrrolidine (4a) (975 mg, 3.797 mmol) in DMF (10 mL) was added 2,6-difluoro-4-hydroxybenzaldehyde (5a) (0.719 g, 4.55 mmol) followed by Cs2CO3 (2.47 g, 7.58 mmol). The reaction was stirred at 100 °C for 3 h. After completion, the reaction mixture was cooled to room temperature, diluted with water (15 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated to give a crude residue. The crude was further purified by silica gel column chromatography eluting with 30-40% EtOAc in petroleum ether to give 2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)benzaldehyde (6) (400 mg, 37%). MS (ESI) m / z 288.13 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ10.1(s,1H),6.83(d,J=11.2Hz,2H),5.017-5.010(m,1H),4.53(t,J=5.6Hz,1H),4.42(t,J= 6Hz,1H),3.38(s,1H),3.38(s,1H),2.83-2.64(m,3H),2.47(d,J=1.6Hz,1H),2.37-2.32(m,2H),1.86-1.73(m,3H).

[0250] Step 1: To a stirred solution of 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (10 g, 58.77 mmol) in t-BuOH (100 mL) was added Et3N (16.5 mL, 117.53 mmol) followed by diphenylphosphoryl azide (DPPA) (15.16 mL, 70.52 mmol). The reaction was stirred at room temperature for 2 h and then at 90 °C for 16 h. After completion, the reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated to give semi-pure crude. The crude product thus obtained was purified by silica gel column chromatography eluting with 10-20% EtOAc in petroleum ether to give methyl 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylate (1) (9.5 g, 60% yield). 1 H NMR (400MHz, DMSO-d6) δ7.62 (s, 1H), 3.59 (s, 3H), 2.12 (s, 6H), 1.37 (s, 9H).

[0251] Step 2: To a solution of methyl 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylate (1) (9.5 g, 39.37 mmol) in DCM (95 mL) at 0 °C, TFA (38 mL, 4 vol) was added at 0 °C. The reaction was stirred at room temperature for 2 h. After completion of the reaction, it was directly evaporated. The residue was triturated with diethyl ether to give 11 g (46.18 mmol, quantitative yield) of methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate·TFA (2). MS (ESI) m / z 240.26 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ8.67(s,2H), 3.63(s,3H), 2.24(s,6H).

[0252] Step 3: To a stirred solution of 1-(1H-indol-3-yl)propan-2-one (3) (10.8 g, 62.34 mmol) in MeOH (60 mL) was added methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate·TFA (2) (11 g, 46.18 mmol) followed by AcOH (11 mL, 1 vol). The reaction was stirred at room temperature for 3 h. NaCNBH3 (5.8 g, 92.36 mmol) was then added and the reaction mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was neutralized by a saturated solution of NaHCO3 and extracted with EtOAc (3×50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to give a crude residue. The crude material was further purified by silica gel column chromatography eluting with 10-15% MeOH in DCM to give methyl 3-((1-(1H-indol-3-yl)propan-2-yl)amino)bicyclo[1.1.1]pentane-1-carboxylate (4) (2.5 g, 18% yield). MS (ESI) m / z 299.226 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ10.88(s,1H),7.48(d,J=8Hz,1H),7.32(d,J=8.0Hz,1H),7.1 2(s,J=0.8Hz,1H),7.04(t,J=7.2Hz,1H),6.97(t,J=7.2Hz,1H),4.38(t,J=5.6Hz,1H ),3.58(s,3H),3.165(d,J=5.2Hz,1H),2.94-2.99(m,1H),2.83-2.78(dd,J=14.0,5. 2Hz, 1H), 2.52-2.55 (m, 1H), 2.29 (s, 1H), 1.955-2.00 (m, 6H), 0.94 (d, J = 6.4Hz, 3H).

[0253] Step 4: Methyl 3-((1-(1H-indol-3-yl)propan-2-yl)amino)bicyclo[1.1.1]pentane-1-carboxylate (4, racemic) (2.5 g) was purified by chiral SFC to give methyl (S)-3-((1-(1H-indol-3-yl)propan-2-yl)amino)bicyclo[1.1.1]pentane-1-carboxylate 5 (peak-1) (1 g, 40% yield) and methyl (R)-3-((1-(1H-indol-3-yl)propan-2-yl)amino)bicyclo[1.1.1]pentane-1-carboxylate 5 (peak-2) (1.1 g, 44% yield). 5 (peak-1) MS (ESI) m / z 299.32 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ10.79(s,1H),7.48(d,J=8Hz,1H),7.32(d,J=8.0Hz, 1H),7.12(d,J=2.0Hz,1H),7.04(t,J=7.2Hz,1H),6.967(t,J=7.2Hz,1H),3. 58(s,3H),3.17(d,J=5.2Hz,1H),2.96-2.97(brm,1H),2.78-2.83(dd,J=14H z,5.2Hz,1H),2.50-2.55(m,1H),1.95-2.00(m,6H),0.937(d,J=6.4Hz,3H). 5 (Peak-2): MS (ESI) m / z 299.32 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ10.79(s,1H),7.48(d,J=8Hz,1H),7.32(d,J=8.0Hz, 1H),7.12(d,J=2.0Hz,1H),7.04(t,J=7.2Hz,1H),6.967(t,J=7.2Hz,1H),3. 58(s,3H),3.17(d,J=5.2Hz,1H),2.96-2.97(brm,1H),2.78-2.83(dd,J=14H z,5.2Hz,1H),2.50-2.55(m,1H),1.95-2.00(m,6H),0.937(d,J=6.4Hz,3H). Absolute stereochemistry was arbitrarily assigned to intermediate 5 (peak-1) and intermediate 5 (peak-2).

[0254] Step 5: To a stirred solution of methyl (S)-3-((1-(1H-indol-3-yl)propan-2-yl)amino)bicyclo[1.1.1]pentane-1-carboxylate (5peak-1) (1 g, 3.35 mmol) in EtOH (10 mL), 2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)benzaldehyde (6) (1.06 g, 3.69 mmol) was added followed by tartaric acid (0.754 mg, 5.03 mmol). The reaction was stirred at 80 °C for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was neutralized by a saturated solution of NaHCO3 and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to give a crude residue. The crude was purified by silica gel column chromatography eluting with 30-40% EtOAc in petroleum ether to give methyl 3-((1S,3S)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentane-1-carboxylate (7) (690 mg, 36.27% yield). MS (ESI) m / z 569.45[M+1] + .

[0255] Step 6: To a stirred solution of methyl 3-((1S,3S)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentane-1-carboxylate (7) (690 mg, 1.21 mmol) in MeOH (10 mL) was added NH3 (7M in MeOH, 14 mL, 20 volumes). The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude was further purified by silica gel column chromatography eluting with 0-10% MeOH in DCM to give 3-((1S,3S)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentane-1-carboxamide (8) (670 mg, quantitative yield). MS(ESI) m / z 554.221[M+H] + ;

[0256] Step 7: 3-((1S,3S)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentane-1-carboxamide (8) (0.2 g, 0.361 mmol) was purified by chiral SFC to give 3-((1S,3S)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-1,3,4 ,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentane-1-carboxamide (compound 32) (55 mg, yield 27.5%) 3-((1S,3S)-1-(2,6-difluoro-4-(((R)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentane-1-carboxamide (compound 33) (55 mg, 0.099 mmol, yield 27.5%) was obtained. Compound 32: MS (ESI) m / z 551.36 [MH] - ; 1 H NMR(400MHz,DMSO-d6)δ10.47(s,1H),7.37(d,J=8Hz,1H),7.14-7.19(m,2 H),6.90-7.00(m,2H),6.84(s,1H),6.65(d,J=11.2Hz,1H),5.21(s,1H),4 .98(s,1H),4.42(t,J=6Hz,1H),4.54(t,J=6Hz,1H),3.57(brs,1H),2.62- 2.93(m,2H),2.29-2.57(m,8H),1.70-1.91(m,8H),1.08(d,J=6.4Hz,3H). Compound 33:MS(ESI)m / z 551.40[MH] - ; 1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),7.37(d,J=8Hz,1H),7.14-7.19(m,2 H),6.90-7.00(m,2H),6.84(s,1H),6.65(d,J=11.2Hz,1H),5.21(s,1H),4 .98(s,1H),4.42(t,J=6Hz,1H),4.54(t,J=6Hz,1H),3.57(brs,1H),2.62- 2.93(m,2H),2.29-2.57(m,8H),1.70-1.91(m,8H),1.07(d,J=6.4Hz,3H). Absolute stereochemistry was arbitrarily assigned to compound 32 and compound 33.

[0257] Example 34 3-((1R,3R)-1-(2,6-difluoro-4-(((R)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentane-1-carboxamide (compound 34) Example 35 3-((1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentane-1-carboxamide (compound 35)

[0258] [ka]

[0259] Step 1: To a stirred solution of methyl (R)-3-((1-(1H-indol-3-yl)propan-2-yl)amino)bicyclo[1.1.1]pentane-1-carboxylate (Int-5, peak-2 from Examples 32 and 33) (1.1 g, 3.68 mmol) in EtOH (11 mL), 2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)benzaldehyde (1) (1.16 g, 4.06 mmol) was added followed by tartaric acid (0.83 mg, 5.52 mmol). The reaction was stirred at 80° C. for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated to give the crude product. The crude was purified by silica gel column chromatography eluting with 60-70% EtOAc in petroleum ether to give methyl 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentane-1-carboxylate (2) (750 mg, 36% yield). MS (ESI) m / z 568.94 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.49(s,1H),7.37(d,J=8Hz,1H),7.18(d,J=8.0Hz,1H),6.91-7.00(m,2H),6.63(d,J=11.2Hz,2H),5.22(s,1H),4.88-4.8 97(brs,1H),4.52-4.9(m,1H),4.4-4.3(m,1H),3.55-3.59(m,4H),2.27- 2.94(m,8H),1.98-2.04(m,4H),1.74-1.85(m,6H),1.06(d,J=6.4Hz,3H).

[0260] Step 2: To a stirred solution of methyl 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentane-1-carboxylate (2) (750 mg, 1.32 mmol) in MeOH (7.5 mL) was added NH3 (7M in MeOH, 15 mL, 20 vol). The reaction was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude material was further purified by silica gel column chromatography eluting with 0-10% MeOH in DCM to give 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentane-1-carboxamide (3) (770 mg, quantitative yield). MS (ESI) m / z 554.11 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.47(s,1H),7.37(d,J=8Hz,1H),7.15-7.19(m,2H),6 .90-7.00(m,2H),6.84(s,1H),6.61(d,J=11.2Hz,2H),5.21(s,1H),4.98(brs, 1H),4.52-4.55(m,1H),4.4-4.43(m,1H),4.07-4.11(m,5H),3.57(brs,1H),3. 16-3.17(m,14H),2.37-2.93(m,7H),1.70-1.91(m,9H),1.07(d,J=6.4Hz,3H).

[0261] Step 3: 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentane-1-carboxamide (3) (0.2 g, 0.361 mmol) was purified by chiral SFC to give 3-((1R,3R)-1-(2,6-difluoro-4-(((R)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-1 ,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentane-1-carboxamide (compound 34) (55 mg, yield 27.5%) and 3-((1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentane-1-carboxamide (compound 35) (55 mg, yield 27.5%) were obtained. Compound 34: MS (ESI) m / z 551.40 [MH] - ; 1 H NMR(400MHz,DMSO-d6)δ10.47(s,1H),7.37(d,J=8Hz,1H),7.15-7.19(m,2H),6.90-7.00(m,2H),6.83(s,1H),6.61(d,J=11.2Hz,2H),5.21(s,1 H),4.98(brs,1H),4.47(dt,J=47.2Hz,6Hz,2H),3.57(brs,1H),2.51-2.93(m,6H),2.28-2.48(m,4H),1.70-1.91(m,8H),1.07(d,J=6.4Hz,3H). Compound 35:MS(ESI)m / z 551.40[MH] - ; 1H NMR(400MHz,DMSO-d6)δ10.47(s,1H),7.37(d,J=8Hz,1H),7.15-7.19(m,2H),6.90-7.00(m,2H),6.83(s,1H),6.61(d,J=11.2Hz,2H),5.21(s,1 H),4.98(brs,1H),4.47(dt,J=47.2Hz,6Hz,2H),3.57(brs,1H),2.51-2.93(m,6H),2.28-2.48(m,4H),1.70-1.91(m,8H),1.07(d,J=6.4Hz,3H). Absolute stereochemistry was arbitrarily assigned to compound 34 and compound 35.

[0262] Example 36 3-((1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentane-1-carbonitrile (compound 36) Example 37 3-((1R,3R)-1-(2,6-difluoro-4-(((R)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentane-1-carbonitrile (compound 37)

[0263] [ka]

[0264] Step 1: To a stirred solution of 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentane-1-carboxamide (Example 34, Intermediate 3) (370 mg, 0.67 mmol) in dioxane (37 mL), pyridine (0.12 mL, 1.473 mmol) was added followed by TFAA (0.1 mL, 0.737 mmol). The resulting mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with 10% MeOH / DCM (2×50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to give the crude product which was purified by reverse phase (RP) preparative HPLC to give 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentane-1-carbonitrile (120 mg, yield: 33%).

[0265] Step 2: 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentane-1-carbonitrile (racemic) (120 mg, 0.22 mmol) was purified by chiral SFC to give 3-((1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-1,3,4,9-tetrahydro 3-((1R,3R)-1-(2,6-difluoro-4-(((R)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentane-1-carbonitrile (compound 36) (44.6 mg, 0.082 mmol, 36.67% yield) and 3-((1R,3R)-1-(2,6-difluoro-4-(((R)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentane-1-carbonitrile (compound 37) (49.1 g, 0.091 mmol, 41% yield) were obtained. The stereochemistry of compound 36A (peak-1) and compound 36B (peak-2) was tentatively assigned. Compound 36:MS(ESI)m / z 533.33[MH] - ; 1H NMR(400MHz,DMSO-d6)δ10.51(s,1H),7.37(d,J=7.6Hz,1H),7.18(d,J=8.0Hz,1H),6.90(t,J =6.8Hz,1H),6.93(t,J=7.2Hz,1H),6.62(d,J=10.8Hz,1H),5.22(s,1H),4.89(s,1H),4.54(t, J=6Hz,1H),4.42(t,J=6Hz,1H),3.53(brs,1H),2.91-2.85(m,1H),2.83-2.81(m,1H),2.71-2. 49(m,3H),2.50-2.06(m,7H),2.07(d,J=9.2Hz,3H),1.86-1.74(m,3H),1.07(d,J=6.4Hz,3H). HPLC: 98.05%, LCMS: 99.86% and chiral SFC: 99.90%. Compound 37:MS(ESI)m / z 533.33[MH] - ; 1 H NMR(400MHz,DMSO-d6)δ10.51(s,1H),7.37(d,J=7.6Hz,1H),7.18(d,J=8.0Hz,1H),6.90(t,J =6.8Hz,1H),6.93(t,J=7.2Hz,1H),6.62(d,J=10.8Hz,1H),5.22(s,1H),4.89(s,1H),4.54(t, J=6Hz,1H), 4.41(t,J=6Hz,1H), 3.53(brs,1H), 2.91-2.85(m,1H), 2.83-2.81(m,1H), 2.71-2.49(m,3H), 2.50-2.06(m,7H), 2.07(d,J=9.2Hz,3H), 1.86-1.74(m,3H), 1.07(d,J=6.4Hz,3H). HPLC: 96.80%, LCMS: 99.05% and chiral SFC: 97.33%. Absolute stereochemistry was arbitrarily assigned to compound 36 and compound 37.

[0266] Example 38 (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (compound 38)

[0267] [ka]

[0268] Step 1: To a solution of 4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenol (prepared according to a procedure similar to that described for Int-4 from Example 24) (500 mg, 1.45 mmol) in DMF (5 mL), Cs2CO3 (942 mg, 2.9 mmol) and tert-butyl 3-iodoazetidine-1-carboxylate (1) (492 mg, 1.74 mmol) were added. The resulting mixture was stirred at 100 °C for 3 h. After completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography eluting with 30% EtOAc in n-pentane to give tert-butyl 3-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenoxy)azetidine-1-carboxylate (2) (406 mg, 0.81 mmol, 56%). MS (ESI) m / z 500.4 [M+H] + ; 1 H NMR(400MHz,CDCl3)δ7.50-7.48(dd,J=7.6,4Hz,1H),7.27-7.19(m,1H),7.11-7.05 (m,3H),6.65(d,J=8.8Hz,2H),4.85(m,2H),4.30-4.25(q,2H),3.97-3.95(q,2H),3 .65(m,1H),3.59(m,1H),3.09-3.08(dd,J=9.3,2.4Hz,1H),2.5d(d,1H),2.21(s,1H) ),1.76(d,J=9.6Hz,3H),1.58(d,J=9.6Hz,3H),1.55(s,9H),1.15(d,J=6.4Hz,3H).

[0269] Step 2: To a solution of tert-butyl 3-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenoxy)azetidine-1-carboxylate (2) (400 mg, 0.8 mmol) in 1,4-dioxane (2 mL) cooled at 0° C., 4M HCl in 1,4-dioxane (2 ml) was added. The reaction mixture was then stirred at room temperature for 16 hours. After completion of the reaction, it was directly evaporated. The crude product was triturated with diethyl ether to give 349 mg (0.8 mmol, quantitative yield) of (1R,3R)-1-(4-(azetidin-3-yloxy)phenyl)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (3). MS (ESI) m / z 400.43 [M+H] + .

[0270] Step 3: To a solution of (1R,3R)-1-(4-(azetidin-3-yloxy)phenyl)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (3) (270 mg, 0.62 mmol) in DMF (3 mL) was added 1-fluoro-3-iodopropane (4) (140 mg, 0.74 mmol) and K2CO3 (257 mg, 1.86 mmol) at room temperature. The reaction mixture was stirred at RT for 16 h. After completion of the reaction, the reaction mixture was diluted with water (5 mL) and extracted with EtOAc (2 x 15 mL). The combined organic layers were collected, dried over Na2SO4, filtered and evaporated. The crude product was purified by RP preparative HPLC to give 74.4 mg (0.16 mmol, 27%) of (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (compound 38). MS (ESI) m / z 458.33 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ10.4(s,1H),7.37(d,J=7.6Hz,1H),7.20-7.17(m,3H), 7.00-6.90(m,2H),6.74(d,J=8.8Hz,1H),2.74(s,1H),4.73(q,1H),4.48(t,J=6 .0Hz,1H),4.38(t,J=6.0Hz,1H),3.72-3.69(m,2H),3.44(q,1H),2.93-2.89(m ,3H),2.58-2.49(m,3H),2.20(s,1H),1.74-1.58(m,8H),1.10(d,J=6.8Hz,3H).

[0271] Example 39 (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-1-(4-((1-propylazetidin-3-yl)oxy)phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (compound 39)

[0272] [ka]

[0273] Step 1: To a stirred solution of 4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenol (Example 24, Intermediate-4) (1 g, 2.89 mmol) in DMF (5 mL) and DMSO (0.5 mL), K2CO3 (799 mg, 5.79 mmol) was added followed by tert-butyl 3-iodoazetidine-1-carboxylate (1) (899 mg, 3.17 mmol). The reaction mixture was stirred at 80 °C for 3 h. After completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to give semi-pure crude. The crude product thus obtained was purified by silica gel column chromatography eluting with 20-25% EtOAc in petroleum ether to give tert-butyl 3-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)azetidine-1-carboxylate (2) (460 mg, 0.92 mmol, 32% yield). MS (ESI) m / z 500.82 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ7.50-7.48(m,1H),7.27-7.22(m,2H),7.17-7.17(m,1H),7.09-7. 06(m,2H),6.65(d,J=8.8Hz,2H),4.86-4.83(m,2H),4.30-4.18(m,2H),4.06-3.95(m,2H ),3.66(br,1H),3.16-3.12(dd,J=8.4,2.2Hz,1H),2.67-2.56(d,J=8.8,Hz,1H),2.21( s,1H),1.78(d,J=8.8Hz,3H),1.58(d,J=9.2Hz,6H),1.48(s,9H),1.18(d,J=6.8Hz,3H).

[0274] Step 2: To a stirred solution of tert-butyl 3-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)azetidine-1-carboxylate (2) (400 mg, 1.12 mmol) in 1,4-dioxane (2 mL) was added 4M HCl in 1,4-dioxane (2 mL) dropwise at 0° C. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, it was evaporated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography eluting with 20-25% EtOAc in petroleum ether to give (1R,3R)-1-(4-(azetidin-3-yloxy)phenyl)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (3) (348 mg, 0.69 mmol, quantitative yield). MS (ESI) m / z 400.36 [MH] + ; 1 H NMR (400MHz, DMSO-d6) δ11.77-11.66(br,1H),11.04-10.85(br,1H). 10.34-10.31(br,1H). 9.64-9.43(br,3H),7.75-6.95(br,14H),5.58(br,2H),5.25(br,2H),4.60(b r,3H),3.96(br,6H),2.70(br,2H),2.28(br,6H),1.64(br,3H),1.44(br,6H).

[0275] Step 3: To a stirred solution of (1R,3R)-1-(4-(azetidin-3-yloxy)phenyl)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole hydrochloride (3) (200 mg, 0.46 mmol) in DMF (1 mL) was added K2CO3 (187 mg, 1.38 mmol) and 1-iodopropane (4) (117 mg, 0.69 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, it was diluted with water (50 mL) and extracted with 10% MeOH in DCM (3 x 50 mL). The organic layer was collected, dried over Na2SO4, filtered and evaporated. The crude product was purified by RP preparative HPLC to give 25.2 mg (0.06 mmol, 12%) of (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-1-(4-((1-propylazetidin-3-yl)oxy)phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (compound 39). MS (ESI) m / z 442.41 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ10.28(s,1H),7.37(d,J=7.2Hz,1H),7.20-7.17(m,3H),6.11-6.90(m,2H),6.74(d,J=8.4Hz,2H),4.88(s,1H),4.71 (t,J=6.0Hz,1H),3.69-3.67(q,2H),3.48(q,1H),2.88-2.82(m,3H),2.56-2.50(m,1H),2.38(q,J=5.6Hz,2H),2.22( s,1H),1.73(d,J=8.0Hz,3H),1.56(d,J=9.2Hz,3H),1.31-1.41(m,2H),1.10(d,J=6.8Hz,3H),0.84(d,J=7.2Hz,3H).

[0276] Example 40 N-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidin-3-amine (compound 40)

[0277] [ka]

[0278] To a solution of (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(4-bromophenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (400 mg, 0.98 mmol) (intermediate 2 from Example 31) in 1,4-dioxane (10 mL), 1-(3-fluoropropyl)azetidin-3-amine (3) (194 mg, 1.47 mmol), NaOt-Bu (188.2 mg, 1.96 mmol) were added. The reaction mixture was degassed under argon for 30 min. Then, Brettphos-3 generation precatalyst (44.39 mg, 0.05 mmol) was added and the reaction mixture was degassed again for 30 min. Then, it was heated to 110° C. for 16 h. After completion of the reaction, it was cooled to room temperature and filtered through a bed of celite. The filtrate was diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were collected, dried over Na2SO4, filtered and evaporated. The crude product was purified by RP preparative HPLC to give 128.1 mg (0.27 mmol, 29%) of N-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidin-3-amine (compound 40). MS (ESI) m / z 457.38[M+1] + . 1H NMR(400MHz,DMSO-d6)δ10.28(s,1H),7.35(d,J=7.2Hz,1H),7.18(d,J=8.0Hz,1H),6.98-6.89 (m,4H),6.42(d,J=8.4Hz,2H),5.93(d,J=6.8Hz,1H),4.52(s,1H),4.49(t,J=6.0Hz,1H),4.37( t,J=6.0Hz,1H),3.91-3.89(m,1H),3.62(q,2H),3.45-4.43(q,1H),2.86-2.70(dd,J=8.4,2.4 Hz,1H),2.74(q,2H),2.58-2.40(m,3H),2.19(s,1H),1.75-1.57(m,8H),1.08(d,J=6.4Hz,3H).

[0279] Example 41 5-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3-fluoro-N-(1-(3-fluoropropyl)azetidin-3-yl)pyridin-2-amine (compound 41)

[0280] [ka]

[0281] Step 1: To a stirred solution of (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(6-bromo-5-fluoropyridin-3-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (1 g, 2.08 mmol) in toluene (10 mL), 6-bromo-5-fluoronicotinaldehyde (1) (465 mg, 2.28 mmol) was added followed by AcOH (0.18 mL, 3.12 mmol). The reaction was stirred at 80° C. for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to give semi-pure product. The crude product thus obtained was purified by silica gel column chromatography eluting with 10-12% EtOAc in petroleum ether to give (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(6-bromo-5-fluoropyridin-3-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (2) (450 mg, 1.06 mmol, 51% yield). MS (ESI) m / z 426.17 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.33(s,1H),7.74-7.71(dd,J=8.8,1.6Hz,1H),7 .40(d,J=7.6Hz,1H),7.19(d,J=7.6Hz,1H),7.01(t,J=7.2Hz,1H),6.94(d,J=7.6Hz,1H ),5.06(s,1H),3.58-3.57(q,1H),3.05-2.96(dd,J=14.8,4.8Hz,1H),2.62(d,J=2.4Hz ,1H),2.25(s,1H),1.78(d,J=9.6Hz,3H),1.58(d,J=9.2Hz,3H),1.09(d,J=6.8Hz,3H).

[0282] Step 2: To a stirred solution of (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(6-bromo-5-fluoropyridin-3-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (2) (360 mg, 0.84 mmol) in 1,4-dioxane (10 mL) was added 1-(3-fluoropropyl)azetidin-3-amine (3) (223 mg, 1.69 mmol) and NaOt-Bu (162.2 mg, 1.69 mmol). The reaction mixture was degassed under argon for 30 min. Then, Brettphos-3rd generation precatalyst (38 mg, 0.04 mmol) was added and the reaction mixture was degassed again for 30 min. It was then heated at 110° C. for 16 h. After completion of the reaction, it was cooled to room temperature and filtered through a bed of celite. The filtrate was diluted with water (50 mL) and extracted with 10% MeOH in DCM (2×50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by RP preparative HPLC to give 5-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3-fluoro-N-(1-(3-fluoropropyl)azetidin-3-yl)pyridin-2-amine (compound 41) (73.9 mg, 0.15 mmol, 18% yield). MS (ESI) m / z 476.38 [MH] - ; 1 H NMR(400MHz,DMSO-d6)δ10.39(s,1H),7.83(s,1H),7.37(d,J=7.6Hz,1H),7.17(d,J=7 .6Hz,1H),7.19-6.90(m,4H),4.53(s,1H),4.51-4.47(q,2H),4.39(t,J=6.0Hz,1H),3 .59(t,J=7.4Hz,1H),3.57-3.51(q,2H),2.94-2.85(m,3H),2.58-2.47(m,3H),2.25(s ,1H),1.78(d,J=8.8Hz,3H),1.68(m,2H),1.54(d,J=8.8Hz,3H),1.08(d,J=8.8Hz,3H).

[0283] Example 42 (S)-N-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine (compound 42)

[0284] [ka]

[0285] Step 1: To a stirred solution of (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(6-bromo-5-fluoropyridin-3-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (1 g, 4.16 mmol) in toluene (10 mL) was added 4-bromobenzaldehyde (1) (840 mg, 4.58 mmol) followed by AcOH (0.36 mL, 6.24 mmol). The reaction mixture was stirred at 80° C. for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to give semi-pure crude. The crude product thus obtained was purified by silica gel column chromatography eluting with 12-15% EtOAc in petroleum ether to give (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(4-bromophenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (2) (709 mg, 1.74 mmol, 42% yield). MS (ESI) m / z 407.33 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),7.84(d,J=2.0Hz,1H),7.48(d,J=8.4Hz,2H),7 .38(d,J=7.6Hz,1H),7.28(d,J=8.0Hz,2H),6.99(t,J=7.2Hz,1H),6.93(t,J=7.6Hz, 1H),4.91(s,1H),3.46(q,1H),2.92-2.91(dd,J=8.8,1.6Hz,1H),2.55(d,J=2.4Hz,1 H),2.22(s,1H),1.76(d,J=9.6Hz,3H),1.58(d,J=9.2Hz,3H),1.10(d,J=6.8Hz,3H).

[0286] Step 2: To a stirred solution of (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(4-bromophenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (2) (150 mg, 0.37 mmol) in 1,4-dioxane (5 mL) was added (S)-1-(3-fluoropropyl)pyrrolidin-3-amine (3) (108 mg, 0.74 mmol) and NaOt-Bu (71 mg, 0.74 mmol). The reaction mixture was degassed under argon for 30 min. Then, Brettphos-3rd generation precatalyst (16.76 mg, 0.02 mmol) was added and the reaction mixture was degassed again for 15 min. Then, it was heated at 110 °C for 16 h. After completion of the reaction, it was cooled to room temperature and filtered through a bed of celite. The filtrate was diluted with water (50 mL) and extracted with 10% MeOH in DCM (2 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by RP preparative HPLC to give (SN-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine (compound 42) (19.5 mg, 0.04 mmol, 11% yield). MS (ESI) m / z 473.57 [MH] + ; 1H NMR(400MHz,DMSO-d6)δ10.23(s,1H),7.50(d,J=7.6Hz,1H),7.19(d,J=8.0Hz,1H),6.97-6.89(m,4H),6 .46(d,J=8.0Hz,2H),5.59(d,J=6.8Hz,1H),4.78(s,1H),4.53(t,J=6.0Hz,1H),4.43(t,J=7.4Hz,1H),3. 84(q,1H),3.49(q,1H),2.94-2.91(dd,J=6.8,1.6Hz,1H),2.78(t,J=4.4Hz,1H),2.58-2.42(m,5H),2.38 (br,1H),2.19(s,1H),2.19(br,1H),1.78(d,J=8.4Hz,3H),1.56(d,J=7.6Hz,3H),1.09(d,J=6.8Hz,3H).

[0287] Example 43 (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-1-(6-((1-propylazetidin-3-yl)oxy)pyridin-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (compound 43)

[0288] [ka]

[0289] Step 1: To a solution of 5-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-2-ol (Example 27-Int-2) (0.47 g, 1.29 mmol) in DMF (5 mL), CS2CO3 (631 mg, 1.94 mmol) and tert-butyl 3-iodoazetidine-1-carboxylate (2) (438 mg, 1.55 mmol) were added. The reaction mixture was stirred at 100° C. for 3 h. After completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography eluting with 50% EtOAc in petroleum ether to give tert-butyl 3-((5-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-2-yl)oxy)azetidine-1-carboxylate (3) (343 mg, 0.66 mmol, 51%). MS (ESI) m / z 501.6 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.37(s,1H),8.10(d,J=2.0Hz,1H),7.57-7.54(dd,J=8.4,2.0Hz,1H),7.38(d,J=7 .6Hz,1H),7.19(d,J=8.0Hz,1H),6.99-6.91(m,2H),6.79(d,J=8.4Hz,1H),5.28(br,1H),4.93(s,1H),4.62 -4.58(br,2H),4.26(br,2H),4.08(br,1H),3.77(br,2H),3.52(br,1H),2.97(dd,J=8.4,2.4Hz,1H),2.61- 2.51(m,1H),2.24(s,1H),1.77(d,J=5.6Hz,3H),1.55(d,J=9.6Hz,3H),1.39(s,9H),1.22(d,J=6.8Hz,3H).

[0290] Step 2: To a solution of tert-butyl 3-((5-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-2-yl)oxy)azetidine-1-carboxylate (3) (340 mg, 0.65 mmol) in DCM (2 mL) cooled to 0° C., TFA (2 ml) was added dropwise. The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, it was directly evaporated. The crude product was triturated with diethyl ether to give 260 mg (0.57 mmol, quantitative yield) of (1R,3R)-1-(6-(azetidin-3-yloxy)pyridin-3-yl)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (4). MS (ESI) m / z 401.3 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.47(s,1H),8.07(d,J=2.0Hz,1H),7.53-7.51(dd,J=8.4,2.4Hz,1H),7.38(d,J=7. 6Hz,1H),7.18(d,J=8.0Hz,1H),6.99-6.91(m,2H),6.73(d,J=8.4Hz,1H),5.33-5.30(t,J=7.2Hz,1H),4.91( s,1H),4.22-4.18(br,4H),4.77(br,2H),3.59-3.48(br,8H),3.18(s,10H),2.98(dd,J=8.4,2.4Hz,1H),2.6 2-2.50(m,1H),2.24(s,1H),1.74(d,J=5.6Hz,3H),1.55(d,J=9.6Hz,3H),1.38(s,2H),1.22(d,J=6.8Hz,3H).

[0291] Step 3: To a solution of (1R,3R)-1-(6-(azetidin-3-yloxy)pyridin-3-yl)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (4) (260 mg, 0.57 mmol) in DMF (3 mL), 1-iodopropane (5) (94.4 mg, 0.68 mmol), TEA (236 mg, 1.71 mmol) were added at room temperature. The reaction mixture was stirred at RT for 16 h. After completion of the reaction, the reaction mixture was diluted with water (5 mL) and extracted with EtOAc (2×15 mL). The combined organic layers were collected, dried over Na2SO4, filtered and evaporated. The crude product was purified by RP preparative HPLC to give 70.4 mg (0.15 mmol, 25%) of (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-1-(6-((1-propylazetidin-3-yl)oxy)pyridin-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (compound 43). MS (ESI) m / z 441.38 [M+H] - , 1 H NMR(400MHz,DMSO-d6)δ10.4(s,1H),8.08(d,J=2Hz,1H),7.53-7.50(dd,J=8.4,2.4Hz,1H),7.38(d,J=7.6Hz,1 H),7.18(d,J=8.0Hz,1H),7.00-6.91(m,2H),6.72(d,J=8.8,Hz,1H),5.09(t,J=7.2Hz,1H),4.91(s,1H),3.66( q,2H),3.51(m,1H),3.02-2.88(br,3H),2.66-2.52(m,1H),2.36(q,J=6.8,2.4Hz,2H),2.23(s,1H),1.78-1.70 (d,J=9.6Hz,3H),1.59-1.55(d,J=8.8Hz,3H),1.35-1.24(m,3H),1.22(d,J=9.2Hz,3H),0.83(t,J=7.6Hz,3H).

[0292] Example 44 5-((1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-N-((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)pyrazin-2-amine (compound 44)

[0293] [ka]

[0294] Step 1A: To a solution of 5-bromopyrazine-2-carbonitrile (A) (1.02 g, 5.54 mmol) in toluene (10 mL) cooled to -78 °C, DIBAL-H (1 M in DCM) (8.3 ml, 8.32 mmol) was added. It was then stirred at room temperature for 26 h. After completion of the reaction, the reaction was diluted with MeOH (4 mL) and stirred at room temperature for 30 min, followed by addition of 10% H2SO4 (55 mL). The resulting solution was stirred for 1.75 h and extracted with EtOAc (100 mL, 50 mL). After removing the solvent under reduced pressure, the crude product was purified by silica gel column chromatography to give 660 mg (1.07 mmol, 64%) of 5-bromopyrazine-2-carbaldehyde (Intermediate 6). 1 H NMR (400MHz, CDCl3) δ10.14 (s, 1H), 8.92 (d, J = 1.2Hz, 1H), 8.85 (d, J = 1.2Hz, 1H).

[0295] Step 1: To a stirred solution of (R)-N-(1-(1H-indol-3-yl)propan-2-yl)bicyclo[1.1.1]pentan-1-amine (400 mg, 1.66 mmol) in toluene (10 mL), 5-bromopyrazine-2-carbaldehyde (1) (339.2 mg, 1.83 mmol) was added followed by AcOH (0.16 mL, 2.49 mmol). The reaction was stirred at 90° C. for 16 h. After completion of the reaction, it was cooled to room temperature. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were collected, dried over Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography to give 440 mg (1.07 mmol, 51%) of (1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(5-bromopyrazin-2-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (2). MS(ESI) m / z 409.2[M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ10.4(s,1H),8.83(d,J=1.6Hz,1H),8.42(d,J=2.4Hz,1H),7.41(d ,J=7.6Hz,1H),7.19(d,J=8.0Hz,1H),7.06-6.92(m,2H),5.09(s,1H),4.08(t,J=5.2Hz,1 H),3.69-3.66(m,1H),3.19-3.17(d,2H),2.98-2.94(dd,J=8.4,2.4Hz,1H),2.88-2.59(d d,J=9.2,2.4Hz,1H),1.78(d,J=7.2Hz,3H),1.57(d,J=6.8Hz,3H),1.14(d,J=6.8Hz,3H).

[0296] Step 2: To a stirred solution of (1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(5-bromopyrazin-2-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (2) (300 mg, 0.73 mmol) in 1,4-dioxane (10 mL) was added (S)-1-(3-fluoropropyl)pyrrolidin-3-amine (3) (213 mg, 1.46 mmol) and NaOt-Bu (140.1 mg, 1.46 mmol). The reaction mixture was degassed under argon for 30 min. Then, Brettphos-3rd generation precatalyst (33.06 mg, 0.03 mmol) was added and the reaction mixture was degassed again for 30 min. The reaction mixture was heated at 110 °C under microwave irradiation for 1 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, it was cooled to room temperature and filtered through a bed of celite. The filtrate was diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by RP preparative HPLC to give 5-((1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-N-((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)pyrazin-2-amine (compound 44) ​​(81 mg, 0.17 mmol, 23% yield). MS(ESI) m / z 475.16[MH] + ; 1H NMR(400MHz,DMSO-d6)δ10.28(s,1H),7.87(d,J=1.2Hz,1H),7.80(d,J=1.2Hz,1H),7.37(d,J=7.6Hz,1H),7.18(d ,J=7.6Hz,1H),7.10(d,J=6.8Hz,1H),6.99-6.88(m,2H),4.89(s,1H),4.53(t,J=6.0Hz,1H),4.44(t,J=6.4Hz,1H) ),4.36(q,1H),3.56(q,1H),2.94-2.91(dd,J=6.8,1.6Hz,1H),2.78(t,J=4.8Hz,1H),2.58-2.42(m,5H),2.38(br ,1H),2.23(s,1H),2.18(br,2H),1.88(m,2H),1.78(d,J=8.4Hz,3H),1.56(d,J=7.6Hz,3H),1.09(d,J=6.8Hz,3H).

[0297] Example 45 2-(3-((5-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-2-yl)amino)azetidin-1-yl)ethan-1-ol (compound 45)

[0298] [ka]

[0299] To a solution of N-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)azetidin-3-amine (1, Example 31-Intermediate 5) (100 mg, 0.25 mmol) in DMF (1 mL) was added K2CO3 (85.6 mg, 0.62 mmol) and 2-bromoethan-1-ol (2) (37.5 mg, 0.3 mmol) at 0 °C. The reaction was stirred at RT for 16 h. After completion of the reaction, the reaction was diluted with water (3 x 5 mL) and extracted with 10% MeOH in DCM (2 x 15 mL). The combined organic layers were collected, dried over Na2SO4, filtered and evaporated. The crude product was purified by RP preparative HPLC to give 4.8 mg (0.01 mmol, yield = 4%) of 2-(3-((5-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-2-yl)amino)azetidin-1-yl)ethan-1-ol (compound 45). MS (ESI) m / z 444.20 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δ10.27(s,1H),7.89(d,J=2.0Hz,1H),7.36(d,J=7.6Hz,1H),7.19-7.15(m,2H),6 .89-6.99(m,2H),6.83(d,J=7.2Hz,1H),6.35(d,J=8.4Hz,1H),4.78(s,1H),4.34-4.38(m,1H),3.64(t,J =7.2Hz,1H),3.49-3.52(m,1H),3.37(t,J=6.4Hz,1H),2.95(d,J=14.6Hz,4.8Hz,1H),2.85(t,J=7.2Hz, 2H),2.53-2.54(m,3H),2.23(s,1H),1.74(d,J=8.4Hz,3H),1.59(d,J=9.2Hz,3H),1.08(d,J=6.8Hz,3H).

[0300] Example 46 2-(3-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)azetidin-1-yl)ethan-1-ol (compound 46)

[0301] [ka]

[0302] To a solution of (1R,3R)-1-(4-(azetidin-3-yloxy)phenyl)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (Example 39-Int-3) (300 mg, 0.69 mmol) in DMF (3 mL) was added K2CO3 (284 mg, 2.06 mmol) and 2-iodoethan-1-ol (1) (106.8 mg, 0.62 mmol) at room temperature. The reaction was stirred at RT for 16 h. After completion of the reaction, it was diluted with water (10 mL) and extracted with 10% MeOH in DCM (2 x 30 mL). The combined organic layers were collected, dried over Na2SO4, filtered and evaporated. The crude product was purified by RP preparative HPLC to give 53.3 mg (0.12 mmol, 17%) of 2-(3-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)azetidin-1-yl)ethan-1-ol (compound 46). MS (ESI) m / z 442.41 [M+H] - ; 1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),7.37(d,J=7.6Hz,1H),7.20-7.17(m,3H),7.0 0-6.90(m,2H),6.73(d,J=8.8Hz,1H),4.73(s,1H),4.72(q,1H),4.40(t,J=6.0Hz,1 H),3.78(q,1H),3.46(q,1H),3.38-3.33(m,2H),2.99-2.88(m,3H),2.59-2.49(m,6 H),2.20(s,1H),1.78(d,J=8.4Hz,3H),1.57(d,J=8.4Hz,3H),1.10(d,J=6.8Hz,3H).

[0303] Example 47 (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(4-((1-cyclopropylazetidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (compound 47)

[0304] [ka]

[0305] (1R,3R)-1-(4-(azetidin-3-yloxy)furan) in DCM (25 mL) To a stirred solution of (bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (Example 39, Int-3) (0.25 g, 0.6257 mmol), cyclopropylboronic acid (80.6 mg, 0.9386 mmol) was added, followed by DIPEA (0.17 mL, 1.2514 mmol) and Cu(OAc)2 (227.3 mg, 1.2514 mmol). The resulting reaction mixture was stirred at ambient temperature for 2 days under oxygen balloon pressure. After completion of the reaction, the reaction mixture was evaporated. The crude product was purified by silica gel column chromatography eluting with 2-5% MeOH in DCM to give 120 mg of 68% pure product. The crude material was further purified by reversed-phase HPLC, followed by lyophilization of the resulting pure fractions to give (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(4-bromophenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (2) (17.0 mg, 0.038 mmol, 6%) (47). MS (ESI) m / z 440.01 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ10.3(s,1H),7.37(d,J=7.6Hz,1H),7.20-7.17(m,3H),6.97(t,J=7.2Hz,1H),6.9 2(t,J=7.6Hz,1H),6.74(d,J=8.4Hz,2H),4.87(s,1H),4.69-4.66(m,1H),3.72-3.68(m,2H),3.45-3.43( m,1H),3.41-3.31(m,2H),2.91-2.87(m,1H),2.59-2.54(m,1H),2.20(s,1H),1.91-1.89(m,1H),1.72(d, J=9.2Hz,3H),1.59-1.56(d,J=9.2Hz,3H),1.10(d,J=13.6Hz,3H),0.34-0.32(m,2H),0.23-0.22(m,2H).

[0306] Example 48 6-((1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-N-(1-(prop-2-yn-1-yl)azetidin-3-yl)pyridin-3-amine (compound 48)

[0307] [ka]

[0308] Step 1A: To an ice-cold stirred solution of tert-butyl azetidin-3-yl carbamate hydrochloride (1a) (1 g, 4.81 mmol) in THF (10 mL) was added 5 M aqueous NaOH (5.76 mL, 28.84 mmol) followed by 3-bromoprop-1-yne (2a) (624 mg, 5.29 mmol) at 0° C. The reaction mixture was then stirred at room temperature for 16 h. After completion of the reaction, it was diluted with water (50 mL) and extracted with 10% MeOH in DCM (3×50 mL). The organic layer was collected, dried over Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography to give 700 mg (3.33 mmol, 69%) of tert-butyl (1-(prop-2-yn-1-yl)azetidin-3-yl)carbamate (3a). 1 H NMR(400MHz,DMSO-d6)δ7.30(d,J=6.8Hz,1H),4.02-3.95(m,1H),3.39(t,J=6.8Hz,2H),3.16-3.13(m3H),2.91(t,J=6.4Hz,2H),1.36(s,9H)

[0309] Step 2A: To a stirred solution of tert-butyl (1-(prop-2-yn-1-yl)azetidin-3-yl)carbamate (3a) (700 mg, 3.33 mmol) in DCM (6 mL) was added TFA (3 mL) at 0° C. Then the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, it was evaporated. The residue was then dissolved in 10% MeOH in DCM and K2CO3 (2.29 g, 16.6 mmol) was added at 0° C. The reaction mixture was stirred for 20 min and then filtered. The filtrate was evaporated to give 310 mg (2.81 mmol, 84%) of 1-(prop-2-yn-1-yl)azetidin-3-amine (3). MS (ESI) m / z 111.06 [MH] + ; 1 H NMR (400MHz, DMSO-d6) δ3.48-3.22(m,2H), 3.18-3.11(m,5H), 2.68(m,2H), 1.88(br,2H).

[0310] Step 1: To a stirred solution of (R)-N-(1-(1H-indol-3-yl)propan-2-yl)bicyclo[1.1.1]pentan-1-amine (500 mg, 2.07 mmol) in toluene (10 mL), 5-bromopicolinaldehyde (1) (424.5 mg, 2.28 mmol) was added followed by AcOH (0.18 mL, 3.10 mmol). The reaction was stirred at 90° C. for 16 h. After completion of the reaction, it was cooled to room temperature. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were collected, dried over Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography to give 400 mg (0.98 mmol, 47%) of (1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(5-bromopyridin-2-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (2). MS(ESI) m / z 408.21[M+1] + ; 1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),8.41(s,1H),7.55-7.51(m,2H),7.42(d,J =7.6Hz,1H),7.22(d,J=6.2Hz,1H),6.99-6.92(m,2H),4.99(s,1H),3.54-3.50( q,1H),3.01-2.96(dd,J=15.2,8.0Hz,1H),2.62-2.53(dd,J=14.8,7.6Hz,1H),2 .24(s,1H),1.76(d,J=9.6Hz,3H),1.58(d,J=9.2Hz,3H),1.10(d,J=6.8Hz,3H).

[0311] Step 2: To a stirred solution of (1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(5-bromopyridin-2-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (2) (500 mg, 1.22 mmol) in 1,4-dioxane (10 mL) was added 1-(prop-2-yn-1-yl)azetidin-3-amine (3) (202 mg, 1.84 mmol) and NaOt-Bu (234 mg, 2.44 mmol). The reaction mixture was degassed under argon for 30 min. Then Brettphos-3rd generation precatalyst (55 mg, 0.06 mmol) was added and the reaction mixture was degassed again for 30 min. It was then heated at 110° C. for 16 h. After completion of the reaction, it was cooled to room temperature and filtered through a bed of celite. The filtrate was diluted with water (50 mL) and extracted with 10% MeOH in DCM (2×50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by RP preparative HPLC to give 6-((1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-N-(1-(prop-2-yn-1-yl)azetidin-3-yl)pyridin-3-amine (compound 48) (25.7 mg, 0.06 mmol, 5% yield). MS (ESI) m / z 438.29 [MH] + ; 1H NMR(400MHz,DMSO-d6)δ10.24(s,1H),7.82(d,J=2.4Hz,1H),7.35(d,J=7.6Hz,1H),7.19(d,J=7.6Hz,1 H),6.95(d,J=8.4Hz,1H),6.93-6.91(m,2H),6.78(dd,J=8.4,2.8Hz,1H),6.22(d,J=6.4Hz,1H),4.86(s ,1H),3.94(q,1H),3.59-3.56(br,3H),3.33(d,J=4.8Hz,2H),3.38(q,1H),2.96-2.91(m,3H),2.58(m,1 H),2.58-2.42(m,5H),2.38(s,1H),1.73(d,J=8.4Hz,3H),1.52(d,J=7.6Hz,3H),1.09(d,J=6.4Hz,3H).

[0312] Example 49 1-(6-((1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-3-yl)-N-(3-fluoropropyl)azetidin-3-amine (compound 49)

[0313] [ka]

[0314] Step 1: To a solution of (R)-N-(1-(1H-indol-3-yl)propan-2-yl)bicyclo[1.1.1]pentan-1-amine (5 g, 20.81 mmol) in toluene (50 mL), 5-bromopicolinaldehyde (1) (3.46 g, 18.73 mmol) and acetic acid (1.87 g, 31.22 mmol) were added. The reaction mixture was stirred at 80° C. for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature and then quenched with saturated sodium bicarbonate solution (30 mL) at 0° C. The reaction mixture was diluted with water (150 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography eluting with 70% EtOAc in n-pentane to give (1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(5-bromopyridin-2-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (2) (4 g, 9.82 mmol, yield=47%). MS(ESI) m / z 408.25[M+H] + , 1 H NMR(400MHz,DMSO-d6)δ10.32(s,1H),8.66(d,J=2Hz,1H),7.92-7.89(dd,J=2.4Hz,8. 4Hz,1H),7.38(d,J=7.2Hz,1H),7.29(d,J=8.4Hz,1H),7.185(d,J=8Hz,1H),6.99-6.9 0(m,2H),4.98(s,1H),3.59-3.58(m,1H),3.00-2.97(m,1H),2.63-2.58(dd,J=2.4Hz, 14.8Hz, 1H), 2.23 (s, 1H), 1.75-1.72 (m, 3H), 1.53-1.49 (m, 3H), 1.10 (d, J = 6.8Hz, 3H).

[0315] Step 2: A solution of (1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(5-bromopyridin-2-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (2) (3.5 g, 8.57 mmol) and tert-butyl azetidin-3-ylcarbamate (2.21 g, 12.85 mmol) in 1,4-dioxane (20 mL) was degassed with nitrogen for 10 min. Then, NaOtBu (1.64 g, 17.14 mmol) was added followed by Brettphos (233 mg, 0.25 mmol). The reaction mixture was again degassed with nitrogen for 10 min and stirred at 110 °C for 16 h. The reaction mixture was cooled to room temperature and filtered through a bed of celite. The filtrate was diluted with water (200 mL) and extracted with EtOAc (2×200 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography eluting with 50% EtOAc in n-pentane to give tert-butyl (1-(6-((1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-3-yl)azetidin-3-yl)carbamate (4) (900 mg, 2.20 mmol, yield=21%). MS (ESI) m / z 500.90 [M+H] + , 1H NMR(400MHz,DMSO-d6)δ10.17(s,1H),7.74(d,J=2.8Hz,1H),7.54(d,J=7.2Hz,1H),7.35(d,J=7.6Hz,1H),7.18( d,J=8Hz1H),6.97-6.88(m,2H),6.75-6.73(dd,J=2.8Hz,8.4Hz,1H),4.90(s,1H),4.42(s,1H),4.12-4.07(m,2H) ),3.61-3.54(m,3H),2.98-2.93(dd,J=4.8Hz,15.2Hz1H),2.591-2.54(dd,J=2.4Hz,14.8Hz,1H),2.20(s,1H),1 .98(s,1H),1.71(d,J=8.4Hz,3H),1.50(d,J=9.2Hz,3H),1.39(s,9H),1.20-1.19(m,2H),1.09(d,J=6.4Hz,3H).

[0316] Step 3: To a solution of tert-butyl (1-(6-((1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-3-yl)azetidin-3-yl)carbamate (4) (700 mg, 1.40 mmol) in DCM (3.5 mL) was added trifluoroacetic acid (3.5 mL) at 0° C. The reaction was stirred at RT for 2 h. The reaction mixture was diluted with DCM (50 mL), quenched with saturated sodium bicarbonate solution (20 mL) and washed with water (20 mL). The organic layer was concentrated to give 1-(6-((1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-3-yl)azetidin-3-amine (5) (550 mg, 1.37 mmol, yield=85%). MS(ESI) m / z 400.62[M+H] + . 1H NMR(400MHz,DMSO-d6)δ10.16(s,1H),7.74(d,J=2.4Hz,1H),7.35(d,J=7.6Hz,1H),7.17(d,J=8Hz,1H) ,7.04(d,J=8.4Hz1H),6.97-6.88(m,2H),6.75-6.72(dd,J=2.8Hz,8.4Hz,1H),5.75(s,1H),4.90(s,1H) ),4.09-4.05(m,2H),3.86(t,J=6Hz,3H),3.56(br,2H),3.439(m,2H),2.98-2.94(dd,J=3.6Hz,13.6Hz 1H),2.591-2.58(m,1H),2.20(s,1H),1.78-1.71(m,1H),1.50(d,J=9.2Hz,3H),1.09(d,J=6.8Hz,3H).

[0317] Step 4: To a solution of 1-(6-((1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-3-yl)azetidin-3-amine (5) (255 mg, 0.639 mmol) in DMF (2.5 mL) was added 1-fluoro-3-iodopropane (120 mg, 0.639 mmol) followed by potassium carbonate (97 mg, 0.703 mmol). The reaction mixture was heated at 100° C. for 16 h. The reaction mixture was quenched with ice-cold water (30 mL) and extracted with EtOAc (2×80 mL). The organic layer was washed with brine solution (2×50 mL). The combined organic layers were collected, dried over Na2SO4, filtered and evaporated to give the crude product. The crude was purified by preparative HPLC to give 1-(6-((1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-3-yl)azetidin-3-amine (compound 49) (24 mg, 0.052 mmol, yield=9%). MS(ESI) m / z 460.3 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ10.4(s,1H),7.735(d,J=2.8Hz,1H),7.358(d,J=7.6Hz,1H),7.170(d,J=7. 6Hz,1H),7.04(d,J=8.8Hz,1H),6.97-6.88(m,2H),6.74-6.71(dd,J=2.8Hz,8.4Hz,1H),4.904(s,1H) ),4.551(m,1H),4.43(m,1H),4.071(m,2H),3.577(br,1H),3.561(br,1H),3.459(m,2H),2.95(m,1H) ),2.58-2.54(m,2H),2.203(s,1H),1.79-1.70(m,5H),1.541-1.490(m,3H),1.088(d,J=6.8Hz,3H).

[0318] Example 50 (3-((1R,3R)-1-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentan-1-yl)methanol (compound 50) Example 51 (3-((1S,3S)-1-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentan-1-yl)methanol (compound 51)

[0319] [ka]

[0320] Step 1: To a solution of (3-((1-(1H-indol-3-yl)propan-2-yl)amino)bicyclo[1.1.1]pentan-1-yl)methanol (4.2 g, 15.54 mmol) in toluene (40 mL), 4-formylphenyl acetate (1) (1.40 g, 13.99 mmol) and acetic acid (1.87 g, 23.31 mmol) were added. The reaction mixture was stirred at 80° C. for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature and quenched with saturated sodium bicarbonate solution (40 mL) at 0° C. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography eluting with 70% EtOAc in n-pentane to give 4-((1R)-2-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenylacetate (2) (1.5 g, 3.60 mmol, yield=23%). MS(ESI) m / z 415[MH] + ; 1 H NMR(400MHz,DMSO-d6)δ10.37(s,1H),7.39-7.33(m,3H),7.20(d,J=8Hz1H),7.05-6.90(m,4H),4.95(s,1H),4.33(m,1H),3.48 -3.40(m,1H),2.95-2.87(m,1H),2.61-2.56(m,1H),2.21(s,3H),1.62-1.56(m,3H),1.42(d,J=9.2Hz,3H),1.23-1.15(m,4H).

[0321] Step 2: To a solution of 4-((1R)-2-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenylacetate (1.7 g, 4.08 mmol) in methanol (20 mL) was added K2CO3 (2) (1.12 g, 8.17 mmol). The reaction mixture was stirred at RT for 16 h. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 70 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography eluting with 70% EtOAc in n-pentane to give 4-((1R)-2-(3-(hydroxyethyl)bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenol (3) (1 g, 2.67 mmol, yield=65%). MS(ESI) m / z 375.39[M+1] + ; 1 H NMR(400MHz,DMSO-d6))δ10.27(s,1H),7.36(d,J=7.6Hz,1H),7.18(d,J=8Hz,1H),7.0 8(d,J=8.4Hz,1H),6.98-6.89(m,2H),6.66(d,J=8.4Hz,2H),4.79(s,1H),4.310(t,1H) ),4.028(q,J=6.8Hz,1H),3.48-3.31(m,2H),2.94-2.87(m,2H),2.63-2.56(m,1H),1. 98(s,1H),1.573(m,4H),1.40(d,J=9.2Hz,3H),1.23-1.15(m,3H),1.08(d,J=8Hz,3H).

[0322] Step 3: To a stirred solution of 4-((1R)-2-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenol (3) (1 g, 2.67 mmol) and tert-butyl 3-iodoazetidine-1-carboxylate (4) (907 mg, 3.20 mmol) in DMF (10 mL) was added Cs2CO3 (1.74 g, 5.34 mmol). The reaction mixture was stirred at 100 °C for 4 h. After completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to give semi-pure crude. The crude product thus obtained was purified by silica gel column chromatography eluting with 20-25% EtOAc in petroleum ether to give tert-butyl 3-(4-((1R)-2-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)azetidine-1-carboxylate (5) (1 g, 1.88 mmol, 71% yield). MS (ESI) m / z 530.34 [M+1] + ; 1 H NMR(400MHz,DMSO-d6))δ10.27(s,1H),7.37(d,J=7.6Hz,1H),7.23-7.18(m,3H),6.97-6.91(m,2H),6.74(d,J=8Hz,2H),4.94(br,1H),4.8 5(s,1H),4.33-4.27(m,3H),3.76(br,1H),2.89(m,1H),2.59-2.49(m,2H),1.56(d,J=8Hz,3H),1.41-1.36(m,12H),1.09(d,J=4.4Hz,3H).

[0323] Step 4: To a stirred solution of tert-butyl 3-(4-((1R)-2-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)azetidine-1-carboxylate (5) (1 g, 1.12 mmol) in DCM (5 mL) was added dropwise 4M HCl in 1,4-dioxane (5 mL) at RT. The reaction mixture was stirred at RT for 3 h. After completion of the reaction, it was evaporated and co-distilled with DCM (2×5 mL) to give (3-((1R)-1-(4-(azetidin-3-yloxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentan-1-yl)methanol hydrochloride (6) (800 mg, 1.71 mmol, quantitative yield). MS (ESI) m / z 430.48 [M+H] + .

[0324] Step 5: To a stirred solution of ((3-((1R)-1-(4-(azetidin-3-yloxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentan-1-yl)methanol hydrochloride (6) (800 mg, 1.71 mmol) in DMF (10 mL) was added K2CO3 (711 mg, 5.15 mmol) followed by 1-fluoro-3-iodopropane (7) (484 mg, 2.57 mmol) at RT. The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, it was diluted with water (50 mL) and diluted with EtOAc. (100 mL). The organic layer was washed with brine solution (2 x 20 mL). The organic layer was collected, dried over Na2SO4, filtered and evaporated. The crude product was purified by RP preparative HPLC to give 140 mg (286 mmol, yield = 16%) of (3-((1R)-1-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentan-1-yl)methanol (7; racemic). MS (ESI) m / z 490.52 [M+1] + ;1 H NMR(400MHz,DMSO-d6)δ10.26(s,1H),7.36(d,J=7.6Hz,1H),7.20-7.18(dd,J=3.6 Hz,8.4Hz,3H),6.98-6.89(m,2H),6.74(d,J=8.8Hz,2H),4.84(s,1H),4.72(t,J=6 .0Hz,1H),4.507(m,3H),4.38(m,3H),4.32(brs,1H),3.71(m,3H),3.47-3.46(m,1 H),2.91(brs,3H),1.68-1.54(m,5H),1.40(d,J=9.2Hz,3H),1.08(d,J=6.4Hz,3H).

[0325] Step 6: 140 mg of (3-((1R)-1-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentan-1-yl)methanol (7; racemic) was purified by chiral SFC purification to give 44.7 mg of (3-((1R, 3R)-1-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentan-1-yl)methanol (compound 50) with 96.86% LCMS purity (chiral HPLC: 99.20%) MS (LCMS) m / z 488.39 [MH] + . 1H NMR(400MHz,DMSO-d6)δ10.16(s,1H),7.36(d,J=7.6Hz,1H),7.20-7.18(dd,J=3.6Hz,8.4Hz,3H),6.98-6.89(m,2H),6.74(d,J=8.8Hz,2H),4.84(s, 1H),4.72(t,J=6.0Hz,1H),4.52-4.37(m,2H),4.32(br,1H),3.73-3.70(m ,2H),3.47-3.46(m,1H),3.317(s,2H),2.92-2.89(m,3H),2.58-2.49(m,3H ), 1.70-1.57 (m, 5H), 1.40 (d, J = 9.2 Hz, 3H), 1.08 (d, J = 6.4 Hz, 3H), and 34.7 mg of (3-((1S,3S)-1-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentan-1-yl)methanol (compound 51), 97.53% LCMS purity (chiral HPLC: 99.12%) MS (LCMS) m / z 488.35 [MH] + . 1 H NMR(400MHz,DMSO-d6)δ10.16(s,1H),7.36(d,J=7.6Hz,1H),7.20-7.18(dd,J=3.6Hz,8.4Hz ,3H),6.98-6.89(m,2H),6.74(d,J=8.8Hz,2H),4.84(s,1H),4.72(t,J=6.0Hz,1H),4.52-4. The stereochemistry of compounds 50 and 51 was tentatively assigned.

[0326] Example 52 (3-((1R,3R)-3-Methyl-1-(4-((1-propylazetidin-3-yl)oxy)phenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentan-1-yl)methanol (compound 52) Example 53 (3-((1S,3S)-3-Methyl-1-(4-((1-propylazetidin-3-yl)oxy)phenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentan-1-yl)methanol (compound 53)

[0327] [ka]

[0328] Compounds 52 and 53 were prepared following procedures similar to those described above for Examples 50 and 51. Compound 52: MS (LCMS) m / z 470.43 [MH] + . 1 H NMR(400MHz,DMSO-d6)δ10.25(s,1H),7.36(d,J=7.6Hz,1H),7.18-7.20(m,3H),6.89-6.98(m,2H), 6.73(d,J=8.4Hz,2H),4.84(s,1H),4.72(t,J=5.6Hz,1H),4.32(t,J=5.6Hz,1H),3.68-3.71(m,2H), 3.47-3.46(m,1H),3.31(S,2H),2.85-2.90(m,3H),2.50-2.53(m,1H),2.38(t,J=7.2,2H),1.56(d,J =9.6Hz,3H),1.40(d,J=9.2Hz,3H),1.26-1.31(m,2H),1.08(d,J=6.8Hz,3H),0.83(t,J=7.4Hz,3H). Compound 53:MS(LCMS)m / z 470.43[MH] + . 1H NMR(400MHz,DMSO-d6)δ10.25(s,1H),7.36(d,J=7.6Hz,1H),7.20-7.18(m,3H),6.98-6.89(m,2 H),6.73(d,J=12Hz,2H),4.84(s,1H),4.72(t,J=6.0Hz,1H),4.32(t,J=5.6Hz,1H),3.71-3.67(m ,2H),3.47-3.46(m,1H),2.90-2.85(m,3H),2.57-2.53(m,1H),2.36(t,J=7.2,2H),1.56(d,J=8. 8Hz,3H), 1.40(d,J=9.2Hz,3H),1.31-1.26(m,2H),1.08(d,J=6.4Hz,3H),0.83(t,J=7.2Hz,3H). Absolute stereochemistry was arbitrarily assigned to Compound 52 and Compound 53.

[0329] Example 54 5-((1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-N-((S)-1-propylpyrrolidin-3-yl)pyrazin-2-amine (compound 54)

[0330] [ka]

[0331] Compound 54 was prepared following a procedure similar to that described for Example 41. MS (ESI) m / z 457.3 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ10.29(s,1H),7.86(s,1H),7.80(s,1H),7.37(d,J=7.6Hz,1H),7.18(d,J=7.6Hz,1H),7.09 (d,J=7.6Hz,1H),6.99-6.90(m,2H),4.89(s,1H),4.19(br,1H),3.56(q,J=7.2,1.6Hz,1H),2.94-2.91(dd,J=6.8,1 .6Hz,1H),2.73(q,J=7.8,2.4Hz,1H),2.58-2.42(m,2H),2.39(br,1H),2.33(br,3H),2.23(s,1H),2.16(br,1H),1. 74(d,J=8.4Hz,3H),1.56(d,J=7.6Hz,4H),1.42(q,J=8.8,2.4Hz,2H),1.13(d,J=6.8Hz,3H),0.84(t,J=7.6Hz,3H).

[0332] Example 55 6-((1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-N-((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)pyridin-3-amine (compound 55)

[0333] [ka]

[0334] Compound 55 was prepared following a procedure similar to that described for Example 41. MS(ESI) m / z 472.4 [MH] - ; 1H NMR(400MHz,DMSO-d6)δ10.22(s,1H),7.87(d,J=2.4Hz,1H),7.35(d,J=7.6Hz,1H),7.18(d,J=8.0Hz,1H),6.97-6.88( m,3H),6.88-6.80(dd,J=8.8,2.8Hz,1H),5.89(d,J=6.8Hz,1H),4.86(s,1H),4.53(t,J=6.8Hz,1H),4.44(t,J=7.2Hz, 1H),3.84(q,1H),3.56(q,1H),2.94-2.91(dd,J=6.8,1.6Hz,1H),2.78(t,J=4.8Hz,1H),2.58-2.42(m,5H),2.38(br,1 H),2.23(s,1H),2.19(br,1H),1.88-1.76(m,2H),1.78(d,J=8.4Hz,3H),1.56(d,J=7.6Hz,3H),1.09(d,J=6.8Hz,3H).

[0335] Example 56 N-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)-1-(2-fluoroethyl)azetidin-3-amine (compound 56)

[0336] [ka]

[0337] Compound 56 was prepared following a procedure similar to that described for Example 41. MS(ESI) m / z 479.4[M+H] - ; 1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),7.34(d,J=7.6Hz,1H),7.17(d,J=7.6Hz,1H),6.97-6.9(m ,2H),6.64(d,J=6.8Hz,1H),6.09(d,J=12Hz,2H),5.14(s,1H),4.45(t,J=7.6Hz,1H),4.36(t,J= 7.6Hz,1H),3.94(q,1H),3.68(m,2H),3.55(br,1H),2.86(m,3H),2.73(t,J=7.6Hz,1H),2.66(t ,J=7.6Hz,1H),2.22(s,1H),1.77(d,J=9.6Hz,3H),1.58(d,J=8.8Hz,3H),1.06(d,J=9.2Hz,3H).

[0338] Example 57 5-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-N-(1-(3-fluoropropyl)azetidin-3-yl)pyrimidin-2-amine (compound 57)

[0339] [ka]

[0340] Compound 57 was prepared following a procedure similar to that described for Example 41. MS(ESI) m / z 460.28[M+H] + ; 1H NMR(400MHz,DMSO-d6)δ10.45(s,1H),8.12(s,2H),7.57(d,J=6.8Hz,1H),7.38(d,J =7.6Hz,1H),7.19(d,J=8.0Hz,1H),6.91-6.99(m,2H),4.79(s,1H),4.39-4.51(m,3 H),3.50-3.57(m,3H),2.91(m,1H),2.80-2.83(m,2H),2.50-2.53(m,1H),2.42-2.4 9(m,2H),2.25(s,1H),1.75-1.77(m,3H),1.60-1.68(m,5H),1.09(d,J=6.8Hz,3H).

[0341] Example 58 (3-((1R,3R)-1-(4-((1-(3-fluoropropyl)azetidine- 3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentan-1-yl)methanol (compound 58) Example 59 (3-((1S,3S)-1-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentan-1-yl)methanol (compound 59)

[0342] [ka]

[0343] Step 1: To a stirred solution of (3-((1-(1H-indol-3-yl)propan-2-yl)amino)bicyclo[1.1.1]pentan-1-yl)methanol (Example 17 Int-3) (2.1 g, 7.76 mmol) in methanol (10 mL), 4-bromobenzaldehyde (1) (1.5 g, 8.10 mmol) was added followed by tartaric acid (1.66 g, 11.09 mmol). The reaction mixture was stirred at 60° C. for 16 h. After completion of the reaction monitored by TLC, it was cooled to room temperature. The reaction mixture was diluted with NaHCO3 solution (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were collected, dried over Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography to give 1.1 g (2.51 mmol, 26% yield) of (3-(1-(4-bromophenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentan-1-yl)methanol (2). MS(ESI) m / z 437.1[M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ7.49(d,J=6.4Hz,1H),7.42(d,J=8.4Hz,2H),7.26(d,J=7.6Hz,1H) ,7.21-7.17(m,2H),7.12-7.08(m,2H),5.29(s,1H),4.84(s,1H),4.14-4.09(m,1H),3.67-3 .64(m,1H),3.57(s,2H),3.16-3.11(m,1H),2.64-2.60(m,1H),2.17(s,1H),2.04(s,2H),1. 71(t,J=27.2Hz,3H),1.51(t,J=25.6Hz,3H),1.25(t,J=14.4Hz,2H),1.15(d,J=6.8Hz,3H).

[0344] Step 2: To a solution of (3-(1-(4-bromophenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentan-1-yl)methanol (2) (1 g, 2.28 mmol) in 1,4-dioxane (10 mL) was added 1-(3-fluoropropyl)azetidin-3-amine (3) (453.3 mg, 3.42 mmol) and NaOt-Bu (439.4 mg, 4.57 mmol). The reaction mixture was degassed under argon for 30 min. Then, Brettphos-3rd generation precatalyst (70 mg, 0.68 mmol) was added and the reaction mixture was degassed again for 30 min before it was heated to 110 °C for 16 h. After completion of the reaction, it was cooled to room temperature and filtered through a bed of celite. The filtrate was diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were collected, dried over Na2SO4, filtered and evaporated. The crude product was purified by RP prep-HPLC to give 800 mg (1.63 mmol, 72% yield) of (3-(1-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentan-1-yl)methanol (4). MS (ESI) m / z 489.5 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.12(s,1H),7.35(d,J=6.4Hz,1H),7.18(d,J=8.4Hz,2H),6.99-6 .88(m,4H),6.42(d,J=8.4Hz,2H),5.92(d,J=6.8Hz,1H),4.84(s,1H),4.40-4.29(m,2H),3. 90-3.88(m,1H),3.62(t,J=12.8Hz,2H),3.48-3.46(m,1H),2.95-2.88(m,1H),2.72-2.69( m,2H),2.50-2.40(m,3H),1.68-1.54(m,5H),1.41(d,J=9.21Hz,3H),1.08(d,J=6.8Hz,3H).

[0345] Step 3: (3-(1-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentan-1-yl)methanol (4, racemic) (364 mg, 0.74 mmol) was purified by chiral SFC to give (3-((1R,3R)-1-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentan-1-yl)methanol (compound 58) (109 mg, 0.29 mmol, 30% yield) MS (ESI) m / z 487.32[MH] -;1 H NMR(400MHz,DMSO-d6)δ10.18(s,1H),7.35(d,J=6.4Hz,1H),7.18(d,J=8.4Hz,2H),6.99-6.88(m,4H),6.42(d,J=8.4Hz,2H),5.92(d,J=6.8Hz,1H) ,4.74(s,1H),6.50(t,J=12Hz,1H),4.40-4.29(m,2H),3.90-3.88(m,1H), 3.62(t,J=12.8Hz,2H),3.48-3.46(m,1H),3.31(s,2H),2.95-2.88(m,1H) , 2.72-2.69 (m, 2H), 2.47-2.40 (m, 2H), 2.50-2.40 (m, 3H), 1.68-1.54 (m, 5H), 1.41 (d, J = 9.21 Hz, 3H), 1.08 (d, J = 6.8 Hz, 3H) and (3-((1S,3S)-1-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentan-1-yl)methanol (compound 59) MS (ESI) m / z 487.32 [MH] - ; 1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),7.35(d,J=6.4Hz,1H),7.18(d,J=8.4Hz,2H),6.99-6.88(m,4H),6. 42(d,J=8.4Hz,2H),5.92(d,J=6.8Hz,1H),4.74(s,1H),6.50(t,J=12Hz,1H),4.40-4.29(m,2H),3.90-3.8 8 (m, 1H), 3.62 (t, J = 12.8 Hz, 2H), 3.48-3.46 (m, 1H), 3.31 (s, 2H), 2.95-2.88 (m, 1H), 2.72-2.69 (m, 2H), 2.47-2.40 (m, 2H), 2.50-2.40 (m, 3H), 1.68-1.54 (m, 5H), 1.41 (d, J = 9.21 Hz, 3H), 1.08 (d, J = 6.8 Hz, 3H). The absolute stereochemistry was arbitrarily assigned to compounds 58 and 59.

[0346] Example 60 2-((1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-N-(1-(3-fluoropropyl)azetidin-3-yl)pyrimidin-5-amine (compound 60)

[0347] [ka]

[0348] Compound 60 was prepared following a procedure similar to that described for Example 30. MS(ESI) m / z 459.47 [MH] - ; 1H NMR(400MHz,DMSO-d6)δ10.25(s,1H),8.03(s,1H),7.35(d,J=7.6Hz,1H),7.14(d,J=8.0Hz, 1H),6.97-6.9(m,2H),6.49(d,J=7.2Hz,1H),5.02(s,1H),4.52(t,J=7.6Hz,1H),4.39(t,J= 7.6Hz,1H),4.03(q,1H),3.66(m,3H),2.86(dd,1H),2.76(q,2H),2.58-2.44(m,3H),2.21(s ,1H),1.76(d,J=9.6Hz,3H),1.75-1.54(m,2H),1.51(d,J=8.8Hz,3H),1.14(d,J=9.2Hz,3H).

[0349] Example 61 (1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(5-((1-(3-fluoropropyl)azetidin-3-yl)oxy)pyrimidin-2-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (compound 61)

[0350] [ka]

[0351] Compound 61 was prepared following a procedure similar to that described for Example 38. MS(ESI) m / z 460.39 [MH] - ; 1 H NMR(400MHz,DMSO-d6)δ10.31(s,1H),8.41(s,1H),7.37(d,J=7.6Hz,1H),7.15(d,J=7.6Hz,1H),6.9-6.99(m,2H),5.15(s,1H),4.93-4.96(m,1H) ,4.43(dt,J=47.6Hz,6Hz,2H),3.65-3.76(m,3H),2.92-2.97(m,1H),3.0 5-3.09(m,2H),2.5-2.6(m,3H),1.53-1.76(m,8H),1.14(d,J=6.8Hz,3H).

[0352] Example 62 N-(4-((1R,3R)-2-(3-(fluoromethyl)bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidin-3-amine (compound 62) Example 63 N-(4-((1S,3S)-2-(3-(fluoromethyl)bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidin-3-amine (compound 63)

[0353] [ka]

[0354] Compounds 62 and 63 were prepared following procedures similar to those described above for Examples 58 and 59. Compound 62: MS (ESI) m / z 489.45 [MH] + ; 1 H NMR(400MHz,DMSO-d6)δ10.19(s,1H),7.35(d,J=7.2Hz,1H),7.18(d,J=8.0Hz,1H), 7.0-6.88(m,4H),6.43(d,J=8.4Hz,2H),5.94(d,J=6.8Hz,1H),4.75(brs,1H),4.52- 4.28(m,4H),3.93-3.88(m,1H),3.63-3.59(m,2H),3.50-3.46(m,1H),2.94-2.89(m, 1H),2.73-2.69(m,2H),2.56-2.45(m,3H),1.73-1.52(m,8H),1.06(d,J=6.4Hz,3H). Compound 63:MS(LCMS)m / z 470.43[MH] + . 1H NMR(400MHz,DMSO-d6)δ10.25(s,1H),7.36(d,J=7.6Hz,1H),7.20-7.18(m,3H),6.98-6.89(m,2 H),6.73(d,J=12Hz,2H),4.84(s,1H),4.72(t,J=6.0Hz,1H),4.32(t,J=5.6Hz,1H),3.71-3.67(m ,2H),3.47-3.46(m,1H),2.90-2.85(m,3H),2.57-2.53(m,1H),2.36(t,J=7.2,2H),1.56(d,J=8. 8Hz,3H), 1.40(d,J=9.2Hz,3H),1.31-1.26(m,2H),1.08(d,J=6.4Hz,3H),0.83(t,J=7.2Hz,3H). Absolute stereochemistry was arbitrarily assigned to compound 62 and compound 63.

[0355] Example 64 1-Allyl-N-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)azetidin-3-amine (Compound 64)

[0356] [ka]

[0357] Compound 64 was prepared following a procedure similar to that described for Example 49. MS(ESI) m / z 439.49[M+H] + ; 1H NMR(400MHz,DMSO-d6)δ10.24(s,1H),7.35(d,J=7.6Hz,1H),7.18(d,J=8.0Hz,1H),6.98-6.88(m,4H),6 .42(d,J=8.4Hz,2H),5.92(d,J=7.2Hz,1H),5.76-5.66(m,1H),5.17-5.12(m,2H),4.76(s,1H),3.91-3.8 8(m,1H),3.61-3.58(m,2H),3.45-3.43(m,1H),3.01(d,J=6.0Hz,1H),2.89-2.85(m,1H),2.76-2.72(m, 2H),2.57-2.49(m,1H),2.19(s,1H),1.72(d,J=9.6Hz,3H),1.58(d,J=9.2Hz,3H),1.09(d,J=6.8Hz,3H).

[0358] Example 65 N-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(prop-2-yn-1-yl)azetidin-3-amine (compound 65)

[0359] [ka]

[0360] Compound 65 was prepared following a procedure similar to that described for Example 49. MS(ESI) m / z 435.46[MH] - ; 1H NMR(400MHz,DMSO-d6)δ10.23(s,1H),7.35(d,J=7.6Hz,1H),7.18(d,J=7.6Hz,1H),6. 99-6.9(m,4H),6.42(d,J=8.8Hz,2H),5.99(d,J=6Hz,1H),4.77(s,1H),3.93(br,1H), 3.71(br,2H),3.48(br,1H),3.40-3.22(m,3H),3.08(br,2H),2.86(dd,1H),2.55(br, 1H),2.21(s,1H),1.76(d,J=9.6Hz,3H),1.51(d,J=8.8Hz,3H),1.14(d,J=9.2Hz,3H).

[0361] Example 66 (R)-1-(3-((1R,3R)-1-(2,6-difluoro-4-((1-(3 -fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentan-1-yl)ethan-1-ol (compound 66) Example 67 (R)-1-(3-((1S,3S)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentan-1-yl)ethan-1-ol (compound 67)

[0362] [ka]

[0363] Step 1: t-To a stirred solution of 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (25 g, 147.006 mmol) in BuOH (60 mL) was added Et3N (40.7 mL, 294.116 mmol) followed by DPPA (37.91 mL, 176.47 mmol). After the reaction mixture was stirred at room temperature for 2 h, it was stirred at 90 °C for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated to give the crude product, which was purified by silica gel column chromatography eluting with 10-20% EtOAc in petroleum ether to give methyl 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylate (2A) (25 g, 60% yield). 1 H NMR (400MHz, CDCl3) δ4.97 (brs, 1H), 3.68 (s, 3H), 2.28 (s, 6H), 1.44 (s, 9H).

[0364] Step 2: To a stirred solution of methyl 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylate (2A) (25 g, 103.67 mmol) in THF (200 mL), MeNH(OMe) HCl (15.16 g, 155.51 mmol) was added, followed by i- PrMgCl (2M in THF) (103.6 mL, 207.34 mmol) was added. The reaction mixture was stirred at 0° C. for 4 h. After completion, the reaction mixture was quenched with a saturated solution of NH4Cl and extracted with EtOAc (2×200 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated to give the crude product, which was was purified by silica gel column chromatography eluting with 30-40% EtOAc in petroleum ether to give tert-butyl (3-(methoxy(methyl)carbamoyl)bicyclo[1.1.1]pentan-1-yl)carbamate (2B) (27 g, 99.87 mmol, 48% yield). MS (ESI) m / z 271.26 [M+1] + .

[0365] Step 3: To a stirred solution of tert-butyl (3-(methoxy(methyl)carbamoyl)bicyclo[1.1.1]pentan-1-yl)carbamate (2B) (27 g, 99.87 mmol) in THF (270 mL) at 0 °C, MeMgBr (3 M in DEE) (265.7 ml, 797.36 mmol) was added. The reaction mixture was stirred at 0 °C for 4 h. After completion, the reaction mixture was quenched with a saturated solution of NH4Cl and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated to give the crude product, which was purified by silica gel column chromatography eluting with 20-30% EtOAc in petroleum ether to give tert-butyl (3-acetylbicyclo[1.1.1]pentan-1-yl)carbamate (2C) (8.6 g, 65% yield). MS(ESI)m / z170.08[M-56] + ; 1 H NMR (400MHz, CDCl3) δ4.95 (brs, 1H), 2.26 (s, 6H), 2.14 (s, 3H), 1.45 (s, 9H).

[0366] Step 4: To a stirred solution of tert-butyl (3-acetylbicyclo[1.1.1]pentan-1-yl)carbamate (2C) (8.6 g, 38.17 mmol) in MeOH (60 mL) was added NaBH4 (2D) (2.9 g, 76.44 mmol) at 0 °C. The reaction was then warmed to RT and stirred for 2 h. After completion, the reaction mixture was concentrated under reduced pressure, diluted with water (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated to give the crude product. It was further purified by silica gel column chromatography eluting with 20-30% EtOAc in petroleum ether to give tert-butyl (3-(1-hydroxyethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (2D) (4 g, quantitative yield). MS(ESI)m / z 172.08[M-56] + (M- t Bu); 1H NMR(400MHz,DMSO-d6)δ7.37(brs,1H),4.34(d,J=4.8Hz,1H),3.68-3.62(m,1H), 1.72(d,J=9.2Hz,3H),1.65(d,J=9.2Hz,3H),1.36(s,9H),0.95(d,J=6.4Hz,3H).

[0367] Step 5: To a solution of tert-butyl (3-(1-hydroxyethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (2D) (4 g, 17.59 mmol) in 1,4-dioxane (40 mL) at 0 °C, 4 M HCl in 1,4-dioxane (60 mL) at the same temperature was added. The reaction mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was evaporated and neutralized by a saturated solution of NaHCO3 (30-50 mL). It was then extracted with 10% MeOH / DCM (3 x 50 mL) and the combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated to give the desired product 1-(3-aminobicyclo[1.1.1]pentan-1-yl)ethan-1-ol (2.5 g, quantitative yield). MS (ESI) m / z 128.08 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ8.13(brs,2H),4.54(brs,1H),3.69(d,J=6.4Hz,1H),3.16(s,1H),1.71-1.80(m,6H),0.98(d,J=6.4Hz,3H).

[0368] Step 6: 1-(3-aminobicyclo[1.1.1]pentan-1-yl)ethan-1-ol (2E, racemic) (2.5 g, 19.65 mmol) was purified by chiral SFC to give (R)-1-(3-aminobicyclo[1.1.1]pentan-1-yl)ethan-1-ol (Int-2) (0.670 g, 5.26 mmol, 26.80% yield) ) 1H NMR (400 MHz, DMSO-d6) δ 4.23 (d, J = 4.8 Hz, 2H), 3.61 (q, J = 4.4 Hz, 1H), 2.02 (s, 2H), 1.52-1.43 (m, 6H), 0.94 (d, J = 6.4 Hz, 3H); and (S)-1-(3-aminobicyclo[1.1.1]pentan-1-yl)ethan-1-ol (0.740 g, 5.81 mmol, 29.60% yield). 1 H NMR (400MHz, DMSO-d6) δ4.23(d,J=4.8Hz,2H),3.61(q,J=4.4Hz,1H),2.02(s,2H),1.52-1.43(m,6H),0.94(d,J=6.4Hz,3H) were obtained.

[0369] Step 7: To a stirred solution of 1-(1H-indol-3-yl)propan-2-one (1) (1 g, 5.77 mmol) in MeOH (10 mL) was added (R)-1-(3-aminobicyclo[1.1.1]pentan-1-yl)ethan-1-ol (2) (0.670 g, 5.199 mmol) followed by AcOH (1 mL). The reaction mixture was stirred at room temperature for 3 h. NaCNBH3 (0.727 g, 11.54 mmol) was then added and the resulting reaction mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was diluted with water (15 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated to give the crude product. The crude material was further purified by column chromatography on silica gel eluting with 40-60% EtOAc in petroleum ether to give (1R)-1-(3-((1-(1H-indol-3-yl)propan-2-yl)amino)bicyclo[1.1.1]pentan-1-yl)ethan-1-ol (3) (1.1 g, 51% yield). MS (ESI) m / z 285.71 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),7.48(d,J=7.6Hz,1H),7.32(d,J=8.0Hz,1H) ,7.11(s,1H),7.05(t,J=7.2Hz,1H),6.96(t,J=7.6Hz,1H),4.30(d,J=4.0Hz,1H),4 .08(s,1H),3.16(s,2H),3.65(t,J=5.6Hz,1H),2.99(brs,1H),2.84(dd,J=14.0,4. 8Hz, 1H), 2.56 (d, J=7.6Hz, 1H), 1.90 (s, 1H), 1.62-1.49 (m, 6H), 0.98-0.93 (m, 6H).

[0370] Step 8: To a stirred solution of (1R)-1-(3-((1-(1H-indol-3-yl)propan-2-yl)amino)bicyclo[1.1.1]pentan-1-yl)ethan-1-ol (3) (1.1 g, 3.51 mmol) in EtOH (10 mL) was added 4-bromo-2,6-difluorobenzaldehyde (5) (0.694 g, 3.16 mmol) followed by tartaric acid (0.789 mg, 5.265 mmol). The reaction mixture was stirred at 80° C. for 16 h. After completion, the reaction mixture was cooled to room temperature, neutralized by a saturated solution of NaHCO3, and extracted with 10% MeOH in DCM (2×50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated to give the crude product. The crude was further purified by silica gel column chromatography eluting with 50-70% EtOAc in petroleum ether to give (1R)-1-(3-(1-(4-bromo-2,6-difluorophenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentan-1-yl)ethan-1-ol (5) (600 mg, 1.23 mmol, 25% yield). MS (ESI) m / z 489.25 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ10.51(s,1H),7.39(t,J=8.8Hz,3H),7.30(d,J=7.2Hz,1H),7. 17(d,J=8.0Hz,1H),7.01-6.92(m,3H),5.27(s,1H),4.27(t,J=3.2Hz,1H),3.64-3.55( m,1H),3.29(d,J=6.4Hz,1H),3.01-2.93(m,1H),2.81-2.57(m,1H),1.62-1.53(m,4H) ,1.38(dd,J=28Hz,9.2Hz,3H),1.19-1.16(m,2H),1.1-1.00(m,7H),0.99-0.89(m,3H).

[0371] Step 9: To a stirred solution of (1R)-1-(3-(1-(4-bromo-2,6-difluorophenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentan-1-yl)ethan-1-ol (5) (600 mg, 1.23 mmol) in 1,4-dioxane (10 mL) was added 1-(3-fluoropropyl)azetidin-3-amine (6) (350 mg, 2.46 mmol) and NaOt-Bu (236 mg, 2.46 mmol). The reaction mixture was then degassed under an argon atmosphere for 30 min. Afterwards, Brettphos-3rd generation precatalyst (112 mg, 0.123 mmol) was added and the reaction mixture was degassed again for 30 min before being heated at 110 °C for 16 h. After completion of the reaction, it was cooled to room temperature and filtered through a bed of celite. The filtrate was diluted with water (10 mL) and extracted with 10% MeOH in DCM (2×30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by reverse phase preparative HPLC to give (1R)-1-(3-(1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentan-1-yl)ethan-1-ol (230 mg, 31% yield) (6).

[0372] Step 10: (1R)-1-(3-(1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentan-1-yl)ethan-1-ol (6) (230 mg, 0.426 mmol) was purified by chiral SFC to give ( R)-1-(3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentan-1-yl)ethan-1-ol (compound 66) (55 mg, 0.102 mmol, 24% yield) MS (ESI) m / z 537.42 [MH] - ; 1 H NMR(400MHz,DMSO-d6)δ10.36(s,1H),7.34(d,J=7.6Hz,1H),7.17(d,J=8.0Hz,1H),6.97-6.88(m,2H),6. 60(d,J=6.8Hz,1H),6.08(d,J=12.0Hz,1H),5.12(s,1H),4.50(t,J=6.0Hz,1H),4.38(t,J=6.0Hz,1H),4.2 4(d,J=4.4Hz,1H),3.93(q,1H),3.63-3.54(brm,1H),2.91(dd,J=8.0,3.6Hz,1H),2.73(t,J=6.4Hz,1H), 2.51-2.43(m,3H),1.69-1.57(m,5H),1.35(d,J=9.2Hz,3H),1.04(d,J=6.4Hz,3H),0.89(d,J=6.4Hz,3H). UPLC: 95.82%, LCMS: 97.59% and Chiral SFC: 99.87%; and (R)-1-(3-((1S,3S)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentan-1-yl)ethan-1-ol (compound 67) (60 mg, 26% yield) MS (ESI) m / z 537.42 [MH] -; 1 H NMR(400MHz,DMSO-d6)δ10.36(s,1H),7.34(d,J=7.6Hz,1H),7.17(d,J=8.0Hz,1H),6.97-6. 88(m,2H),6.60(d,J=6.8Hz,1H),6.08(d,J=12.0Hz,1H),5.12(s,1H),4.50(t,J=6.0Hz,1H) ,4.38(t,J=6.0Hz,1H),4.24(d,J=4.4Hz,1H),3.93(q,1H),3.63-3.54(m,1H),2.91(dd,J=1 4.0,3.6Hz,1H),2.73(t,J=6.4Hz,1H),2.51-2.43(m,3H),1.61-1.68(m,5H),1.42(d,J=9.2H z, 3H), 1.05 (d, J = 6.4 Hz, 3H), 0.895 (d, J = 6.4 Hz, 3H). HPLC: 95.02%, LCMS: 95.48% and chiral SFC: 99.70% were obtained. The absolute stereochemistry was arbitrarily assigned to compound 66 and compound 67.

[0373] Example 68 (S)-1-(3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentan-1-yl)ethan-1-ol (compound 68) Example 69 (S)-1-(3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentan-1-yl)ethan-1-ol (compound 69)

[0374] [ka]

[0375] Compounds 68 and 69 were prepared following procedures similar to those described above for Examples 66 and 67. Compound 68: MS (ESI) m / z 537.42 [MH] - ; 1 H NMR(400MHz,DMSO-d6)δ10.36(s,1H),7.34(d,J=7.6Hz,1H),7.17(d,J=8.0Hz,1H),6.95(t,J=6.8Hz,1H),6.90 (t,J=7.6Hz,1H),6.60(d,J=6.8Hz,1H),6.08(d,J=12.0Hz,1H),5.12(s,1H),4.50(t,J=6.0Hz,1H),4.38(t,J=6 .0Hz,1H),4.24(d,J=4.4Hz,1H),3.93(q,1H),3.63-3.54(m,1H),2.91(dd,J=14.0,3.6Hz,1H),2.73(t,J=6.4Hz ,1H),2.51-2.43(m,3H),1.69-1.57(m,5H),1.35(d,J=9.2Hz,3H),1.04(d,J=6.4Hz,3H),0.89(d,J=6.4Hz,3H). UPLC:96.55%LCMS:97.73%, Chiral SFC:99.79%;Compound 69:MS(ESI)m / z 537.52[MH] - ; 1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),7.34(d,J=7.6Hz,1H),7.17(d,J=8.0Hz,1H),6.95(t,J=6.8Hz,1H),6.90 (t,J=7.6Hz,1H),6.60(d,J=6.8Hz,1H),6.08(d,J=12.0Hz,1H),5.12(s,1H),4.50(t,J=6.0Hz,1H),4.38(t,J=6 0.0Hz,1H), 4.24(d,J=4.4Hz,1H), 3.93(q,1H), 3.63-3.54(m,1H), 2.91(dd,J=14.0,3.6Hz,1H), 2.73(t,J=6.4Hz,1H), 2.51-2.43(m,3H), 1.69-1.57(m,5H), 1.35(d,J=9.2Hz,3H), 1.04(d,J=6.4Hz,3H), 0.89(d,J=6.4Hz,3H). HPLC: 95.59% LCMS: 97.09%, Chiral SFC: 99.80%. Absolute stereochemistry was arbitrarily assigned to compound 68 and compound 69.

[0376] Example 70 (3-((1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentan-1-yl)methanol (compound 70) Example 71 (3-((1S,3S)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentan-1-yl)methanol (compound 71)

[0377] [ka]

[0378] Compounds 70 and 71 were prepared following procedures similar to those described above for 66 and 67. Compound 70: MS (ESI) m / z 539.3 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.45(s,1H),7.34(d,J=7.6Hz,1H),7.17(d,J=8.0Hz,1H),6.88-6.97(m,2H),6.31( d,J=6.8Hz,1H),6.12(d,J=12Hz,2H),5.20(S,1H),4.52-4.56(t,J=12.0Hz,1H),4.34-4.43(m,2H),3.80(bs, 1H),3.60(bs,1H),3.40(m,2H),2.99(m,1H),2.75(m,1H),2.61(m,1H),2.40-2.50(m,4H),2.30(m,1H),1.76 -1.82(m,2H),1.50-1.52(m,4H),1.44(d,J=9.2Hz,3H),1.04(d,J=6.8Hz,3H);Compound 71:MS(ESI)m / z539.3[M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.45(s,1H),7.34(d,J=7.6Hz,1H),7.18(d,J=7.6Hz,1H),6.89-6.97(m,2H),6.3 2(d,J=6.8Hz,1H),6.12(d,J=12Hz,2H),5.15(S,1H),4.41-4.56(m,2H),4.35(m,1H),3.8(bs,1H),3.6(bs , 1H), 3.32-3.35(m, 2H), 2.99(m, 1H), 2.74-2.77(t, J-6.8 Hz, 1H), 2.61(m, 1H), 2.41-2.45(m, 5H), 2.21(m, 1H), 1.78-1.84(m, 2H), 1.61(d, J=9.2 Hz, 4H), 1.42(d, J=9.2 Hz, 3H), 1.23(s, 2H), 1.04(d, J=6.8 Hz, 3H). Absolute stereochemistry was arbitrarily assigned to compound 70 and compound 71.

[0379] Example 72 (S)-N-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-propylpyrrolidin-3-amine (compound 72)

[0380] [ka]

[0381] Compound 72 was prepared following a procedure similar to that described for Example 49. MS (ESI) m / z 455.3 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.23(s,1H),7.36(d,J=7.6Hz,1H),7.19(d,J=8.0Hz,1H),6.96-6.90(m,4H),6 .46(d,J=8.8Hz,2H),5.58(d,J=6.8Hz,1H),4.76(s,1H),3.85(brs,1H),3.48-3.31(m,1H),2.89-2.78( m,1H),2.76-2.74(m,1H),2.52-2.49(m,2H),2.45-2.41(m,1H),2.33-2.27(m,3H),2.20-2.10(m,2H),1 .73(d,J=9.6Hz,3H),1.60-1.52(m,4H),1.44-1.38(m,2H),1.10(d,J=6.8Hz,3H),0.85(t,J=7.2Hz,3H).

[0382] Example 73 (3R,4S)-N-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-4-fluoro-1-(3-fluoropropyl)pyrrolidin-3-amine (compound 73) Example 74 (3S,4R)-N-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-4-fluoro-1-(3-fluoropropyl)pyrrolidin-3-amine (compound 74)

[0383] [ka]

[0384] Compounds 73 and 74 were prepared following procedures similar to those described above for Examples 66 and 67. Compound 73 (110 mg, 20% yield). MS (ESI) m / z 489.42 [MH] - , 1 H NMR(400MHz,DMSO-d6)δ10.25(s,1H),7.36(d,J=8Hz,1H),7.19(d,J=8Hz,1H),6.89-6.98(m,4H),6. 62(d,J=8.4Hz,2H),5.59(d,J=8.4Hz,1H),5.05-5.19(m,1H),4.78(s,1H),4.53(t,J=6Hz,1H),4.42( t,J=6Hz,1H),3.9-4.0(m,1H),3.44-3.46(m,1H),3.1-3.15(m,1H),2.86-2.98(m,2H),2.52-2.72(m ,3H),2.41-2.46(m,2H),2.12(s,1H),1.72-1.84(m,5H),1.59(d,J=9.2Hz,3H),1.1(d,J=6.8Hz,3H). Compound 74 (134 mg, 24% yield). MS(ESI)m / z489.49[MH] - , 1H NMR(400MHz,DMSO-d6)δ10.25(s,1H),7.36(d,J=8Hz,1H),7.19(d,J=8Hz,1H),6.89-6.98(m,4H),6.62( d,J=8.4Hz,2H),5.59(d,J=8.4Hz,1H),5.05-5.19(m,1H),4.78(s,1H),4.53(t,J=6Hz,1H),4.42(t,J=6 Hz, 1H), 3.9-4.0(m, 1H), 3.44-3.46(m, 1H), 3.1-3.15(m, 1H), 2.86-2.98(m, 2H), 2.52-2.72(m, 3H), 2.41-2.46(m, 2H), 2.12(s, 1H), 1.72-1.84(m, 5H), 1.59(d, J = 9.2 Hz, 3H), 1.23(s, 1H), 1.1(d, J = 6.8 Hz, 3H). Absolute stereochemistry was arbitrarily assigned to compound 73 and compound 74.

[0385] Example 75 (3R,4R)-N-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-4-fluoro-1-(3-fluoropropyl)pyrrolidin-3-amine (compound 75)

[0386] [ka]

[0387] Step 1: To a stirred solution of (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(4-bromophenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (Int-2, Example 31) (500 mg, 1.13 mmol) in 1,4-dioxane (10 mL) was added tert-butyl (3R,4R)-3-amino-4-fluoropyrrolidine-1-carboxylate (1) (276.6 mg, 1.35 mmol) and NaOt-Bu (217.1 mg, 2.26 mmol). The reaction mixture was degassed under argon for 30 min. Then Brettphos-3rd generation precatalyst (30.73 mg, 0.03 mmol) was added and the reaction mixture was degassed again for 30 min. It was then heated at 110° C. for 16 h. After completion of the reaction, it was cooled to room temperature and filtered through a bed of Celite. The filtrate was diluted with water (50 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by RP preparative HPLC to give tert-butyl (3R,4R)-3-((4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)amino)-4-fluoropyrrolidine-1-carboxylate (2) (440 mg, 0.847 mmol, 67% yield). MS (ESI) m / z 531.46 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.26(s,1H),7.36(d,J=7.6Hz,1H),7.19(d,J=8.4Hz,1H),7.04( d,J=7.6Hz,2H),6.98-6.88(m,2H),6.54(d,J=8.4Hz,2H),5.89(q,1H),5.08-4.92(d,1H) ,4.82(s,1H),4.04(q,1H),3.68-3.40(m,4H),2.88-2.86(dd,1H),2.60-2.50(m,1H),2.2 0(s,1H),1.73(d,J=9.6Hz,3H),1.56(d,J=8.4Hz,3H),1.42(s,9H),1.11(d,J=9.2Hz,3H).

[0388] Step 2: To a solution of tert-butyl (3R,4R)-3-((4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)amino)-4-fluoropyrrolidine-1-carboxylate (2) (440 mg, 0.829 mmol) in dioxane (2 mL) was added 4N HCl in dioxane (2 ml) at 0° C. Then it was stirred at room temperature for 3 hours. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was evaporated under reduced pressure to give the crude product, which was then triturated with diethyl ether (15 mL) to give (3R,4R)-N-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4b]indol-1-yl)phenyl)-4-fluoropyrrolidin-3-amine (3) (350 mg, 0.812 mmol, 90%). MS (ESI) m / z 431.4 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.26(s,1H),7.37(d,J=7.6Hz,1H),7.19(d,J=8.4Hz,1H),7. 04(d,J=7.6Hz,2H),6.98-6.88(m,2H),6.54(d,J=8.4Hz,2H),5.63(d,J=6.0Hz,1H),4 .78(t,J=7.6Hz,2H),3.82-3.67(q,1H),3.46(m,1H),3.04-2.86(m,4H),2.62-2.50(m ,2H),2.20(s,1H),1.73(d,J=9.6Hz,3H),1.57(d,J=8.8Hz,3H),1.08(d,J=9.2Hz,3H).

[0389] Step 3: To a solution of (3R,4R)-N-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-4-fluoropyrrolidin-3-amine (3) (350 mg, 0.812 mmol) in DMF (3 mL) was added 1-fluoro-3-iodopropane (4) (183.1 mg, 0.974 mmol) and K2CO3 (168.3 mg, 1.21 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, it was diluted with water (5 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were collected, dried over Na2SO4, filtered and evaporated. The crude product was purified by RP preparative HPLC to give (3R,4R)-N-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-4-fluoro-1-(3-fluoropropyl)pyrrolidin-3-amine (compound 75) (89.8 mg, 0.18 mmol, 29%). MS (ESI) m / z 489.48 [M+H] - ; 1 H NMR(400MHz,DMSO-d6)δ10.25(s,1H),7.36(d,J=7.6Hz,1H),7.19(d,J=8.0Hz,1H),7.02(d,J=7.6Hz ,2H),6.98-6.9(m,2H),6.54(d,J=7.6Hz,2H),5.76(d,J=6.0Hz,1H),4.78(t,J=7.6Hz,2H),4.56(t, J=7.6Hz,1H),4.44(t,J=7.6Hz,1H),3.92-3.86(m,1H),3.46(m,1H),3.04-2.86(m,2H),2.76-2.50( m,4H),2.21(s,1H),2.12(m,1H),1.73(d,J=9.6Hz,3H),1.58(d,J=8.8Hz,3H),1.14(d,J=9.2Hz,3H).

[0390] Example 76 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentane-1-carboxamide (compound 76) Example 77 3-((1S,3S)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentane-1-carboxamide (compound 77)

[0391] [ka]

[0392] Compounds 76 and 77 were prepared following procedures similar to those described above for Examples 58 and 59. Compound 76: MS (ESI) m / z 536.40 [MH] - ; 1 H NMR(400MHz,DMSO-d6)δ7.35(d,J=7.2Hz,1H),7.17(m,2H),6.98-6.89(m,2H),6.83(s, 1H),6.65(d,J=6.8Hz,1H),6.1(d,J=12Hz,2H),5.12(s,1H),4.5(dt,J=47,6Hz,2H),3.9 4(q,J=6.8Hz,1H),3.56-3.64(m,3H),2.94-2.89(m,1H),2.73(t,J=7.2Hz,2H),2.54-2 .46(m,3H),1.89(d,J=8.8Hz,3H),1.81(s,1H),1.73-1.6(m,5H),1.05(d,J=6.8Hz,3H). HPLC: 96.32%, LCMS: 99.11%, chiral SFC: 99.94%. Compound 77:MS(ESI)m / z538.36[M+H] + ; 1H NMR(400MHz,DMSO-d6)δ7.36(d,J=7.2Hz,1H),7.17(m,2H),6.98-6.89(m,2H),6.83(s, 1H),6.65(d,J=6.8Hz,1H),6.1(d,J=12Hz,2H),5.12(s,1H),4.5(dt,J=47,6Hz,2H),3.9 4 (q, J = 6.8 Hz, 1H), 3.56-3.64 (m, 3H), 2.94-2.89 (m, 1H), 2.73 (t, J = 7.2 Hz, 2H), 2.54-2.46 (m, 3H), 1.89 (d, J = 8.8 Hz, 3H), 1.81 (s, 1H), 1.73-1.6 (m, 5H), 1.05 (d, J = 6.8 Hz, 3H). HPLC: 97.10%, LCMS: 98.08%, Chiral SFC: 96.81%. Absolute stereochemistry was arbitrarily assigned to compound 76 and compound 77.

[0393] Example 78 (3S,4R)-4-((4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)amino)-1-(3-fluoropropyl)pyrrolidin-3-ol (compound 78)

[0394] [ka]

[0395] Compound 78 was prepared following a procedure similar to that described for Example 49 with LCMS purity: 97.96%, UPLC purity: 95.06% and chiral purity: 96.53%. MS (ESI) m / z 489.4 [M+H] +。1HNMR(400MHz,DMSO-d6)δ10.22(s,1H),7.39(d,J=7.2Hz,1H),7.21(d,J=7.6Hz,1H),6.97-6.89(m, 4H),6.55-6.53(d,J=8Hz,2H),5.12-5.11(d,J=4Hz,1H),4.921(bs,1H),4.79(s,1H),4.53-4.38(d t,J1=47.6Hz,J2=6.0Hz,2H),4.18(brs,1H),3.71-3.69(m,1H),3.45-3.44(m,1H),3.03-2.97(m,2 H),2.86(m,1H),2.57-2.44(m,3H),2.33-2.29(d,3H),1.81-1.72(m,5H),1.11-1.09(d,J=8.0Hz3H)

[0396] Example 79 (3S,4S)-4-((4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)amino)-1-(3-fluoropropyl)pyrrolidin-3-ol (compound 79) Example 80 (3R,4R)-4-((4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)amino)-1-(3-fluoropropyl)pyrrolidin-3-ol (compound 80)

[0397] [ka]

[0398] Compounds 79 and 80 were prepared following procedures similar to those described above for Examples 66 and 67. Compound 79. MS (LCMS) m / z 489.4 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ10.21(s,1H),7.35(d,J=7.6Hz,1H),7.193(d,J=8Hz,1H),6.98-6 .89(m,4H),6.54(d,J=8.4Hz,2H),5.59(d,J=6Hz,1H),4.77(s,1H),4.41-4.51(dt,J=47. 2Hz,2H),3.87(brs,1H),3.48-3.32(m,2H),2.93-2.76(m,2H),2.91-2.75(m,1H),2.50-2 .30(m,5H),2.19(s,1H),1.81-1.71(m,5H),1.58(d,J=9.2Hz,3H),1.08(d,J=6.4Hz,3H). Compound 80. MS(LCMS)m / z 489.3[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.21(s,1H),7.35(d,J=7.6Hz,1H),7.193(d,J=8Hz,1H),6.98-6 .89(m,4H),6.54(d,J=8.4Hz,2H),5.59(d,J=6Hz,1H),4.77(s,1H),4.41-4.51(dt,J=47. 2Hz,2H), 3.87(brs,1H), 3.48-3.32(m,2H), 2.93-2.76(m,2H), 2.91-2.75(m,1H), 2.50-2.30(m,5H), 2.19(s,1H), 1.81-1.71(m,5H), 1.58(d,J=9.2Hz,3H), 1.08(d,J=6.4Hz,3H). Absolute stereochemistry was arbitrarily assigned to compound 79 and compound 80.

[0399] Example 81 N-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(2-fluoroethyl)azetidin-3-amine (compound 81)

[0400] [ka]

[0401] Compound 81 was prepared following a procedure similar to that described for Example 49. MS(ESI) m / z 443.5[M+H] - ; 1 H NMR (400MHz, DMSO- d6)δ10.22(s,1H),7.35(d,J=7.6Hz,1H),7.18(d,J=8.0Hz,1H),6.98-6.9(m,4H),6.42(d,J=8 .8Hz,2H),5.94(d,J=6.8Hz,1H),4.76(s,1H),4.45(t,J=7.6Hz,1H),4.36(t,J=7.6Hz,1H),3.9 2(q,1H),3.68(m,2H),3.45(br,1H),2.84(m,3H),2.73(t,J=7.6Hz,1H),2.66(t,J=7.6Hz,1H) ,2.51(s,1H),2.22(s,1H),1.73(d,J=9.2Hz,3H),1.56(d,J=8.4Hz,3H),1.09(d,J=9.2Hz,3H).

[0402] Example 82 N-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-((R)-2-fluoropropyl)azetidin-3-amine (compound 82) Example 83 N-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-((S)-2-fluoropropyl)azetidin-3-amine (compound 83)

[0403] [ka]

[0404] Compounds 82 and 83 were prepared following procedures similar to those described above for Examples 66 and 67. Compound 82 MS (ESI) m / z 457.3 [M+H] - ,1 H NMR(400MHz,DMSO-d6)δ10.22(s,1H),7.35(d,J=7.6Hz,1H),7.18(d,J=7.6Hz,1H),6. 98-6.89(m,4H),6.42(d,J=8.4Hz,2H),5.95(d,J=3.6Hz,1H),4.77(s,1H),4.21(br,1) H),3.98(q,1H),3.76(br,1H),3.42(q,1H),2.93(br,3H),2.55(m,3H),2.19(s,1H),1 .73(d,J=7.6Hz,3H),1.59(d,J=9.2Hz,3H),1.27-1.19(m,3H),1.22(d,J=8.4Hz,3H). Compound 83. MS(ESI)m / z459.4[M+H] + , 1 H NMR(400MHz,DMSO-d6)δ10.22(s,1H),7.35(d,J=7.6Hz,1H),7.18(d,J=7.6Hz,1 H),6.99-6.89(m,4H),6.43(d,J=8.0Hz,2H),5.99(br,1H),4.67(s,1H),4.05(b r,1H),3.88(q,2H),3.44(q,1H),2.93(br,3H),2.55(m,3H),2.19(s,1H),1.73( d,J=7.6Hz,3H),1.59(d,J=9.2Hz,3H),1.27-1.19(m,3H),1.22(d,J=8.4Hz,3H). Absolute stereochemistry was arbitrarily assigned to compound 82 and compound 83.

[0405] Example 84 (3R,4R)-N-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-butyl-4-fluoropyrrolidin-3-amine (compound 84)

[0406] [ka]

[0407] Compound 84 was prepared following a procedure similar to that described for Example 49. MS(ESI) m / z 487.3[M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.23(s,1H),7.36(d,J=7.6Hz,1H),7.18(d,J=8.0Hz,1H),7.02(d,J=8.0Hz,2H), 6.98-6.89(m,2H),6.53(d,J=8.4Hz,2H),5.75(d,J=6.0Hz,1H),4.78(t,J=7.6Hz,2H),3.47-3.28(m,1H),3 .46(q,1H),3.28(m,1H),3.0-2.86(m,2H),2.56(m,2H),2.36(br,2H),2.21(s,1H),2.08(br,1H),1.72(d,J =7.6Hz,3H),1.56(d,J=8.4Hz,1H),1.43(m,2H),1.31(m,2H),1.11(d,J=7.6Hz,3H),0.88(t,J=7.2Hz,3H).

[0408] Example 85 (3R,4S)-N-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-4-fluoro-1-propylpyrrolidin-3-amine (compound 85) Example 86 (3S,4R)-N-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-4-fluoro-1-propylpyrrolidin-3-amine (compound 86)

[0409] [ka]

[0410] Step 1: To a stirred solution of (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(4-bromophenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (800 mg, 1.9607 mmol) in 1,4-dioxane (10 mL) was added tert-butyl (3R,4S)-3-amino-4-fluoropyrrolidine-1-carboxylate (1) (435 mg, 2.1568 mmol) and NaOt-Bu (752.0 mg, 7.8431 mmol). The reaction mixture was degassed under argon for 30 min. Then Brettphos-3rd generation precatalyst (53 mg, 0.0588 mmol) was added and the reaction mixture was degassed again for 30 min and then heated at 110 °C for 16 h. After completion, the reaction mixture was cooled to room temperature and filtered through a bed of Celite. The filtrate was diluted with water (50 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by RP preparative HPLC to give tert-butyl (3R,4S)-3-((4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)amino)-4-fluoropyrrolidine-1-carboxylate (2) (550 mg, 52% yield). MS (ESI) m / z 531.6 [M+H]

[0411] Step 2: To a solution of tert-butyl (3R,4S)-3-((4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)amino)-4-fluoropyrrolidine-1-carboxylate (2) (550 mg, 0.001039 mmol) in dioxane (5 mL) at 0° C. was added 4N HCl in dioxane (2 ml) at 0° C. The reaction was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was evaporated under reduced pressure to give the crude material which was triturated with diethyl ether (15 mL) to give (3R,4S)-N-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-4-fluoropyrrolidin-3-amine (3) (300 mg, 71%). MS (ESI) m / z 431.51[M+H].

[0412] Step 3: To a solution of (3R,4S)-N-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-4-fluoropyrrolidin-3-amine (3) (700 mg, 1.6269 mmol) in DMF (5 mL) was added 3-iodo Doped propane (4) (183.1 mg, 1.9523 mmol) and TEA (0.67 ml, 4.8807 mmol) were added at room temperature. The reaction was stirred at room temperature for 16 hours. After completion, the reaction mixture was cooled to room temperature, diluted with water (5 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were collected, dried over Na2SO4, filtered and evaporated to give a crude residue. The crude was purified by RP prep-HPLC to give (3R,4S)-N-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-4-fluoro-1-propylpyrrolidin-3-amine (500 mg, 1.0586 mmol, 65%). MS(ESI)m / z 473.61[M+H]

[0413] Step 4: (3R,4S)-N-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-4-fluoro-1-propylpyrrolidin-3-amine (500 mg, 1.0586 mmol) was purified by chiral SFC to give (3R,4S)-N-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H 1H-pyrido[3,4-b]indol-1-yl)phenyl)-4-fluoro-1-propylpyrrolidin-3-amine (compound 85) (0.0566 g, 1.1983 mmol, 11%), and (3S,4R)-N-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-4-fluoro-1-propylpyrrolidin-3-amine (compound 86) (0.1537 g, 30%) were obtained. Compound 85: MS (ESI) m / z 471.40 [MH]: 1H NMR(400MHz,DMSO-d6)δ10.24(s,1H),7.35(d,J=7.6Hz,1H),7.19(d,J=8.0Hz,1H),6.98-6.9 (m,4H),6.61(d,J=8.4Hz,2H),5.56(d,J=8.8Hz,1H),5.01-5.03(m,1H),4.78(s,1H),3.46-3 .44(m,1H),2.93-2.86(m,2H),2.85-2.66(m,2H),2.43-2.34(m,3H),2.19(s,1H),1.74(m,3H) ),1.59(d,J=8Hz,3H),1.44-1.38(q,J=16Hz,2H),1.09(d,J=4Hz,3H),0.85(t,J=9.6Hz,3H).Compound 86:MS(ESI)m / z 471.40[MH]-;1H NMR(400MHz,DMSO-d6)δ10.24(s,1H),7.35(d,J=8.8Hz,1H),7.19(d,J=8.0Hz,1H),6.98-6.89(m,4H),6. 62(d,J=8.4Hz,2H),5.17(s,1H),4.78(brs,1H),4.1-3.8(m,1H),3.45(d,J=6.4Hz,2H),3.2(dd,1H),2.95 (t,J=8.0Hz,1H),2.86(dd,J=4.8Hz,1H),2.72-2.75(m,2H),2.48-2.3(m,3H),2.20(s,1H),1.73,(d,J=8. 8Hz,3H), 1.59(d,J=9.2Hz,3H),1.44-1.41(q,J=7.62H),1.10(d,J=6.4Hz,3H),0.87-0.83(t,J=7.2,3H). Absolute stereochemistry was arbitrarily assigned to compound 85 and compound 86.

[0414] Example 87 (3R,4R)-N-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-4-fluoro-1-propylpyrrolidin-3-amine (compound 87)

[0415] [ka]

[0416] Compound 87 was prepared following a procedure similar to that described for Example 49. MS(ESI) m / z 473.37[M+H] + ; 1H NMR(400MHz,DMSO-d6)δ10.25(s,1H),7.36(d,J=7.6Hz,1H),7.19(d,J=8.0Hz,1H),7.02(d,J=8.0Hz, 2H),6.98-6.9(m,2H),6.53(d,J=7.6Hz,2H),5.75(d,J=6.0Hz,1H),4.78(t,J=7.6Hz,2H),3.92-3.78( m,1H),3.44(q,1H),3.33(m,1H),2.92-2.86(m,2H),2.56-2.38(m,2H),2.38(q,2H),2.12(m,1H),2.09 (q,1H),1.74(d,J=9.6Hz,3H),1.59(d,J=8.8Hz,3H),1.39(q,2H),1.14(d,J=9.2Hz,3H),0.86(t,3H).

[0417] Example 88 N-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(2,2-difluoropropyl)azetidin-3-amine (compound 88)

[0418] [ka]

[0419] Compound 88 was prepared following a procedure similar to that described for Example 49. MS(ESI) m / z 477.3 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ10.21(s,1H),7.35(d,J=7.6Hz,1H),7.18(d,J=8.0Hz,1H),6 .98-6.88(m,4H),6.42(d,J=8.4Hz,2H),5.94(d,J=6.8Hz,1H),4.77(s,1H),3.96(q,J =6.4Hz,1H),3.72(t,J=6.8Hz,2H),3.46-3.42(m,1H),2.95-2.85(m,3H),2.79(t,J=1 4.0Hz, 2H), 2.57-2.49 (m, 1H), 2.19 (s, 1H), 1.75-1.52 (m, 9H), 1.10 (d, J = 6.4Hz, 3H).

[0420] Example 89 (3S,5S)-N-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-5-methyl-1-propylpyrrolidin-3-amine (compound 89)

[0421] [ka]

[0422] Compound 89 was prepared according to a procedure similar to that described for Example 49. MS (LCMS) m / z 469.4 [M+H], 1H NMR (400MHz, DMSO-d6) δ 10.21 (s, 1H), 7.35 (d, J = 7.6Hz, 1H), 7.21 (d, J = 7.6Hz, 1H), 6.97-6.89 (m, 4H), 6.46 (d, J = 8.40Hz, 2H), 5.54 (d, J = 6.8Hz, 1H), 4.76 (s, 1H), 3.75 (q, J = 6.4Hz, 1H), 3.45 (t, J = 9.2Hz 1H), 2.89-2.85 (m, 1H), 2 .64(d,J=11.6Hz,2H),2.57-2.49(m,2H),2.45(s,1H),2.19(s,1H),1.98-1.96(m,1H),1.92-1.88(m,1H),1.73-1 .68(m,5H),1.59(d,J=9.2Hz,3H),1.10-1.09(d,J=6.0Hz,3H),1.05-1.04(d,J=6.40Hz,3H),0.85(t,J=7.2Hz,3H)

[0423] Example 90 3-((1S,3S)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentane-1-carbonitrile (compound 90) Example 91 3-((1S,3S)-1-(2,6-difluoro-4-(((R)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)bicyclo[1.1.1]pentane-1-carbonitrile (compound 91)

[0424] [ka]

[0425] Compounds 90 and 91 were prepared following procedures similar to those described above for Examples 32 and 33. Compound 90: MS (ESI) m / z 533.41 [MH] - ; 1 H NMR(400MHz,DMSO-d6)δ10.51(s,1H),7.37(d,J=7.6Hz,1H),7.18(d,J=8.0Hz,1H),6. 98(dt,J=46Hz,7.6Hz,2H),6.62(d,J=11.2Hz,1H),5.22(s,1H),4.89(s,1H),4.48(dt, J=47Hz,6Hz,2H),3.53(brs,1H),2.91-2.85(m,1H),2.83-2.81(m,1H),2.71-2.56(m,3 H),2.50-2.24(m,7H),2.07(d,J=8.8Hz,3H),1.86-1.74(m,3H),1.07(d,J=6.4Hz,3H). HPLC: 98.77%, LCMS: 99.78% and chiral SFC: 99.89%. Compound 91:MS(ESI)m / z 533.38[MH] - ; 1 H NMR(400MHz,DMSO-d6)δ10.51(s,1H),7.37(d,J=7.6Hz,1H),7.18(d,J=8.0Hz,1H),6.90(t,J =6.8Hz,1H),6.93(t,J=7.2Hz,1H),6.62(d,J=10.8Hz,1H),5.22(s,1H),4.89(s,1H),4.54(t, J=6Hz,1H), 4.41(t,J=6Hz,1H), 3.53(brs,1H), 2.91-2.85(m,1H), 2.83-2.81(m,1H), 2.71-2.49(m,3H), 2.50-2.24(m,7H), 2.07(d,J=8.8Hz,3H), 1.86-1.74(m,3H), 1.07(d,J=6.4Hz,3H). HPLC: 98.94%, LCMS: 99.74% and chiral SFC: 99.90%. Absolute stereochemistry was arbitrarily assigned to compound 90 and compound 91.

[0426] Example 92 N-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3-fluoro-5-methoxyphenyl)-1-(3-fluoropropyl)azetidin-3-amine (Compound 92)

[0427] [ka]

[0428] Compound 92 was prepared following a procedure similar to that described for Example 49. MS(ESI) m / z 507.30[M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ10.16(s,1H),7.31(d,J=7.2Hz,1H),7.16(d,J=7.6Hz,1H),6.9- 6.86(m,2H),6.31(d,J=6.8Hz,1H),6.02(s,1H),5.72(dd,J=14Hz,3.6Hz,1H),5.32(s,1 H),4.52-4.37(dt,J1=47.6Hz,J2=6.0Hz,2H),3.95-3.92(m,1H)3.77(s,3H),3.65-3.60 (m,3H),2.89-2.85(m,1H),2.74-2.69(m,2H),2.47-2.44(m,3H),2.17(s,1H),1.74-1.5 5(m,8H),1.23(m,1H),1.05(d,J=6.4Hz,3H).

[0429] Example 93 N-((1-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)piperidin-4-yl)methyl)propan-1-amine (compound 93)

[0430] [ka]

[0431] Step 1: To a stirred solution of (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(4-bromophenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (Example 31, Intermediate 2) (1 g, 2.46 mmol) in toluene (10 mL), 4-(dimethoxymethyl)piperidine (0.58 g, 3.69 mmol) and NaO t Bu (0.7 g, 7.39 mmol) was added. The reaction mixture was degassed under argon for 15 min. Then Pd2(dba)3 (0.22 g, 0.246 mmol) and X-Phos (0.23 g, 0.49 mmol) were added and the reaction mixture was degassed again for 10 min. It was then heated at 110° C. for 16 h. After completion, the reaction mixture was cooled to room temperature and filtered through a celite pad. The filtrate was diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by column chromatography (40-45% EtOAc:petroleum ether) to give (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (0.7 g, 0.11 mmol, 58% yield). MS(ESI) m / z 486.66[M+H] + ;

[0432] Step 2: To a solution of (1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-1-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (2) (1.6 g, 3.298 mmol) in THF (16 mL) was added 2N H2SO4 (66 ml, 40 V) at 0° C. The reaction mixture was further stirred at RT for 1 h. After completion of the reaction, the reaction mixture was carefully quenched with 5M NaOH (30 mL) and extracted with (10% MeOH:DCM) (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 1-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)piperidine-4-carbaldehyde (0.8 g, 55% yield) (3). The crude product was carried on directly to the next step without purification.

[0433] Step 3: To a stirred solution of 1-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)piperidine-4-carbaldehyde (300 mg, 0.6829 mmol) in trifluoroethanol (3 mL) at 40 °C, propan-1-amine (3) (403 mg, 6.8296 mmol) was added. The reaction mixture was stirred at the same temperature for 5 min, followed by the addition of NaBH4 (129 mg, 3.4145 mmol) and further stirring for 1 h. The reaction was monitored by TLC (10% MeOH:DCM). The reaction mixture was cooled to room temperature, filtered through Celite, and the filtrate was concentrated. The residue was purified by RP preparative HPLC to give N-((1-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)piperidin-4-yl)methyl)propan-1-amine (compound 93) (52.3 mg, 0.1078 mmol, yield: 15%), HPLC purity: 99.12%, LCMS purity: 99.21%, chiral SFC: 99.38%. MS(ESI) m / z 481.63[MH] + ; 1 H NMR(400MHz,DMSO-d6)δ10.3(s,1H),7.37-7.35(d,J=7.6Hz,1H),7.20-7.18(d,J=7.6Hz,1H),7.10-7.08(d,J=8.8Hz, 2H),6.98-6.89(m,2H),6.85-6.83(d,J=8.8Hz,2H),4.85(s,1H),3.62(d,J=12.4Hz,2H),3.49-3.45(m,1H),2.95-2.90 (dd,J=4.4Hz,J=14.8Hz,1H),2.58(t,J=14.8Hz,3H),2.47-2.39(m,4H),2.21(s,1H),1.74(t,J=10Hz,5H),1.58(d,J= 9.2Hz,4H),1.43(q,J=7.6Hz,J=14.8Hz,2H),1.18(d,J=2.8Hz,2H),1.10(d,J=6.8Hz,3H),0.83-0.87(t,J=7.2Hz,3H),

[0434] Example 94 6-((1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-N-(1-(3-fluoropropyl)azetidin-3-yl)-5-methoxypyridin-3-amine (compound 94)

[0435] [ka]

[0436] Compound 94 was prepared following a procedure similar to that described for Example 49 (47.4 mg, 0.0969 mmol, 14.23%) with HPLC purity: 97.60%, LCMS: 97.99%, and chiral SFC: 97.99%. MS(ESI) m / z 488.40 [MH] + ; 1 H NMR(400MHz,DMSO-d6)δ10.34(s,1H),7.34(d,J=7.2Hz,1H),7.23(d,J=2Hz,1H),7.13(d,J=7.6Hz,1H), 6.97-6.87(m,2H),6.53(d,J=2Hz,1H),6.21(d,J=7.2Hz,1H),6.51(d,J=2.0Hz,1H),5.41(s,1H),3.59(s ,1H),4.50-4.37(dt,J1=47.2Hz,J2=6.0Hz,1H),3.99(t,J=6.8Hz,1H),3.80(d,J=7.6Hz,3H),3.66(t,J =6.8Hz,2H),2.79-2.72(m,4H),2.58-2.47(m,2H),2.20(s,1H),1.79-1.60(m,8H)1.15(d,J=7.2Hz,3H),

[0437] Example 95 (3R,4R)-4-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidin-3-ol (compound 95) Example 96 (3S,4S)-4-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidin-3-ol (compound 96)

[0438] [ka]

[0439] Compounds 95 and 96 were prepared following procedures similar to those described above for Examples 32 and 33. Compound 95: MS (LCMS) m / z 490.3 [M+H]+ 1 H NMR(400MHz,DMSO-d6))δ10.32(s,1H),7.37(d,J=7.6Hz,1H),7.19(dd,J1=7.6Hz,J2=2.4Hz ,3H),6.99-6.89(m,2H),6.86(d,J=8.8Hz,2H),5.31(brs,1H),4.89(s,1H),4.54-4.39(m,3 H),3.49(q,1H),4.07(s,1H),2.94-2.88(m,3H),2.61-2.50(m,2H),2.50-2.44(m,2H),2.30 (t,J=5.2Hz,1H),2.20(s,1H),1.80-1.72(m,5H),1.59-1.52(m,3H),1.11(d,J=6.4Hz,3H). LCMS purity 99.48% (chiral HPLC: 99.92%). Compound 96:MS(LCMS)m / z490.30[M+H]+ 1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),7.37(d,J=7.6Hz,1H),7.20(m,3H),7.01-6.92(m,2H),6.86( d,J=8.8Hz,2H),5.30(brs,1H),4.89(s,1H),4.53-4.39(dt,J1=47.2Hz,J2=6Hz,2H),4.47-4.49(m, 1H), 4.10(s,1H), 3.46(s,1H), 2.96-2.88(m,3H), 2.61-2.52(m,2H), 2.52-2.45(m,2H), 2.31(q,J1=9.6Hz,J2=5.2Hz1H), 2.21(s,1H), 1.80-1.72(m,5H), 1.57(d,J=9.2Hz,3H), 1.10(d,J=6.8Hz,3H). LCMS purity 99.69% (chiral HPLC: 99.69%). Absolute stereochemistry was arbitrarily assigned to compound 95 and compound 96.

[0440] Example A Breast cancer cell proliferation assay (MCF-7) MCF7 were grown and maintained in culture medium (phenol red-free DMEM / F12 (Hyclone SH30272.01) NEAA (Gibco 11140-050) sodium pyruvate (Gibco 11360-070) and charcoal stripped FBS (Gemini 100-119)). Cells were adjusted to a concentration of 3,000 cells per mL in the above culture medium and cells were incubated (37 °C, 5% CO2). The next day, 10-point serial dilutions of compounds were added to the cells at final concentrations ranging from 10 to 0.000005 μM for the test compounds (17β-estradiol was used as a control). Additional cells were seeded in 30 wells to serve as a comparison for day 1 (pre-treatment). After 5 days of compound exposure, Cell Titer-Glo reagent was added to the cells and the relative luminescence units (RLU) of each well were determined. Cell Titer-Glo was also added to 32 μL medium without cells to obtain background values. The plates were allowed to incubate at room temperature for 10 minutes to allow the luminescence signal to stabilize, and the luminescence signal was recorded on the EnSpire. The relative increase in cell number for each sample is determined as follows: (RLU sample-RLU background / RLU estrogen only treated cells-RLU background)×100=% inhibition. The results are summarized in Table 2.

[0441] Example B ER degradation determination by Western blot MCF-7 cells were seeded in 6-well plates in experimental medium at 300,000 cells / mL (3 mL / well) and incubated for 48 h at 37 °C, 5% CO2. The next day, 10x solutions of compounds were made in DMSO and the solutions were added to the cells to achieve a final concentration of 10 μM. DMSO controls were included to allow for determination of the relative efficacy of test compounds. Fulvestrant was used as a positive control for ER-α degradation and 4-OH tamoxifen as a control for receptor stabilization. After incubating cells with compounds for 18-24 h, cell lysates were prepared (2x cell lysis buffer: 100 mM Tris, pH 8, 300 mM NaCl, 2% NP40, 1% sodium deoxycholate, 0.04% SDS, 2 mM EDTA), mixed thoroughly, and incubated on ice. Protein concentrations were quantified using a BCA kit. Proteins were separated on a 4%-20% NuPAGE® Novex® 4-12% Bis-Tris protein gel using 1×MES running buffer. The gel was then transferred onto a nitrocellulose membrane. The blot was probed with an antibody against ESR1 protein (Santa Cruz, sc-8005). GAPDH protein was used as an internal control. The results are summarized in Table 2.

[0442] [Table 11]

[0443] [Table 12]

[0444] I C 50 :A=Single IC 50 ≤ 25nM; B = single IC 50 ≧25nM and ≦250n M;C = single IC 50 >= 250 nM. ND: Not determined.

[0445] Example C Pharmacokinetic Determination Female CD-1 mice weighing 20-30 g were randomly grouped into three groups, one group was administered with a dose of 3.0 mg / kg of test compound by intravenous injection, and the other two groups were administered with a dose of 10.0 mg / kg of test compound by oral administration. The formulation of the IV group was DMSO / PEG400 / 30% HP-β-CD (5 / 20 / 75), and the formulation of the PO group was 25% HP-β-CD in 25 mM citrate buffer (pH 3.0). After administration, blood samples of the intravenous injection group were collected at pre-dose, 0.0833, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours, and blood samples of the oral administration group were collected at pre-dose, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours. Both blood and brain samples were taken 2 hours after dosing for the second PO group.Standard curves were plotted based on the appropriate range of sample concentrations, and the concentrations of test compounds in plasma and brain samples were determined by using LC-MS / MS.Pharmacokinetic parameters were calculated according to the drug concentration-time curves using non-compartmental methods by WinNonLin (Phoenix™, version 6.1) or other similar software.The results are summarized in Table 3.

[0446] [Table 13]

[0447] [Table 14]

[0448] ND: Undecided. B / P ratio: brain concentration versus plasma concentration at 2 hours post-dose.

[0449] Example D Efficacy studies in the MCF-7 human breast cancer orthotopic model MCF-7 tumor cell lines were maintained in vitro as monolayer cultures in DMEM medium supplemented with 15% heat-inactivated fetal bovine serum at 37°C in an atmosphere of 5% CO2 in air. Medium was renewed every 2-3 days and tumor cells were routinely subcultured at 80%-90% confluence by trypsin-EDTA for no more than 4-5 passages. Growing cells in the exponential phase were harvested and counted for tumor inoculation.

[0450] Each mouse received 95% viable tumor cells (1.5 × 10 cells) in 200 μL of serum-free DMEM Matrigel mixture (1:1 ratio) for tumor development. 7 ) single cell suspension was inoculated subcutaneously onto the second right mammary fat pad. The mean tumor size was 195 mm 3 Treatment was initiated when

[0451] Tumor size was measured twice a week using a caliper and tumor volume (mm 3 ) throughout the test using the formula: TV = a × b 2 / 2, where "a" and "b" were the long and short diameters of the tumor, respectively. TV was estimated using the formula: (1-(T d -T0) / (C d -C0)) × 100% was used to calculate the tumor growth inhibition (TGI, an index of antitumor efficacy) value. d and C d is the mean tumor volume of treated and control animals, and T0 and C0 are the mean tumor volumes of treated and control animals at the start of the experiment. Tumor regression was defined as the individual tumor volume reduction (end TV compared to initial TV). The tumor regression rate was calculated using the formula: (1-(T d Calculated using / T0)) × 100%.

[0452] Plasma samples were collected for PK analysis at seven time points (0.25, 0.5, 1, 2, 4, 8, and 24 hours) after the last dose. Tumor samples were collected for PK analysis at three time points (2, 8, and 24 hours) after the last dose.

[0453] Tumor growth inhibition and PK data are summarized in Table 4.

[0454] Table 4. In vivo efficacy

[0455] [Table 15]

[0456] Moreover, although the above has been described in some detail with reference to the figures and examples for clarity and understanding, it will be understood by those skilled in the art that numerous and various modifications may be made without departing from the spirit of the present disclosure. It should therefore be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather encompass all modifications and alternative forms consistent with the true scope and spirit of the present invention.

Claims

1. A compound of formula (I) having the structure: 【Chemistry 1】 During the ceremony, each X １ , X ２ , X ３ and X ４ is independently N or CR ２ and Y is a bond, alkenyl (C １～６ Alkenyl or C １～３ alkenyl, etc.), -O(CR ３ R ４ ) ｍ -, or -NH(CR ５ R ６ ) ｎ - and R １ H, F, OH, CN, alkyl (C １～６ Alkyl or C １～３ alkyl, haloalkyl (C １～６ Haloalkyl or C １～３ haloalkyl, etc.), alkoxy (C １～６ Alkoxy or C １～３ alkoxy, amide, or hydroxyalkyl (C １～６ Hydroxyalkyl or C １～３ hydroxyalkyl, Each R ２ , R ３ , R ４ , R ５ and R ６ are independently H, halogen (such as F, Cl, or Br), alkoxy (C １～６ Alkoxy or C １～３ alkoxy, etc.), or alkyl (C １～６ Alkyl or C １～３ alkyl, etc.), R ７ is H or a halogen (such as F, Cl or Br), m and n are each 0, 1 or 2; A is halogen, CN, OH, alkyl (C １～６ Alkyl or C １～３ Alkyl, etc.), alkenyl (C １～６ Alkenyl or C １～３ alkenyl, etc.), alkynyl (C １～６ Alkynyl or C １～３ alkynyl, etc.), cycloalkyl (C ３～６ cycloalkyl, haloalkyl (C １～６ Haloalkyl or C １～３ haloalkyl, haloalkylamino (C １～６ Haloalkylamino or C １～３ haloalkylamino, haloalkoxy (C １～６ Haloalkoxy or C １～３ haloalkoxy, etc.), hydroxyalkyl (C １～６ Hydroxyalkyl or C １～３ hydroxyalkyl, etc.), or cyanoalkyl (C １～６ Cyanoalkyl or C １～３ heterocyclyl (such as azetidinyl or pyrrolidinyl), optionally substituted with one or more substituents selected from A compound, or a pharma- ceutically acceptable salt thereof.

2. X1, X ２ , X ３ and X ４ However, each ２ 2. The compound of claim 1, wherein:

3. R １ is H, or a pharma- ceutically acceptable salt thereof.

4. R １ is hydroxyalkyl (C １～６ Hydroxyalkyl or C １～３ hydroxyalkyl, or a pharma- ceutically acceptable salt thereof.

5. R ２ is H, or a pharma- ceutically acceptable salt thereof.

6. R ２ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein is halogen (such as F, Cl or Br).

7. Y is -O(CR ３ R ４ ) ｍ The compound of claim 1, wherein R is -, or a pharma- ceutically acceptable salt thereof.

8. 8. The compound of claim 7, wherein m is 0, or a pharma- ceutically acceptable salt thereof.

9. 8. The compound of claim 7, or a pharma- ceutically acceptable salt thereof, wherein m is 1 or 2.

10. R ３ and R ４ or a pharma- ceutically acceptable salt thereof.

10. The compound of claim 9, wherein at least one of:

11. Y is -NH(CR ５ R ６ ) ｎ The compound of claim 1, wherein R is -, or a pharma- ceutically acceptable salt thereof.

12. 12. The compound of claim 11, or a pharma- ceutically acceptable salt thereof, wherein n is 0.

13. 12. The compound of claim 11, or a pharma- ceutically acceptable salt thereof, wherein n is 1 or 2.

14. R ５ and R ６ or a pharma- ceutically acceptable salt thereof.

14. The compound of claim 13, wherein at least one of:

15. R ７ is H, or a pharma- ceutically acceptable salt thereof.

16. 2. The compound of claim 1, wherein A is an unsubstituted 3-6 membered N-containing heterocyclyl, such as azetidinyl or pyrrolidinyl, or a pharma- ceutically acceptable salt thereof.

17. A is F, CN, C １～３ Alkyl, C ３～６ Cycloalkyl, C １～３ Fluoroalkyl, C １～３ Fluoroalkylamino, C １～３ Fluoroalkoxy, C １～３ Hydroxyalkyl, or C １～３ 2. The compound of claim 1, which is a 3-6 membered N-containing heterocyclyl (such as azetidinyl or pyrrolidinyl) substituted with cyanoalkyl, or a pharma- ceutically acceptable salt thereof.

18. 18. The compound of claim 17, or a pharma- ceutically acceptable salt thereof, wherein A is substituted with F.

19. 18. The compound of claim 17, or a pharma- ceutically acceptable salt thereof, wherein A is substituted with CN.

20. A is C １～３ 20. The compound of claim 17, or a pharma- ceutically acceptable salt thereof, which is substituted with alkyl.

21. A is C ３～６ 20. The compound of claim 17, or a pharma- ceutically acceptable salt thereof, which is substituted with cycloalkyl.

22. A is C １～３ 20. The compound of claim 17, or a pharma- ceutically acceptable salt thereof, which is substituted with fluoroalkyl.

23. A is C １～３ 20. The compound of claim 17, or a pharma- ceutically acceptable salt thereof, which is substituted with fluoroalkylamino.

24. A is C １～３ 20. The compound of claim 17, or a pharma- ceutically acceptable salt thereof, which is substituted with fluoroalkoxy.

25. A is C １～３ 18. The compound of claim 17, or a pharma- ceutically acceptable salt thereof, which is substituted with hydroxyalkyl.

26. A is C １～３ 20. The compound of claim 17, or a pharma- ceutically acceptable salt thereof, which is substituted with cyanoalkyl.

27. 13. A pharmaceutical composition comprising an effective amount of a compound of claim 1, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, diluent, excipient, or combination thereof.

28. 28. A pharmaceutical composition according to claim 27 for use in a method for inhibiting cell growth, comprising: The method further comprises identifying a cell having an estrogen receptor alpha that mediates a growth characteristic of the cell; contacting said cell with an effective amount of the compound of claim 1, or a pharma- ceutically acceptable salt thereof.

29. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, having a structure selected from compound structures 1 to 96 set forth in the table below. 【Table 1】 【Table 2】 【Table 3】 【Table 4】 【Table 5】 【Table 6】 【Table 7】 【Table 8】 【Table 9】 【Table 10】 【Table 11】 【Table 12】 【Table 13】 【Table 14】 【Table 15】 【Table 16】 【Table 17】 【Table 18】 【Table 19】 【Table 20】 【Table 21】 【Table 22】 【Table 23】 【Table 24】 【Table 25】

30. A compound, or a pharma- ceutically acceptable salt thereof, having a structure selected from compounds 1, 2, 6, 10, 15, 16, 18, 19, 20, 23, 31, 38, 39, 40, 42, 50, 52, 58, 70, 72, and 75 set forth in the table below. 【Table 26】 【Table 27】 【Table 28】 【Table 29】 【Table 30】 【Table 31】

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