Factor d inhibitors

Abstract

The present invention relates to benzopyrazole compounds and analogs thereof. Disclosed are compounds of Formula (I) and pharmaceutically acceptable salts thereof. The compounds are inhibitors of the complement system. Also provided are pharmaceutical compositions comprising a compound of Formula (I), and methods relating to the use of the compounds and compositions to treat and prevent diseases and conditions characterized by aberrant complement system activity.

Description

[0001] This application is a divisional application. The original application was filed on February 1, 2017, with application number 201780021413.X (PCT / US2017 / 015953) and the invention title "Benzopyrazole Compounds and Their Analogs".

[0002] Related applications

[0003] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 289,653, filed February 1, 2016, the contents of which are incorporated herein by reference. Background Technology

[0004] The complement system is a branch of an organism's immune system that enhances the ability of antibodies and phagocytes to destroy and remove foreign particles (such as pathogens) from the organism. The complement system comprises a group of plasma proteins that work together to attack the extracellular form of pathogens and induce a series of inflammatory responses to help fight infection. Complement activation can occur through several pathways. For example, complement activation can occur spontaneously in response to certain pathogens or through antibody binding to pathogens. When complement proteins are activated, a cascade is triggered, through which one complement protein induces the activation of the next protein in the sequence. The activation of a small amount of complement protein at the beginning of the pathway is greatly amplified by each successive enzymatic reaction, resulting in a disproportionately large complement response. (Marrides, S. Pharmacological Reviews, 1998, Vol. 50, pp. 59-88). In healthy organisms, regulatory mechanisms exist to prevent uncontrolled complement activation.

[0005] When activated, complement proteins bind to pathogens, making them susceptible to phagocytosis by phagocytes carrying complement receptors. Small fragments of these proteins then act as chemical attractants, recruiting more phagocytes to complement activation sites and activating them as well. Subsequently, complement proteins create pores or pinholes in the invading organism, causing damage. While complement plays a vital role in protecting the body from foreign organisms, it can also damage healthy cells and tissues. Inappropriate complement activation is involved in a long list of pathologies affecting the immune, renal, cardiovascular, and nervous systems (Morgan, B., *European Journal of Clinical Investigation*, 1994, Vol. 24, pp. 219-228). Summary of the Invention

[0006] In some aspects, the present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof:

[0007]

[0008] Among them, each occurrence is independent:

[0009] R 1 Indicates an aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, or alkenyl group that may be optionally substituted.

[0010] R 2 and R 3 Each of the following can be independently represented as an alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, hydroxyalkyl, (alkathio)alkyl, aralkyl, heteroaralkyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, or (heterocycloalkyl)alkyl;

[0011] Or R 2 and R 3 Together with the carbon atom it is bonded to, it forms an optionally substituted cycloalkyl or heterocycloalkyl ring;

[0012] R 4 The alkyl, alkenyl, ynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aralkyl, heteroaralkyl, hydroxyalkyl, or haloalkyl groups are represented by H or optionally substituted alkyl.

[0013] X represents NH, CH2, CHF, CF2, CH(C1-C6)alkyl or C((C1-C6)alkyl)2;

[0014] Y does not exist or represents CH2, C(O), CR 15 R 16 S(O)2 or optionally substituted (C3-C7) cycloalkylene, arylene or heteroarylene;

[0015] R a H represents (C1-C6) alkyl, (heterocyclic) alkyl, or (C3-C7) cycloalkyl, which may be substituted.

[0016] m is an integer from 1 to 6;

[0017] n is 0 or 1;

[0018] R 15 and R 16 Each is independently selected from the following groups: H, hydroxyl, halogen, -C(O)OR 17 -OR 17 -C(O)NR 17 R 18 -NR 17 R 18Alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaryl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, and (heterocycloalkyl)alkyl, wherein the alkyl, aryl, aralkyl, heteroaryl, heteroaryl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, and (heterocycloalkyl)alkyl are optionally selected from one or more of -CN, -OR 17 -NR 17 R 18 Substituents of the group consisting of halogens and alkyl groups;

[0019] or R 15 and R 16 It can form, together with intermediate atoms, optional substituted carbon rings or heterocycles;

[0020] R 17 and R 18 Each is independently selected from the group consisting of: H, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl and (heterocycloalkyl)alkyl;

[0021] or R 17 and R 18 When attached to the same atom, it can form an optionally substituted heterocycle together with the intermediate atom;

[0022] express

[0023] Z 1 and Z 3 Each can be represented independently as C or N;

[0024] Z 2 Indicates N, CH, or CF;

[0025] Z 4 Indicates N or CR 8 ;

[0026] Z 5 Indicates N or CR 5 ;

[0027] Z 6 Indicates N or CR 6 ;

[0028] Z 7 Indicates N or CR 9 ;

[0029] Z 8 and Z 9 Each can be represented independently as N or CR. 19 ;

[0030] R 5 and R 6 Each can be independently represented as H, halogen, -CN, -NO2, or -OR. 13 -NR 13 R 14 -C(O)R 13 -C(O)OR 13 -C(O)NR 13 R 14 -OC(O)R 13 -NR 13 C(O)R 14 -OC(O)NR 13 R 14 -OC(O)OR 13 -NR 13 C(O)OR 14 -NR 13 C(O)NR 13 R 14 -OS(O) p (R 13 -NR 13 S(O) p (R 14 ), or optionally substituted alkyl, alkenyl, alkynyl, haloalkyl, aralkyl, heteroaryl, heteroaryl, aryl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl or (heterocycloalkyl)alkyl;

[0031] L represents -H, -CN, -C(O)R 7 -CH(OH)R 7 or -S(O) p (alkyl);

[0032] R 7 Each time it appears, it independently represents H, NH2, CH3, OH, CF3, CH2OH, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, halogen(C1-C6)alkyl, NH(C1-C6)alkyl, N((C1-C6)alkyl)2;

[0033] R 8 and R 9 Each can be used independently to represent H, halogen, and -OR. 13 -NR 13 R 14 -C(O)R 13 -C(O)OR 13 -C(O)NR 13 R 14-OC(O)R 13 -NR 13 C(O)R 14 -OC(O)NR 13 R 14 -OC(O)OR 13 -NR 13 C(O)OR 14 -NR 13 C(O)NR 13 R 14 -OS(O) p (R 13 -NR 13 S(O) p (R 14 ), or optionally substituted alkyl, alkenyl, ynyl, haloalkyl, aralkyl, heteroaryl, heteroaryl or aryl;

[0034] or R 5 and R 8 、or R 5 and R 6 、or R 6 and R 9 It can form, together with intermediate atoms, optional substituted heterocycles or carbocycles;

[0035] R 13 and R 14 Each time it appears, it independently represents H or optionally substituted alkyl, alkenyl, ynyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, or (heterocycloalkyl)alkyl; or, when R 13 and R 14 When attached to the same atom, R 13 and R 14 Together with the aforementioned atoms, they can form optionally substituted heterocycles;

[0036] R 19 Each occurrence is independently represented by H, F, CN, -C(O)R. 7 -CH(OH)R 7 or -S(O) p (alkyl);

[0037] J represents H or NH2; and

[0038] p is 0, 1, or 2;

[0039] Where Z 1 Is it N, or if express Then X represents CH2.

[0040] In some aspects, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

[0041] In some aspects, the present invention provides a method for treating or preventing a disease or condition characterized by abnormal complement system activity. The method comprises the step of administering a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to a subject in need, thereby treating or preventing the disease or condition characterized by abnormal complement system activity. In some embodiments, the disease or condition characterized by abnormal complement system activity is an immune disorder. In some embodiments, the disease or condition characterized by abnormal complement system activity is a central nervous system disorder. In some embodiments, the disease or condition characterized by abnormal complement system activity is a neurodegenerative disease or a nervous system disorder. In some embodiments, the disease or condition characterized by abnormal complement system activity is a kidney disease. In some embodiments, the disease or condition characterized by abnormal complement system activity is a cardiovascular disease. In some embodiments, diseases or conditions characterized by abnormal complement system activity are selected from the group consisting of: paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, organ transplant rejection, myasthenia gravis, neuromyelitis optica, membranoproliferative glomerulonephritis, dense deposit disease, cold agglutinin disease, and catastrophic antiphospholipid syndrome. Detailed Implementation

[0042] Inhibitors of the complement system have been reported and can be used in treatments and compositions suitable for the treatment or prevention of various immune disorders, neurodegenerative diseases, and central nervous system diseases. This article provides compounds of formula (I) suitable for the treatment or prevention of diseases or conditions characterized by abnormal complement system activity.

[0043] definition

[0044] In this text, the article “a / an” is used to refer to one or more (i.e., at least one) grammatical objects of the article. For example, “an element” means one element or more elements.

[0045] The term "heteroatom" is widely accepted in the field and refers to an atom of any element other than carbon and hydrogen. Illustrated heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur, and selenium, and may be oxygen, nitrogen, or sulfur.

[0046] As used herein, the term "alkyl" is a specific term and refers to a saturated aliphatic group, including straight-chain alkyl, branched-chain alkyl, cycloalkyl (alicyclic), alkyl-substituted cycloalkyl, and cycloalkyl-substituted alkyl. In some embodiments, the straight-chain or branched alkyl has about 30 or fewer carbon atoms in its main chain (e.g., the straight chain is C1-C1). 30The side chain is C3-C. 30 ), and or, about 20 or fewer, or 10 or fewer. In some embodiments, the term "alkyl" refers to C1-C 10 Alkyl. In some embodiments, the term "alkyl" refers to a C1-C6 alkyl group, such as a C1-C6 straight-chain alkyl group. In some embodiments, the term "alkyl" refers to a C3-C6 alkyl group. 12 Branched alkyl groups. In some embodiments, the term "alkyl" refers to a C3-C8 branched alkyl group. Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

[0047] The term "cycloalkyl" refers to a monocyclic, bicyclic, or bridged saturated carbon ring, each having 3 to 12 carbon atoms. Some cycloalkyl groups have 5 to 12 carbon atoms in their ring structure, and some may have 6 to 10 carbon atoms. Cycloalkyl groups are preferably (C3-C7) cycloalkyl groups, which represent monocyclic saturated carbon rings having 3 to 7 carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl ring systems include bridged monocyclic and fused bicyclic rings. Bridged monocyclic rings contain a monocyclic cycloalkyl ring in which two non-adjacent carbon atoms of the monocyclic ring are bridged by an alkylene bridge of one to three additional carbon atoms (i.e., in the form -(CH2)). w - A bridging group, where w is 1, 2, or 3) connected. Representative examples of bicyclic systems include, but are not limited to, bicyclic [3.1.1]heptane, bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane, bicyclic [3.2.2]nonane, bicyclic [3.3.1]nonane, and bicyclic [4.2.1]nonane. Fused bicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ring fused to a phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocyclic, or monocyclic heteroaryl group. The bridging or fused bicyclic cycloalkyl group is connected to the parent molecule moiety via any carbon atom contained within the monocyclic cycloalkyl ring. The cycloalkyl group may optionally be substituted. In some embodiments, the fused bicyclic cycloalkyl group is a 5- or 6-membered monocyclic cycloalkyl ring fused with a phenyl ring, a 5- or 6-membered monocyclic cycloalkyl group, a 5- or 6-membered monocyclic cycloalkenyl group, a 5- or 6-membered monocyclic heterocyclic group, or a 5- or 6-membered monocyclic heteroaryl group, wherein the fused bicyclic cycloalkyl group is optionally substituted.

[0048] As used herein, the term "(cycloalkyl)alkyl" refers to an alkyl group substituted with one or more cycloalkyl groups. An example of a cycloalkyl alkyl group is cyclohexylmethyl.

[0049] As used herein, the term "heterocyclic alkyl" refers to a group comprising, but is not limited to, monocyclic, bicyclic, and tricyclic non-aromatic ring systems, which may be fully saturated or may contain one or more unsaturated units. For the avoidance of ambiguity, the degree of unsaturation does not result in an aromatic ring system, and the group has 3 to 12 atoms, including at least one heteroatom, such as nitrogen, oxygen, or sulfur. For illustrative purposes, but not to be construed as limiting the scope of the invention, the following are examples of heterocycles: aziridinyl, azirinyl, oxiranyl, thiiranyl, thiirenyl, dioxiranyl, diazirinyl, diazepanyl, 1,3-dioxanyl, and dioxolanyl. 1,3-Dithiolanyl, 1,3-Dithianyl, Imidazolyl, Isothiazolinyl, Isothiazolinyl, Isothiazolinyl, Azetyl, Oxetanyl, Oxetyl, Thietanyl, Thietanyl, Diazetidinyl, Dioxetanyl, Dioxetenyl, Dithietanyl, Dithietanyl The heterocyclic alkyl group is substituted with one or more of the substituents described below. The heterocyclic alkyl group may optionally be substituted with one or more of the substituents described below.

[0050] As used herein, the term "(heterocyclic alkyl) alkyl" refers to an alkyl group that is substituted with one or more heterocyclic alkyl groups (i.e., heterocyclic groups).

[0051] As used herein, the term "alkenyl" refers to a straight-chain or branched hydrocarbon group containing 2 to 10 carbons and at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl groups include, but are not limited to, vinyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl. The unsaturated bond of the alkenyl group can be located anywhere in the part and, with respect to the double bond, can have either a (Z) or (E) configuration.

[0052] As used herein, the term "alkynyl" refers to a straight-chain or branched hydrocarbon group containing 2 to 10 carbon atoms and at least one carbon-carbon triple bond. Representative examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

[0053] The term "alkylene" is recognized in the field and, as used herein, refers to a divalent group obtained by removing two hydrogen atoms from an alkyl group as defined above. In one embodiment, alkylene refers to a disubstituted alkane, i.e., an alkane substituted at both positions by substituents such as halogens, azides, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, amino, nitro, mercapto, imino, amide, phosphonate, phosphonite, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclic, aromatic or heteroaromatic moiety, fluoroalkyl (e.g., trifluoromethyl), cyano, etc. That is, in one embodiment, "substituted alkyl" is "alkylene".

[0054] The term "amino" is a specialized term and, as used herein, refers to both unsubstituted and substituted amines, such as portions that can be represented by the following general formula:

[0055]

[0056] Where R a R b and R c Each can independently represent hydrogen, alkyl, alkenyl, or -(CH2). x -R d , or R a and R b Together with the N atom it is attached to, it forms a heterocycle with 4 to 8 atoms in the ring structure; R d This represents an aryl, cycloalkyl, cycloalkenyl, heterocyclic, or polycyclic group; and x is zero or an integer in the range of 1 to 8. In some embodiments, R a or R b Only one of them can be a carbonyl group, for example, R a R bIt does not form an imide when combined with nitrogen. In other embodiments, R a and R b (and optional R) c Each can independently represent hydrogen, alkyl, alkenyl, or -(CH2). x -R d In some embodiments, the term "amino" refers to -NH2.

[0057] In some embodiments, the term "alkylamino" refers to -NH (alkyl).

[0058] In some embodiments, the term "dialkylamino" refers to -N(alkyl)2.

[0059] As used herein, the term "amide group" refers to -NHC(=O)-, where the amide group is partially bonded to the parent molecule via nitrogen. Examples of amide groups include alkyl amide groups, such as CH3C(=O)N(H)- and CH3CH2C(=O)N(H)-.

[0060] The term "acyl" is a specialized term and, as used herein, refers to any group / radical in the form of RCO-, where R is any organic group, such as alkyl, aryl, heteroaryl, aralkyl, and heteroarylalkyl. Representative acyl groups include acetyl, benzoyl, and malonyl.

[0061] As used herein, the term "aminoalkyl" refers to an alkyl group substituted with one or more amino groups. In one embodiment, the term "aminoalkyl" refers to aminomethyl.

[0062] The term "aminoacyl" is a specialized term and, as used herein, refers to an acyl group substituted with one or more amino groups.

[0063] As used in this article, the term "aminothionyl" refers to an analog of amino acyl, in which the O in RC(O)- is replaced by sulfur, and thus the form is RC(S)-.

[0064] The term "phosphoryl group" is a specialized term and, as used herein, can generally be represented by the following formula:

[0065]

[0066] Where Q50 represents S or O, and R59 represents hydrogen, a lower alkyl, or an aryl group; for example, -P(O)(OMe)- or -P(O)(OH)2. When used to replace, for example, an alkyl group, the phosphoryl group of the phosphoryl alkyl group can be represented by the following general formula:

[0067]

[0068] Q50 and R59 are each defined independently as above, and Q51 represents O, S, or N; for example, -OP(O)(OH)OMe or -NH-P(O)(OH)2. When Q50 is S, the phosphoryl group is a "thiophosphate".

[0069] As used herein, the term "aminophosphoryl" refers to a phosphoryl group substituted with at least one amino group as defined herein; for example, -P(O)(OH)NMe2.

[0070] As used in this article, the terms "azide" or "azido group" refer to the -N3 group.

[0071] As used in this article, the term "carbonyl" refers to -C(=O)-.

[0072] As used in this article, the term "thiocarbonyl" refers to -C(=S)-.

[0073] As used herein, the term "alkylphosphoryl" means a phosphoryl group substituted with at least one alkyl group as defined herein; for example, -P(O)(OH)Me.

[0074] As used herein, the term "alkylthio" refers to an alkyl-S- group. The term "(alkylthio)alkyl" refers to an alkyl group substituted with an alkylthio group.

[0075] As used in this article, the term "carboxyl group" refers to the -CO2H group.

[0076] The term "aryl" is a specialized term and, as used herein, refers to monocyclic, bicyclic, and polycyclic aromatic hydrocarbon groups, such as those found in benzene, naphthalene, anthracene, and pyrene. Aryl groups typically contain 6 to 10 carbon ring atoms (i.e., (C6-C1)). 10 (Aryl). The aromatic ring may be substituted at one or more ring positions by one or more substituents, such as halogens, azides, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, amino, nitro, mercapto, imino, amide, phosphonate, phosphonite, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclic, aromatic or heteroaromatic moiety, fluoroalkyl (e.g., trifluoromethyl), cyano, etc. The term "aryl" also includes polycyclic systems having two or more rings, wherein two adjacent rings share two or more carbons (the rings are "fused rings"), wherein at least one ring is an aromatic hydrocarbon, for example, the other rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic. In some embodiments, the term "aryl" refers to phenyl.

[0077] The term “heteroaryl” is a specialized term and, as used herein, refers to a monocyclic, bicyclic, or polycyclic aromatic group having a total of 3 to 12 atoms, including one or more heteroatoms such as nitrogen, oxygen, or sulfur, in its ring structure. Exemplary heteroaryl groups include azaindolyl, benzo(b)thiophenyl, benzoimidazolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzooxadiazolyl, furanyl, imidazolyl, imidazopyridyl, indolyl, indololinyl, inazolyl, isoindololinyl, isoxazolyl, isothiazolyl, isoquinolinyl, oxadiazolyl, oxazolyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrroloyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, quinolinyl, quinazolinyl, triazolyl, thiazolyl, phenylthio, tetrahydroindolyl, tetraazolyl, thiadiazolyl, thiophenyl, thiomorpholinyl, triazolyl, or tropanyl, etc. "Heteroaryl" can be substituted at one or more ring positions by one or more substituents, such as halogens, azides, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, amino, nitro, mercapto, imino, amide, phosphonate, phosphonite, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclic group, aromatic or heteroaromatic moiety, fluoroalkyl (such as trifluoromethyl), cyano, etc. The term "heteroaryl" also includes polycyclic systems having two or more rings, wherein two adjacent rings share two or more carbons (the rings are "fused rings"), wherein at least one ring is an aromatic group having one or more heteroatoms in the ring structure; for example, other rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic groups.

[0078] The term “aralkyl” or “arylalkyl” is a specialized term and, as used herein, refers to an alkyl group substituted with an aryl group, wherein the portion is attached to the parent molecule by the alkyl group.

[0079] The terms “heteroarylalkyl” or “heteroarylalkyl” are specialized terms and, as used herein, refer to an alkyl group substituted with a heteroaryl group, which is attached to the parent molecule moiety by the alkyl group.

[0080] As used herein, the term "alkoxy" means an alkyl group as defined herein that is attached to a parent molecule via an oxygen atom. Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentoxy, and hexoxy.

[0081] The term "alkoxyalkyl" refers to an alkyl group that has been substituted with an alkoxy group.

[0082] The term "alkoxycarbonyl" means that an alkoxy group, as defined herein, is attached to a parent molecule moiety via a carbonyl group represented by -C(=O)-, as defined herein. Representative examples of alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl.

[0083] As used herein, the term "alkyl carbonyl" means an alkyl group as defined herein attached to a parent molecule moiety by a carbonyl group as defined herein. Representative examples of alkyl carbonyl groups include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.

[0084] As used herein, the term "aryl carbonyl" means an aryl group as defined herein attached to a parent molecule moiety via a carbonyl group as defined herein. Representative examples of aryl carbonyl groups include, but are not limited to, benzoyl and (2-pyridyl)carbonyl groups.

[0085] As used herein, the terms “alkylcarbonyloxy” and “arylcarbonyloxy” mean an alkyl or aryl carbonyl group as defined herein, attached to a parent molecule moiety by an oxygen atom. Representative examples of alkylcarbonyloxy groups include, but are not limited to, acetoxy, ethylcarbonyloxy, and tert-butylcarbonyloxy groups. Representative examples of arylcarbonyloxy groups include, but are not limited to, phenylcarbonyloxy groups.

[0086] The term "alkenoxy" or "alkenoxyl" means an alkenyl group, as defined herein, attached to a parent molecule moiety by an oxygen atom. Representative examples of alkenoxy groups include, but are not limited to, 2-propen-1-oxy (i.e., CH2=CH-CH2-O-) and ethoxy (i.e., CH2=CH-O-).

[0087] As used herein, the term "aryloxy group" means an aryl group, as defined herein, attached to a portion of the parent molecule by an oxygen atom.

[0088] As used herein, the term "heteroaryl group" means, as defined herein, a heteroaryl group attached to a portion of the parent molecule by an oxygen atom.

[0089] As used herein, the term "carbocyclic" refers to a fully saturated monocyclic or polycyclic (e.g., bicyclic, tricyclic, etc.) hydrocarbon group containing 3 to 12 carbon atoms or having one or more unsaturated bonds, and to avoid ambiguity, the degree of unsaturation does not result in an aromatic ring system (e.g., phenyl). Examples of carbocyclic groups include 1-cyclopropyl, 1-cyclobutyl, 2-cyclopentyl, 1-cyclopentenyl, 3-cyclohexyl, 1-cyclohexenyl, and 2-cyclopentenylmethyl.

[0090] The term "cyano" is a specialized term and, as used herein, refers to -CN.

[0091] The term "halogen" is a specialized term and, as used herein, refers to -F, -Cl, -Br, or -I.

[0092] As used herein, the term "haloalkyl" means that some or all of the hydrogen atoms in an alkyl group as defined herein are replaced by halogen atoms.

[0093] The term "hydroxyl group" is a specialized term and, as used herein, refers to -OH.

[0094] As used herein, the term "hydroxyalkyl" means at least one hydroxyl group as defined herein attached to a parent molecule moiety by an alkyl group as defined herein. Representative examples of hydroxyalkyl groups include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and 2-ethyl-4-hydroxyheptyl.

[0095] As used herein, the term "silyl" includes hydrocarbon derivatives of silyl (H3Si-) (i.e., (hydrol)3Si-), where the hydrocarbon group is a monovalent group formed by removing a hydrogen atom from a hydrocarbon, such as ethyl or phenyl. The hydrocarbon group can be a combination of different groups, and can be diverse to provide a variety of silyl groups, such as trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBS / TBDMS), triisopropylsilyl (TIPS), and [2-(trimethylsilyl)ethoxy]methyl (SEM).

[0096] As used herein, the term "silyloxy group" means, as defined herein, a silyl group attached to a portion of the parent molecule by an oxygen atom.

[0097] Certain compounds contained in the compositions of this invention may exist in specific geometric or stereoisomeric forms. Additionally, the compounds of this invention may also be optically active. This invention covers all such compounds, including their cis and trans isomers, (R) and (S) enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures, and other mixtures, all of which fall within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents, such as alkyl groups. All such isomers and mixtures thereof are intended to be included in this invention.

[0098] If, for example, a specific enantiomer of the compound of the present invention is desired, then the specific enantiomer can be prepared by asymmetric synthesis or by derivatization using a chiral auxiliary agent. In the case of derivatization using a chiral auxiliary agent, the resulting diastereomeric mixture is isolated and the auxiliary agent group is cleaved to provide the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group such as an amino group or an acidic functional group such as a carboxyl group, a diastereomeric salt is formed with an acid or base having suitable optical activity, and then the resulting diastereomeric salt is resolved by stepwise crystallization or chromatographic means well known in the art, followed by recovery of the pure enantiomer.

[0099] It should be understood that “substitution” or “being substituted” includes implicit restrictions: such substitution must conform to the allowed valence states of the substituted atom and substituent, and the substitution must produce a stable compound, for example, a compound that will not spontaneously transform due to, for example, rearrangement reactions, cleavage reactions, decomposition reactions, cyclization reactions, elimination reactions or other reactions.

[0100] The term "substituted" also encompasses all permissible substituents, including those in organic compounds. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents in organic compounds. Illustrative substituents include, for example, those described above. For a suitable organic compound, permissible substituents may be one or more and may be the same or different. For the purposes of this invention, nitrogen heteroatoms may have hydrogen substituents and / or any permissible substituents in the organic compounds described herein that satisfy the heteroatom valence state. This invention is not intended to be limited in any way to permissible substituents in organic compounds.

[0101] As used herein, the term "protecting group" refers to a temporary substituent that protects a potentially reactive functional group from undue chemical transformation. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketals, respectively. A review of protecting group chemistry exists (Greene, TW; Wuts, PGM, *Protective Groups in Organic Synthesis*, 2nd ed.; Wiley: New York, 1991). The protected forms of the compounds of this invention are included within the scope of this invention.

[0102] For the purposes of this invention, chemical elements are identified according to the periodic table on the inside cover of the 67th edition of the CAS Handbook of Chemistry and Physics, 1986-87.

[0103] Other chemical terms used herein are used as is customary in the field, as illustrated by reference to the McGraw-Hill Dictionary of Chemical Terms (edited. Parker, S., 1985), McGraw-Hill, San Francisco, which is incorporated herein by reference. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0104] As used herein, the term "pharmaceutically acceptable salt" includes salts derived from inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, phosphoric acid, formic acid, acetic acid, lactic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, glycolic acid, salicylic acid, citric acid, methanesulfonic acid, benzenesulfonic acid, benzoic acid, malonic acid, trifluoroacetic acid, trichloroacetic acid, naphthalene-2-sulfonic acid, and other acids. Pharmaceutically acceptable salt forms may include those where the ratio of salt molecules is not 1:1. For example, a salt may contain more than one inorganic or organic acid molecule per molecule of base, such as two hydrochloric acid molecules per molecule of compound I. As another example, a salt may contain less than one inorganic or organic acid molecule per molecule of base, such as two compound I molecules per molecule of tartaric acid.

[0105] As used herein, the terms “carrier” and “pharmaceuticalally acceptable carrier” refer to a diluent, adjuvant, excipient, or mediator that is administered or formulated together with a compound for drug delivery. Non-limiting examples of such pharmaceutically acceptable carriers include liquids such as water, saline, and oils; and solids such as gum arabic, gelatin, starch paste, talc, keratin, colloidal silica, urea, etc. Additionally, adjuvants, stabilizers, thickeners, lubricants, flavoring agents, and coloring agents may be used. Other examples of suitable drug carriers are described in EW Martin’s Remington’s Pharmaceutical Sciences, which is incorporated herein by reference in its entirety.

[0106] As used herein, the term "treatment" means preventing, stopping, or slowing the progression of a subject's disease or condition, or eliminating the disease or condition. In one embodiment, "treatment" means stopping or slowing the progression of a subject's disease or condition, or eliminating the disease or condition. In another embodiment, "treatment" means reducing at least one objective manifestation of a subject's disease or condition.

[0107] As used in this article, the term "effective amount" refers to an amount sufficient to produce the desired biological effect.

[0108] As used in this article, the term "therapeutic effective amount" refers to an amount sufficient to produce the desired therapeutic effect.

[0109] As used herein, the term “inhibition” means a reduction in an objectively measurable amount or degree. In various embodiments, “inhibition” means a reduction of at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% compared to a relevant control. In one embodiment, “inhibition” means a 100% reduction, i.e., cessation or elimination.

[0110] As used herein, the term "subject" refers to a mammal. In various embodiments, the subject is a mouse, rat, rabbit, cat, dog, pig, sheep, horse, cow, or non-human primate. In one embodiment, the subject is a human.

[0111] compound

[0112] This invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof:

[0113]

[0114] Among them, each occurrence is independent:

[0115] R 1 Indicates an aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, or alkenyl group that may be optionally substituted.

[0116] R 2 and R 3 Each of the following can be independently represented as an alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, hydroxyalkyl, (alkathio)alkyl, aralkyl, heteroaralkyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, or (heterocycloalkyl)alkyl;

[0117] or R 2 and R 3 Together with the carbon atom it is bonded to, it forms an optionally substituted cycloalkyl or heterocycloalkyl ring;

[0118] R 4 The alkyl, alkenyl, ynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aralkyl, heteroaralkyl, hydroxyalkyl, or haloalkyl groups are represented by H or optionally substituted alkyl.

[0119] X represents NH, CH2, CHF, CF2, CH(C1-C6)alkyl or C((C1-C6)alkyl)2;

[0120] Y does not exist or represents CH2, C(O), CR 15 R 16S(O)2 or optionally substituted (C3-C7) cycloalkylene, arylene or heteroarylene;

[0121] R a H represents (C1-C6) alkyl, (heterocyclic) alkyl, or (C3-C7) cycloalkyl, which may be optionally substituted.

[0122] m is an integer from 1 to 6;

[0123] n is 0 or 1;

[0124] R 15 and R 16 Each is independently selected from the following groups: H, hydroxyl, halogen, -C(O)OR 17 -OR 17 -C(O)NR 17 R 18 -NR 17 R 18 Alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaryl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, and (heterocycloalkyl)alkyl, wherein the alkyl, aryl, aralkyl, heteroaryl, heteroaryl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, and (heterocycloalkyl)alkyl are optionally selected from one or more of -CN, -OR 17 -NR 17 R 18 Substituents of the group consisting of halogens and alkyl groups;

[0125] or R 15 and R 16 It can form, together with intermediate atoms, optional substituted carbon rings or heterocycles;

[0126] R 17 and R 18 Each is independently selected from the group consisting of: H, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl and (heterocycloalkyl)alkyl;

[0127] or R 17 and R 18 When attached to the same atom, it can form an optionally substituted heterocycle together with the intermediate atom;

[0128] express

[0129] Z 1 and Z 3 Each can be represented independently as C or N;

[0130] Z 2 Indicates N, CH, or CF;

[0131] Z 4 Indicates N or CR 8 ;

[0132] Z 5 Indicates N or CR 5 ;

[0133] Z 6 Indicates N or CR 6 ;

[0134] Z 7 Indicates N or CR 9 ;

[0135] Z 8 and Z 9 Each can be represented independently as N or CR. 19 ;

[0136] R 5 and R 6 Each can be independently represented as H, halogen, -CN, -NO2, or -OR. 13 -NR 13 R 14 -C(O)R 13 -C(O)OR 13 -C(O)NR 13 R 14 -OC(O)R 13 -NR 13 C(O)R 14 -OC(O)NR 13 R 14 -OC(O)OR 13 -NR 13 C(O)OR 14 -NR 13 C(O)NR 13 R 14 -OS(O) p (R 13 -NR 13 S(O) p (R 14 ), or optionally substituted alkyl, alkenyl, alkynyl, haloalkyl, aralkyl, heteroaryl, heteroaryl, aryl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl or (heterocycloalkyl)alkyl;

[0137] L represents -H, -CN, -C(O)R 7 -CH(OH)R 7 or -S(O) p(alkyl);

[0138] R 7 Each time it appears, it independently represents H, NH2, CH3, OH, CF3, CH2OH, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, halogen(C1-C6)alkyl, NH(C1-C6)alkyl, N((C1-C6)alkyl)2;

[0139] R 8 and R 9 Each can be used independently to represent H, halogen, and -OR. 13 -NR 13 R 14 -C(O)R 13 -C(O)OR 13 -C(O)NR 13 R 14 -OC(O)R 13 -NR 13 C(O)R 14 -OC(O)NR 13 R 14 -OC(O)OR 13 -NR 13 C(O)OR 14 -NR 13 C(O)NR 13 R 14 -OS(O) p (R 13 -NR 13 S(O) p (R 14 ), or optionally substituted alkyl, alkenyl, ynyl, haloalkyl, aralkyl, heteroaryl, heteroaryl or aryl;

[0140] or R 5 and R 8 、or R 5 and R 6 、or R 6 and R 9 It can form, together with intermediate atoms, optional substituted heterocycles or carbocycles;

[0141] R 13 and R 14 Each time it appears, it independently represents H or optionally substituted alkyl, alkenyl, ynyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, or (heterocycloalkyl)alkyl; or, when R 13 and R 14 When attached to the same atom, R 13and R 14 Together with the aforementioned atoms, they can form optionally substituted heterocycles;

[0142] R 19 Each occurrence is independently represented by H, F, CN, -C(O)R. 7 -CH(OH)R 7 or -S(O) p (alkyl);

[0143] J represents H or NH2; and

[0144] p is 0, 1, or 2;

[0145] Where Z 1 Is it N, or if express Then X represents CH2.

[0146] In a preferred embodiment, n is 1.

[0147] In some embodiments, R 1 The aryl or heteroaryl group is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, -CN, alkoxy, haloalkoxy, alkyl, haloalkyl, alkenyl, dialkylamino, heterocyclic alkyl, aryl, and heteroaryl.

[0148] In some embodiments, R 1 The aryl or heteroaryl group is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, alkoxy, haloalkoxy, alkyl, haloalkyl, alkenyl, dialkylamino, aryl, and heteroaryl.

[0149] In R 1 In embodiments representing an aryl or heteroaryl group substituted with one or more substituents including aryl or heteroaryl substituents, the aryl or heteroaryl substituents may be additionally substituted with one or more substituents selected from the group consisting of alkyl groups and halogens.

[0150] In some embodiments, R 1 The aryl or heteroaryl group is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, alkoxy, haloalkoxy, alkyl, haloalkyl, alkenyl, and dialkylamino.

[0151] In some embodiments, R 1 This indicates an aryl or heteroaryl group substituted with one or more substituents, at least one of which is a halogen. For example, R 1 It can represent a phenyl group that has been substituted with chlorine and fluorine groups.

[0152] In other embodiments, R 1 The phenyl, pyridyl, pyrazinyl, or pyrimidinyl group is optionally substituted with one or more substituents selected from the group consisting of: halogen, alkoxy (e.g., methoxy), haloalkoxy (e.g., trifluoromethoxy), alkyl (e.g., methyl), haloalkyl (e.g., trifluoromethyl), alkenyl (e.g., vinyl), and dialkylamino (e.g., dimethylamino).

[0153] In an alternative embodiment, R 1 It is an alkyl or alkenyl group that is optionally substituted. For example, R 1 It can be a (C1-C6) alkyl or (C2-C6) alkenyl group optionally substituted with halogen, hydroxyl, alkoxy or haloalkoxy.

[0154] In other embodiments, R 1 It is an optionally substituted cycloalkyl or heterocycloalkyl group. For example, R 1 It may be a cycloalkyl or heterocycloalkyl group optionally substituted with one or more substituents selected from the group consisting of: halogen, hydroxyl, (C1-C6)alkyl, (C1-C6)alkoxy, and halo(C1-C6)alkyl. In some embodiments, R 1 It is a heterocyclic alkyl group (e.g., tetrahydroquinolinyl) fused with an aryl or heteroaryl ring at two adjacent positions.

[0155] In some embodiments, R 1 It is a heteroaryl group that is optionally substituted and Y is absent; or R 1 It is an aryl group that is optionally substituted and Y is CH2.

[0156] In some embodiments, Y is absent or represents CH2.

[0157] In some embodiments, Y is absent. Alternatively, Y is CH2.

[0158] Alternatively, Y can be an optionally substituted (C3-C7) cycloalkylene group. For example, Y can be a fluorinated cyclopropylene group.

[0159] In other alternative embodiments, Y may be an optionally substituted arylene or heteroarylene. For example, Y may be an optionally substituted phenylene or pyridylene.

[0160] In an alternative embodiment, Y is CR 15 R 16 In some such embodiments, R 15 and R 16The group selected from H, alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, aralkyl, heteroarylalkyl, (cycloalkyl)alkyl, and (heterocyclic)alkyl, wherein the alkyl, aryl, aralkyl, heteroaryl, heteroaryl, cycloalkyl, (cycloalkyl)alkyl, heterocyclic, and (heterocyclic)alkyl are optionally selected by one or more of -CN, -OR 17 -NR 17 R 18 Substituents of the group consisting of halogens and alkyl groups, and further wherein R 17 and R 18 Each is independently selected from the group consisting of H and alkyl groups.

[0161] Or, Y is CR 15 R 16 And R 15 and R 16 Together with the intermediate atom, it forms an optionally substituted carbon ring or heterocycle, such as a cyclopropyl ring.

[0162] In some embodiments, Y represents CH(C1-C6)alkyl. Alternatively, Y represents CH(C1-C6)alkyl, wherein the (C1-C6)alkyl is substituted with a hydroxyl, alkoxy, or di(alkyl)amino group.

[0163] In some embodiments, R 2 and R 3 Each of the following can be independently represented as H or optionally substituted alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, hydroxyalkyl, (alkylthio)alkyl, aralkyl, heteroaralkyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, or (heterocycloalkyl)alkyl.

[0164] In some embodiments, R 2 It is H and R 3 The alkyl group is represented by H or an alkyl group that is optionally substituted, such as alkoxyalkyl, hydroxyalkyl, (alkylthio)alkyl, aralkyl, heteroaralkyl, cycloalkyl, or (cycloalkyl)alkyl.

[0165] In some embodiments, R 2 and R 3 Both represent H.

[0166] Or, R 2 and R 3 Both can represent alkyl groups, such as methyl.

[0167] In other embodiments, R 2 and R 3 Together with intermediate atoms, they form optional substituted carbon rings or heterocycles.

[0168] In some embodiments, R 4H represents an alkyl group, cycloalkyl group, (cycloalkyl)alkyl group, heterocycloalkyl group, aralkyl group, hydroxyalkyl group, or haloalkyl group, which may be optionally substituted; preferably, R represents an alkyl group, cyclo ... 4 H represents an alkyl or cycloalkyl group that is optionally substituted.

[0169] In some embodiments, R 4 The group represents H or alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aralkyl, heteroaralkyl, hydroxyalkyl, or haloalkyl, each optionally substituted by one or more substituents independently selected from the group consisting of: halo, alkoxy, alkyl, hydroxy, hydroxyalkyl, haloalkyl, -NH2, -NH(alkyl), -N(alkyl)2, -C(O)O(alkyl), -C(O)NH2, -S(O)2(alkyl), -NHS(O)2(alkyl), and -NHC(O)(O(alkyl)).

[0170] In an exemplary embodiment, R 4 express

[0171] In some embodiments, R a It indicates (C1-C6) alkyl, (heterocyclic) alkyl or (C3-C7) cycloalkyl that are optionally substituted with hydroxyl or dialkylamino groups.

[0172] In some embodiments, R a This indicates H, (C1-C6) alkyl, or (C3-C7) cycloalkyl. In other embodiments, R... a H is represented. Alternatively, in some embodiments, R is represented. a It represents (C1-C6) alkyl.

[0173] In some embodiments, m is an integer from 1 to 4. In some embodiments, m is 1 or 2. Preferably, m is 1.

[0174] In some embodiments, express

[0175] or, express

[0176] In other embodiments, express

[0177] In some embodiments, It can represent Where R 8 L and Z 2 As defined above. For example, It can represent In some of these embodiments, R 8 Preferably, it is NH2 or Cl. In other embodiments of this kind, L represents H or CN.

[0178] In some embodiments, L represents -C(O)R 7 .

[0179] In some embodiments, the compound of formula (I) has the structure of formula (Ia):

[0180]

[0181] In some embodiments, the compound of formula (I) has the structure of formula (Ib):

[0182]

[0183] In some embodiments, the compound of formula (I) has the structure of formula (Ic):

[0184]

[0185] In some embodiments, the compound of formula (I) has the structure of formula (Id):

[0186]

[0187] In some embodiments of compounds of formula (Ic) or (Id), X is NH.

[0188] In some embodiments of the compound of formula (I), if Z 1 If it is N, then X is CH2. In other embodiments, Z 1 If it is C, then X is NH.

[0189] In some embodiments of compounds of formula (Ia), (Ib), (Ic), or (Id), Z 4 Indicates CR 8 Z 5 Indicates CR 5 Z 6 Indicates CR 6 And Z 7 Indicates CR 9 .

[0190] In some embodiments, Z 4 and Z 7 Each represents CH.

[0191] In some embodiments, Z 5 Indicates CR 5 And Z 6 Indicates CR 6 ;and

[0192] R 5 and R 6 Each can be independently represented by H, halogen, and -NR. 13 R 14 -C(O)R 13 -C(O)OR 13 -C(O)NHR 14 -NHC(O)NR 13 R 14 -NHS(O)2(R 14 ), or optionally substituted alkyl, alkenyl, ynyl, heteroaryl or aryl.

[0193] In some of these embodiments, R 13 and R 14 Each time it appears, it independently represents H or optionally substituted aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, or (cycloalkyl)alkyl.

[0194] In other embodiments, R 5 and R 6 Each independently represents an alkyl, alkenyl, ynyl, heteroaryl, or aryl group substituted with H or optionally by one or more substituents selected from the group consisting of: aryl, heteroaryl, silyl, alkyl, amino, alkylamino, dialkylamino, -C(O)(alkyl), heterocyclic alkyl, and halogen. Alternatively, R 5 and R 6 Each independently represents an alkyl, alkenyl, ynyl, heteroaryl, or aryl group, or an alkyl group, which is optionally substituted with H by one or more substituents selected from the group consisting of: aryl, heteroaryl, silyl, alkyl, amino, alkylamino, dialkylamino, -C(O)(alkyl), and halogen.

[0195] In some embodiments, R 13 and R 14 Each time it appears, it independently represents H or optionally substituted by one or more substituents independently selected from the following: alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaryl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl or (heterocycloalkyl)alkyl: halogen, alkoxy, alkyl, hydroxy, hydroxyalkyl, haloalkyl, -NH2, -NH(alkyl), -N(alkyl)2, -C(O)O(alkyl), -C(O)NH2, -S(O)2(alkyl), -NHS(O)2(alkyl) and -NHC(O)(O(alkyl)).

[0196] In some embodiments, R 5 and R 6 Each can be used independently to represent H, halogen, and -OR. 13 -NR 13 R14 -C(O)R 13 -C(O)OR 13 -C(O)NR 13 R 14 -OC(O)R 13 -NR 13 C(O)R 14 -OC(O)NR 13 R 14 -OC(O)OR 13 -NR 13 C(O)OR 14 -NR 13 C(O)NR 13 R 14 -OS(O) p (R 13 -NR 13 S(O) p (R 14 ), or optionally substituted alkyl, alkenyl, alkynyl, haloalkyl, aralkyl, heteroaryl, heteroaryl, aryl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl or (heterocycloalkyl)alkyl.

[0197] In some embodiments, R 5 R 6 R 8 and R 9 Each of the following independently represents an alkyl, alkenyl, alkynyl, haloalkyl, aralkyl, heteroaryl, heteroaryl, aryl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, or (heterocycloalkyl)alkyl: aryl, heteroaryl, silyl, alkyl, amino, alkylamino, dialkylamino, -C(O)(alkyl), hydroxyl, alkoxy, aryloxy, heteroaryloxy, and halogen.

[0198] In some embodiments, R 5 R 6 R 8 and R 9 Each of the following independently represents an alkyl, alkenyl, alkynyl, heteroaryl, or aryl group substituted with H or optionally by one or more substituents selected from the group consisting of: aryl, heteroaryl, silyl, alkyl, amino, alkylamino, dialkylamino, -C(O)(alkyl), hydroxyl, alkoxy, aryloxy, heteroaryloxy, and halogen.

[0199] In some embodiments, R 5 R 6 R 8 and R 9 Each can be independently represented as H or -CH(OH)R50 -CH(NH2)R 50 -CH(OR) 51 )R 50 -CH(NHR) 51 )R 50 -C(NH2)(R 51 (R) 50 ), -C(OH)(R 51 (R) 50 ) and -NH(CO)CR 5 R 6 R 50 ;where R 50 and R 51 Each of the following groups is independently selected from alkyl, alkenyl, alkynyl, haloalkyl, aralkyl, heteroaryl, heteroaryl, aryl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, and (heterocycloalkyl)alkyl.

[0200] In some embodiments, R 5 R 6 and R 8 Each is H.

[0201] In some embodiments, R 5 R 6 and R 9 Each is H.

[0202] In some embodiments, R 5 R 8 and R 9 Each is H.

[0203] In some embodiments, R 6 R 8 and R 9 Each is H.

[0204] In some embodiments, R 7 It represents NH2, CH3, or CF3.

[0205] In some embodiments, R 7 It represents NH2.

[0206] In some embodiments, the compounds of the present invention are selected from the group consisting of the compounds in the table below or pharmaceutically acceptable salts thereof:

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239] Pharmaceutical Composition

[0240] This invention provides pharmaceutical compositions, each comprising one or more compounds of the present invention and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical compositions comprise compounds of the present invention and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical compositions comprise multiple compounds of the present invention and pharmaceutically acceptable carriers.

[0241] In some embodiments, the pharmaceutical compositions of the present invention contain at least one additional pharmaceutically active agent in addition to the compounds of the present invention. The at least one additional pharmaceutically active agent may be a medicament suitable for treating diseases or conditions characterized by abnormal complement system activity.

[0242] The pharmaceutical compositions of the present invention can be prepared by combining one or more of the compounds of the present invention with a pharmaceutically acceptable carrier and optionally one or more additional pharmaceutical active agents.

[0243] How to use

[0244] This invention provides compounds suitable for treating or preventing diseases or conditions characterized by abnormal complement system activity.

[0245] In some aspects, the present invention provides a compound of the present invention suitable for use as a medicine, or a pharmaceutically acceptable salt thereof.

[0246] In some aspects, the present invention provides a method for treating or preventing a disease or condition characterized by abnormal complement system activity. The method includes the steps of administering a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to a subject in need, thereby treating or preventing a disease or condition characterized by abnormal complement system activity. The disease or condition characterized by abnormal complement system activity is treated by reducing complement system activity in the subject.

[0247] Alternatively, in some aspects, the present invention provides compounds of the present invention or pharmaceutically acceptable salts thereof for treating diseases or conditions characterized by abnormal complement system activity.

[0248] Alternatively, in some aspects, the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts thereof for the manufacture of medicaments for treating diseases or conditions characterized by abnormal complement system activity.

[0249] As used in this article, "a disease or condition characterized by abnormal complement system activity" refers to any disease or condition in which a reduction in complement system activity is desired. For example, in cases of inappropriate or excessive activation of the complement system, a reduction in complement system activity is desirable.

[0250] In some embodiments, the disease or condition characterized by abnormal complement system activity is an immune disorder.

[0251] In some embodiments, the disease or condition characterized by abnormal complement system activity is a central nervous system disease.

[0252] In some embodiments, the disease or condition characterized by abnormal complement system activity is kidney disease.

[0253] In some embodiments, the disease or condition characterized by abnormal complement system activity is a cardiovascular disease.

[0254] In some embodiments, the disease or condition characterized by abnormal complement system activity is a neurodegenerative disease or a nervous system disease.

[0255] In some embodiments, diseases or conditions characterized by abnormal complement system activity are selected from the group consisting of: paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, organ transplant rejection, myasthenia gravis, neuromyelitis optica, membranoproliferative glomerulonephritis, dense deposit disease, cold agglutinin disease, and catastrophic antiphospholipid syndrome.

[0256] In some embodiments, the disease or condition is paroxysmal nocturnal hemoglobinuria.

[0257] In some embodiments, the disease or condition is atypical hemolytic uremic syndrome.

[0258] In some embodiments, the disease or condition is organ transplant rejection.

[0259] In some embodiments, the disease or condition is myasthenia gravis.

[0260] In some embodiments, the disease or condition is neuromyelitis optica.

[0261] In some embodiments, the disease or condition is membranoproliferative glomerulonephritis.

[0262] In some embodiments, the disease or condition is a dense deposit disease.

[0263] In some embodiments, the disease or condition is a cold agglutinin disease.

[0264] In some embodiments, the disease or condition is catastrophic antiphospholipid syndrome.

[0265] In other embodiments, diseases or conditions characterized by abnormal complement system activity include adult respiratory distress syndrome, myocardial infarction, pulmonary inflammation, hyperacute rejection (transplant rejection), sepsis, cardiopulmonary bypass, burns, asthma, restenosis, multiple organ dysfunction syndrome, Guillain-Barré syndrome, hemorrhagic shock, paroxysmal nocturnal hemoglobinuria, glomerulonephritis, systemic lupus erythematosus, rheumatoid arthritis, infertility, Alzheimer's disease, organ rejection (transplantation), myasthenia gravis, multiple sclerosis, platelet storage, or hemodialysis.

[0266] Preparations, routes of administration and administration

[0267] The compounds of this invention can be formulated as pharmaceutical compositions and administered to mammalian hosts, such as human patients, in various forms suitable for a chosen route of administration, such as oral or non-enteral, intravenous, intraperitoneal, intramuscular, local, or subcutaneous routes. This invention also covers other routes of administration.

[0268] Therefore, the compounds of the present invention can be administered systemically in combination with pharmaceutically acceptable mediators, such as oral administration, including inert diluents or assimilated edible carriers. They can be encapsulated in hard or soft-shell gelatin capsules, compressed into tablets, or directly incorporated into the patient's diet. For oral therapeutic administration, the active compound can be combined with one or more excipients and used in the form of ingestible tablets, buccal lozenges, tablets, capsules, elixirs, suspensions, syrups, rice paper wafers, etc. Such compositions and formulations should contain at least 0.1% of the active compound. The percentage of the composition and formulation can, of course, vary, and is preferably between about 2% and about 60% by weight of the specified unit dosage form. The amount of active compound in such therapeutically useful compositions is the amount that will yield an effective dose.

[0269] Tablets, lozenges, pills, capsules, etc., may also contain the following diluents and carriers: binders, such as astragalus gum, gum arabic, corn starch, or gelatin; excipients, such as dicalcium phosphate; disintegrants, such as corn starch, potato starch, alginic acid, etc.; lubricants, such as magnesium stearate; and sweeteners, such as sucrose, fructose, lactose, or aspartame; or flavorings, such as peppermint, wintergreen oil, or cherry flavoring. When the unit dosage form is a capsule, in addition to the above types of materials, it may also contain a liquid carrier, such as vegetable oil or polyethylene glycol. Various other materials may exist as coatings or otherwise alter the physical form of the solid unit dosage form. For example, tablets, pills, or capsules may be coated with gelatin, wax, shellac, or sugar. Syrups or elixirs may contain active compounds, sucrose or fructose as sweeteners, methylparaben and propylparaben as preservatives, dyes, and flavorings such as cherry or orange flavorings. Of course, any materials used in the preparation of any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in dosage. Additionally, active compounds can be incorporated into sustained-release formulations and devices.

[0270] The active compound can also be administered by infusion or injection, intravenously or intraperitoneally. Solutions of the active compound or its salts can be prepared in water or physiologically acceptable aqueous solutions, optionally mixed with a non-toxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, triacetin, and mixtures thereof, and in oils. Under normal storage and use conditions, these formulations contain preservatives to prevent microbial growth.

[0271] Suitable drug dosage forms for injection or infusion may include sterile aqueous solutions or dispersions, or sterile powders containing the active ingredient for the provisional preparation of sterile injectable or infusionable solutions or dispersions, optionally encapsulated in liposomes. In all cases, the final dosage form should be a sterile fluid and stable under the conditions of manufacture and storage. The liquid carrier or mediator may be a solvent or liquid dispersion medium, comprising, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glycerides, and suitable mixtures thereof. Appropriate flowability may be maintained, for example, by forming liposomes, by maintaining the desired particle size in the case of dispersions, or by using surfactants. Prevention of microbial activity may be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. In many cases, isotonic agents, such as sugars, buffers, or sodium chloride, are preferred. Prolonged absorption of the injectable composition may be achieved by using agents with delayed absorption in the composition, such as aluminum monostearate and gelatin.

[0272] Sterile injectable solutions are prepared by incorporating the desired amount of the active compound into a suitable solvent containing the various other ingredients listed above, followed by filtration sterilization if necessary. In the case of sterile powders used to prepare sterile injectable solutions, preparation methods may include vacuum drying and freeze-drying techniques, which yield a powder containing the active ingredient plus any additional desired components present in the pre-sterile filtered solution.

[0273] Regarding topical administration, the compounds of the present invention can be applied in their pure form, i.e., when they are liquids. However, it is generally desirable to combine them with dermatologically acceptable carriers for application to the skin as compositions or formulations, said carriers being either solid or liquid.

[0274] Suitable solid carriers include finely powdered solids such as talc, clay, microcrystalline cellulose, silica, alumina, etc. Suitable liquid carriers include water, alcohol or glycol or water-alcohol / glycol blends, wherein the compounds of the present invention can be effectively dissolved or dispersed, optionally with the aid of a non-toxic surfactant. Adjuvants, such as fragrances and additional antimicrobial agents, may be added to optimize properties for a specific application. The resulting liquid compositions can be applied from absorbent pads for impregnating bandages and other dressings, or sprayed onto infected areas using a pump or aerosol sprayer.

[0275] Thickeners, such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified cellulose or modified mineral materials, can also be used to form spreadable pastes, gels, ointments, soaps, etc., together with a liquid carrier, so that they can be applied directly to the user's skin.

[0276] Examples of dermatological compositions suitable for delivering the compounds of the present invention to the skin are known in the art; see, for example, Jacquet et al. (U.S. Patent No. 4,608,392, incorporated herein by reference), Geria (U.S. Patent No. 4,992,478, incorporated herein by reference), Smith et al. (U.S. Patent No. 4,559,157, incorporated herein by reference), and Wortzman (U.S. Patent No. 4,820,508, incorporated herein by reference).

[0277] The appropriate dosage of the compounds of the present invention can be determined, at least first, by comparing their in vitro and in vivo activities in animal models. Methods for extrapolating effective dosages in mice and other animals to humans are known in the art; see, for example, U.S. Patent No. 4,938,949 (incorporated herein by reference).

[0278] The amount of a compound or its active salt required for therapeutic use will vary not only with the specific compound or salt selected, but also with the route of administration, the nature of the condition being treated, and the patient's age and condition, and will ultimately be determined by the nurse or clinician.

[0279] However, in general, the appropriate dose will be in the range of about 0.5 to about 100 mg per kilogram of recipient body weight per day, such as about 3 to about 90 mg per kilogram of body weight per day, about 6 to about 75 mg per kilogram of body weight per day, about 10 to about 60 mg per kilogram of body weight per day, or about 15 to about 50 mg per kilogram of body weight per day.

[0280] The compounds of the present invention can be conveniently formulated in unit dosage forms; for example, each unit dosage form contains 5 to 1000 mg, 10 to 750 mg, or 50 to 500 mg of the active ingredient. In one embodiment, the present invention provides a composition comprising the compound of the present invention formulated in such unit dosage forms. The desired dosage can be conveniently presented as a single dose or as multiple doses administered at suitable time intervals, for example, as two, three, four, or more sub-dose per day. The sub-dose itself can be further divided into, for example, multiple discrete, loosely spaced administrations.

[0281] The compounds of this invention can also be used in combination with other therapeutic agents, such as other agents suitable for treating or preventing local ischemia, blood loss or reperfusion injury.

[0282] Other delivery systems may include time-release, delayed-release, or sustained-release delivery systems, as those well known in the art. These systems avoid repeated administration of the active compound, increasing convenience for both the patient and the physician. Many types of release delivery systems are available and are known to those skilled in the art. Long-term sustained-release implants may be desired. As used herein, long-term release means a delivery system or implant constructed and arranged to deliver a therapeutic level of the active ingredient for at least 30 days, preferably 60 days.

[0283] In some embodiments, the compounds of the present invention are formulated for intraocular administration, such as by direct injection or insertion, or in combination with an intraocular medical device.

[0284] The compounds of the present invention can be formulated for deposition in medical devices, which may include any of a variety of conventional grafts, stents, including stent grafts, catheters, balloons, baskets, or other devices that can be deployed or permanently implanted into a body cavity. As a specific example, it is desirable to have devices and methods for delivering the compounds of the present invention to body areas that have been treated with interventional techniques.

[0285] In exemplary embodiments, the compounds of the present invention can be deposited within a medical device such as a scaffold and delivered to the treatment site to treat a part of the body.

[0286] Stents have been used as delivery media for therapeutic agents (i.e., drugs). Intravascular stents are generally permanently implanted in coronary or peripheral blood vessels. Stent designs include those described in U.S. Patent Nos. 4,733,655 (Palmaz), 4,800,882 (Gianturco), or 4,886,062 (Wiktor). These designs include metallic and polymeric stents, as well as self-expanding and balloon-expandable stents. Stents can also be used to deliver drugs to sites in contact with the vascular system, as disclosed in U.S. Patent Nos. 5,102,417 (Palmaz), 5,419,760 (Narciso, Jr.), and 5,429,634 (Narciso, Jr.), and international patent applications such as WO 91 / 12779 (Medtronic, Inc.) and WO 90 / 13332 (Cedars-Sanai Medical Center).

[0287] The term "deposition" refers to the encapsulation, adsorption, placement, or other incorporation of a compound into a device by methods known in the art. For example, a compound may be embedded in and released from a polymeric material that encapsulates or covers a medical device ("matrix type"), or surrounded by and released from said polymeric material ("reservoir type"). In the latter example, the compound may be embedded within or coupled to a polymeric material using one or more techniques known in the art for producing such materials. In other formulations, the compound may be attached to the surface of a medical device without coating, for example, by means of a removable adhesive, and released over time, or removed by active mechanical or chemical processes. In other formulations, the compound may be in a permanently fixed form that provides the compound at the implantation site.

[0288] In some embodiments, compounds may be incorporated into the polymer composition during the formation of a biocompatible coating for a medical device, such as a scaffold. The coatings produced from these components are generally homogeneous and suitable for coating a variety of devices designed for implantation.

[0289] Depending on the desired release rate or the desired degree of polymer stability, the polymer can be either biostable or bioabsorbable. However, in this embodiment, bioabsorbable polymers are often preferred because, unlike biostable polymers, bioabsorbable polymers do not persist for long after implantation and do not cause any adverse chronic local reactions. Usable bioabsorbable polymers include, but are not limited to, poly(L-lactic acid), polycaprolactone, polyglycolide (PGA), poly(lactide-co-glycolide) (PLLA / PGA), poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester, polyanhydride, poly(glycolic acid), poly(D-lactic acid), poly(L-lactic acid), poly(D,L-lactic acid), poly(D,L-lactide) (PLA), poly(L-lactide) (PLLA), poly(glycolic acid-co-trimethylene carbonate) (PGA / PTMC), and polyethylene oxide. Oxide (PEO), polydioxanone (PDS), polyphosphates, polyphosphate urethanes, poly(amino acids), cyanoacrylates, poly(trimethylene carbonate), poly(imino carbonate), copoly(ether-ester) (e.g., PEO / PLA), polyalkylene oxalate, polyphosphazenes, and biomolecules such as fibrin, fibrinogen, cellulose, starch, collagen, and hyaluronic acid, poly(ε-caprolactone), polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyran, polycyanoacrylates, crosslinked or amphoteric block copolymers of hydrogels, and other suitable bioabsorbable polymers known in the art.In addition, biostable polymers with relatively low chronic tissue reactions, such as polyurethanes, silicones, and polyesters, can be used, as well as other polymers that can be dissolved and cured or polymerized on the medical device, such as polyolefins, polyisobutylene, and ethylene-α-olefin copolymers; acrylic polymers and copolymers, vinyl halide polymers and copolymers, such as polyvinyl chloride; polyvinylpyrrolidone; polyvinyl ethers, such as polyvinyl methyl ether; polyvinylidene halides, such as polyvinylidene fluoride and polyvinylidene chloride; polyacrylonitrile, polyvinyl ketone; polyvinyl aromatic compounds, such as polystyrene, polyethylene esters, such as polyvinyl acetate; copolymers of vinyl monomers with each other and with olefins, such as ethylene-methyl methacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl acetate copolymers; pyran copolymers; polyhydroxy- Propyl-methacrylamide-phenol; polyhydroxyethyl-asparagine-phenol; polyethylene oxide-polylysine substituted with palmitoyl residues; polyamides, such as nylon 66 and polycaprolactam; alkyd resins, polycarbonates; polyoxymethylene; polyimide; polyether; epoxy resins, polyurethane; rayon; triacetate rayon; cellulose, cellulose acetate, cellulose butyrate; cellulose acetate butyrate; cellophane; nitrocellulose; cellulose propionate; cellulose ethers; and carboxymethyl cellulose.

[0290] Polymer and semi-permeable polymer matrices can be used to form molded products such as valves, stents, tubes, and prostheses.

[0291] In some embodiments of the invention, the compounds of the invention are coupled with a polymer or semi-permeable polymer matrix formed as a scaffold or scaffold-graft device.

[0292] Polymers are typically applied to the surface of implantable devices by spin coating, dip coating, or spray coating. Additional methods known in the art can also be used for this purpose. Spray coating methods include conventional methods as well as microdeposition techniques using inkjet dispensers. Alternatively, photopatterning can be used to place the polymer only on specific portions of the implantable device, thereby depositing the polymer onto the implantable device. This coating provides a uniform layer around the device, which improves the diffusion of various analytes through the device coating.

[0293] In some embodiments of the invention, the compound is formulated for release from a polymer coating into an environment in which a medical device is placed. Preferably, at least one of several well-known techniques involving a polymer carrier or layer to control elution is used to release the compound in a controlled manner over an extended timeframe (e.g., several months). Some of these techniques are described in U.S. Patent Application 2004 / 0243225A1, the entire disclosure of which is incorporated herein by reference.

[0294] Furthermore, as described, for example, in U.S. Patent No. 6,770,729, which is incorporated herein by reference in its entirety, the reagents and reaction conditions of the polymer composition can be manipulated to control the release of compounds from the polymer coating. For example, the diffusion coefficients of one or more polymer coatings can be adjusted to control the release of compounds from the polymer coating. In a variation of this subject matter, the diffusion coefficients of one or more polymer coatings can be controlled to adjust the ability of analytes present in the environment where the medical device is placed (e.g., analytes that contribute to the partial decomposition or hydrolysis of the polymer) to approach one or more components within the polymer composition (and, for example, thereby modulating the release of compounds from the polymer coating). Yet another embodiment of the invention includes a device having multiple polymer coatings, each having multiple diffusion coefficients. In such embodiments of the invention, the release of compounds from the polymer coatings can be modulated by these multiple polymer coatings.

[0295] In yet another embodiment of the invention, the release of the compound from the polymer coating is controlled by adjusting one or more properties of the polymer composition, such as the presence of one or more endogenous or exogenous compounds, or the pH of the polymer composition. For example, certain polymer compositions may be designed to release compounds in response to a decrease in the pH of the polymer composition.

[0296] Reagent test kit

[0297] The present invention also provides a kit comprising the compound of the present invention or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent, packaging material, and instructions for administering the compound of the present invention or a pharmaceutically acceptable salt thereof and the other therapeutic agent to a mammal for the treatment or prevention of a disease or condition characterized by abnormal complement system activity. In one embodiment, the mammal is a human.

[0298] Those skilled in the art will understand that, given the information known to those skilled in the art, other suitable modifications and adjustments to the compositions and methods described herein will be apparent and can be made without departing from the scope of the invention or any of its embodiments.

[0299] Example

[0300] The invention has now been described in detail, and will be more fully understood by referring to the following examples, which are included for illustrative purposes only and are not intended to limit the invention.

[0301] Process 1

[0302]

[0303] Procedure 1 describes the general synthesis of compounds of type (1f) and / or (1g). These compounds are prepared in such a manner that (1a) or (1b), consisting of an activated carbonyl compound carrying a leaving group (Lv), reacts with a free or protected amine under coupling conditions to produce (1c). Compound (1d) is prepared by reacting the free or protected amine with (1c); the protecting group is removed using standard conditions to form (1e). In a final step, compound (1e) is coupled with the activated carbonyl group using a coupling agent to form an amide compound (1f), which is then used to prepare a substituted urea compound (1g) from (1e) using a structurally different isocyanate.

[0304] Process 2

[0305]

[0306] Preparation of (S)-1-(2-((1-((6-bromopyridin-2-yl)amino)-3-methyl-1-oxobut-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (2f)

[0307] Step 1: Preparation of (S)-(1-((6-bromopyridin-2-yl)amino)-3-methyl-1-oxobut-2-yl)carbamate tert-butyl ester (2c)

[0308] Ethyl 2-ethoxyquinoline-1(2H)-carboxylate (EEDQ, 1.43 g, 5.78 mmol) was added to a solution of Boc-L-valine (2a) (1.32 g, 6.07 mmol) and 6-bromopyridin-2-amine (2b) (1.0 g, 5.78 mmol) in THF (20 mL). The resulting mixture was refluxed for 4 days, cooled to room temperature, diluted with EtOAc (100 mL), and washed with KHSO4 (1 N, 2 × 30 mL) and saline (20 mL). The organic layer was dried, concentrated under vacuum, and the residue obtained was purified by rapid column chromatography [silica gel (12 g), eluted with EtOAc (0-50%) / hexane] to give (S)-1-(6-bromopyridin-2-ylamino)-3-methyl-1-oxobut-2-ylcarbamate tert-butyl ester (2c) (121 mg, 0.325 mmol, 6% yield) as a semi-solid. 1H NMR (300MHz, DMSO-d6) δ10.78(s,1H),8.09(d,J=8.1Hz,1H), 7.73(t,J=7.9Hz,1H),7.34(d,J=7.7Hz,1H),6.98(d,J=8.4Hz,1H),4.06-3.94(m, 1H), 2.05-1.92 (m, 1H), 1.37 (s, 9H), 0.93-0.86 (m, 6H); MS (ES+): 394.4 (M+Na).

[0309] Step 2: Preparation of (S)-2-amino-N-(6-bromopyridin-2-yl)-3-methylbutyramide (2d)

[0310] At room temperature, tert-butyl carbamate (2c) (120 mg, 0.322 mmol) was added to a stirred solution of (S)-1-(6-bromopyridin-2-ylamino)-3-methyl-1-oxobutyric-2-ylcarbamate (10 mL) in DCM, and the mixture was stirred for 16 hours. The reaction mixture was concentrated under vacuum to remove DCM and excess TFA, yielding (S)-2-amino-N-(6-bromopyridin-2-yl)-3-methylbutyramide (2d), which was used as is in the next step without further purification; MS (ES+): 273.3 (M+1).

[0311] Step 3: Preparation of (S)-1-(2-((1-((6-bromopyridin-2-yl)amino)-3-methyl-1-oxobut-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (2f)

[0312] To the TFA salt (120 mg, 0.441 mmol) of (S)-2-amino-N-(6-bromopyridin-2-yl)-3-methylbutyramide (2d) in the above DMF (4 mL), 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (116 mg, 0.529 mmol, prepared according to the procedure reported by Altmann, Eva et al. in PCT International Application WO 2012 / 093101), DIPEA (0.308 mL, 1.764 mmol), and HATU (201 mg, 0.529 mmol) were added, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc (100 mL), washed with water (3×) and brine, dried, filtered, and concentrated to dryness under vacuum. The residue obtained was purified by rapid column chromatography [silica gel (12 g), eluted with 0-60% EtOAc / MeOH (9:1) / hexane] to give (S)-1-(2-((1-((6-bromopyridin-2-yl)amino)-3-methyl-1-oxobut-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (2f) (38 mg, 18% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ11.01(s,1H),8.57(d,J=8.1Hz,1H),8.13(dd,J=21.3,8.2Hz,2H), 7.81-7.56(m,3H),7.39(dd,J=23.5,7.5Hz,3H),7.25(t,J=7.5Hz,1H),5.41-5.23(m, 2H), 4.46 (t, J=7.2Hz, 1H), 2.15-2.00 (m, 1H), 1.00-0.83 (m, 7H); MS (ES+): 496.4 (M+Na).

[0313] Process 3

[0314]

[0315] Preparation of (S)-1-(2-((1-((3-chlorophenyl)amino)-3-methyl-1-oxobut-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (3d)

[0316] Step 1: Preparation of (S)-1-(3-chlorophenylamino)-3-methyl-1-oxobutyl-2-ylcarbamate tert-butyl ester (3b)

[0317] Boc-L-valine (2a) (1.73 g, 7.84 mmol) and 3-chloroaniline (3a) (1.0 g, 7.84 mmol) were reacted according to the procedure reported in step-1 of process 2. After treatment and purification, (S)-1-(3-chlorophenylamino)-3-methyl-1-oxobut-2-ylcarbamate tert-butyl ester (3b) (1.72 g, 5.26 mmol, 67% yield) was obtained as a white solid. 1 HNMR(300MHz,DMSO-d6)δ10.20(s,1H),7.84(s,1H),7.46(d,J=8.0Hz, 1H),7.34(t,J=8.0Hz,1H),7.11(d,J=7.4Hz,1H),6.99(d,J=8.1Hz,1H),3.89(t,J= 7.7Hz, 1H), 2.09-1.80 (m, 1H), 1.39 (s, 9H), 0.89 (d, J = 6.4Hz, 6H); MS (ES + ):349.4 (M+Na).

[0318] Step 2: Preparation of (S)-2-amino-N-(3-chlorophenyl)-3-methylbutyramide (3c)

[0319] (S)-1-(3-chlorophenylamino)-3-methyl-1-oxobut-2-ylcarbamate tert-butyl ester (3b) (750 mg, 2.30 mmol) was reacted with TFA (2.62 g, 22.95 mmol) according to the procedure reported in step 2 of process 2. After treatment and purification by chromatography [silica gel (12 g), eluted with EtOAc / MeOH (9:1) / hexane from 0 to 60%], (S)-2-amino-N-(3-chlorophenyl)-3-methylbutyramide (3c) (355 mg, 1.57 mmol, 68% yield) was obtained as a white solid. 1 HNMR (300MHz, DMSO-d6) δ7.86-7.78(m,1H),7.49(d,J=7.9Hz,1H), 7.39(t,J=7.9Hz,1H),7.18(d,J=7.8Hz,1H),3.66(d,J=5.6Hz,1H),2.21-2.05(m, 1H), 0.97 (t, J=7.1Hz, 6H); MS (ES+): 227.3 (M+1).

[0320] Step 3: Preparation of (S)-1-(2-((1-((3-chlorophenyl)amino)-3-methyl-1-oxobut-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (3d)

[0321] (S)-2-amino-N-(3-chlorophenyl)-3-methylbutyramide (3c) (145 mg, 0.64 mmol) was reacted with 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) according to the procedure reported in steps 3 of process 2. After treatment and purification by chromatography [silica gel (12 g), eluted with 0-60% EtOAc / MeOH (9:1) / hexane], (S)-1-(2-((1-((3-chlorophenyl)amino)-3-methyl-1-oxobut-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (3d) (50 mg, 0.117 mmol, 18% yield) was obtained as a yellow solid. 1 H NMR(300MHz, DMSO-d6)δ10.38 (s,1H),8.69(d,J=8.3Hz,1H),8.18(d,J=7.9Hz,1H),7.83(s,1H),7.76-7.59(m,2H), 7.52-7.31(m,4H),7.26(t,J=7.2Hz,1H),7.13(d,J=7.7Hz,1H),5.43-5.22(m,2H), 4.33(t,J=7.5Hz,1H),2.22-1.86(m,1H),0.95(t,J=6.5Hz,6H); MS(ES+):450.4 (M+Na)

[0322] Process 4

[0323]

[0324] Preparation of (S)-1-(2-((1-((6-bromopyridin-2-yl)amino)-3-methyl-1-oxobut-2-yl)(methyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (4d)

[0325] Step 1: Preparation of (S)-(1-((6-bromopyridin-2-yl)amino)-3-methyl-1-oxobut-2-yl)(methyl)carbamate tert-butyl ester (4b)

[0326] (S)-2-(tert-butoxycarbonyl(methyl)amino)-3-methylbutyric acid (4a) (500 mg, 2.16 mmol) reacted with 6-bromopyridin-2-amine (2b) (374 mg, 2.16 mmol) according to the procedure reported in step-1 of process 2. After treatment and chromatographic purification on silica gel (12 g), (S)-(1-((6-bromopyridin-2-yl)amino)-3-methyl-1-oxobut-2-yl)(methyl)carbamate tert-butyl ester (4b) (135 mg, 0.35 mmol, 16% yield) in a semi-solid state was obtained. 1H NMR (300MHz, DMSO-d6) δ10.92(s,1H),8.08(d,J=8.1Hz,1H),7.74(t,J=7.9Hz,1H),7.36 (d,J=8.0Hz,1H),2.85(s,3H),2.75(s,1H),2.21-2.07(m,1H),1.40(s,9H),0.93-0.83 (m,6H);MS(ES+):410.4(M+Na);(ES - ),386.3(M-1).

[0327] Step 2: Preparation of (S)-N-(6-bromopyridin-2-yl)-3-methyl-2-(methylamino)butyramide (4c)

[0328] (S)-(1-((6-bromopyridin-2-yl)amino)-3-methyl-1-oxobut-2-yl)(methyl)carbamate tert-butyl ester (4b) (125 mg, 0.32 mmol) was reacted with TFA (369 mg, 3.24 mmol) according to the procedure reported in step 2 of process 2, and after treatment, (S)-N-(6-bromopyridin-2-yl)-3-methyl-2-(methylamino)butanamide (4c) in the form of TFA salt was used as is in the next step without further purification; MS (ES+): 288.3 (M+1).

[0329] Step 3: Preparation of (S)-1-(2-((1-((6-bromopyridin-2-yl)amino)-3-methyl-1-oxobut-2-yl)(methyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (4d)

[0330] The TFA salt of (S)-N-(6-bromopyridin-2-yl)-3-methyl-2-(methylamino)butanamide (4c) (99 mg, 0.247 mmol) was reacted with 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (65.1 mg, 0.297 mmol) according to the procedure reported in steps 3 of process 2. After treatment and purification by chromatography [silica gel (12 g), eluted with 0-60% EtOAc / MeOH (9:1) / hexane], (S)-1-(2-((1-((6-bromopyridin-2-yl)amino)-3-methyl-1-oxobut-2-yl)(methyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (4d) (53 mg, 0.11 mmol, 44% yield) as a white solid. 1H NMR(300MHz,DMSO-d6)δ10.92(s,1H),8.25-8.02(m,2H),7.87-7.65 (m,1H),7.65-7.50(m,2H),7.46-7.31(m,3H),7.31-7.18(m,1H),5.78-5.44(m,2H) ,4.84(d,J=10.8Hz,1H),3.27-2.88(m,3H),2.44-2.09(m,1H),1.12-0.79(m,6H); MS (ES+):488.4(M+1).

[0331] Process 5

[0332]

[0333] Preparation of (S)-1-(2-((1-((6-bromopyridin-2-yl)amino)-1-oxopropyl-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (5d)

[0334] Step 1: Preparation of (S)-(1-((6-bromopyridin-2-yl)amino)-1-oxopropyl-2-yl)carbamate tert-butyl ester (5b)

[0335] (S)-2-(tert-Butyloxycarbonylamino)propionic acid (5a) (1.15 g, 6.07 mmol) reacted with 6-bromopyridin-2-amine (2b) (1.0 g, 5.78 mmol) according to the procedure reported in step-1 of Procedure 2. After treatment and chromatographic purification, (S)-(1-((6-bromopyridin-2-yl)amino)-1-oxoprop-2-yl)carbamate tert-butyl ester (5b) (250 mg, 0.73 mmol, 13% yield) was obtained as a clear oil; MS (ES-): 342.4 (M-1).

[0336] Step 2: Preparation of (S)-2-amino-N-(6-bromopyridin-2-yl)propionamide (5c)

[0337] (S)-(1-((6-bromopyridin-2-yl)amino)-1-oxopropyl-2-yl)carbamate tert-butyl ester (5b) (225 mg, 0.65 mmol) and TFA (745 mg, 6.54 mmol) were reacted according to the procedure reported in step 2 of process 2, and after treatment, (S)-2-amino-N-(6-bromopyridin-2-yl)propionamide (5c) as a TFA salt was obtained and used in the next step without further purification; MS (ES+): 245.2 (M+1).

[0338] Step 3: Preparation of (S)-1-(2-((1-((6-bromopyridin-2-yl)amino)-1-oxopropyl-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (5d)

[0339] The TFA salt of (S)-2-amino-N-(6-bromopyridin-2-yl)propionamide (5c) (125 mg, 0.35 mmol) and 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (92 mg, 0.419 mmol) were reacted according to the procedure reported in steps 3 of process 2. After treatment and purification by chromatography [silica gel (12 g), eluted with 0-60% EtOAc / MeOH (9:1) / hexane], (S)-1-(2-((1-((6-bromopyridin-2-yl)amino)-1-oxoprop-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (5d) (18 mg, 12% yield) as a white solid were obtained. 1 H NMR (300MHz, DMSO-d6) δ10.96(s,1H),8.75(d,J=6.9Hz,1H),8.16(d,J=8.2Hz,1H),8.07(d,J=8.2 Hz, 1H), 7.79-7.56 (m, 3H), 7.47-7.30 (m, 3H), 7.30-7.18 (m, 1H), 5.26 (s, 2H), 4.71-4.36 (m, 1H), 1.34 (d, J = 7.1Hz, 3H); MS (ES+): 467.4 (M+Na).

[0340] Process 6

[0341]

[0342] Preparation of (R)-1-(2-((1-((6-bromopyridin-2-yl)amino)-3-methyl-1-oxobut-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (6d)

[0343] Step 1: Preparation of (R)-(1-((6-bromopyridin-2-yl)amino)-3-methyl-1-oxobut-2-yl)carbamate tert-butyl ester (6b)

[0344] (R)-2-((tert-butyloxycarbonyl)amino)-3-methylbutyric acid (6a) (1.0 g, 4.6 mmol) reacted with 6-bromopyridin-2-amine (2b) (1.0 g, 5.80 mmol) according to the procedure reported in step-1 of process 2. After treatment and chromatographic purification, (R)-(1-((6-bromopyridin-2-yl)amino)-3-methyl-1-oxobut-2-yl)carbamate tert-butyl ester (6b) (523 mg, 31% yield) was obtained as a white semi-solid. 1 H NMR (300MHz, DMSO-d6) δ10.78(s,1H),8.09 (d,J=8.2Hz,1H),7.83-7.66(m,1H),7.34(d,J=7.6Hz,1H),6.97(d,J=8.4Hz,1H), 4.03 (t, J=7.8Hz, 1H), 2.07-1.87 (m, 1H), 1.40 (s, 9H), 0.92-0.84 (m, 6H); MS (ES+): 394.4 (M+Na).

[0345] Step 2: Preparation of (R)-2-amino-N-(6-bromopyridin-2-yl)-3-methylbutyramide (6c)

[0346] (R)-(1-((6-bromopyridin-2-yl)amino)-3-methyl-1-oxobut-2-yl)carbamate tert-butyl ester (6b) (490 mg, 1.32 mmol) reacted with TFA (750 mg, 6.58 mmol) according to the procedure reported in step 2 of process 2. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with MeOH / CHCl 30 to 20%], (R)-2-amino-N-(6-bromopyridin-2-yl)-3-methylbutyramide (6c) (185 mg, 0.680 mmol, 52% yield) was obtained as a white solid. 1 H NMR (300MHz, DMSO-d6) δ8.13(d,J=8.1Hz,1H),7.74(t,J=7.9Hz, 1H),7.34(d,J=7.7Hz,1H),3.22(d,J=5.2Hz,1H),2.02-1.85(m,1H),0.91(d,J=6.8 Hz, 3H), 0.82 (d, J = 6.8Hz, 3H); MS (ES+): 272.3 (M+1).

[0347] Step 3: Preparation of (R)-(1-((6-bromopyridin-2-yl)amino)-3-methyl-1-oxobut-2-yl)carbamate tert-butyl ester (6b)

[0348] (R)-2-amino-N-(6-bromopyridin-2-yl)-3-methylbutyramide (6c) (91 mg, 0.33 mmol) reacted with 2-(3-carbamoyl-1H-indazol-1-yl)acetic acid (2e) (88 mg, 0.4 mmol) according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 40%], (R)-(1-((6-bromopyridin-2-yl)amino)-3-methyl-1-oxobut-2-yl)carbamate tert-butyl ester (6b) (65 mg, 0.14 mmol, 41% yield) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ11.12-10.90(m, 1H),8.58(d,J=7.8Hz,1H),8.14(dd,J=21.5,8.0Hz,2H),7.84-7.53(m,3H),7.50-7 .10(m,4H),5.43-5.19(m,2H),4.57-4.34(m,1H),2.18-2.00(m,1H),0.94(s,6H);MS (ES+):473.4(M+1).

[0349] Process 7

[0350]

[0351] Preparation of 1-(2-((2-((6-bromopyridin-2-yl)amino)-2-oxoethyl)(cyclopropyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (7d)

[0352] Step 1: Preparation of tert-butyl (2-((6-bromopyridin-2-yl)amino)-2-oxoethyl)(cyclopropyl)carbamate (7b)

[0353] 2-((tert-Butoxycarbonyl)(cyclopropyl)amino)acetic acid (7a) (0.5 g, 2.32 mmol) was reacted with 6-bromopyridin-2-amine (2b) (0.4 g, 2.32 mmol) according to the procedure reported in step-1 of Procedure 2. After treatment and purification by chromatography [silica gel (12 g), eluted with MeOH / CHCl 30-20%], tert-butyl (2-((6-bromopyridin-2-yl)amino)-2-oxoethyl)(cyclopropyl)carbamate (7b) contaminated with 6-bromopyridin-2-amine (2b) was obtained.

[0354] Step 2: Preparation of N-(6-bromopyridin-2-yl)-2-(cyclopropylamino)acetamide (7c)

[0355] The tert-butyl (2-((6-bromopyridin-2-yl)amino)-2-oxoethyl)(cyclopropyl)carbamate (7b) from step-1 above was reacted with TFA (0.9 mL, 11.61 mmol) according to the procedure reported in step-2 of process 2, and after treatment, N-(6-bromopyridin-2-yl)-2-(cyclopropylamino)acetamide (7c) in the form of TFA salt; MS (ES+): 272.3 (M+2).

[0356] Step 3: Preparation of 1-(2-((2-((6-bromopyridin-2-yl)amino)-2-oxoethyl)(cyclopropyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (7d)

[0357] The N-(6-bromopyridin-2-yl)-2-(cyclopropylamino)acetamide (7c) TFA salt (90 mg, 0.33 mmol) from step-2 above was reacted with 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (88 mg, 0.4 mmol) according to the procedure reported in step-3 of procedure 2. After treatment and purification by chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 40%], 1-(2-((2-((6-bromopyridin-2-yl)amino)-2-oxoethyl)(cyclopropyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (7d) (24 mg, 0.051 mmol, 15% yield, three steps) as a white solid.

[0358] 1 H NMR(300MHz,DMSO-d6)δ10.96(s,1H),8.17(d,J=8.1Hz,1H),8.02(d,J=8.1Hz,1H),7.81-7.59(m,3H),7 .51-7.18(m,4H),5.70(s,2H),4.18(s,2H),3.15-3.05(m,1H),1.15-0.77(m,4H); MS(ES+):471.4(M+1).

[0359] Process 8

[0360]

[0361] Preparation of 1-(2-((2-((6-bromopyridin-2-yl)amino)-2-oxoethyl)(methyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (8d)

[0362] Step 1: Preparation of tert-butyl (2-((6-bromopyridin-2-yl)amino)-2-oxoethyl)(methyl)carbamate (8b)

[0363] 2-((tert-Butoxycarbonyl)(methyl)amino)acetic acid (8a) (2 g, 10.57 mmol) was reacted with 6-bromopyridin-2-amine (2b) (1.52 g, 8.81 mmol) according to the procedure reported in step-1 of process 2. After treatment and purification by chromatography [silica gel (24 g), eluted with EtOAc (0-50%) / hexane], tert-butyl (2-((6-bromopyridin-2-yl)amino)-2-oxoethyl)(methyl)carbamate (8b) (685 mg, 1.99 mmol, 23% yield) as a white solid. 1 H NMR (300MHz, DMSO-d6) δ10.90(d,1H),8.06(t,J=7.8Hz,1H),7.74(td,J=8.0,3.6 Hz, 1H), 7.34 (d, J = 7.7Hz, 1H), 4.01 (d, J = 7.5Hz, 2H), 2.84 (d, J = 8.0Hz, 3H), 1.35 (d, J = 27.9Hz, 9H); MS (ES+): 344.3 (M+1).

[0364] Step 2: Preparation of N-(6-bromopyridin-2-yl)-2-(methylamino)acetamide (8c)

[0365] (2-((6-bromopyridin-2-yl)amino)-2-oxoethyl)(methyl)carbamate tert-butyl ester (8b) (650 mg, 1.89 mmol) reacted with TFA (0.73 mL, 9.44 mmol) according to the procedure reported in step 2 of process 2. After treatment and purification by chromatography [silica gel (12 g), eluted with MeOH / CHCl 30 to 20%], N-(6-bromopyridin-2-yl)-2-(methylamino)acetamide (8c) (285 mg, 1.17 mmol, 62% yield) was obtained as a grayish-white solid. 1 H NMR (300MHz, DMSO-d6) δ11.38(s,1H),8.93(s,2H),8.05(d,J=7.9Hz,1H),7.81(t,J =8.0Hz,1H),7.51-7.32(m,1H),3.98(s,2H),2.62(s,3H); MS(ES+):244.3(M+1).

[0366] Step 3: Preparation of 1-(2-((2-((6-bromopyridin-2-yl)amino)-2-oxoethyl)(methyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (8d)

[0367] N-(6-bromopyridin-2-yl)-2-(methylamino)acetamide (8c) (90 mg, 0.37 mmol) and 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (88 mg, 0.4 mmol) were reacted according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by chromatography [silica gel (12 g), eluted with CMA80 / CHCl30 to 30%], 1-(2-((2-((6-bromopyridin-2-yl)amino)-2-oxoethyl)(methyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (8d) (67 mg, 0.15 mmol, 41% yield, three steps) were obtained as a yellow solid. 1 H NMR(300MHz,DMSO-d6) δ11.30-10.84(2s,11.22,10.94,1H),8.23-8.00(m,2H),7.87-7.56(m,3H),7.49-7.21( m,4H),5.54(2s,5.61,5.46,2H),4.34(2s,4.47,4.20,2H),3.04(2s,3.23,2.85,3H); MS (ES+):467.4(M+Na).

[0368] Process 9

[0369]

[0370] Preparation of (S)-1-(2-((1-((3-chloro-2-fluorobenzyl)amino)-1-oxopropyl-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (9e)

[0371] Step 1: Preparation of (S)-2-(2-(3-carbamoyl-1H-indazole-1-yl)acetamido)tert-butyl propionate (9b)

[0372] (S)-2-propionate tert-butyl ester (9a) (767 mg, 4.22 mmol) was reacted with 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (1.02 g, 4.64 mmol) according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by chromatography [silica gel (40 g), eluted with CMA80 / CHCl30 to 40%], tert-butyl (S)-2-(2-(3-carbamoyl-1H-indazole-1-yl)acetamamido)propionate (9b) (965 mg, 2.79 mmol, 66% yield) as a white solid. 1H NMR(300MHz,DMSO-d6)δ8.73(d,J=7.1Hz,1H),8.17(d,J=8.2Hz, 1H),7.77-7.57(m,2H),7.49-7.33(m,2H),7.26(t,J=7.5Hz,1H),5.22(s,2H),4.23- 4.06 (m, 1H), 1.38 (s, 9H), 1.30 (d, J = 7.3Hz, 3H); MS (ES+): 369.5 (M+Na); 345.4 (M-1).

[0373] Step 2: Preparation of (S)-2-(2-(3-carbamoyl-1H-indazole-1-yl)acetamido)propionic acid (9c)

[0374] (S)-2-(2-(3-carbamoyl-1H-indazole-1-yl)acetamyl)propionate tert-butyl ester (9b) (900 mg, 2.6 mmol) reacted with TFA (1.2 mL, 15.59 mmol) according to the procedure reported in step 2 of process 2, and after treatment, (S)-2-(2-(3-carbamoyl-1H-indazole-1-yl)acetamyl)propionate (9c) (750 mg, 2.58 mmol, 99% yield) in the form of TFA salt was used in the next step without further purification.

[0375] Step 3: Preparation of (S)-1-(2-((1-((3-chloro-2-fluorobenzyl)amino)-1-oxopropyl-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (9e)

[0376] The (S)-2-(2-(3-carbamoyl-1H-indazole-1-yl)acetamamido)propionic acid (9c) (100 mg, 0.35 mmol) TFA salt from step-2 above was reacted with 3-chloro-2-fluorobenzylmethylamine (9d) (66.0 mg, 0.413 mmol) according to the procedure reported in step-3 of process 2. After treatment and purification by [silica gel (12 g), eluted with CMA80 / CHCl30 to 50%], (S)-1-(2-((1-((3-chloro-2-fluorobenzyl)amino)-1-oxopropyl-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (9e) (22 mg, 0.05 mmol, 15% yield) as a white solid. 1H NMR(300 MHz, DMSO-d6)δ8.68(d,J=7.2Hz,1H),8.64-8.57(m,1H),8.17(d,J=8.0Hz,1H), 7.72(s,1H),7.64(d,J=8.6Hz,1H),7.57-7.33(m,3H),7.34-7.19(m,2H),7.19-7 .06(m,1H),5.25(s,2H),4.44-4.20(m,3H),1.28(d,J=6.9Hz,3H);MS(ES+):454.4 (M+Na); 430.4(M-1).

[0377] Process 10

[0378]

[0379] Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(cyclopropyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (10c)

[0380] Step 1: Preparation of tert-butyl (2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(cyclopropyl)carbamate (10a)

[0381] 2-((tert-Butoxycarbonyl)(cyclopropyl)amino)acetic acid (7a) (250 mg, 1.16 mmol) was reacted with 3-chloro-2-fluorobenzylamine (9d) (185 mg, 1.16 mmol) according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by chromatography [silica gel (40 g), eluted with EtOAc / hexane 0 to 50%], tert-butyl (2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(cyclopropyl)carbamate (10a) (365 mg, 1.02 mmol, 88% yield) was obtained as a clear oil. 1 HNMR(300MHz,DMSO-d6)δ8.42(t,J=5.9Hz,1H),7.53-7.42(m,1H), 7.34-7.23(m,1H),7.22-7.11(m,1H),4.33(d,J=5.7Hz,2H),3.76(s,2H),2.6 7-2.54(m,1H),1.46-1.10(m,9H),0.68-0.43(m,4H); MS(ES+):379.4(M+Na).

[0382] Step 2: Preparation of N-(3-chloro-2-fluorobenzyl)-2-(cyclopropylamino)acetamide (10b)

[0383] (2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(cyclopropyl)carbamate tert-butyl ester (10a) (365 mg, 1.02 mmol) reacted with TFA (0.54 mL, 6.97 mmol) according to the procedure reported in step 2 of process 2, and after treatment, N-(3-chloro-2-fluorobenzyl)-2-(cyclopropylamino)acetamide (10b) (265 mg, 0.715 mmol, 61.5% yield) in the form of TFA salt was used in the next step without further purification; MS (ES+) 257.3 (M+1).

[0384] Step 3: Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(cyclopropyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (10c)

[0385] The N-(3-chloro-2-fluorobenzyl)-2-(cyclopropylamino)acetamide (10b) (150 mg, 0.41 mmol) TFA salt from step-2 above was reacted with 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (106 mg, 0.49 mmol) according to the procedure reported in step-3 of process 2. After treatment and purification by [silica gel (12 g), eluted with CMA80 / CHCl 30 to 40%], 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(cyclopropyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (10c) (85 mg, 0.19 mmol, 46% yield) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ8.51(t,J=5.8Hz,1H),8.18(d,J=8.1Hz,1H),7.74(s, 1H),7.64(d,J=8.5Hz,1H),7.52-7.33(m,3H),7.31-7.16(m,2H),7.16-7.05(m,1H),5 .67(s,2H),4.33(d,J=5.5Hz,2H),3.98(s,2H),3.14-2.99(m,1H),1.08-0.95(m,2H), 0.95-0.86(m,2H); 19 F NMR (282MHz, DMSO) δ-121.33; MS (ES+): 458.5 (M+1); 456.5 (M-1).

[0386] Process 11

[0387]

[0388] Preparation of 3-(3-(2-(3-chloro-2-fluorobenzylamino)-2-oxoethyl)-3-cyclopropylureoyl)-1H-indole-1-carboxamide (11b)

[0389] A suspension of 1-carbamoyl-1H-indole-3-carbonyl azide (11a) (50 mg, 0.22 mmol, prepared according to the procedure reported by Altmann, Eva et al. in PCT International Application WO 2012 / 093101) in toluene (10 mL) was refluxed for 1.5 h. The resulting clear solution was cooled to room temperature and N-(3-chloro-2-fluorobenzyl)-2-(cyclopropylamino)acetamide (10b) (56.0 mg, 0.22 mmol) in a solution of THF (5 mL) and triethylamine (0.061 μL, 0.44 mmol) was added. The reaction mixture was stirred at room temperature for 3 h and concentrated under vacuum. The residue obtained by rapid column chromatography [silica gel (24 g), eluted with CMA80 / CHCl 30 to 40%] yielded 3-(3-(2-(3-chloro-2-fluorobenzylamino)-2-oxoethyl)-3-cyclopropylureoyl)-1H-indole-1-carboxamide (11b) as a white solid (42 mg, 0.092 mmol, 42% yield); 1 H NMR (300MHz, DMSO-d6) δ8.47 (t, J=5.9Hz, 1H), 8.33-8.23(m,2H),8.03(s,1H),7.67(d,J=7.7Hz,1H),7.55-7.39(m,1H),7.37-7.23( m,2H),7.23-7.14(m,2H),4.36(d,J=5.7Hz,2H),3.99(s,2H),2.99-2.84(m,1H),1.01 -0.88(m,2H),0.80(d,J=3.8Hz,2H); 19 F NMR (282MHz, DMSO-d6) δ-121.33 (t, J=6.9 Hz); MS (ES+) 458.5 (M+1).

[0390] Process 12

[0391]

[0392] Preparation of 1-(2-(1-(3-chloro-2-fluorobenzylamino)-2-methyl-1-oxopropyl-2-ylamino)-2-oxoethyl)-1H-indazole-3-carboxamide (12d)

[0393] Step 1: Preparation of tert-butyl 2-(2-(3-chloro-2-fluorophenyl)prop-2-ylamino)-2-oxoethylcarbamate (12b)

[0394] 2-(tert-Butoxycarbonylamino)-2-methylpropionic acid (12a) (650 mg, 3.2 mmol) was reacted with 3-chloro-2-fluorobenzylmethylamine (9d) (425 mg, 2.67 mmol) according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by chromatography [silica gel (12 g), eluted with EtOAc / hexane 0-50%], tert-butyl 2-(2-(3-chloro-2-fluorophenyl)prop-2-ylamino)-2-oxoethylcarbamate (12b) (752 mg, 2.18 mmol, 82% yield) as a white solid. 1 H NMR (300MHz, DMSO-d6) δ8.16 (s, 1H), 7.51-7.28 (m, 2H), 7.18-7.04 (m, 1H), 6.99 (s, 1H), 4.29 (d, J = 5.5Hz, 2H), 1.46-1.33 (m, 9H), 1.30 (s, 6H); 19 F NMR (282 MHz, DMSO-d6) δ-121.85; MS (ES+): 345.4 (M+1), 367.4 (M+Na).

[0395] Step 2: Preparation of 2-amino-N-(2-(3-chloro-2-fluorophenyl)prop-2-yl)acetamide (12c)

[0396] 2-(2-(3-chloro-2-fluorophenyl)prop-2-ylamino)-2-oxoethylcarbamate tert-butyl ester (12b) (700 mg, 2.030 mmol) and TFA (0.94 mL, 12.18 mmol) were reacted according to the procedure reported in step 2 of process 2, and after treatment, 2-amino-N-(2-(3-chloro-2-fluorophenyl)prop-2-yl)acetamide (12c) TFA salt (725 mg, 2.02 mmol, 100% yield) in a semi-solid state was used in the next step without further purification; 1 H NMR (300 MHz, DMSO-d6)8.93(t,J=5.6Hz,1H),8.21(s,2H),7.50(td,J=7.4,2.1Hz,1H),7.31- 7.14(m,2H),4.40(d,J=5.5Hz,2H),1.48(s,6H); 19 F NMR (282MHz, DMSO) δ-73.40, -121.12; MS (ES+): 245.3 (M+1).

[0397] Step 3: Preparation of 1-(2-(1-(3-chloro-2-fluorobenzylamino)-2-methyl-1-oxopropyl-2-ylamino)-2-oxoethyl)-1H-indazole-3-carboxamide (12d)

[0398] The 2-amino-N-(2-(3-chloro-2-fluorophenyl)prop-2-yl)acetamide (12c) (300 mg, 0.836 mmol) TFA salt from step-2 above was reacted with 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (220 mg, 1.0 mmol) according to the procedure reported in step-3 of process 2. After treatment and purification by [silica gel (12 g), eluted with CMA80 / CHCl 30 to 40%], 1-(2-(1-(3-chloro-2-fluorobenzylamino)-2-methyl-1-oxopropyl-2-ylamino)-2-oxoethyl)-1H-indazole-3-carboxamide (12d) (185 mg, 0.42 mmol, 50% yield) as a white solid. 1 H NMR (300MHz, DMSO-d6) δ8.58(s,1H),8.36(t,J=5.9Hz,1H),8.19(d,J=8.1Hz,1H),7.69 (s,1H),7.62-7.53(m,1H),7.46-7.32(m,3H),7.30-7.14(m,2H),6.92(t,J=7.9Hz,1H),5.24(s,2H),4.32(d,J=5.6Hz,2H),1.41(s,6H); 19 F NMR (282MHz, DMSO-d6) δ -121.89; MS (ES+) 446.5 (M+1), 468.5 (M+Na).

[0399] Process 13

[0400]

[0401] Preparation of (R)-1-(2-((1-((3-chloro-2-fluorobenzyl)amino)-3-methoxy-1-oxopropyl-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (13d)

[0402] Step 1: Preparation of (R)-(1-((3-chloro-2-fluorobenzyl)amino)-3-methoxy-1-oxopropyl-2-yl)carbamate tert-butyl ester (13b)

[0403] (R)-2-((tert-Butoxycarbonyl)amino)-3-methoxypropionic acid (13a) (382 mg, 1.74 mmol) was reacted with 3-chloro-2-fluorobenzylamine (9d) (232 mg, 1.45 mmol) according to the procedure reported in step 3 of process 2, and after treatment, (R)-(1-((3-chloro-2-fluorobenzyl)amino)-3-methoxy-1-oxopropyl-2-yl)carbamate tert-butyl ester (13b) was used as is in the next step; MS (ES+): 383.4 (M+Na).

[0404] Step 2: Preparation of (R)-2-amino-N-(3-chloro-2-fluorobenzyl)-3-methoxypropionamide (13c)

[0405] (R)-(1-((3-chloro-2-fluorobenzyl)amino)-3-methoxy-1-oxopropyl-2-yl)carbamate tert-butyl ester (13b) (525 mg, 1.45 mmol) reacted with TFA (2.02 mL, 26.2 mmol) according to the procedure reported in step 2 of process 2, and after treatment, yielded (R)-2-amino-N-(3-chloro-2-fluorobenzyl)-3-methoxypropionamide (13c) TFA salt (379 mg, 1.45 mmol, 100% yield), which was used in the next step without further purification; MS (ES+): 261.3 (M+1).

[0406] Step 3: Preparation of (R)-1-(2-((1-((3-chloro-2-fluorobenzyl)amino)-3-methoxy-1-oxopropyl-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (13d)

[0407] The (R)-2-amino-N-(3-chloro-2-fluorobenzyl)-3-methoxypropionamide (13c) (379 mg, 1.45 mmol) TFA salt from step-2 above was reacted with 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (382 mg, 1.75 mmol) according to the procedure reported in step-3 of process 2. After treatment and purification by chromatography [silica gel (24 g), eluted with MeOH / CHCl 30 to 40%], (R)-1-(2-((1-((3-chloro-2-fluorobenzyl)amino)-3-methoxy-1-oxoprop-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (13d) (32 mg, 5% yield) as a white solid. 1¹H NMR (300MHz, DMSO-d⁶) δ 8.78–8.66 (m, 2H), 8.18 (dt, J = 8.2, 1.0 Hz, 1H), 7.72 (s, 1H, D₂O exchangeable), 7.64 (d, J = 8.5 Hz, 1H), 7.54–7.35 (m, 3H, 1H, D₂O exchangeable), 7.31–7.22 (m, 2H), 7.20–7.10 (m, 1H), 5.30 (d, J = 2.3 Hz, 2H), 4.57–4.47 (m, 1H), 4.46–4.28 (m, 2H), 3.65–3.50 (m, 2H), 3.28 (s, 3H); 19 F NMR (282MHz, DMSO-d6) δ-121.28; MS (ES+): 484.5 (M+Na); (ES-) 496.4 (M+Cl).

[0408] Process 14

[0409]

[0410] Preparation of 1-(2-((1-((3-chloro-2-fluorobenzyl)carbamoyl)cyclopentyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (14d)

[0411] Step 1: Preparation of tert-butyl (1-((3-chloro-2-fluorobenzyl)carbamoyl)cyclopentyl)carbamate (14b)

[0412] 1-((tert-Butoxycarbonyl)amino)cyclopentanecarboxylic acid (14a) (650 mg, 2.85 mmol) was reacted with 3-chloro-2-fluorobenzylamine (9d) (379 mg, 2.37 mmol) according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by chromatography [silica gel (12 g), eluted with EtOAc / hexane 0-50%], tert-butyl 1-((3-chloro-2-fluorobenzyl)carbamoyl)cyclopentyl)carbamate (14b) (650 mg, 1.73 mmol, 74% yield) was obtained as a white solid. 1 H NMR (300MHz, DMSO-d6)8.15-8.06(m,1H),7.43(t,J=7.1Hz,1H),7.35(t,J= 7.1Hz,1H),7.19-7.06(m,2H),4.31(d,J=5.9Hz,2H),2.07-1.92(m,2H),1.89-1 .71(m,3H),1.65-1.55(m,3H),1.38(s,9H); MS(ES+):371.4(M+1),393.4(M+Na).

[0413] Step 2: Preparation of 1-amino-N-(3-chloro-2-fluorobenzyl)cyclopentaneformamide (14c)

[0414] (1-((3-chloro-2-fluorobenzyl)carbamoyl)cyclopentyl)carbamate tert-butyl ester (14b) (650 mg, 1.75 mmol) reacted with TFA (1.35 mL, 17.53 mmol) according to the procedure reported in step 2 of process 2, and after treatment, a clear oily 1-amino-N-(3-chloro-2-fluorobenzyl)cyclopentanecarboxamide (14c) TFA salt (675 mg, 1.75 mmol, 100% yield) was obtained and used in the next step without further purification; 1 H NMR(300MHz, DMSO-d6)δ8.86(t,J=5.2Hz,1H),8.17(s,2H),7.50(t,J=7.4Hz,1H),7.32-7.13(m, 2H),4.40(d,J=5.2Hz,2H),4.13(s,1H),2.10(s,2H),1.86(d,J=15.6Hz,6H); 19 F NMR (282MHz, DMSO) delta -73.25 (TFA); -121.06; MS (ES+): 271.3 (M+1).

[0415] Step 3: Preparation of 1-(2-((1-((3-chloro-2-fluorobenzyl)carbamoyl)cyclopentyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (14d)

[0416] The 1-amino-N-(3-chloro-2-fluorobenzyl)cyclopentanecarboxamide (14c) (117 mg, 0.53 mmol) TFA salt from step-2 above was reacted with 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (116 mg, 0.53 mmol) according to the procedure reported in step-3 of process 2. After treatment and purification by chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 40%], 1-(2-((1-((3-chloro-2-fluorobenzyl)carbamoyl)cyclopentyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (14d) (62 mg, 0.13 mmol, 30% yield) as a white solid. 1H NMR (300MHz, DMSO-d6)δ8.63(s,1H),8.37(t,J=5.9Hz,1H),8.17(d,J=8.1Hz,1H),7.65 (s,1H),7.57(d,J=8.5Hz,1H),7.45-7.31(m,3H),7.31-7.20(m,1H),7.20-7.09(m, 1H),6.91(t,J=7.9Hz,1H),5.25(s,2H),4.33(d,J=5.7Hz,2H),2.15-1.97(m,2H),1.96-1.80(m,2H),1.77-1.59(m,4H); 19 F NMR (282MHz, DMSO-d6) δ-121.99; MS (ES+): 472.5 (M+1).

[0417] Process 15

[0418]

[0419] Preparation of (S)-1-(2-((1-((3-chloro-2-fluorobenzyl)amino)-1-oxo-3-phenylprop-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (15d)

[0420] Step 1: Preparation of (S)-(1-((3-chloro-2-fluorobenzyl)amino)-1-oxo-3-phenylprop-2-yl)carbamate tert-butyl ester (15b)

[0421] (S)-2-((tert-Butoxycarbonyl)amino)-3-phenylpropionic acid (15a) (475 mg, 1.79 mmol) was reacted with 3-chloro-2-fluorobenzylamine (9d) (238 mg, 1.49 mmol) according to the procedure reported in step 3 of process 2, and after treatment, (S)-(1-((3-chloro-2-fluorobenzyl)amino)-1-oxo-3-phenylprop-2-yl)carbamate tert-butyl ester (15b) was obtained, which was used as is in the next step; MS (ES-): 441.4 (M+Cl).

[0422] Step 2: Preparation of (S)-2-amino-N-(3-chloro-2-fluorobenzyl)-3-phenylpropionamide (15c)

[0423] (S)-(1-((3-chloro-2-fluorobenzyl)amino)-1-oxo-3-phenylprop-2-yl)carbamate tert-butyl ester (15b) (607 mg, 1.5 mmol) was reacted with TFA according to the procedure reported in step-2 of process 2, and after treatment, (S)-2-amino-N-(3-chloro-2-fluorobenzyl)-3-phenylpropanamide (15c) TFA salt (458 mg, 1.49 mmol, 83%) was used in the next step without further purification; MS (ES+): 307.4 (M+1), (ES-) 305.2 (M-1).

[0424] Step 3: Preparation of (S)-1-(2-((1-((3-chloro-2-fluorobenzyl)amino)-1-oxo-3-phenylprop-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (15d)

[0425] The (S)-2-amino-N-(3-chloro-2-fluorobenzyl)-3-phenylpropanamide (15c) (458 mg, 1.49 mmol) TFA salt from step-2 above was reacted with 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (393 mg, 1.79 mmol) according to the procedure reported in step-3 of process 2. After treatment and purification by chromatography [silica gel (24 g), eluted with MeOH / CHCl 30 to 40%], (S)-1-(2-((1-((3-chloro-2-fluorobenzyl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (15d) (66 mg, 13% yield) as a grayish-white solid. 1 HNMR(300MHz,DMSO-d6)δ8.79-8.67(m,2H),8.15(dt,J=8.2,1.0Hz,1H),7.65(s, 1H),7.47(td,J=7.5,1.9Hz,1H),7.42-7.35(m,3H),7.30-7.19(m,6H),7.14-7.00(m, 2H),5.31-5.08(m,2H),4.64-4.53(m,1H),4.44-4.21(m,2H),3.11-2.97(m,1H),2.92- 2.75(m,1H); 19 F NMR (282MHz, DMSO-d6) δ-121.21; MS (ES+): 530.5 (M+Na); (ES-): 506.5 (M-1), 542.4 (M+Cl).

[0426] Process 16

[0427]

[0428] Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (16d)

[0429] Step 1: Preparation of tert-butyl (2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)carbamate (16b)

[0430] 2-((tert-Butoxycarbonyl)amino)acetic acid (16a) (4 g, 22.83 mmol) was reacted with 3-chloro-2-fluorobenzylamine (9d) (3.31 g, 20.76 mmol) according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by chromatography [silica gel (80 g), eluted with EtOAc / hexane 0 to 60%], tert-butyl 2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)carbamate (16b) (4.09 g, 12.91 mmol, 62% yield) was obtained as a white solid. 1 H NMR(300MHz,DMSO-d6)δ8.37(t,J=5.8Hz,1H),7.53-7.41(m,1H),7.35-7.23(m,1H),7.24- 7.12(m,1H),7.05(t,J=6.0Hz,1H),4.33(d,J=5.8Hz,2H),3.57(d,2H),1.38(s,9H); 19 F NMR (282MHz, DMSO) δ-121.38; MS (ES+): 339.4 (M+Na)

[0431] Step 2: Preparation of 2-amino-N-(3-chloro-2-fluorobenzyl)acetamide (16c)

[0432] (2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)carbamate tert-butyl ester (16b) (4.08 g, 12.88 mmol) and TFA (4.96 mL, 64.4 mmol) were reacted according to the procedure reported in step 2 of process 2, and after treatment, a white solid 2-amino-N-(3-chloro-2-fluorobenzyl)acetamide (16c) TFA salt (9.07 mmol, 70% yield) was obtained and used in the next step without further purification; 1H NMR (300MHz, DMSO-d6) δ8.94(t,J =5.7Hz,1H),8.04(s,3H),7.56-7.45(m,1H),7.40-7.29(m,1H),7.27-7.15(m,1H), 4.41(d,J=5.7Hz,2H),3.62(s,2H); 19 F NMR(282MHz,DMSO-d6)δ-73.32,-120.87; MS(ES + )217.2(M+1).

[0433] Step 3: Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (16d)

[0434] The 2-amino-N-(3-chloro-2-fluorobenzyl)acetamide (16c) (160 mg, 0.48 mmol) TFA salt from step-2 above was reacted with 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (127 mg, 0.58 mmol) according to the procedure reported in step-3 of process 2. After treatment and purification by chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 40%], 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (16d) (120 mg, 0.29 mmol, 59% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ8.59(t,J=5.7Hz,1H),8.54(t,J=5.7Hz,1H),8.18(d,J=8.0Hz,1H), 7.75-7.61(m,2H),7.54-7.34(m,3H),7.33-7.20(m,2H),7.20-7.10(m,1H),5.26(s,2H),4.36(d,J=5.6Hz,2H),3.82(d,J=5.5Hz,2H); 19 F NMR (282MHz, DMSO-d6) δ -121.23; MS (ES+): 418.5 (M+1), 440.4 (M+Na); 416.3 (M-1).

[0435] Process 17

[0436]

[0437] Preparation of 3-(3-(2-((6-bromopyridin-2-yl)amino)-2-oxoethyl)-3-cyclopropylureo)-1H-indole-1-carboxamide (17a)

[0438] N-(6-bromopyridin-2-yl)-2-(cyclopropylamino)acetamide (7c) was reacted with 1-carbamoyl-1H-indole-3-carbonyl azide (11a) (50 mg, 0.22 mmol) according to the procedure reported in Procedure 11. After treatment and purification by rapid column chromatography (silica gel 24 g, eluted with CHCl3-CMA 800-40%), 3-(3-(2-((6-bromopyridin-2-yl)amino)-2-oxoethyl)-3-cyclopropylureoyl)-1H-indole-1-carboxamide (17a) (108 mg, 0.23 mmol, 76% yield) was obtained as a white solid. 1 H NMR(300MHz,DMSO-d6)δ10.95(s,1H),8.35-8.22(m, 2H),8.07(d,J=8.2Hz,1H),8.02(s,1H),7.78-7.64(m,2H),7.42(s,2H),7.34(d,J=7. 7Hz,1H),7.31-7.15(m,2H),4.19(s,2H),3.06-2.89(m,1H),1.05-0.87(m,2H),0.85- 0.72(m,2H); MS(ES+): 471.4(M+1), 493.4(M+Na).

[0439] Process 18

[0440]

[0441] Preparation of (S)-1-(2-((1-((3-chloro-2-fluorobenzyl)amino)-1-oxohexyl-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (18d)

[0442] Step 1: Preparation of (S)-(1-((3-chloro-2-fluorobenzyl)amino)-1-oxohex-2-yl)carbamate tert-butyl ester (18b)

[0443] (S)-2-((tert-Butoxycarbonyl)amino)hexanoic acid (18a) (0.42 g, 1.8 mmol) and 3-chloro-2-fluorobenzylamine (9d) (0.239 g, 1.5 mmol) were reacted according to the procedure reported in step 3 of process 2, and after treatment, (S)-(1-((3-chloro-2-fluorobenzyl)amino)-1-oxohex-2-yl)carbamate tert-butyl ester (18b) was obtained, which was used as is in the next step.

[0444] Step 2: Preparation of (S)-2-amino-N-(3-chloro-2-fluorobenzyl)hexamethylene (18c)

[0445] (S)-(1-((3-chloro-2-fluorobenzyl)amino)-1-oxohexyl-2-yl)carbamate tert-butyl ester (18b) (0.56 g, 1.5 mmol) reacted with TFA (2.08 mL, 26.9 mmol) according to the procedure reported in step 2 of process 2, and after treatment, yielded (S)-2-amino-N-(3-chloro-2-fluorobenzyl)hexamethylene (18c) TFA salt (9.07 mmol, 70% yield), which was used as is in the next step; MS (ES+): 273.4 (M+1).

[0446] Step 3: Preparation of (S)-1-(2-((1-((3-chloro-2-fluorobenzyl)amino)-1-oxohexyl-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (18d)

[0447] The (S)-2-amino-N-(3-chloro-2-fluorobenzyl)hexamethylene (18c) (408 mg, 1.5 mmol) TFA salt from step-2 above was reacted with 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (393 mg, 1.8 mmol) according to the procedure reported in step-3 of process 2, and after treatment, (S)-1-(2-((1-((3-chloro-2-fluorobenzyl)amino)-1-oxohexyl-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (18d) (56 mg, 0.12 mmol, 8% yield) as a grayish-white solid. 1 ¹H NMR (300MHz, DMSO-d⁶) δ 8.76–8.62 (m, 2H, D₂O exchangeable), 8.24 (d, J = 8.1 Hz, 1H), 7.76 (s, 1H, D₂O exchangeable), 7.69 (d, J = 8.6 Hz, 1H), 7.60–7.42 (m, 3H), 7.32 (t, J = 7.7 Hz, 2H), 7.20 (t, J = 7.8 Hz, 1H), 5.32 (s, 2H), 4.53–4.26 (m, 3H), 1.81–1.56 (m, 2H), 1.31 (s, 4H), 0.96–0.86 (m, 3H); 19 F NMR (282MHz, DMSO-d6) δ-121.09; MS (ES+): 496.5 (M+Na), 472.5 (M-1).

[0448] Process 19

[0449]

[0450] Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(isopropyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (19d)

[0451] Step 1: Preparation of (2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(isopropyl)carbamate tert-butyl ester (19b)

[0452] 2-((tert-Butoxycarbonyl)(isopropyl)amino)acetic acid (19a) (300 mg, 1.38 mmol) was reacted with 3-chloro-2-fluorobenzylamine (9d) (200 mg, 1.26 mmol) according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by chromatography [silica gel (12 g), eluted with EtOAc / hexane 0 to 60%], tert-butyl (2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(isopropyl)carbamate (19b) (395 mg, 1.1 mmol, 88% yield) as a white solid. 1 H NMR (300MHz, DMSO-d6) δ8.35 (s, 1H), 7.47 (t, J = 7.5Hz, 1H), 7.37-7.25(m,1H),7.23-7.10(m,1H),4.32(d,J=5.7Hz,2H),4.28-3.95(m, 1H),3.75-3.57(m,2H),1.40(s,3H),1.26(s,6H),1.12-0.95(m,6H); MS(ES + )381.4(M+Na).

[0453] Step 2: Preparation of N-(3-chloro-2-fluorobenzyl)-2-(isopropylamino)acetamide (19c)

[0454] (2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(isopropyl)carbamate tert-butyl ester (19b) (340 mg, 0.95 mmol) and TFA (0.37 mL, 4.74 mmol) were reacted according to the procedure reported in step 2 of process 2, and after treatment, N-(3-chloro-2-fluorobenzyl)-2-(isopropylamino)acetamide (19c) TFA salt (348 mg, 0.93 mmol, 99% yield) was obtained as a white solid and used in the next step without further purification; 1H NMR (300 MHz, DMSO-d6) δ9.04 (t, J=5.7Hz, 1H), 8.81 (s, 2H), 7.57-7.46 (m, 1H), 7.40-7.30 (m, 1H),7.26-7.16(m,1H),4.42(d,J=5.6Hz,2H),3.78-3.77(m,2H),3.37-3.20(m,1H), 1.20(d,J=6.5Hz,6H); 19 F NMR (282MHz, DMSO-d6) δ-73.83 (TFA peak), -120.79; MS (ES+) 259.4 (M+1).

[0455] Step 3: Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(isopropyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (19d)

[0456] The N-(3-chloro-2-fluorobenzyl)-2-(isopropylamino)acetamide (19c) (160 mg, 0.43 mmol) TFA salt from step-2 above was reacted with 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (113 mg, 0.52 mmol) according to the procedure reported in step-3 of process 2. After treatment and purification by chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 40%], 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(isopropyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (19d) (115 mg, 0.25 mmol, 58% yield) as a white solid. 1 H NMR (300MHz, DMSO-d6) δ8.83, 8.36 (2t, J = 5.7Hz, 1H), 8.18 (d, J = 8.0Hz, 1H),7.71(s,1H),7.63-7.47(m,2H),7.47-7.31(m,3H),7.29-6.99(m,2H),5.59,5.45 (2s,2H),4.61-4.39(m,2H),4.36-4.10(m,2H),3.91-3.75(m,1H),1.23,0.99(2dd,J= 72.0,6.4Hz,6H); 19 F NMR (282 MHz, DMSO-d6) δ -120.94, -121.48; MS (ES+): 460.5 (M+1); (ES-): 458.5 (M-1); (Based on NMR, the compound is a mixture of 2:3 rotational isomers)

[0457] Process 20

[0458]

[0459] Preparation of (S)-1-(2-((1-((3-chloro-2-fluorobenzyl)amino)-1-oxo-3-(thien-2-yl)propyl-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (20d)

[0460] Step 1: Preparation of (S)-(1-((3-chloro-2-fluorobenzyl)amino)-1-oxo-3-(thien-2-yl)propyl-2-yl)carbamate tert-butyl ester (20b)

[0461] (S)-2-((tert-Butoxycarbonyl)amino)-3-(thiophen-2-yl)propionic acid (20a) (428 mg, 1.58 mmol) reacted with 3-chloro-2-fluorobenzylamine (9d) (252 mg, 1.58 mmol) according to the procedure reported in step 3 of process 2, and after treatment, yielded (S)-(1-((3-chloro-2-fluorobenzyl)amino)-1-oxo-3-(thiophen-2-yl)prop-2-yl)carbamate tert-butyl ester (20b), which was used as is in the next step; MS (ES-): 448.4 (M+Cl).

[0462] Step 2: Preparation of (S)-2-amino-N-(3-chloro-2-fluorobenzyl)-3-(thiophen-2-yl)propionamide (20c)

[0463] (S)-(1-((3-chloro-2-fluorobenzyl)amino)-1-oxo-3-(thiophen-2-yl)prop-2-yl)carbamate tert-butyl ester (20b) (652 mg, 1.58 mmol) was reacted with TFA (2.19 mL, 28.4 mmol) according to the procedure reported in step 2 of process 2, and after treatment, (S)-2-amino-N-(3-chloro-2-fluorobenzyl)-3-(thiophen-2-yl)propionamide (20c) TFA salt was obtained, which was used in the next step without further purification; MS (ES+): 313.3 (M+1).

[0464] Step 3: Preparation of (S)-1-(2-((1-((3-chloro-2-fluorobenzyl)amino)-1-oxo-3-(thiophen-2-yl)propyl-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (20d)

[0465] The (S)-2-amino-N-(3-chloro-2-fluorobenzyl)-3-phenylpropanamide (15c) (494 mg, 1.58 mmol) TFA salt from step-2 above was reacted with 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (415 mg, 1.9 mmol) according to the procedure reported in step-3 of process 2, and after treatment, (S)-1-(2-((1-((3-chloro-2-fluorobenzyl)amino)-1-oxo-3-(thiophen-2-yl)prop-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (20d) (86 mg, 11% yield) as a grayish-white solid; 1 H NMR (300MHz, DMSO-d6) δ8.91- 8.70 (m, 2H), 8.17 (dt, J=8.2, 1.0Hz, 1H), 7.67 (s, 1H), 7.55-7.35 (m, 5H), 7.30-7.21 (m, 1H),7.17-7.04(m,2H),6.98-6.92(m,1H),6.92-6.87(m,1H),5.37-5.09(m,2H ),4.66-4.50(m,1H),4.46-4.22(m,2H),3.33-3.21(m,1H),3.17-2.99(m,1H); 19 F NMR (282 MHz, DMSO-d6) δ-121.19; MS (ES+): 514.53 (M+1), 536.5 (M+Na), 512.5 (M-1).

[0466] Process 21

[0467]

[0468] Preparation of (S)-1-(2-((1-((3-chloro-2-fluorobenzyl)amino)-4-(methylthio)-1-oxobut-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (21d)

[0469] Step 1: Preparation of (S)-(1-((3-chloro-2-fluorobenzyl)amino)-4-(methylthio)-1-oxobut-2-yl)carbamate tert-butyl ester (21b)

[0470] (S)-2-((tert-Butoxycarbonyl)amino)-4-(methylthio)butyric acid (21a) (391 mg, 1.57 mmol) was reacted with 3-chloro-2-fluorobenzylamine (9d) (250 mg, 1.57 mmol) according to the procedure reported in step 3 of process 2, and after treatment, (S)-(1-((3-chloro-2-fluorobenzyl)amino)-4-(methylthio)-1-oxobut-2-yl)carbamate tert-butyl ester (21b) was obtained, which was used as is in the next step; MS (ES-): 391.4 (M-1).

[0471] Step 2: Preparation of (S)-2-amino-N-(3-chloro-2-fluorobenzyl)-4-(methylthio)butyramide (21c)

[0472] (S)-(1-((3-chloro-2-fluorobenzyl)amino)-4-(methylthio)-1-oxobut-2-yl)carbamate tert-butyl ester (21b) from the above steps reacted with TFA (3 mL) according to the procedure reported in step-2 of process 2, and after treatment, yielded (S)-2-amino-N-(3-chloro-2-fluorobenzyl)-4-(methylthio)butyramide (21c) TFA salt, which was used in the next step without further purification; MS (ES+): 291.3 (M+1).

[0473] Step 3: Preparation of (S)-1-(2-((1-((3-chloro-2-fluorobenzyl)amino)-4-(methylthio)-1-oxobut-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (21d)

[0474] (S)-2-amino-N-(3-chloro-2-fluorobenzyl)-4-(methylthio)butyramide (21c) (0.254 g, 0.931 mmol) TFA salt from step-2 above was reacted with 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (136 mg, 0.62 mmol) according to the procedure reported in step-3 of process 2. After treatment and purification by rapid column chromatography [silica gel (24 g), eluted with CMA80 / CHCl 30 to 40%], (S)-1-(2-((1-((3-chloro-2-fluorobenzyl)amino)-4-(methylthio)-1-oxobut-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (21d) (33 mg, 0.067 mmol, 11% yield) as a white solid. 1H NMR (300MHz, DMSO-d6) δ8.75-8.60(m,2H),8.17(d,J=8.1Hz,1H),7.71(s,1H),7.63(d,J=8.5Hz,1H),7.58-7.35(m,3H),7.31-7.20 (m,2H),7.15(q,J=8.8,7.8Hz,1H),5.27(s,2H),4.47-4.27(m,3H),2.48-2.36(m,2H),2.04(s,1H),2.02(s,2H),2.01-1.67(m,2H); 19 F NMR (282MHz, DMSO-d6) δ-121.12 (d, J=7.1 Hz); MS (ES+): 492.5 (M+1); MS (ES-): 490.5 (M-1); 526.5 (M+Cl).

[0475] Process 22

[0476]

[0477] Preparation of (S)-1-(2-((1-((3-chloro-2-fluorobenzyl)amino)-4-methyl-1-oxopent-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (22d)

[0478] Step 1: Preparation of (S)-(1-((3-chloro-2-fluorobenzyl)amino)-4-methyl-1-oxopent-2-yl)carbamate tert-butyl ester (22b)

[0479] (S)-2-((tert-Butoxycarbonyl)amino)-4-methylpentanoic acid (22a) (362 mg, 1.57 mmol) was reacted with 3-chloro-2-fluorobenzylamine (9d) (250 mg, 1.57 mmol) according to the procedure reported in step 3 of process 2, and after treatment, (S)-(1-((3-chloro-2-fluorobenzyl)amino)-4-methyl-1-oxopentan-2-yl)carbamate tert-butyl ester (22b) was used as is in the next step; MS (ES+): 395.4 (M+Na).

[0480] Step 2: Preparation of (S)-2-amino-N-(3-chloro-2-fluorobenzyl)-4-methylpentanamide (22c)

[0481] (S)-(1-((3-chloro-2-fluorobenzyl)amino)-4-methyl-1-oxopentan-2-yl)carbamate tert-butyl ester (22b) from the above steps reacted with TFA (3 mL) according to the procedure reported in step-2 of process 2, and after treatment, yielded (S)-2-amino-N-(3-chloro-2-fluorobenzyl)-4-methylpentanamide (22c) TFA salt, which was used in the next step without further purification; MS (ES+): 273.4 (M+1).

[0482] Step 3: Preparation of (S)-1-(2-((1-((3-chloro-2-fluorobenzyl)amino)-4-methyl-1-oxopent-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (22d)

[0483] (S)-2-amino-N-(3-chloro-2-fluorobenzyl)-4-methylpentanamide (22c) (0.25 g, 0.93 mmol) TFA salt from step-2 above was reacted with 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (136 mg, 0.62 mmol) according to the procedure reported in step-3 of process 2. After treatment and purification by rapid column chromatography [silica gel (24 g), eluted with CMA80 / CHCl 30 to 40%], (S)-1-(2-((1-((3-chloro-2-fluorobenzyl)amino)-4-methyl-1-oxopentan-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (22d) (65 mg, 0.14 mmol, 22% yield) as a pale white solid. 1 H NMR(300MHz,DMSO-d6)δ8.69(t,J=5.8Hz,1H),8.62(d,J =8.0Hz,1H),8.17(d,J=8.1Hz,1H),7.70(s,1H),7.61(d,J=8.5Hz,1H),7.52-7.35(m,3H),7.32-7.19(m,2H),7.13(t,J=7.9 Hz,1H),5.25(s,2H),4.42-4.24(m,3H),1.70-1.54(m,1H),1.55-1.42(m,2H),0.90(d,J=6.4Hz,3H),0.83(d,J=6.4Hz,3H); 19 F NMR (282MHz, DMSO-d6) δ-121.23; MS (ES+) 474.5 (M+1), 496.5 (M+Na); MS (ES-) 508.5

[0484] Process 23

[0485]

[0486] Preparation of (S)-1-(2-((1-((3-chlorobenzyl)amino)-1-oxopropyl-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (23b)

[0487] (S)-2-(2-(3-carbamoyl-1H-indazole-1-yl)acetamyl)propionic acid (9c) (200 mg, 0.69 mmol) TFA salt reacted with (3-chlorophenyl)methylamine (23a) (98 mg, 0.69 mmol) according to the procedure reported in step 3 of process 2, and after treatment, (S)-1-(2-((1-((3-chlorobenzyl)amino)-1-oxopropyl-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (23b) (126 mg, 0.3 mmol, 44% yield) as a yellow solid; 1 H NMR (300MHz, DMSO-d6) δ8.67(d,J=7.4Hz,1H),8.59(t,J=6.0Hz,1H),8.17(d,J=8.1Hz,1 H),7.72(s,1H),7.64(d,J=8.5Hz,1H),7.47-7.15(m,7H),5.41-5.16(m,2H),4.43-4.23 (m, 3H), 1.29 (d, J = 7.0Hz, 3H); MS (ES+): 414.5 (M+1); ES (-): 412.4 (M-1).

[0488] Process 24

[0489]

[0490] Preparation of 1-(2-(benzyl(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (24b)

[0491] Step 1: Preparation of 2-(phenylmethylamino)-N-(3-chloro-2-fluorophenylmethyl)acetamide (24a)

[0492] Benzaldehyde (143 mg, 1.343 mmol) and acetic acid (0.12 mL, 2.01 mmol) were added to a solution of 2-amino-N-(3-chloro-2-fluorobenzyl)acetamide (16c) (320 mg, 1.48 mmol) in THF (10 mL). The resulting mixture was stirred for 50 min, and NaBH4 (102 mg, 2.69 mmol) was added and stirred overnight at room temperature. The reaction was quenched with an aqueous solution of NaHCO3 (2N, 20 mL), stirred for 30 min, and diluted with EtOAc (100 mL). The organic layer was separated, washed with brine, dried, filtered, and concentrated under vacuum to give 2-(benzylamino)-N-(3-chloro-2-fluorobenzyl)acetamide (24a) (240 mg, 0.78 mmol, 58% yield), which was used in the next step without further purification. MS (ES+): 307.3 (M+1)

[0493] Step 2: Preparation of 1-(2-(benzyl(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (24b)

[0494] 2-(benzylamino)-N-(3-chloro-2-fluorobenzyl)acetamide (24a) (240 mg, 0.78 mmol) was reacted with 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (171 mg, 0.78 mmol) according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 40%], 1-(2-(benzyl(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (24b) (38 mg, 0.075 mmol, 10% yield) as a white solid. 1 ¹H NMR (300MHz, DMSO-d⁶) δ 8.79 and 8.52 (2t, J = 5.9Hz, 1H), 8.25–8.11 (m, 1H), 7.80–7.66 (m, 1H), 7.66–7.56 (m, 1H), 7.56–7.36 (m, 5H), 7.34–7.10 (m, 6H), 5.58 (s, 2H), 4.83 and 4.46 (2s, 2H), 4.43 and 4.34 (2d, J = 5.6Hz, 2H), 4.21 and 3.95 (s, 2H); 19F NMR (282MHz, DMSO-d6) δ -121.06, -121.35; MS (ES+): 508.5 (M+1); (ES-) 506.5 (M-1); (Based on NMR, the compound is a mixture of 2:1 rotational isomers)

[0495] Process 25

[0496]

[0497] Preparation of 3-(3-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-3-isopropylureo)-1H-indole-1-carboxamide (25a)

[0498] N-(3-chloro-2-fluorobenzyl)-2-(isopropylamino)acetamide (19c) (90 mg, 0.35 mmol) reacted with 1-carbamoyl-1H-indole-3-carbonyl azide (11a) (80 mg, 0.35 mmol) according to the procedure reported in Procedure 11. After treatment and purification by rapid column chromatography (silica gel 24 g, eluted with CMA80 / CHCl 30-30%), 3-(3-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-3-isopropylureoyl)-1H-indole-1-carboxamide (25a) (9 mg, 6% yield) as a yellow solid was obtained. 1 ¹H NMR (300MHz, DMSO-d⁶) δ 8.92 (s, ¹H, D₂O exchangeable), 8.82–8.70 (m, ¹H, D₂O exchangeable), 8.30–8.22 (m, ¹H), 7.98 (s, ¹H), 7.62 (d, J = 7.7Hz, ¹H), 7.54–7.32 (m, 4H, 2H, D₂O exchangeable), 7.30–7.21 (m, ¹H), 7.20–7.11 (m, 2H), 4.56–4.33 (m, 3H), 3.97 (s, 2H), 1.10 (d, J = 6.6Hz, 6H); 19 F NMR (282MHz, DMSO-d6) δ-121.07; MS (ES+): 460.5 (M+1), 482.49 (M+Na); MS (ES-): 458.44 (M-1).

[0499] Process 26

[0500]

[0501] Preparation of (S)-1-(2-((1-((3-chloro-2-fluorobenzyl)amino)-3-hydroxy-1-oxopropyl-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (26d)

[0502] Step 1: Preparation of (S)-(1-((3-chloro-2-fluorobenzyl)amino)-3-hydroxy-1-oxopropyl-2-yl)carbamate tert-butyl ester (26b)

[0503] (S)-2-((tert-butyloxycarbonyl)amino)-3-hydroxypropionic acid (26a) (389 mg, 1.9 mmol) and 3-chloro-2-fluorobenzylamine (9d) (252 mg, 1.58 mmol) were reacted according to the procedure reported in step 3 of process 2, and after treatment, (S)-(1-((3-chloro-2-fluorobenzyl)amino)-3-hydroxy-1-oxopropyl-2-yl)carbamate tert-butyl ester (26b) was obtained, which was used as is in the next step; MS(ES+): 369.4 (M+Na), MS(ES-): 381.3 (M+Cl).

[0504] Step 2: Preparation of (S)-2-amino-N-(3-chloro-2-fluorobenzyl)-3-hydroxypropionamide (26c)

[0505] (S)-(1-((3-chloro-2-fluorobenzyl)amino)-3-hydroxy-1-oxopropyl-2-yl)carbamate tert-butyl ester (26b) (548 mg, 1.58 mmol) from the above steps reacted with TFA (2.19 mL, 28.4 mmol) according to the procedure reported in step-2 of process 2, and after treatment, yielded (S)-2-amino-N-(3-chloro-2-fluorobenzyl)-3-hydroxypropionamide (26c) TFA salt, which was used in the next step without further purification; MS (ES+): 247.3 (M+1).

[0506] Step 3: Preparation of (S)-1-(2-((1-((3-chloro-2-fluorobenzyl)amino)-3-hydroxy-1-oxopropyl-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (26d)

[0507] (S)-2-amino-N-(3-chloro-2-fluorobenzyl)-3-hydroxypropionamide (26c) (390 g, 1.58 mmol) TFA salt from step-2 above was reacted with 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (416 mg, 1.9 mmol) according to the procedure reported in step-3 of procedure 2. After treatment and purification by rapid column chromatography [silica gel (24 g), eluted with CMA80 / CHCl30 to 100%], (S)-1-(2-((1-((3-chloro-2-fluorobenzyl)amino)-3-hydroxy-1-oxopropyl-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (26d) (16 mg, 2% yield) as a grayish-white solid. 1 ¹H NMR (300MHz, DMSO-d⁶) δ 8.67–8.57 (m, 2H, D₂O exchangeable), 8.18 (dt, J = 8.2, 1.0Hz, 1H), 7.73 (s, 1H, D₂O exchangeable), 7.64 (dt, J = 8.6, 0.9Hz, 1H), 7.52–7.37 (m, 3H), 7.33–7.22 (m, 2H), 7.17–7.09 (m, 1H), 5.40–5.22 (m, 2H), 5.13 (t, J = 5.3Hz, 1H, D₂O exchangeable), 4.42–4.29 (m, 3H), 3.70–3.59 (m, 2H); 1 H NMR(300MHz, DMSO-d6D2O)δ8.17-8.09(m,1H),7.62-7.55(m,1H),7.46-7.36(m,2H),7.34-7.17(m,2H), 7.06(t,J=7.9Hz,1H),5.40-5.14(m,2H),4.32(s,2H),4.28(t,J=5.4Hz,1H),3.76-3.54 (m,2H); MS(ES+): 448.5(M+1), 470.5(M+Na); MS(ES-): 446.4(M-1), 482.4(M+Cl).

[0508] Process 27

[0509]

[0510] Preparation of (S)-1-(2-((1-((3-chloro-2-fluorobenzyl)amino)-3-cyclopropyl-1-oxopropyl-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (27d)

[0511] Step 1: Preparation of (S)-(1-((3-chloro-2-fluorobenzyl)amino)-3-cyclopropyl-1-oxopropyl-2-yl)carbamate tert-butyl ester (27b)

[0512] (S)-2-((tert-Butoxycarbonyl)amino)-3-cyclopropylpropionic acid (27a) (575 mg, 2.51 mmol, prepared according to the method reported in U.S. Patent Application Publication 20110230462 by Hendricks, Robert Than et al.) was reacted according to the procedure reported in step 3 of process 2, and after treatment, (S)-(1-((3-chloro-2-fluorobenzyl)amino)-3-cyclopropyl-1-oxopropyl-2-yl)carbamate tert-butyl ester (27b) was obtained, which was used as is in the next step; MS(ES+): 393.3 (M+Na); MS(ES-): 405.4 (M+Cl).

[0513] Step 2: Preparation of (S)-2-amino-N-(3-chloro-2-fluorobenzyl)-3-cyclopropylpropionamide (27c)

[0514] (S)-(1-((3-chloro-2-fluorobenzyl)amino)-3-cyclopropyl-1-oxopropyl-2-yl)carbamate tert-butyl ester (27b) (930 mg, 2.51 mmol) from the above steps reacted with TFA (3.48 mL, 45.1 mmol) according to the procedure reported in step-2 of process 2, and after treatment, yielded (S)-2-amino-N-(3-chloro-2-fluorobenzyl)-3-cyclopropylpropionamide (27c) TFA salt, which was used in the next step without further purification; MS (ES+): 271.3 (M+1).

[0515] Step 3: Preparation of (S)-1-(2-((1-((3-chloro-2-fluorobenzyl)amino)-3-cyclopropyl-1-oxopropyl-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (27d)

[0516] The (S)-2-amino-N-(3-chloro-2-fluorobenzyl)-3-cyclopropylpropionamide (27c) (679 g, 2.51 mmol) TFA salt from step-2 above was reacted with 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (660 mg, 3.01 mmol) according to the procedure reported in step-3 of process 2, and after treatment, (S)-1-(2-((1-((3-chloro-2-fluorobenzyl)amino)-3-cyclopropyl-1-oxopropyl-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (27d) (93 mg, 8% yield) as a grayish-white solid; 1H NMR (300MHz, DMSO-d6) δ8.73-8.56(m,2H), 8.17(d,J=8.1Hz,1H),7.69(s,1H),7.63(d,J=8.4Hz,1H),7.52-7.36(m,3H),7.25(t,J =7.4Hz,2H),7.13(t,J=7.9Hz,1H),5.26(s,2H),4.45-4.25(m,3H),1.7 3-1.36(m,2H),0.79-0.63(m,1H),0.46-0.25(m,2H),0.15-0.01(m,2H); 19 F NMR (282MHz, DMSO-d6) δ 120.97; MS (ES+): 472.5 (M+1), 494.5 (M+Na); (ES-): 470.4 (M-1), 506.5 (M+Cl).

[0517] Process 28

[0518]

[0519] Preparation of 1-(2-((2-((6-bromopyridin-2-yl)amino)-2-oxoethyl)(isopropyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (28c)

[0520] Step 1: Preparation of tert-butyl (2-((6-bromopyridin-2-yl)amino)-2-oxoethyl)(isopropyl)carbamate (28a)

[0521] 2-((tert-Butoxycarbonyl)(isopropyl)amino)acetic acid (19a) (0.65 g, 2.99 mmol) and 6-bromopyridin-2-amine (2b) (0.78 g, 4.49 mmol) were reacted according to the procedure reported in step-1 of process 2. After treatment and purification by chromatography [silica gel (12 g), eluted with MeOH / CHCl 30-20%], tert-butyl (2-((6-bromopyridin-2-yl)amino)-2-oxoethyl)(isopropyl)carbamate (28a) was obtained, which was used in the next step without further purification.

[0522] Step 2: Preparation of N-(6-bromopyridin-2-yl)-2-(isopropylamino)acetamide (28b)

[0523] The tert-butyl (2-((6-bromopyridin-2-yl)amino)-2-oxoethyl)(isopropyl)carbamate (28a) from step-1 above was reacted with TFA (1.15 mL, 14.96 mmol) according to the procedure reported in step-2 of process 2. After treatment and purification by chromatography [silica gel (12 g), eluted with CMA80 / CHCl30 to 20%], N-(6-bromopyridin-2-yl)-2-(isopropylamino)acetamide (28b) (340 mg, 1.25 mmol, 42%) was used in the next step without further purification; MS (ES+): 272.3 (M+1).

[0524] Step 3: Preparation of 1-(2-((2-((6-bromopyridin-2-yl)amino)-2-oxoethyl)(isopropyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (28c)

[0525] N-(6-bromopyridin-2-yl)-2-(isopropylamino)acetamide (28b) (100 mg, 0.26 mmol) and 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (62 mg, 0.29 mmol) were reacted according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 40%], 1-(2-((2-((6-bromopyridin-2-yl)amino)-2-oxoethyl)(isopropyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (28c) (70 mg, 0.15 mmol, 57% yield) as a white solid were obtained. 1 ¹H NMR (300 MHz, DMSO-d⁶) δ 11.17 and 10.77 (2 s, 1H), 8.24–7.95 (m, 2H), 7.87–7.54 (m, 3H), 7.51–7.14 (m, 4H), 5.62 and 5.46 (2 s, 2H), 4.606–4.332 (m, 1H), 4.43 and 4.03 (2 s, 2H), 1.25 (d, J = 6.3 Hz, 3H), 1.04 (d, J = 6.8 Hz, 3H); MS (ES⁺): 473.4 (M⁺¹); (Based on NMR, the compound is a mixture of rotational isomers in a ratio of 1.2:1).

[0526] Process 29

[0527]

[0528] Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(isopentyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (29b)

[0529] Step 1: Preparation of N-(3-chloro-2-fluorobenzyl)-2-(isopentylamino)acetamide (29a)

[0530] 2-Amino-N-(3-chloro-2-fluorobenzyl)acetamide (16c) (337 mg, 1.56 mmol) reacted with isovaleraldehyde (147 mg, 1.711 mmol) according to the procedure reported in step-1 of procedure 24. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with EtOAc / hexane 0 to 60%], N-(3-chloro-2-fluorobenzyl)-2-(isopentylamino)acetamide (29a) (120 mg, 0.42 mmol, 27% yield) was obtained as a clear oil. 1 H NMR(300MHz, DMSO-d6)δ8.34(t,J=5.8Hz,1H),7.52-7.39(m,1H),7.32-7.23(m,1H),7.21-7.11(m, 1H),4.36(d,J=5.9Hz,2H),3.11(s,2H),2.48-2.39(m,2H),1.66-1.43(m,1H),1.36-1.16(m,3H),0.82(d,J=6.6Hz,6H); 19 F NMR(282MHz, DMSO-d6)δ-121.38; MS(ES+): 287.4(M+1); (ES-): 285.3(M-1).

[0531] Step 2: Preparation of N-(3-chloro-2-fluorobenzyl)-2-(isopentylamino)acetamide (29a)

[0532] N-(3-chloro-2-fluorobenzyl)-2-(isopentylamino)acetamide (29a) (100 mg, 0.35 mmol) was reacted with 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (84 mg, 0.384 mmol) according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 40%], N-(3-chloro-2-fluorobenzyl)-2-(isopentylamino)acetamide (29a) (100 mg, 0.21 mmol, 59% yield) was obtained as a white solid. 1¹H NMR (300MHz, DMSO-d⁶) δ 8.85 and 8.49 (2t, J = 5.6Hz, 1H), 8.18 (d, J = 8.1Hz, 1H), 7.76–7.66 (m, 1H), 7.62–7.47 (m, 2H), 7.47–7.33 (m, 3H), 7.29–7.09 (m, 2H), 5.56 and 5.47 (2s, 2H), 4.46 and 4.34 (2d, J = 5.4Hz, 2H), 4.23 and 3.94 (2s, 2H), 3.52–3.39 (m, 1H), 3.30–3.15 (m, 1H), 1.66–1.37 (m, 2H), 1.37–1.15 (m, 1H), 0.93 and 0.80 (2d, 2H). J = 6.4 Hz, 6H; 19 F NMR (282MHz, DMSO-d6) δ -120.92, -121.31; MS (ES+): 473.4 (M+1); (Based on NMR, the compound is a mixture of 3:2 rotational isomers).

[0533] Process 30

[0534]

[0535] Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(neopentyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (30b)

[0536] Step 1: Preparation of N-(3-chloro-2-fluorobenzyl)-2-(neopentylamino)acetamide (30a)

[0537] 2-Amino-N-(3-chloro-2-fluorobenzyl)acetamide (16c) (300 mg, 1.39 mmol) was reacted with trimethylacetaldehyde (131 mg, 1.523 mmol) according to the procedure reported in step-1 of procedure 24. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with EtOAc / hexane 0 to 60%], N-(3-chloro-2-fluorobenzyl)-2-(neopentylamino)acetamide (30a) (200 mg, 0.7 mmol, 50% yield) was obtained as a clear oil. 1H NMR (300 MHz, DMSO-d6) δ8.55(d,J=5.5Hz,1H),7.79(t,J=7.5Hz,1H),7.60(t,J=7.1Hz,1H), 7.50(t,J=7.8Hz,1H),4.69(d,J=5.9Hz,2H),3.44(s,2H),2.90-2.74(m,2H),2.41(s, 1H),1.16(d,J=2.9Hz,9H); 19 F NMR (282MHz, DMSO-d6) δ-121.08; MS (ES+): 287.4 (M+1); (ES-) 285.3 (M-1).

[0538] Step-2: Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(neopentyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (30b)

[0539] N-(3-chloro-2-fluorobenzyl)-2-(neopentylamino)acetamide (30a) (130 mg, 0.45 mmol) and 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (109 mg, 0.5 mmol) were reacted according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 40%], 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(neopentyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (30b) (100 mg, 0.21 mmol, 45% yield) as a white solid were obtained. 1 H NMR(300MHz, DMSO-d6)δ8.83(t,J=5.7Hz,1H),8.18(d,J=8.1Hz,1H),7.81-7.58(m,1H),7.57- 7.46(m,2H),7.46-7.31(m,3H),7.30-7.15(m,2H),5.61-5.37(m,2H),4.47(d,J=5.4Hz,2H),4.32(s,2H),3.04(s,2H),1.14-0.71(m,9H); 19 F NMR (282MHz, DMSO-d6) δ -120.96; MS (ES+): 488.5 (M+1); (ES-): 486.5 (M-1).

[0540] Process 31

[0541]

[0542] Preparation of (S)-1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-1-cyclopropyl-2-oxoethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (31d)

[0543] Step 1: Preparation of (S)-(2-((3-chloro-2-fluorobenzyl)amino)-1-cyclopropyl-2-oxoethyl)carbamate tert-butyl ester (31b)

[0544] (S)-2-((tert-Butoxycarbonyl)amino)-2-cyclopropylacetic acid (31a) (232 mg, 1.08 mmol, prepared according to the method reported in U.S. Patent Application Publication 2011 / 0230462 by Hendricks, Robert Than et al.) reacted with 3-chloro-2-fluorobenzylamine (9d) (172 mg, 1.08 mmol) according to the procedure reported in step 3 of process 2, and after treatment, (S)-(2-((3-chloro-2-fluorobenzyl)amino)-1-cyclopropyl-2-oxoethyl)carbamate tert-butyl ester (31b) was obtained, which was used as is in the next step; MS (ES-): 391.3 (M+Cl).

[0545] Step 2: Preparation of (S)-2-amino-N-(3-chloro-2-fluorobenzyl)-2-cyclopropylacetamide (31c)

[0546] (S)-(2-((3-chloro-2-fluorobenzyl)amino)-1-cyclopropyl-2-oxoethyl)carbamate tert-butyl ester (31b) (378 mg, 1.06 mmol) from step-1 above was reacted with TFA (1.5 mL, 19.07 mmol) according to the procedure reported in step-2 of process 2, and after treatment, (S)-2-amino-N-(3-chloro-2-fluorobenzyl)-2-cyclopropylacetamide (31c) TFA salt was obtained, which was used in the next step without further purification; MS (ES+): 257.3 (M+1).

[0547] Step 3: Preparation of (S)-1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-1-cyclopropyl-2-oxoethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (31d)

[0548] The (S)-2-amino-N-(3-chloro-2-fluorobenzyl)-2-cyclopropylacetamide (31c) (272 g, 1.06 mmol) TFA salt from step-2 above was reacted with 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (279 mg, 1.27 mmol) according to the procedure reported in step-3 of process 2. After treatment and purification by rapid column chromatography [silica gel (24 g), eluted with CMA80 / CHCl30 to 30%], (S)-1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-1-cyclopropyl-2-oxoethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (31d) (21 mg, 0.046 mmol, 4% yield) as a grayish-white solid. 1 ¹H NMR (300MHz, DMSO-d⁶) δ 8.80 (d, J = 7.8Hz, 1H, D₂O exchangeable), 8.62 (t, J = 5.8Hz, 1H, D₂O exchangeable), 8.17 (d, J = 8.1Hz, 1H), 7.81–7.60 (m, 2H), 7.54–7.36 (m, 3H), 7.32–7.20 (m, 2H), 7.14 (t, J = 7.9Hz, 1H), 5.27 (s, 2H), 4.49–4.24 (m, 2H), 3.77 (t, J = 8.1Hz, 1H), 1.17–1.00 (m, 1H), 0.59–0.41 (m, 3H), 0.37–0.22 (m, 1H); 19 F NMR (282MHz, DMSO-d6) δ-121.16; MS (ES+): 480.5 (M+Na); (ES-): 456.4 (M-1), 492.4 (M+Cl).

[0549] Process 32

[0550]

[0551] Preparation of N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-2-(1,3-dioxoisoindoline-2-yl)-N-isopropylacetamide (32b)

[0552] To a solution of N-(3-chloro-2-fluorobenzyl)-2-(isopropylamino)acetamide (19c) (195 mg, 0.75 mmol), N-ethyl-N-isopropylpropyl-2-amine (0.66 mL, 3.77 mmol), and 2-(1,3-dioxoisoindololin-2-yl)acetic acid (32a) (186 mg, 0.9 mmol) in DMF (6 mL), bromo-tripyrrolidinylphosphine hexafluorophosphate (PyBrop, 422 mg, 0.9 mmol) was added and the mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with brine (100 mL) and extracted with EtOAc (3 × 100 mL). The organic layers were combined, dried, filtered, and evaporated to dryness. The residue obtained by rapid column chromatography [silica gel (24 g), eluted with MeOH / CHCl 30-100%] yielded N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-2-(1,3-dioxoisoindoline-2-yl)-N-isopropylacetamide (32b) as a white solid (103 mg, 0.23 mmol, 31% yield); 1 H NMR(300MHz,DMSO-d6)δ8.73&8.34 (2t,J=5.9Hz,1H),7.97-7.82(m,4H),7.55-7.33(m,2H),7.28-7.06(m,1H),4.64-4.17 (m,5H),4.13&3.81(2s,2H),1.20&0.96(2d,J=6.6Hz,6H); 19 F NMR (282 MHz, DMSO-d6) δ -121.07, -121.49 (based on NMR, the compound is a mixture of two rotational isomers in a ratio of approximately 1:1); MS (ES+): 446.5 (M+1), 468.4 (M+Na); (ES-) 444.5 (M-1); C 22 H 21 Analytical values ​​of ClFN3O4: C, 59.26; H, 4.75; N, 9.42; Experimental values: C, 58.86; H, 4.84; N, 9.36.

[0553] Process 33

[0554]

[0555] Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(cyclopropylmethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (33b)

[0556] Step 1: Preparation of N-(3-chloro-2-fluorobenzyl)-2-((cyclopropylmethyl)amino)acetamide (33a)

[0557] 2-Amino-N-(3-chloro-2-fluorobenzyl)acetamide (16c) (250 mg, 1.15 mmol) was reacted with cyclopropaneformaldehyde (89 mg, 1.27 mmol) according to the procedure reported in step-1 of Procedure 24. After treatment and purification by rapid column chromatography, N-(3-chloro-2-fluorobenzyl)-2-((cyclopropylmethyl)amino)acetamide (33a) (190 mg, 38% yield) was obtained; MS (ES+): 271.3 (M+1).

[0558] Step-2: Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(cyclopropylmethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (33b)

[0559] N-(3-chloro-2-fluorobenzyl)-2-((cyclopropylmethyl)amino)acetamide (33a) (190 mg, 0.7 mmol) and 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (169 mg, 0.77 mmol) were reacted according to the procedure reported in steps 3 of process 2. After treatment and purification by chromatography [silica gel (12 g), eluted with CMA80 / CHCl30 to 60%], 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(cyclopropylmethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (33b) (41 mg, 0.087 mmol, 12% yield) as a white solid were obtained. 1 ¹H NMR (300MHz, DMSO-d6) (mixture of two rotational isomers) δ 8.96–8.39 (m, 1H), 8.18 (d, J = 7.5 Hz, 1H), 7.87–7.66 (m, 1H), 7.62–7.03 (m, 7H), 5.54 (2s, 2H), 4.57–3.98 (m, 4H), 3.46–3.39 (m, 1H), 3.22–2.99 (m, 1H), 1.22–0.69 (m, 1H), 0.62–0.04 (m, 4H); 19 F NMR (282 MHz, DMSO-d6) δ-120.74, 121.14; MS (ES+): 472.5 (M+1), 494.5 (M+Na); 470.6 (M-1).

[0560] Process 34

[0561]

[0562] Preparation of 1-(2-(((2S,3R)-1-((3-chloro-2-fluorobenzyl)amino)-3-hydroxy-1-oxobut-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (34d)

[0563] Step 1: Preparation of ((2S,3R)-1-((3-chloro-2-fluorobenzyl)amino)-3-hydroxy-1-oxobut-2-yl)carbamate tert-butyl ester (34b)

[0564] (2S,3R)-2-((tert-Butoxycarbonyl)amino)-3-hydroxybutyric acid (34a) (481 mg, 2.19 mmol) and 3-chloro-2-fluorobenzylamine (9d) (350 mg, 2.19 mmol) were reacted according to the procedure reported in step 3 of process 2, and after treatment, ((2S,3R)-1-((3-chloro-2-fluorobenzyl)amino)-3-hydroxy-1-oxobut-2-yl)carbamate tert-butyl ester (34b) was obtained, which was used as is in the next step.

[0565] Step 2: Preparation of (2S,3R)-2-amino-N-(3-chloro-2-fluorobenzyl)-3-hydroxybutyramide (34c)

[0566] The ((2S,3R)-1-((3-chloro-2-fluorobenzyl)amino)-3-hydroxy-1-oxobut-2-yl)carbamate tert-butyl ester (34b) (791 mg, 2.19 mmol) from step-1 above was reacted with TFA (3.04 mL, 39.5 mmol) according to the procedure reported in step-2 of process 2, and after treatment, the (2S,3R)-2-amino-N-(3-chloro-2-fluorobenzyl)-3-hydroxybutyramide (34c) TFA salt was obtained, which was used in the next step without further purification.

[0567] Step 3: Preparation of 1-(2-(((2S,3R)-1-((3-chloro-2-fluorobenzyl)amino)-3-hydroxy-1-oxobut-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (34d)

[0568] The (2S,3R)-2-amino-N-(3-chloro-2-fluorobenzyl)-3-hydroxybutyramide (34c) (680 mg, 2.61 mmol) TFA salt from step-2 above was reacted with 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (572 mg, 2.61 mmol) according to the procedure reported in process 32, and after treatment, 1-(2-(((2S,3R)-1-((3-chloro-2-fluorobenzyl)amino)-3-hydroxy-1-oxobut-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (34d) (28 mg, 0.061 mmol, 2% yield) as a grayish-white solid; 1 ¹H NMR (300MHz, DMSO-d⁶) δ 8.50 (t, J = 5.8Hz, ¹H, D₂O exchangeable), 8.39 (d, J = 8.3Hz, ¹H, D₂O exchangeable), 8.17 (d, J = 8.1Hz, ¹H), 7.71 (s, ¹H, D₂O exchangeable), 7.62 (d, J = 8.5Hz, ¹H), 7.52–7.36 (m, ³H), 7.34–7.22 (m, ²H), 7.18–7.05 (m, ¹H), 5.36 (s, ²H), 5.07 (d, J = 4.7Hz, ¹H, D₂O exchangeable), 4.37 (t, J=4.7Hz, 2H), 4.20 (dd, J=8.3, 3.9Hz, 1H), 4.13-4.02 (m, 1H), 1.07 (d, J=6.2Hz, 3H); 19 F NMR (282MHz, DMSO-d6) δ-121.36; MS (ES+): 484.5 (M+Na); (ES-) 460.5 (M-1), 496.4 (M+Cl).

[0569] Process 35

[0570]

[0571] Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(propyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (35d)

[0572] Step 1: Preparation of 2-chloro-N-(3-chloro-2-fluorobenzyl)acetamide (35b)

[0573] At 0 °C, (3-chloro-2-fluorophenyl)methylamine (9d) (1.47 g, 9.21 mmol) was added to a solution of 2-chloroacetyl chloride (35a) (1.04 g, 9.21 mmol) and triethylamine (1.93 mL, 13.81 mmol) in THF (10 mL). The reaction mixture was stirred overnight at room temperature, quenched with water (20 mL), and extracted with DCM (3 × 20 mL). The organic layers were combined, dried, filtered, and concentrated to dryness under vacuum. The residue was purified by chromatography [silica gel (24 g), eluted with EtOAc / MeOH (9:1) / hexane 0 to 40%] to give 2-chloro-N-(3-chloro-2-fluorophenylmethyl)acetamide (35b) (1.2 g, 5.08 mmol, 55% yield) as a white solid. 1 H NMR(300MHz,DMSO-d6) δ8.81(t,J=5.2Hz,1H),7.50(td,J=7.8,1.8Hz,1H),7.35-7.26(m,1H),7.25-7.15(m,1H),4.37(d,J=5.8Hz,2H),4.13(s,2H); 19 FNMR (282MHz, DMSO) δ-121.08; MS (ES+) 236.2 (M+1); 234.1 (M-2).

[0574] Step 2: Preparation of N-(3-chloro-2-fluorobenzyl)-2-(propylamino)acetamide (35c)

[0575] A solution of 2-chloro-N-(3-chloro-2-fluorobenzyl)acetamide (35b) (600 mg, 2.54 mmol) in CH3CN (10 mL) was added with propan-1-amine (300 mg, 5.08 mmol) and K2CO3 (878 mg, 6.35 mmol) and heated at 60 °C for 5 hours. Inorganic solids were removed by filtration and the filtrate was concentrated to dryness under vacuum. The residue was purified by chromatography [silica gel (12 g), eluted with EtOAc / MeOH (9:1) / hexane 0 to 60%] to give N-(3-chloro-2-fluorobenzyl)-2-(propylamino)acetamide (35c) (468 mg, 1.81 mmol, 71% yield) as a yellow oil. 1H NMR(300MHz, DMSO-d6)δ8.35(t,J=5.9Hz,1H),7.53-7.39(m,1H),7.34-7.22(m, 1H),7.22-7.11(m,1H),4.37(d,J=6.0Hz,2H),3.12(s,2H),2.41(t,J=7.1Hz,2H),2.16(s,1H),1.50-1.29(m,2H),0.84(t,J=7.4Hz,3H); 19 F NMR (282MHz, DMSO) δ-121.68; MS (ES+) 259.4 (M+1); 257.3 (M-1).

[0576] Step 3: Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(propyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (35d)

[0577] N-(3-chloro-2-fluorobenzyl)-2-(propylamino)acetamide (35c) (130 mg, 0.50 mmol) and 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (121 mg, 0.55 mmol) were reacted according to the procedure reported in step 3 of process 2, and after treatment, 1-(2-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(propyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (35d) (155 mg, 0.34 mmol, 67% yield) as a white solid were obtained. 1 ¹H NMR (300MHz, DMSO-d6) (mixture of two rotational isomers) δ 8.84 and 8.48 (2t, J = 5.8 Hz, 1H), 8.23–8.13 (m, 1H), 7.71 (d, J = 8.3 Hz, 1H), 7.61–7.03 (m, 7H), 5.56 and 5.47 (2s, 2H), 4.46 and 4.33 (2d, J = 5.7 Hz, 2H), 4.24 and 3.95 (2s, 2H), 3.49–3.38 (m, 1H), 3.25–3.13 (m, 1H), 1.53 (m, 2H), 0.93 and 0.77 (2t, J = 7.3 Hz, 3H); 19 F NMR (282MHz, DMSO-d6) δ -121.25, 121.63; MS (ES+) 482.5 (M+Na); 458.4 (M-1).

[0578] Process 36

[0579]

[0580] Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(ethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (36b)

[0581] Step 1: Preparation of N-(3-chloro-2-fluorobenzyl)-2-(ethylamino)acetamide (36a)

[0582] 2-Chloro-N-(3-chloro-2-fluorobenzyl)acetamide (35b) (600 mg, 2.54 mmol) was reacted with ethylamine hydrochloride (415 mg, 5.08 mmol) according to the procedure reported in step 2 of process 35, and after treatment, N-(3-chloro-2-fluorobenzyl)-2-(ethylamino)acetamide (36a) (494 mg, 2.02 mmol, 79% yield) was obtained as a yellow oil. 1 HNMR (300MHz, DMSO-d6) δ8.39(t,J=5.8Hz,1H),7.53-7.40(m,1H),7.33-7.23(m,1H),7.23-7.13(m,1 H),4.37(d,J=5.9Hz,2H),3.14(s,2H),2.50(q,J=7.1Hz,2H),2.25(s,1H),1.00(t,J=7.1Hz,3H); 19 F NMR (282MHz, DMSO-d6) δ-121.72; MS (ES+) 245.3 (M+1); 243.2 (M-1).

[0583] Step 2: Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(ethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (36b)

[0584] N-(3-chloro-2-fluorobenzyl)-2-(ethylamino)acetamide (36a) (174 mg, 0.71 mmol) and 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (171 mg, 0.78 mmol) were reacted according to the procedure reported in step 3 of process 2, and after treatment, 1-(2-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(ethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (36b) (69 mg, 0.156 mmol, 22% yield) as a white solid were obtained. 1¹H NMR (300MHz, DMSO-d6) (mixture of two rotational isomers) δ 8.85 and 8.49 (2t, J = 5.5Hz, 1H), 8.18 (d, J = 8.1Hz, 1H), 7.71 (d, J = 7.4Hz, 1H), 7.62–7.09 (m, 7H), 5.57 and 5.45 (2s, 2H), 4.46 and 4.34 (2d, J = 5.5Hz, 2H), 4.24 and 3.95 (2s, 2H), 3.56–3.24 (m, 2H), 1.23 and 0.97 (2t, J = 7.1Hz, 3H); 19 F NMR (282 MHz, DMSO-d6) δ -121.28, 121.65; MS (ES+) 468.5 (M+Na); 444.5 (M-1); [Based on NMR, this compound is a mixture of 1:1 rotational isomers].

[0585] Process 37

[0586]

[0587] Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(isobutyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (37b)

[0588] Step 1: Preparation of N-(3-chloro-2-fluorobenzyl)-2-(isobutylamino)acetamide (37a)

[0589] 2-Chloro-N-(3-chloro-2-fluorobenzyl)acetamide (35b) (200 mg, 0.85 mmol) was reacted with isobutylamine (124 mg, 1.7 mmol) according to the procedure reported in step-2 of process 35, yielding N-(3-chloro-2-fluorobenzyl)-2-(isobutylamino)acetamide (37a) (50 mg, 0.18 mmol, 22% yield) as a yellow oil; MS (ES+): 273.4 (M+1); (ES-) 271.3 (M-1).

[0590] Step 2: Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(isobutyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (37b)

[0591] N-(3-chloro-2-fluorobenzyl)-2-(isobutylamino)acetamide (37a) (54 mg, 0.2 mmol) and 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (48 mg, 0.22 mmol) were reacted according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by column chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 40%], 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(isobutyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (37b) (48 mg, 0.1 mmol, 51% yield) as a white solid were obtained. 1 ¹H NMR (300MHz, DMSO-d⁶) δ 8.84 and 8.48 (2t, J = 5.6Hz, 1H), 8.18 (d, J = 8.2Hz, 1H), 7.78–7.65 (m, 1H), 7.59–7.00 (m, 7H), 5.54 and 5.50 (2s, 2H), 4.53–3.86 (m, 4H), 3.34–2.97 (m, 2H), 2.10–1.65 (m, 1H), 0.99 and 0.79 (2d, J = 6.6Hz, 6H); 19 F NMR (282 MHz, DMSO-d6) δ -121.22, 121.64; MS (ES+): 474.5 (M+1); (ES-): 472.4 (M-1); [Based on NMR, this compound is a mixture of 3:2 rotational isomers].

[0592] Process 38

[0593]

[0594] Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(cyclobutyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (38b)

[0595] Step 1: Preparation of N-(3-chloro-2-fluorobenzyl)-2-(cyclobutylamino)acetamide (38a)

[0596] 2-Chloro-N-(3-chloro-2-fluorobenzyl)acetamide (35b) (530 mg, 2.25 mmol) was reacted with cyclobutylamine (319 mg, 4.49 mmol) according to the procedure reported in step 2 of process 35. After treatment and purification by chromatography [silica gel (12 g), eluted with EtOAc / MeOH (9:1) / hexane 0 to 60%], N-(3-chloro-2-fluorobenzyl)-2-(cyclobutylamino)acetamide (38a) (523 mg, 1.93 mmol, 86% yield) was obtained as a yellow oil. 1 H NMR(300MHz, DMSO-d6)δ8.33(t,J=5.9Hz,1H),7.52-7.39(m,1H),7.32-7.23(m,1H),7.23-7.14(m, 1H),4.34(d,J=6.0Hz,2H),3.18-3.07(m,1H),3.05(s,2H),2.37(s,1H),2.11-1.96(m,2H),1.75-1.44(m,4H); 19 F NMR (282MHz, DMSO-d6) δ-121.68; MS (ES+): 271.4 (M+1); (ES-): 269.3 (M-1);

[0597] Step 2: Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(cyclobutyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (38b)

[0598] N-(3-chloro-2-fluorobenzyl)-2-(cyclobutylamino)acetamide (38a) (210 mg, 0.78 mmol) and 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (187 mg, 0.85 mmol) were reacted according to the procedure reported in step 3 of process 2, and after treatment, 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(cyclobutyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (38b) (298 mg, 0.63 mmol, 81% yield) as a grayish-white solid were obtained. 1¹H NMR (300MHz, DMSO-d⁶) δ 8.87 and 8.43 (2t, J = 5.8Hz, 1H), 8.18 (d, J = 7.6Hz, 1H), 7.71 (s, 1H), 7.62–7.02 (m, 7H), 5.56 and 5.42 (s, 2H), 4.75–4.50 (m, 1H), 4.49–4.02 (m, 4H), 2.30–2.09 (m, 2H), 2.03–1.86 (m, 2H), 1.74–1.46 (m, 2H); 19 F NMR (282 MHz, DMSO-d6) δ -121.23, 121.61; MS (ES+): 494.5 (M+Na); ES (-): 470.4 (M-1); [Based on NMR, this compound is a mixture of 2:3 rotational isomers].

[0599] Process 39

[0600]

[0601] Preparation of 1-(2-((2-((((6-bromopyridin-2-yl)methyl)amino)-2-oxoethyl)(isopropyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (39f)

[0602] Step 1: Preparation of ethyl 2-(isopropylamino)acetate (39b)

[0603] A stirred solution of propan-2-amine (22.94 mL, 269 mmol) and ethyl 2-chloroamine (39a) (19.21 mL, 180 mmol) in toluene (200 mL) was heated to reflux for 2 hours, cooled to room temperature, diluted with brine (300 mL), and extracted with EtOAc (2 × 300 mL). The organic layers were combined, dried, filtered, and evaporated to dryness. The residue was purified by rapid column chromatography [80 g silica gel, eluted with EtOAc / hexane 0-30%] to give ethyl 2-(isopropylamino)acetate (39b) (18.78 g, 129 mmol, 72% yield) as a yellow semi-solid; MS (ES+): 146.2 (M+1); (ES-) 180.1 (M+Cl).

[0604] Step 2: Preparation of ethyl acetate 2-(2-(3-carbamoyl-1H-indazole-1-yl)-N-isopropylacetamido) (39c)

[0605] Ethyl 2-(isopropylamino)acetate (39b) (4.42 g, 30.4 mmol) and 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (4.00 g, 18.25 mmol) were reacted according to the procedure reported in step 3 of process 2, and after treatment, 2-(2-(3-carbamoyl-1H-indazole-1-yl)-N-isopropylacetamamido)acetate (39c) was obtained as a dark yellow oil, which was used in the next step.

[0606] Step 3: Preparation of 2-(2-(3-carbamoyl-1H-indazole-1-yl)-N-isopropylacetamido)acetic acid (39d)

[0607] At room temperature, 30 mL of sodium hydroxide (0.762 g, 19.05 mmol) in H2O was added to a solution of 2-(2-(3-carbamoyl-1H-indazole-1-yl)-N-isopropylacetamoxy)acetic acid (39d) (3.00 g, 8.66 mmol) in acetonitrile (30 mL) and stirred overnight. Acetonitrile was removed by vacuum evaporation and the aqueous layer was alkalized with 1N NaOH and washed with diethyl ether. The alkaline aqueous layer was acidified with ice-cold 1N HCl and the obtained solid was collected by filtration and dried under vacuum to give 2-(2-(3-carbamoyl-1H-indazole-1-yl)-N-isopropylacetamoxy)acetic acid (39d) (1.53 g, 4.81 mmol, 55.5% yield) as a yellow solid; MS (ES+): 341.4 (M+Na); (ES-) 317.4 (M-1).

[0608] Step 4: Preparation of 1-(2-((2-(((6-bromopyridin-2-yl)methyl)amino)-2-oxoethyl)(isopropyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (39f)

[0609] 2-(2-(3-carbamoyl-1H-indazole-1-yl)-N-isopropylacetamamido)acetic acid (39d) (0.15 g, 0.47 mmol) was reacted with (6-bromopyridin-2-yl)methylamine (39e) (0.115 g, 0.613 mmol) according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by rapid column chromatography [silica gel 24 g, eluted with MeOH / CHCl 30-100%], 1-(2-((2-(((6-bromopyridin-2-yl)methyl)amino)-2-oxoethyl)(isopropyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (39f) (65 mg, 0.13 mmol, 28% yield) as a grayish-white solid, which, according to NMR analysis, was a mixture of rotational isomers. 1H NMR(300MHz, DMSO-d6)δ8.92&8.46(2t,J=6.1 Hz,1H),8.23-8.12(m,1H),7.78-7.18(m,8H),5.59&5.46(2s,2H),4.63-4.50(m,1H), 4.46(d,J=5.7Hz)&4.31(d,J=6.1Hz)(2d,2H),4.25&3.85(2s,2H),1.25(d,J=6.2 Hz)&1.02(dd,J=6.8,2.0Hz)(d&dd,6H); 1 H NMR(300MHz,DMSO-d6 / D2O)δ8.17- 8.09(m,1H),7.69(t,J=7.7Hz,1H),7.61-7.33(m,4H),7.31-7.16(m,1H),5.57(s)&5. 42(s)(2s,2H),4.59-4.46(m,1H),4.43(s)&4.29(2s,2H),4.19(s,1H),1.22(d,J=6.4 Hz)&1.00(d,J=6.8Hz)(2d,6H);MS(ES+):487.5,489.5(M+2),509.5,511.5(M+Na); (ES-):485.4,487.5(M-1),521.4,523.4(M+Cl).

[0610] Process 40

[0611]

[0612] Preparation of 1-(2-((2-((3-chloro-2-fluorophenyl)amino)-2-oxoethyl)(isopropyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (40b)

[0613] 2-(2-(3-carbamoyl-1H-indazole-1-yl)-N-isopropylacetamamido)acetic acid (39d) (0.15 g, 0.47 mmol) reacted with 3-chloro-2-fluoroaniline (40a) (0.089 g, 0.613 mmol) according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by rapid column chromatography [silica gel 24 g, eluted with MeOH / CHCl 30-30%], 1-(2-((2-(((3-chloro-2-fluorophenyl)amino)-2-oxoethyl)(isopropyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (40b) (51 mg, 0.11 mmol, 24% yield) as a grayish-white solid was obtained. 1H NMR(300MHz, DMSO-d6)δ10.34&9.86(2s,1H),8.29-8.10(m,1H),8.02-7.51(m,3H),7.51-7.06(m, 5H),5.63&5.48(s,2H),4.79-3.92(m,3H),1.26(d,J=6.6Hz)&1.06(d,J=6.8Hz)(2d, 6H); 19 F NMR (282MHz, DMSO-d6) δ -126.60; (Based on NMR, the compound is a mixture of rotational isomers in a ratio of approximately 2:3); MS (ES+): 446.5 (M+1); MS (ES-): 444.4 (M-1), 480.4 (M+Cl).

[0614] Process 41

[0615]

[0616] Preparation of 1-(2-((2-((3-bromo-2-fluorophenyl)amino)-2-oxoethyl)(isopropyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (41b)

[0617] 2-(2-(3-carbamoyl-1H-indazole-1-yl)-N-isopropylacetamamido)acetic acid (39d) (0.15 g, 0.47 mmol) reacted with 3-chloro-2-fluoroaniline (41a) (90 mg, 0.47 mmol) according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by rapid column chromatography [silica gel 24 g, eluted with MeOH / CHCl 30-100%], 1-(2-((2-(((3-bromo-2-fluorophenyl)amino)-2-oxoethyl)(isopropyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (41b) (48 mg, 0.1 mmol, 21% yield) as a grayish-white solid. 1 H NMR(300MHz, DMSO-d6)δ10.34&9.85(2s,1H),8.28-7.02(m,9H),5.63&5.49(2s,2H),4.83-3.91(m, 3H),1.26(d,J=6.5Hz)1.06(d,J=6.9Hz)(2d,6H); 19 F NMR (282MHz, DMSO-d6) δ -118.22 (d, J = 3.7Hz); (Based on NMR, the compound is a mixture of rotational isomers in a ratio of approximately 2:3); MS (ES+): 490.4, 492.5 (M+2); MS (ES-): 488.3, ​​490.3 (M-2).

[0618] Process 42

[0619]

[0620] Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(2-hydroxyethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (42b)

[0621] Step 1: Preparation of N-(3-chloro-2-fluorobenzyl)-2-((2-hydroxyethyl)amino)acetamide (42a)

[0622] 2-Chloro-N-(3-chloro-2-fluorobenzyl)acetamide (35b) (500 mg, 2.12 mmol) was reacted with 2-aminoethanol (259 mg, 4.24 mmol) according to the procedure reported in step 2 of process 35. After treatment and purification by chromatography [silica gel (12 g), eluted with EtOAc / MeOH (9:1) / hexane 0 to 60%], N-(3-chloro-2-fluorobenzyl)-2-((2-hydroxyethyl)amino)acetamide (42a) (402 mg, 1.54 mmol, 73% yield) was obtained as a clear oil. 1 H NMR (300MHz, DMSO-d6)δ8.45(t,J=6.0Hz,1H),7.53-7.40(m,1H),7.33-7.23(m,1H), 7.23-7.11(m,1H),4.54(s,1H),4.36(d,J=6.0Hz,2H),3.52-3.40(m,2H),3.16(s,3H),2.55(t,J=5.6Hz,2H); 19 F NMR (282MHz, DMSO-d6) δ-73.53 (TFA peak), -121.72; MS (ES+): 261.3 (M+1), 283.3 (M+Na); (ES-): 259.3 (M-1).

[0623] Step-2: Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(2-hydroxyethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (42b)

[0624] N-(3-chloro-2-fluorobenzyl)-2-((2-hydroxyethyl)amino)acetamide (42a) (210 mg, 0.81 mmol) reacted with 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (194 mg, 0.89 mmol) according to the procedure reported in step 3 of process 2, and after treatment, 1-(2-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(2-hydroxyethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (42b) (128 mg, 0.28 mmol, 34% yield) as a white solid; 1 ¹H NMR (300MHz, DMSO-d⁶) δ 8.87 and 8.57 (2t, J = 5.8Hz, 1H), 8.18 (d, J = 8.1Hz, 1H), 7.78–7.64 (m, 1H), 7.60–7.00 (m, 7H), 5.66 and 5.43 (2s, 2H), 5.24 and 4.762 (2t, J = 5.1Hz, 1H), 4.49–4.32 (m, 2H), 4.00 (s, 1H), 3.72–3.55 (m, 3H), 3.51–3.39 (m, 1H), 3.34–3.26 (m, 1H); 19 F NMR (282 MHz, DMSO-d6) δ -121.33, 121.63; MS (ES-): 460.5 (M-1); [Based on NMR, this compound is a mixture of two rotational isomers in a ratio of 2:5].

[0625] Process 43

[0626]

[0627] Preparation of 2-(6-amino-4-oxo-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-2-yl)-N-(2-(3-chloro-2-fluorobenzylamino)-2-oxoethyl)-N-isopropylacetamide (43 g)

[0628] Step 1: Preparation of ethyl 3-amino-1-(2-(tert-butoxy)-2-oxoethyl)-1H-pyrazole-4-carboxylate (43c)

[0629] Potassium carbonate (6.55 g, 47.4 mmol) was added to a solution of ethyl 3-amino-1H-pyrazole-4-carboxylate (43a) (5 g, 31.6 mmol) and tert-butyl 2-bromoacetate (5.60 mL, 37.9 mmol) in DMF (20 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc (200 mL), washed with water (2 × 100 mL) and brine (100 mL), dried, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with hexane / EtOAc (1:0 to 2:1) to give ethyl 3-amino-1-(2-(tert-butoxy)-2-oxoethyl)-1H-pyrazole-4-carboxylate (43b) (1.16 g, 14%) as a yellow solid. 1 H NMR (300MHz, DMSO-d6) δ7.93 (s, 1H), 5.37 (s, 2H), 4.69 (s, 2H), 4.17 (q, J = 7.1Hz, 2H), 1.42 (s, 9H), 1.24 (t, J = 7.1Hz, 3H); MS (ES + :270.4 (M+1) and 292.4 (M+Na); and brown gelatinous 5-amino-1-(2-(tert-butoxy)-2-oxoethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (43c) (1.56 g, 18%). 1 H NMR (300MHz, DMSO-d6) δ7.45 (s, 1H), 6.38 (s, 2H), 4.70 (s, 2H), 4.16 (q, J = 7.1Hz, 2H), 1.41 (s, 9H), 1.24 (t, J = 7.1Hz, 3H); MS (ES - ):268.3 (M-1) and 304.3 (M+Cl).

[0630] Step 2: Preparation of (E)-2-(3-(amino(methoxycarbonylamino)methyleneamino)-4-(ethoxycarbonyl)-1H-pyrazole-1-yl)acetic acid (43e)

[0631] A mixture of ethyl 3-amino-1-(2-(tert-butoxy)-2-oxoethyl)-1H-pyrazol-4-carboxylate (43b) (571 mg, 2.12 mmol) and methyl (Z)-(methoxycarbonylamino)(methylthio)methylenecarbamate (43d) (646 mg) was heated overnight at 100 °C with stirring in acetic acid (5 mL). The reaction mixture was cooled to room temperature and wet-milled with CHCl3, then filtered, washed with CHCl3, and dried under vacuum to give (E)-2-(3-(amino(methoxycarbonylamino)methyleneamino)-4-(ethoxycarbonyl)-1H-pyrazol-1-yl)acetic acid (43e) (290 mg, 44%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ11.81(bs,1H),8.34(s,1H),8.07(s,1H),4.97(s,2H),4.28 (q, J=7.1Hz, 2H), 3.54 (s, 3H), 1.30 (t, J=7.1Hz, 3H); MS (ES+): 314 (M+1).

[0632] Step 3: Preparation of (E)-3-(amino(methoxycarbonylamino)methyleneamino)-1-(2-((2-(3-chloro-2-fluorobenzylamino)-2-oxoethyl)(isopropyl)amino)-2-oxoethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (43f)

[0633] (E)-2-(3-(amino(methoxycarbonylamino)methyleneamino)-4-(ethoxycarbonyl)-1H-pyrazol-1-yl)acetic acid (43e) (80 mg, 0.26 mmol) was reacted with N-(3-chloro-2-fluorobenzyl)-2-(isopropylamino)acetamide (19c) (79 mg, 0.306 mmol) according to the procedure reported in step 3 of procedure-2. After treatment and purification by silica gel rapid column chromatography, eluting with CHCl3 / MeOH (1:0 to 19:1), (43f) (64 mg, 45%), as an off-white solid, was obtained. 1¹H NMR (300MHz, DMSO-d6) (in the form of a mixture of two rotational isomers): δ 11.60 (s, 1H), 8.75 & 8.33 (2t, 1H), 8.26 (s, 1H), 8.22 (s, 1H), 8.06 (d, J = 13.5Hz, 1H), 7.59–7.05 (m, 3H), 5.25 & 5.05 (2s, 2H), 4.64–4.50 & 4.17–3.98 (2m, 1H), 4.46–4.22 (m, 4H), 4.07 & 3.83 (2s, 2H), 3.54 (s, 3H), 1.35–0.92 (m, 9H); 19 F NMR (282MHz, DMSO-d6) δ -121.28, -121.69; MS (ES+): 554.6 (M+1) & 556.6 (M+3); MS (ES-): 588.6 and 590.6 (M+Cl).

[0634] Step 4: Preparation of 2-(6-amino-4-oxo-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-2-yl)-N-(2-(3-chloro-2-fluorobenzylamino)-2-oxoethyl)-N-isopropylacetamide (43g)

[0635] To a solution of (E)-3-(amino(methoxycarbonylamino)methyleneamino)-1-(2-((2-(3-chloro-2-fluorobenzylamino)-2-oxoethyl)(isopropyl)amino)-2-oxoethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (43f) (54 mg, 0.097 mmol) in MeOH (8 mL), 1 N sodium hydroxide aqueous solution (0.49 mL, 0.98 mmol) was added and refluxed for 2.5 h. The reaction mixture was cooled to room temperature, concentrated under vacuum to remove MeOH, diluted with water (10 mL), and acidified with 4 N HCl. The obtained solid was collected by filtration and dried under vacuum to obtain 2-(6-amino-4-oxo-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-2-yl)-N-(2-(3-chloro-2-fluorobenzylamino)-2-oxoethyl)-N-isopropylacetamide (43g) (15mg, 34%), which is a white solid. 1¹H NMR (300MHz, DMSO-d6) (mixture of two rotational isomers) δ 10.35 & 10.33 (2s, 1H), 8.74 & 8.36 (2t, 1H), 8.14 & 8.13 (2s, 1H), 7.60-7.07 (m, 3H), 6.20 (bs, 2H), 5.21 & 5.03 (2s, 2H), 4.41 (d, J = 5.6Hz) & 4.33 (d, J = 5.7Hz) (2d, 2H), 4.64-4.48 & 4.21-4.05 (2m, 1H), 4.10 & 3.83 (2s, 2H), 1.15 (d, J = 6.4Hz) & 0.97 (d, J = 6.8Hz) (2d, 6H); 19 F NMR (282MHz, DMSO-d6) δ-121.35,-121.73. MS(ES+):450.5 (M+1).

[0636] Process 44

[0637]

[0638] Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(3-hydroxypropyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (44b)

[0639] Step 1: Preparation of N-(3-chloro-2-fluorobenzyl)-2-((3-hydroxypropyl)amino)acetamide (44a)

[0640] 2-Chloro-N-(3-chloro-2-fluorobenzyl)acetamide (35b) (500 mg, 2.12 mmol) was reacted with 2-aminoethanol (318 mg, 4.24 mmol) according to the procedure reported in step-2 of process 35. After treatment and purification by chromatography [silica gel (12 g), eluted with EtOAc / MeOH (9:1) / hexane 0 to 60%], N-(3-chloro-2-fluorobenzyl)-2-((3-hydroxypropyl)amino)acetamide (44a) (494 mg, 2.02 mmol, 73% yield) was obtained as a clear oil. 1H NMR(300MHz, DMSO-d6)δ8.38(t,J=6.1Hz,1H),7.52-7.42(m,1H),7.33-7.23(m, 1H),7.19(td,J=7.8,1.0Hz,1H),4.37(d,J=5.8Hz,2H),4.14(s,1H),3.45(t,J=6 .3Hz,2H),3.18(s,2H),3.13(s,2H),2.56-2.52(m,1H),1.61-1.49(m,2H); MS(ES + )275.4 (M+1); MS(ES) - ),273.3(M-1).

[0641] Step-2: Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(3-hydroxypropyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (44b)

[0642] N-(3-chloro-2-fluorobenzyl)-2-((3-hydroxypropyl)amino)acetamide (44a) (120 mg, 0.44 mmol) and 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (105 mg, 0.48 mmol) were reacted according to the procedure reported in step 3 of process 2, and after treatment, 1-(2-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(3-hydroxypropyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (44b) (59 mg, 0.12 mmol, 28% yield) in white solid form; 1 ¹H NMR (300MHz, DMSO-d6) (mixture of two rotational isomers) δ 8.86 (t, J = 5.5Hz) & 8.51 (t, J = 5.9Hz) (2t, 1H), 8.18 (d, J = 8.1Hz, 1H), 7.72 (d, J = 7.1Hz, 1H), 7.60-7.06 (m, 7H), 5.63 & 5.45 (2s, 2H), 4.82-4.29 (m, 3H), 4.26 & 3.94 (2s, 2H), 3.65-3.48 (m, 2H), 3.35-3.23 (m, 2H), 1.89-1.46 (m, 2H); 19 F NMR(282MHz,DMSO)δ-121.30,121.64; MS(ES + 476.5 (M+1); MS (ES) -), 510.5 (M+Cl); HPLC, Rt 4.005 min, 93.5338% [Based on NMR, this compound is a mixture of two rotational isomers in a ratio of 2:5].

[0643] Process 45

[0644]

[0645] Preparation of 1-(2-(cyclopropyl(2-((2-fluoro-3-methoxyphenyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (45f)

[0646] Step 1: Preparation of ethyl 2-(cyclopropylamino)acetate (45b)

[0647] Ethyl 2-bromoacetate (45a) (10 g, 59.9 mmol) was reacted with cyclopropylamine (16.88 mL, 240 mmol) in ethanol (80 mL) at room temperature according to the procedure reported in step-1 of process 39, and after treatment, ethyl 2-(cyclopropylamino)acetate (45b) (7.2 g, 50.3 mmol, 84% yield) was obtained as a pale orange liquid. 1 H NMR (300MHz, DMSO-d6)δ4.09(q,J=7.1Hz,2H),3.30(s,2H),2.60(s,1H),2.23-2.09(m, 1H), 1.19 (t, J = 7.1Hz, 3H), 0.37-0.28 (m, 2H), 0.24-0.17 (m, 2H); MS (ES+) 144.2 (M+1).

[0648] Step 2: Preparation of ethyl acetate 2-(2-(3-carbamoyl-1H-indazole-1-yl)-N-cyclopropylacetamyl) (45°C)

[0649] 2-(cyclopropylamino)ethyl acetate (45b) (1.57 g, 10.95 mmol) and 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (2 g, 9.12 mmol) were reacted according to the procedure reported in step 3 of process 2, and after treatment, 2-(2-(3-carbamoyl-1H-indazole-1-yl)-N-cyclopropylacetamamido)ethyl acetate (45c) (2 g, 5.81 mmol, 64% yield) was obtained as a grayish-white solid. 1H NMR (300MHz, DMSO-d6) δ8.22-8.14(m,1H), 7.71(s,1H),7.66-7.59(m,1H),7.47-7.35(m,2H),7.26(ddd,J=7.9,6.9,0.9Hz,1H), 5.69(s,2H),4.16-3.99(m,4H),3.15-3.02(m,1H),1.31-1.21(m,2H),1.17(t,J=7.1Hz, 3H), 1.03-0.88 (m, 2H); MS (ES+): 345.5 (M+1), 367.4 (M+Na), MS (ES-): 379.5 (M+Cl).

[0650] Step 3: Preparation of 2-(2-(3-carbamoyl-1H-indazole-1-yl)-N-cyclopropylacetamyl)acetic acid (45d)

[0651] 2-(2-(3-carbamoyl-1H-indazole-1-yl)-N-cyclopropylacetamoxy)acetic acid (45c) (1.8 g, 5.23 mmol) was hydrolyzed according to the procedure reported in step-3 of process 39, and after treatment, 2-(2-(3-carbamoyl-1H-indazole-1-yl)-N-cyclopropylacetamoxy)acetic acid (45d) (1.5 g, 4.74 mmol, 91% yield) was obtained as a pale orange foam. 1 H NMR (300MHz, DMSO-d6) δ12.76 (s, 1H), 8.18 (dt, J = 8.1, 1.0Hz, 1H), 7.73(s,1H),7.64(dt,J=8.6,0.9Hz,1H),7.47-7.36(m,2H),7.26(ddd,J=8.0,6 .8,0.9Hz,1H),5.68(s,2H),4.00(s,2H),3.12-2.99(m,1H),1.06-0.86(m,4H).

[0652] Step 4: Preparation of 1-(2-(cyclopropyl(2-((2-fluoro-3-methoxyphenyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (45f)

[0653] 2-(2-(3-carbamoyl-1H-indazole-1-yl)-N-cyclopropylacetamoxy)acetic acid (45d) (0.12 g, 0.38 mmol) reacted with 2-fluoro-3-methoxyaniline (0.054 g, 0.379 mmol) (45e) (54 mg, 0.379 mmol) according to the procedure reported in step-1 of process 2. After treatment and purification by rapid column chromatography [silica gel 12 g, eluted with MeOH / EtOAc (9:1) / hexane 0-100%], 1-(2-(cyclopropyl(2-((2-fluoro-3-methoxyphenyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (45f) (70 mg, 0.159 mmol, 42% yield) as a white solid. 1 H NMR (300MHz, DMSO-d6) δ9.83 (s, 1H), 8.18 (dt, J = 8.1, 1.0Hz, 1H), 7.74 (s,1H),7.66(d,J=8.5Hz,1H),7.59-7.34(m,3H),7.32-7.20(m,1H),7.06(td,J=8.3,1 .8Hz,1H),6.98-6.86(m,1H),5.70(s,2H),4.20(s,2H),3.82(s,3H),3.11(s,1H),1.05- 0.91(m,4H); 19 F NMR (282MHz, DMSO-d6) δ-147.62; MS (ES+): 440.5 (M+1), 462.5 (M+Na), MS (ES-): 438.5 (M-1).

[0654] Process 46

[0655]

[0656] Preparation of 1-(2-(cyclopropyl(2-oxo-2-((3-(trifluoromethoxy)phenyl)amino)ethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (46b)

[0657] 2-(2-(3-carbamoyl-1H-indazole-1-yl)-N-cyclopropylacetamoxy)acetic acid (45d) (0.12 g, 0.38 mmol) was reacted with 23-(trifluoromethoxy)aniline (46a) (67 mg, 0.379 mmol) according to the procedure reported in step-1 of process 2. After treatment and purification by rapid column chromatography [silica gel 12 g, eluted with MeOH / EtOAc (9:1) / hexane 0-100%], 1-(2-(cyclopropyl(2-oxo-2-((3-(trifluoromethoxy)phenyl)amino)ethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (46b) (65 mg, 0.137 mmol, 36% yield) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ10.38(s,1H),8.22-8.12(m,1H),7.80-7.71(m,2H),7.70- 7.61(m,1H),7.52-7.33(m,4H),7.30-7.20(m,1H),7.09-6.95(m,1H),5.71(s,2H),4.15(s,2H),3.18-3.06(m,1H),1.11-0.89(m,4H); 19 F NMR (282MHz, DMSO-d6) δ-56.72; MS (ES+): 476.5 (M+1), 498.5 (M+Na), MS (ES-): 474.5 (M-1).

[0658] Process 47

[0659]

[0660] Preparation of (S)-1-(2-((1-((3-chloro-2-fluorobenzyl)amino)-1-oxopent-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (47d)

[0661] Step 1: Preparation of (S)-(1-((3-chloro-2-fluorobenzyl)amino)-1-oxopentan-2-yl)carbamate tert-butyl ester (47b)

[0662] (S)-2-((tert-Butoxycarbonyl)amino)pentanoic acid (47a) (412 mg, 1.9 mmol) was reacted with 3-chloro-2-fluorobenzylamine (9d) (252 mg, 1.58 mmol) according to the procedure reported in step 3 of process 2, yielding (S)-(1-((3-chloro-2-fluorobenzyl)amino)-1-oxopentan-2-yl)carbamate tert-butyl ester (47b) after treatment, which was used as is in the next step. MS (ES+): 381.45 (M+Na); (ES-): 393.34 (M+Cl).

[0663] Step 2: Preparation of (S)-2-amino-N-(3-chloro-2-fluorobenzyl)pentanamide (47c)

[0664] (S)-(1-((3-chloro-2-fluorobenzyl)amino)-1-oxopentan-2-yl)carbamate tert-butyl ester (47b) (567 mg, 1.58 mmol) was reacted with TFA (2.19 mL, 28.4 mmol) according to the procedure reported in step 2 of process 2, and after treatment, (S)-2-amino-N-(3-chloro-2-fluorobenzyl)pentanamide (47c) was used as is in the next step; MS (ES+): 259.4 (M+1).

[0665] Step 3: Preparation of (S)-1-(2-((1-((3-chloro-2-fluorobenzyl)amino)-1-oxopent-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (47d)

[0666] The (S)-2-amino-N-(3-chloro-2-fluorobenzyl)pentanamide (47c) (409 mg, 1.58 mmol) TFA salt from step-2 above was reacted with 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (416 mg, 1.9 mmol) according to the procedure reported in step-3 of process 2. After treatment and purification by chromatography [silica gel (24 g), eluted with MeOH / CHCl 30 to 50%], (S)-1-(2-((1-((3-chloro-2-fluorobenzyl)amino)-1-oxopentan-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (47d) (12 mg, 0.026 mmol, 2% yield) as a grayish-white solid. 1HNMR(300MHz,DMSO-d6)δ8.65(t,J=5.8Hz,1H),8.59(d,J=7.9Hz,1H),8.17(dt,J= 8.2,1.1Hz,1H),7.70(s,1H),7.66-7.59(m,1H),7.53-7.37(m,3H),7.31-7.21(m,2H), 7.19-7.09(m,1H),5.26(s,2H),4.38-4.20(m,3H),1.66-1.53(m,2H),1.33-1.26(m,2H),0.86(t,J=7.4Hz,3H); 19 F NMR (282MHz, DMSO-d6) δ-121.48; MS (ES+): 460.47 (M+1), 482.5 (M+Na); (ES-): 458.40 (M-1), 494.41 (M+Cl).

[0667] Process 48

[0668]

[0669] Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(cyclopentyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (48b)

[0670] Step 1: Preparation of N-(3-chloro-2-fluorobenzyl)-2-(cyclopentylamino)acetamide (48a)

[0671] 2-Chloro-N-(3-chloro-2-fluorobenzyl)acetamide (35b) (500 mg, 2.12 mmol) was reacted with cyclopentylamine (216 mg, 2.54 mmol) according to the procedure reported in step-2 of process 35. After treatment and purification by chromatography [silica gel (12 g), eluted with EtOAc / MeOH (9:1) / hexane 0 to 60%], N-(3-chloro-2-fluorobenzyl)-2-(cyclopentylamino)acetamide (48a) as a clear oil was obtained, which was used as is in the next step; MS (ES+): 285.4 (M+1); MS (ES-): 283.3 (M-1).

[0672] Step-2: Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(cyclopentyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (48b)

[0673] N-(3-chloro-2-fluorobenzyl)-2-(cyclopentylamino)acetamide (48a) (240 mg, 0.84 mmol) and 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (203 mg, 0.93 mmol) were reacted according to the procedure reported in step 3 of process 2, and after treatment, 1-(2-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(cyclopentyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (48b) (315 mg, 0.65 mmol, 77% yield) as a white solid; 1 HNMR (300MHz, DMSO-d6) δ8.84 (t, J = 5.6Hz) and 8.40 (t, J = 5.8Hz) (2t, 1H), 8.18 (d, J=8.1Hz,1H),7.71(s,1H),7.64-7.00(m,7H),5.63&5.45(2s,2H),4.67-4.24(m,3H), 4.19&3.82(2s,2H),2.06-1.84(m,1H),1.75-1.28(m,7H); 19 F NMR (282MHz, DMSO) δ-121.17,121.71; MS (ES + 486.6(M+1); MS(ES) - ), 484.4 (M-1); HPLC, Rt 7.134 min, 96.7156% [Based on NMR, this compound is a mixture of two rotational isomers in a 1:1 ratio].

[0674] Process 49

[0675]

[0676] Preparation of 1-(2-((2-((6-bromopyrazin-2-yl)amino)-2-oxoethyl)(cyclopropyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (49d)

[0677] Step 1: Preparation of N-(6-bromopyrazin-2-yl)-2-chloroacetamide (49b)

[0678] 2-Chloroacetyl chloride (35a) (0.24 mL, 3 mmol) and 6-bromopyrazin-2-amine (49a) (350 mg, 2.01 mmol) were reacted according to the procedure reported in step-1 of process 35, and after treatment, N-(6-bromopyrazin-2-yl)-2-chloroacetamide (49b) (45 mg, 1.8 mmol, 89% yield) was obtained as a deep orange solid. 1H NMR (300MHz, DMSO-d6) δ11.51(s,1H),9.28(d,J=0.6Hz,1H),8.60(d,J=0.6Hz,1H),4.39(s,2H); MS(ES+):250.2,252.2(M,M+2),MS(ES-):248.1,250.1(M-2,M).

[0679] Step 2: Preparation of N-(6-bromopyrazin-2-yl)-2-(cyclopropylamino)acetamide (49c)

[0680] N-(6-bromopyrazin-2-yl)-2-chloroacetamide (49b) (480 mg, 1.92 mmol) was reacted with cyclopropylamine (0.34 mL, 4.79 mmol) according to the procedure reported in step-2 of procedure 35. After treatment and purification by column chromatography [silica gel (24 g), eluted with EtOAc / hexane 0 to 100%], N-(6-bromopyrazin-2-yl)-2-(cyclopropylamino)acetamide (49c) (33 mg, 1.22 mmol, 64% yield) was obtained as an orange solid. 1 H NMR(300MHz, DMSO-d6)δ9.33(s,1H),8.55(s,1H),4.00(s,1H),3.43(s,2H),2.24-2.10(m,1H),0.41- 0.30(m,2H),0.29-0.18(m,2H);MS(ES-):269.2,271.2(M-2,M).

[0681] Step 3: Preparation of 1-(2-((2-((6-bromopyrazin-2-yl)amino)-2-oxoethyl)(cyclopropyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (49d)

[0682] N-(6-bromopyrazin-2-yl)-2-(cyclopropylamino)acetamide (49c) (90 mg, 0.33 mmol) and 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (73 mg, 0.33 mmol) were reacted according to the procedure reported in step 3 of process 2, and after treatment, 1-(2-((2-((6-bromopyrazin-2-yl)amino)-2-oxoethyl)(cyclopropyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (49d) (110 mg, 0.23 mmol, 70% yield) as a white solid were obtained. 1H NMR (300MHz, DMSO-d6) δ11.29(s,1H),9.25(s,1H),8.54(s,1H),8.17(d,J=8.2,1H), 7.72(s,1H),7.69-7.64(m,1H),7.50-7.34(m,2H),7.25(d,J=7.9,1H),5.71(s,2H),4 .22(s,2H),3.20-3.06(m,1H),1.14-0.84(m,4H);MS(ES+):472.4,474.5(M+1,M+3),MS (ES-):470.4,472.4.

[0683] Process 50

[0684]

[0685] Preparation of 1-(2-((3-((6-bromopyridin-2-yl)amino)-3-oxopropyl)(isopropyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (50 d)

[0686] Step 1: Preparation of 3-bromo-N-(6-bromopyridin-2-yl)propionamide (50b)

[0687] 3-Bromopropionyl chloride (50a) (1 g, 5.83 mmol) and 6-bromopyridin-2-amine (2b) (1.01 g, 5.83 mmol) were reacted according to the procedure reported in step-1 of Procedure 35. After treatment and purification by rapid column chromatography [silica gel (24 g), eluted with EtOAc / MeOH (9:1) / hexane 0 to 40%], 3-bromo-N-(6-bromopyridin-2-yl)propionamide (50b) (1.26 g, 4.09 mmol, 70.1% yield) was obtained as a white solid. MS (ES+): 307.2 (M+1).

[0688] Step 2: Preparation of N-(6-bromopyridin-2-yl)-3-(isopropylamino)propionamide (50c)

[0689] 3-Bromo-N-(6-bromopyridin-2-yl)propionamide (50b) (520 mg, 1.69 mmol) was reacted with propan-2-amine (299 mg, 5.07 mmol) according to the procedure reported in step-2 of procedure 35. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with EtOAc / MeOH (9:1) / hexane 0 to 60%], N-(6-bromopyridin-2-yl)-3-(isopropylamino)propionamide (50c) (321 mg, 1.12 mmol, 66% yield) was obtained as a clear oil; MS (ES+): 286.3 (M+1); MS (ES-): 284.3 (M-1).

[0690] Step 3: Preparation of 1-(2-((3-((6-bromopyridin-2-yl)amino)-3-oxopropyl)(isopropyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (50d)

[0691] N-(6-bromopyridin-2-yl)-3-(isopropylamino)propionamide (50c) (230 mg, 0.8 mmol) and 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (194 mg, 0.88 mmol) were reacted according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 40%], 1-(2-((3-(((6-bromopyridin-2-yl)amino)-3-oxopropyl)(isopropyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (50d) (325 mg, 0.67 mmol, 83% yield) as a grayish-white solid were obtained. 1 H NMR(300MHz, DMSO-d6)δ11.06&10.82(2s,1H),8.28-7.99(m,2H),7.86-7.54(m,3H),7.49-7.20(m, 4H),5.60&5.55(2s,2H),4.41-4.12(m,1H),3.71(t,J=7.1Hz)&3.48-3.40(m)(t&m, 2H),2.90(t,J=7.1Hz)&2.63-2.60(m)(t&m,2H),1.25(d,J=6.5Hz)&1.15(d,J=6.8 Hz)(2d,6H); MS(ES+): 487.4(M+1); [Based on NMR, this compound is a mixture of two rotational isomers in a ratio of 4:5].

[0692] Process 51

[0693]

[0694] Preparation of methyl 2-(2-(3-carbamoyl-1H-indazole-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)acetamyl)acetamide (51b)

[0695] Step 1: Preparation of methyl 2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)amino)acetate (51a)

[0696] 2-Chloro-N-(3-chloro-2-fluorobenzyl)acetamide (35b) (500 mg, 2.12 mmol) reacted with methyl 2-aminoacetate (266 mg, 2.12 mmol) according to the procedure reported in step 2 of process 35. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with EtOAc / MeOH (9:1) / hexane 0 to 60%], methyl 2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)amino)acetate (51a) (293 mg, 1.02 mmol, 48% yield) was obtained as a clear oil; MS (ES+) 311.3 (M+Na).

[0697] Step 2: Preparation of 2-(2-(3-carbamoyl-1H-indazole-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)acetamyl)acetate (51b)

[0698] 2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)amino)acetate (51a) (200 mg, 0.69 mmol) reacted with 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (167 mg, 0.76 mmol) according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 60%], 2-(2-(3-carbamoyl-1H-indazole-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)acetamyl)acetate (51b) (36 mg, 0.073 mmol, 11% yield) as a white solid. 1 H NMR (300MHz, DMSO-d6) δ 8.82 (t, J = 5.8Hz) and 8.53 (t, J = 5.3Hz) (2t, 1H), 8.18 (d, J = 7.5Hz, 1H), 7.74 (s, 1H), 7.52–7.09 (m, 7H), 5.54 and 5.51 (2s, 2H), 4.57–4.28 (m, 4H), 4.08 and 3.99 (2s, 2H), 3.75 and 3.61 (2s, 3H);19 F NMR (282MHz, DMSO) δ -121.32, -121.61; MS (ES+): 490.5 (M+1), 512.5 (M+Na); MS (ES-): 488.4 (M-1); [Based on NMR, this compound is a mixture of two rotational isomers in a 5:4 ratio].

[0699] Process 52

[0700]

[0701] Preparation of tert-butyl 3-(2-(3-carbamoyl-1H-indazole-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)acetamyl)azacyclobut-1-carboxylic acid (52b)

[0702] Step 1: Preparation of tert-butyl 3-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)amino)azacyclobutane-1-carboxylic acid (52a)

[0703] 2-Chloro-N-(3-chloro-2-fluorobenzyl)acetamide (35b) (925 mg, 3.92 mmol) reacted with tert-butyl 3-aminoazacyclobutane-1-carboxylate (710 mg, 4.12 mmol) according to the procedure reported in step-2 of process 35. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with EtOAc / MeOH (9:1) / hexane 0 to 60%], tert-butyl 3-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)amino)azacyclobutane-1-carboxylate (52a) (785 mg, 2.11 mmol, 51% yield) was obtained as a clear oil; MS (ES+): 372.4 (M+1); MS (ES-): 370.4 (M-1).

[0704] Step 2: Preparation of tert-butyl 3-(2-(3-carbamoyl-1H-indazole-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)acetamyl)azacyclobut-1-carboxylic acid (52b)

[0705] 3-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)amino)azacyclobutane-1-carboxylic acid tert-butyl ester (52a) (440 mg, 1.18 mmol) reacted with 2-(3-carbamoyl-1H-indazol-1-yl)acetic acid (2e) (285 mg, 1.3 mmol) according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 60%], 3-(2-(3-carbamoyl-1H-indazol-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)acetamyl)azacyclobutane-1-carboxylic acid tert-butyl ester (52b) (325 mg, 0.57 mmol, 48% yield) was obtained as a white solid. 1 H NMR (300MHz, DMSO-d6) δ8.93(t,J=5.6Hz) and 8.59(t,J=5.8Hz)(2t,1H),8.18(d,J=8.1Hz,1H),7.69(d,J=8.7Hz,1H),7.59-7.02 (m,7H),5.60&5.43(2s,2H),5.12-4.74(m,1H),4.48(d,J=5.4Hz)&4.33(d,J=5.6Hz) (2d,2H),4.39&4.10(2s,2H),4.16(t,J=8.7Hz)&4.01-3.76(m)(t&m,4H),1.39&1.35(2s,9H); 19 F NMR (282MHz, DMSO) δ -121.26, 121.61; MS (ES+) 573.7 (M+1); [Based on NMR, this compound is a mixture of two rotational isomers in a 1:1 ratio].

[0706] Process 53

[0707]

[0708] Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(2-fluoroethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (53b)

[0709] Step 1: Preparation of N-(3-chloro-2-fluorobenzyl)-2-((2-fluoroethyl)amino)acetamide (53a)

[0710] 2-Chloro-N-(3-chloro-2-fluorobenzyl)acetamide (35b) (500 mg, 2.12 mmol) reacted with trifluoroethylamine hydrochloride (422 mg, 4.24 mmol) according to the procedure reported in step-2 of procedure 35. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with EtOAc / MeOH (9:1) / hexane 0 to 60%], N-(3-chloro-2-fluorobenzyl)-2-((2-fluoroethyl)amino)acetamide (53a) (224 mg, 0.85 mmol, 40% yield) was obtained as a clear oil. 1 H NMR(300MHz,DMSO-d6)δ8.39(t,J=5.9Hz,1H),7.53-7.44(m,1H),7.31- 7.23(m,1H),7.23-7.13(m,1H),4.60-4.50(m,1H),4.41-4.32(m,3H),3.19(s,2H),2.82 (t,J=5.0Hz,1H),2.72(t,J=5.0Hz,1H),2.47-2.37(m,1H); 19 F NMR (282MHz, DMSO) δ-121.69; MS (ES+) 263.4 (M+1); 261.3 (M-1);

[0711] Step 2: Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(2-fluoroethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (53b)

[0712] N-(3-chloro-2-fluorobenzyl)-2-((2-fluoroethyl)amino)acetamide (53a) (178 mg, 0.68 mmol) reacted with 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (163 mg, 0.745 mmol) according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 60%], 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(2-fluoroethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (53b) (162 mg, 0.349 mmol, 51.5% yield) as a white solid. 1¹H NMR (300MHz, DMSO-d⁶) δ 8.84 (t, J = 5.7Hz) and 8.54 (t, J = 5.8Hz) (2t, 1H), 8.18 (d, J = 7.5Hz, 1H), 7.74 (s, 1H), 7.57–7.07 (m, 7H), 5.59–5.48 (2s, 2H), 4.88–4.62 (m, 1H), 4.61–4.29 (m, 3H), 4.35–4.03 (2s, 2H), 3.97–3.80 (m, 1H), 3.62 (t, J = 4.8Hz) and 3.53 (t, J = 4.8Hz) 4.9 Hz (2t, 1H); MS (ES+): 464.5 (M+1); MS (ES-): 462.4 (M-1); [Based on NMR, this compound is a mixture of two rotational isomers in a 1:1 ratio].

[0713] Process 54

[0714]

[0715] Preparation of 1-(2-((2-(((6-chloropyridin-2-yl)methyl)amino)-2-oxoethyl)(isopropyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (54b)

[0716] 2-(2-(3-carbamoyl-1H-indazole-1-yl)-N-isopropylacetamamido)acetic acid (39d) (0.15 g, 0.47 mmol) reacted with (6-chloropyridin-2-yl)methylamine (54a) (122 mg, 0.57 mmol) according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by rapid column chromatography [silica gel 24 g, eluted with MeOH / CHCl 30-50%], 1-(2-((2-(((6-chloropyridin-2-yl)methyl)amino)-2-oxoethyl)(isopropyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (54b) (101 mg, 0.23 mmol, 48% yield) as a grayish-white solid. 1H NMR(300MHz, DMSO-d6)δ8.93(t,J=6.0Hz)&8.47(t,J=6.1Hz)(2t,1H),8.22-8.13(m,1H), 7.85(t,J=7.8Hz,1H),7.69(d,J=4.4Hz,1H),7.61(d,J=7.9Hz,1H),7.53(dt,J=8.5, 1.0Hz,1H),7.46-7.30(m,3H),7.31-7.16(m,1H),5.60&5.47(2s,2H),4.62-4.50(m, 1H), 4.47 (d, J = 5.8 Hz & 4.32 (d, J = 6.0 Hz) (2d, 2H), 4.23 & 3.86 (2s, 2H), 1.25 (d, J = 6.5 Hz) & 1.02 (d, J = 6.8 Hz) (2d, 6H); (Based on NMR, the compound is a mixture of two rotational isomers in a ratio of approximately 1:2); MS (ES+): 443.5 (M+1), 465.5 (M+Na); (ES-): 441.4 (M-1), 477.4 (M+Cl).

[0717] Process 55

[0718]

[0719] Preparation of 1-(2-(cyclopropyl(2-((6-(dimethylamino)pyridin-2-yl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (55a)

[0720] A solution of 1-(2-((2-(((6-bromopyridin-2-yl)amino)-2-oxoethyl)(cyclopropyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (7d) (105 mg, 0.22 mmol) in dioxane (1 mL) was added to an aqueous solution of dimethylamine (0.56 mL, 4.46 mmol) and heated at 150 °C for 3 h under microwave irradiation. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with EtOAc (2 × 40 mL). The organic layers were combined, washed with brine, dried, filtered, and concentrated under vacuum. The residue obtained by chromatography [silica gel (12 g), eluted with EtOAc / MeOH (9:1) / hexane 0 to 100%] yielded 1-(2-(cyclopropyl(2-((6-(dimethylamino)pyridin-2-yl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (55a) (55 mg, 0.13 mmol, 57% yield) as a white solid; 1HNMR(300MHz,DMSO-d6)δ10.00(s,1H),8.21-8.11(m,1H),7.76 (s,1H),7.66(d,J=8.5Hz,1H),7.52-7.34(m,3H),7.30-7.15(m,2H),6.31(d,J=8.3Hz ,1H),5.70(s,2H),4.19(s,2H),3.17-3.05(m,1H),2.98(s,6H),1.08-0.86(m,4H);MS (ES+): 436.6 (M+1); (ES-): 470.5 (M+Cl).

[0721] Process 56

[0722]

[0723] Preparation of 2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-N-(2-((6-bromopyridin-2-yl)amino)-2-oxoethyl)-N-cyclopropylacetamide (56d)

[0724] Step 1: Preparation of tert-butyl 2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (56b)

[0725] 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (56a) (1.5 g, 9.77 mmol) in acetonitrile (60 mL) reacted with 2-bromoacetic acid tert-butyl ester (2.16 mL, 14.65 mmol) using potassium carbonate (2.7 g, 19.54 mmol) as a base, according to the procedure reported in step-2 of process 35. After treatment and purification by rapid column chromatography [silica gel (40 g), eluted with EtOAc / hexane 0 to 50%], 2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid tert-butyl ester (56b) (2.2 g, 8.22 mmol, 84% yield) as a white solid. 1 H NMR (300MHz, DMSO-d6) δ 8.65 (s, 1H), 7.75 (d, J = 3.6Hz, 1H), 6.68 (d, J = 3.6Hz, 1H), 5.09 (s, 2H), 1.41 (s, 9H); MS (ES+) 268.4 (M+1), MS (ES-) 302.3 (M+Cl).

[0726] Step 2: Preparation of 2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (56c)

[0727] 2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid tert-butyl ester (56b) (512 mg, 1.91 mmol) reacted with concentrated ammonium hydroxide solution (1.5 mL, 38.3 mmol) under microbeam irradiation according to the procedure reported in Procedure 55, and after treatment, 2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (56c) (312 mg, 1.62 mmol, 85% yield) was obtained as a white solid. 1 H NMR (300MHz, DMSO-d6) δ7.98 (s, 1H), 7.02 (d, J = 3.4Hz, 1H), 6.82 (s, 2H), 6.43 (d, J = 3.5Hz, 1H), 4.45 (s, 2H); MS (ES+): 193.2 (M+1); (ES-): 191.2(M-1).

[0728] Step 3: Preparation of 2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-N-(2-((6-bromopyridin-2-yl)amino)-2-oxoethyl)-N-cyclopropylacetamide (56d)

[0729] N-(6-bromopyridin-2-yl)-2-(cyclopropylamino)acetamide (7c) (8 mg, 0.3 mmol) and 2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (56c) (57 mg, 0.3 mmol) were reacted according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 40%], 2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-N-(2-((6-bromopyridin-2-yl)amino)-2-oxoethyl)-N-cyclopropylacetamide (56d) (22 mg, 0.05 mmol, 17% yield) were obtained as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ10.93 (s, 1H), 8.07-7.95 (m, 2H), 7.72 (t, J=8.0Hz, 1H), 7.32 (d, J= 7.7,0.7Hz,1H),7.07(d,J=3.5Hz,1H),6.95(s,2H),6.51(d,J=3.5Hz,1H),5.27(s,2H), 4.16(s,2H),3.11-2.95(m,1H),1.02-0.85(m,4H); MS(ES+):444.5,446.4(M+1,M+3), MS(ES-):442.3,444.4.

[0730] Process 57

[0731]

[0732] Preparation of N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-2-(4-chloro-5-cyano-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-N-isopropylacetamide (57d)

[0733] Step 1: Preparation of tert-butyl 2-(4-chloro-5-cyano-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (57b)

[0734] At room temperature, NaH (60%, in mineral oil, 218 mg, 5.45 mmol) was added to a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-carboxynitrile (57a) (811 mg, 4.54 mmol) in DMF (10 mL), and the mixture was stirred for 5 minutes, followed by the addition of tert-butyl 2-bromoacetate (0.81 mL, 5.45 mmol). The reaction mixture was stirred for 2 hours and quenched with EtOAc (50 mL) and brine (75 mL). The organic layer was separated, washed with water (50 mL), dried, filtered, and concentrated under vacuum. The residue obtained by rapid column chromatography [silica gel (24 g), eluted with MeOH / CHCl 30 to 30%] yielded tert-butyl 2-(4-chloro-5-cyano-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (57b) as a grayish-white solid (989 mg, 3.38 mmol, 74% yield); 1 H NMR (300MHz, DMSO-d6) δ8.86 (s,1H), 8.71 (s,1H), 5.18 (s,2H), 1.42 (s,9H); MS (ES+): 293.4 (M+1), 315.3 (M+Na); (ES-): 291.3 (M-1), 327.4 (M+Cl).

[0735] Step 2: Preparation of 2-(4-chloro-5-cyano-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (57c)

[0736] 2-(4-chloro-5-cyano-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid tert-butyl ester (57b) (500 mg, 1.71 mmol) was reacted with TFA (1.32 mL, 17.08 mmol) according to the procedure reported in step 2 of process 2, and after treatment, 2-(4-chloro-5-cyano-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (57c) (310 mg, 1.31 mmol, 77% yield) was used as is in the next step without further purification; MS (ES+): 237.3 (M+1); (ES-): 235.2 (M-1)

[0737] Step 3: Preparation of N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-2-(4-chloro-5-cyano-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-N-isopropylacetamide (57d)

[0738] N-(3-chloro-2-fluorobenzyl)-2-(isopropylamino)acetamide (19c) (387 mg, 1.5 mmol) reacted with 2-(4-chloro-5-cyano-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (57c) (295 mg, 1.25 mmol) according to the procedure reported in steps 3 of process 2, after treatment and chromatography [first column: silica gel (24 g), with MeOH / CHCl30-10]. 0% elution; second column: silica gel (24 g), eluted with EtOAc / MeOH (9:1) / hexane 0-100% [After purification, N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-2-(4-chloro-5-cyano-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-N-isopropylacetamide (57 d) (115 mg, 0.241 mmol, 19% yield) was obtained as a white solid. 1 H NMR(300MHz,DMSO-d6)δ8.82&8.82(2s,1H),8.79&8.33(2t,1H),8.64&8.61 (2s,1H),7.57-7.33(m,2H),7.30-7.03(m,1H),5.46&5.33(2s,2H),4.62-4.47&4.26- 4.20(2m,1H),4.44(d,J=5.6Hz)&4.30(d,J=5.8Hz)(2d,2H),4.18&3.84(2s,2H), 1.24(d,J=6.4Hz)&0.98(d,J=6.8Hz)(2d,6H); 19F NMR (282MHz, DMSO-d6) δ -121.27, -121.63; [Based on NMR, the compound is a mixture of two rotational isomers in a ratio of approximately 2:3]; MS (ES+): 477.5 (M+1); (ES-): 475.5, 477.5 (M-1).

[0739] Process 58

[0740]

[0741] Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (58b)

[0742] Step 1: Preparation of N-(3-chloro-2-fluorobenzyl)-2-((3,3-difluorocyclobutyl)amino)acetamide (58a)

[0743] 2-Chloro-N-(3-chloro-2-fluorobenzyl)acetamide (35b) (500 mg, 2.12 mmol) and 3,3-difluorocyclobutylamine hydrochloride (502 mg, 3.49 mmol) were reacted according to the procedure reported in step-2 of procedure 35. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with EtOAc / MeOH (9:1) / hexane 0 to 60%], N-(3-chloro-2-fluorobenzyl)-2-((3,3-difluorocyclobutyl)amino)acetamide (58a) (110 mg, 0.36 mmol, 17%) was obtained as a clear oil. 1 HNMR(300MHz,DMSO-d6)δ8.39(t,J=6.0Hz,1H),7.52-7.43(m, 1H),7.33-7.24(m,1H),7.24-7.14(m,1H),4.35(d,J=5.9Hz,2H),3.17-3.03( m,3H),2.80-2.61(m,3H),2.41-2.22(m,2H); MS(ES+):307.3,309.3(M+1,M+3)

[0744] Step 2: Preparation of tert-butyl-1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (58b)

[0745] N-(3-chloro-2-fluorobenzyl)-2-((3,3-difluorocyclobutyl)amino)acetamide (58a) (110 mg, 0.36 mmol) was reacted with 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (86 mg, 0.4 mmol) according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 60%], tert-butyl-1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (58b) (115 mg, 0.23 mmol, 63% yield) as a white solid. 1 ¹H NMR (300MHz, DMSO-d⁶) δ 8.90 (t, J = 5.9Hz) and 8.57 (t, J = 6.6Hz) (2t, 1H), 8.18 (d, J = 8.0Hz, 1H), 7.79–7.63 (m, 1H), 7.56–7.07 (m, 7H), 5.65 and 5.43 (2s, 2H), 4.64–4.02 (m, 5H), 3.12–2.85 (m, 2H), 2.80–2.65 (m, 2H); 19 F NMR (282MHz, DMSO-d6) δ-82.66,-99.20,-121.23,-121.60; MS(ES + ):508.5(M+1); MS(ES) - ):506.5 (M-1); [Based on NMR, this compound is a mixture of two rotational isomers in a ratio of 5:1].

[0746] Process 59

[0747]

[0748] Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(2-hydroxy-2-methylpropyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (59b)

[0749] Step 1: Preparation of N-(3-chloro-2-fluorobenzyl)-2-((2-hydroxy-2-methylpropyl)amino)acetamide (59a)

[0750] 2-Chloro-N-(3-chloro-2-fluorobenzyl)acetamide (35b) (500 mg, 2.12 mmol) was reacted with 1-amino-2-methylprop-2-ol (378 mg, 4.24 mmol) according to the procedure reported in step-2 of procedure 35. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with EtOAc / MeOH (9:1) / hexane 0 to 60%], N-(3-chloro-2-fluorobenzyl)-2-((2-hydroxy-2-methylpropyl)amino)acetamide (59a) (200 mg, 0.69 mmol, 33%) was obtained as a clear oil; MS (ES+) 289.4 (M+1); (ES-) 287.3.

[0751] Step-2: Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(2-hydroxy-2-methylpropyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (59b)

[0752] N-(3-chloro-2-fluorobenzyl)-2-((2-hydroxy-2-methylpropyl)amino)acetamide (59a) (200 mg, 0.69 mmol) was reacted with 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (167 mg, 0.76 mmol) according to the procedure reported in step 3 of process 2. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 60%], 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(2-hydroxy-2-methylpropyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (59b) (239 mg, 0.49 mmol, 70% yield) as a white solid. 1 ¹H NMR (300MHz, DMSO-d⁶) δ 8.83 (t, J = 5.6Hz and 8.49 (t, J = 5.9Hz) (2t, 1H), 8.18 (d, J = 8.1Hz, 1H), 7.71 (d, J = 11.8Hz, 1H), 7.57–7.01 (m, 7H), 5.69 and 5.44 (2s, 2H), 5.08 and 4.59 (2s, 1H), 4.52–4.28 (m, 3H), 4.07 (s, 1H), 3.50 and 3.20 (2s, 2H), 1.24 and 1.03 (2s, 6H); 19 F NMR (282MHz, DMSO) δ -121.34, -121.67; MS (ES+): 490.5 (M+1); MS (ES-): 488.5 (M-1); [Based on NMR, this compound is a mixture of two rotational isomers in a 1:1 ratio].

[0753] Process 60

[0754]

[0755] Preparation of 2-(4-amino-5-cyano-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-isopropylacetamide (60a)

[0756] An aqueous solution of ammonium hydroxide (1.83 mL, 46.9 mmol) was added to a solution of N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-2-(4-chloro-5-cyano-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-N-isopropylacetamide (57d) (80 mg, 0.17 mmol) in dioxane (3 mL), and the mixture was heated at 85 °C for 18 hours. The reaction was cooled to room temperature, and excess solvent was removed under reduced pressure. The residue obtained by wet milling with CHCl3 was collected by filtration and the resulting solid was washed with MeOH and evaporated to dryness to give 2-(4-amino-5-cyano-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-isopropylacetamide (60a) (36 mg, 0.079 mmol, 47% yield) as a white solid. 1 ¹H NMR (300MHz, DMSO-d⁶) δ 8.77 (t, J = 5.8Hz) and 8.31 (t, J = 5.9Hz) (2t, 1H), 8.18 and 8.18 (2s, 1H), 8.07 and 8.06 (2s, 1H), 7.57–7.33 (m, 2H), 7.28–7.06 (m, 1H), 6.84 (s, 2H), 5.25 and 5.12 (2s, 2H), 4.63–4.48 and 4.26–4.19 (2m, 1H), 4.43 (d, J = 5.6Hz) and 4.31 (d, J = 5.8Hz) (2d, 2H), 4.15 and 3.83 (2s, 2H), 1.21 (d, J = 6.4Hz) and 0.97 (d, J = 6.4Hz) =6.8Hz)(2d,6H); 19 F NMR (282MHz, DMSO-d6) δ -121.31, -121.67 [Based on NMR, the compound is a mixture of two rotational isomers in a ratio of approximately 1:1]; MS (ES+): 458.5 (M+1), 480.5 (M+Na); (ES-): 456.4 (M-1), 492.5 (M+Cl).

[0757] Process 61

[0758]

[0759] Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(3-fluoropropyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (61b)

[0760] Step 1: Preparation of N-(3-chloro-2-fluorobenzyl)-2-((3-fluoropropyl)amino)acetamide (61a)

[0761] 2-Chloro-N-(3-chloro-2-fluorobenzyl)acetamide (35b) (494 mg, 2.09 mmol) reacted with 3-fluoropropane-1-amine hydrochloride (250 mg, 2.201 mmol) according to the procedure reported in step-2 of procedure 35. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with EtOAc / MeOH (9:1) / hexane 0 to 60%], N-(3-chloro-2-fluorobenzyl)-2-((3-fluoropropyl)amino)acetamide (61a) (287 mg, 1.04 mmol, 47%) was obtained as a clear oil; MS (ES+): 277.4, 279.3 (M+1, M+3); (ES-): 275.3

[0762] Step 2: Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(3-fluoropropyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (61b)

[0763] N-(3-chloro-2-fluorobenzyl)-2-((3-fluoropropyl)amino)acetamide (61a) (144 mg, 0.52 mmol) reacted with 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (125 mg, 0.57 mmol) according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 60%], 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(3-fluoropropyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (61b) (145 mg, 0.30 mmol, 58% yield) as a white solid. 1¹H NMR (300MHz, DMSO-d⁶) δ 8.87 (t, J = 5.7 Hz) and 8.52 (t, J = 5.9 Hz) (2t, 1H), 8.18 (d, J = 8.1 Hz, 1H), 7.78–7.66 (m, 1H), 7.61–7.07 (m, 7H), 5.58 and 5.45 (2s, 2H), 4.70 and 4.54 (2t, J = 5.6 Hz, 1H), 4.51–4.30 (m, 3H), 4.27 and 3.97 (2s, 2H), 3.62 (t, J = 7.1 Hz) and 3.39–3.33 (t & m, 2H), 2.17–1.96 and 1.90–1.68 (2m, 2H); 19 F NMR (282MHz, DMSO) δ -121.27, -121.62; MS (ES+) 478.5 (M+1); MS (ES-) 476.5 (M-1); [Based on NMR, this compound is a mixture of two rotational isomers in a 5:4 ratio].

[0764] Process 62

[0765]

[0766] Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(oxetanebut-3-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (62b)

[0767] Step 1: Preparation of N-(3-chloro-2-fluorobenzyl)-2-(oxetane-3-ylamino)acetamide (62a)

[0768] 2-Chloro-N-(3-chloro-2-fluorobenzyl)acetamide (35b) (500 mg, 2.12 mmol) reacted with oxetane-3-amine (310 mg, 4.24 mmol) according to the procedure reported in step-2 of procedure 35. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with EtOAc / MeOH (9:1) / hexane 0 to 60%], N-(3-chloro-2-fluorobenzyl)-2-(oxetane-3-ylamino)acetamide (62a) (365 mg, 1.34 mmol, 63% yield) was obtained as a yellow oil; MS (ES+) 273.3, 275.3 (M+1, M+3); (ES-) 271.3 (M-1)

[0769] Step 2: Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(oxetanebut-3-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (62b)

[0770] N-(3-chloro-2-fluorobenzyl)-2-(oxetane-3-ylamino)acetamide (62a) (200 mg, 0.73 mmol) reacted with 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (177 mg, 0.81 mmol) according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 60%], 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(oxetane-3-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (62b) (192 mg, 0.41 mmol, 55% yield) as a white solid. 1 ¹H NMR (300MHz, DMSO-d⁶) δ 8.94 (t, J = 5.7Hz) and 8.59 (t, J = 5.8Hz) (2t, 1H), 8.17 (d, J = 8.2Hz, 1H), 7.68 (d, J = 14.5Hz, 1H), 7.57–7.05 (m, 7H), 5.58 and 5.44 (2s, 2H), 5.12 (t, J = 7.4Hz, 1H), 4.80 (t, J = 7.2Hz) and 4.69 (t, J = 6.7Hz (2t, 2H), 4.58 (t, J = 7.2Hz, 1H), 4.54–4.45 (m, 2H), 4.43 and 4.24 (2s, 2H), 4.34 (d, J = 5.6Hz, 1H); 19 F NMR (282MHz, DMSO) δ -121.26, -121.67; MS (ES+): 474.5 (M+1); MS (ES-): 472.4 (M-1); [Based on NMR, this compound is a mixture of two rotational isomers in a 5:4 ratio].

[0771] Process 63

[0772]

[0773] Preparation of 2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-cyclopropylacetamide (63a)

[0774] N-(3-chloro-2-fluorobenzyl)-2-(cyclopropylamino)acetamide (10b) (85 mg, 0.33 mmol) and 2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (56c) (64 mg, 0.33 mmol) were reacted according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 40%], 2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-cyclopropylacetamide (63a) (42 mg, 0.097 mmol, 29% yield) as a white solid. 1 H NMR (300MHz, DMSO-d6) δ8.44(t,J=5.9Hz,1H),8.01(s,1H),7.47(td,J=7.6,1.8Hz, 1H),7.28-7.19(m,1H),7.15(td,J=7.8,1.0Hz,1H),7.06(d,J=3.5Hz,1H),6.96(s,2H), 6.52(d,J=3.5Hz,1H),5.25(s,2H),4.33(d,J=5.7Hz,2H),3.96(s,2H),3.07-2.94(m,1H),1.01-0.82(m,4H); 19 F NMR (282MHz, DMSO-d6) δ-121.62; MS (ES+): 431.5&433.4 (M+1), MS (ES-): 429.5 (M-1).

[0775] Process 64

[0776]

[0777] Preparation of 1-(2-(azacyclobut-3-yl(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (64b)

[0778] 3-(2-(3-carbamoyl-1H-indazole-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)acetamyl)azacyclobutane-1-carboxylic acid tert-butyl ester (52b) (236 mg, 0.41 mmol) was reacted with TFA (0.19 mL, 2.47 mmol) according to the procedure reported in step 2 of process 2. After treatment and purification by chromatography [silica gel (12 g), eluted with CMA80 / CHCl30 to 60%], 1-(2-(azacyclobutane-3-yl(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (64b) (112 mg, 0.24 mmol, 58% yield) as a white solid; 1 ¹H NMR (300MHz, DMSO-d⁶) δ 8.94 (t, J = 5.7 Hz) and 8.51 (t, J = 6.0 Hz) (2t, 1H), 8.17 (d, J = 8.2 Hz, 1H), 7.68 (bs, 1H), 7.52–7.22 (m, 7H), 5.55 and 5.41 (2s, 2H), 4.91 (m, 1H), 4.47 (d, J = 5.3 Hz) and 4.33 (d, J = 5.5 Hz) (2d, 2H), 4.42 and 4.18 (2s, 2H), 3.62 (d, J = 7.2 Hz, 2H), 3.41 (d, J = 7.6 Hz, 2H), 3.35 (s, 1H); 19 F NMR (282MHz, DMSO) δ -121.28, -121.64; MS (ES+) 473.5 (M+1); MS (ES-) 471.4 (M-1); [Based on NMR, this compound is a mixture of two rotational isomers in a 1:1 ratio].

[0779] Process 65

[0780]

[0781] Preparation of 4-amino-7-(2-((2-(((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(isopropyl)amino)-2-oxoethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (65a)

[0782] An aqueous solution of ammonium hydroxide (0.54 mL, 13.98 mmol) and an aqueous solution of hydrogen peroxide (35%, 0.122 mL, 1.398 mmol) were successively added to a solution of 2-(4-amino-5-cyano-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-isopropylacetamide (60a) (32 mg, 0.07 mmol) in ethanol (5 mL), and the mixture was stirred at room temperature for 16 hours. Excess solvent was removed under reduced pressure, and the residue was purified by rapid column chromatography [silica gel (12 g), eluted with MeOH / CHCl 30-50%] to give 4-amino-7-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(isopropyl)amino)-2-oxoethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (65a) (14 mg, 0.029 mmol, 42% yield) as a white solid. 1 ¹H NMR (300MHz, DMSO-d⁶) δ 8.79 (t, J = 5.7Hz) and 8.35 (t, J = 5.9Hz) (2t, 1H), 8.04 and 8.04 (2s, 1H), 7.90 and 7.88 (2s, 1H), 7.58–7.35 (m, 2H), 7.34–7.07 (m, 3H), 5.21 and 5.08 (2s, 2H), 4.63–4.51 and 4.28–4.23 (2m, 1H), 4.43 (d, J = 5.6Hz) and 4.31 (d, J = 5.8Hz) (2d, 2H), 4.17 and 3.84 (2s, 2H), 1.20 (d, J = 6.4Hz) and 0.97 (d, J = 6.8Hz) (2d, 6H); 19 F NMR (282MHz, DMSO-d6) δ -121.32, -121.70. [Based on NMR, the compound is a mixture of two rotational isomers in a ratio of approximately 1:1]; MS (ES+): 476.5 (M+1), 498.5 (M+Na); (ES-): 474.5 (M-1), 510.3 (M+Cl).

[0783] Process 66

[0784]

[0785] Preparation of 2-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-N-(2-((6-bromopyrazin-2-yl)amino)-2-oxoethyl)-N-cyclopropylacetamide (66d)

[0786] Step 1: Preparation of tert-butyl 2-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acetate (66b)

[0787] 4-Chloro-1H-pyrazolo[3,4-d]pyrimidine (66a) (6.82 g, 44.16 mmol) was reacted with tert-butyl 2-bromoacetate (7.82 mL, 52.96 mmol) using potassium carbonate (9.14 g, 66.13 mmol) as a base, according to the procedure reported in step-2 of procedure 35. After treatment and purification by rapid column chromatography [silica gel (40 g), eluted with EtOAc / hexane 0 to 60%], tert-butyl 2-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acetate (66b) (4.5 g, 16.75 mmol, 38% yield) as a white solid.

[0788] Step 2: Preparation of 2-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acetic acid (66c)

[0789] A solution of tert-butyl 2-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acetate (66b) (300 mg, 1.12 mmol) in methanol-ammonia (3.72 mL, 11.16 mmol) was stirred at room temperature for 2 days, concentrated under vacuum, and purified by chromatography [silica gel (12 g), eluted with EtOAc / MeOH (9:1) / hexane 0 to 100%] to give an intermediate. This material was dissolved in DCM (5 mL), TFA (0.86 mL, 11.16 mmol) was added, and stirred at room temperature for 4 days. The solvent was removed under vacuum, and the resulting residue was suspended in toluene (10 mL) and evaporated. The solid was dried under vacuum to give 2-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acetic acid (66c) (0.14 g, 0.73 mmol, 65% yield) as a grayish-white solid. 1 H NMR (300MHz, DMSO-d6) δ9.24 (s, 1H), 8.64 (s, 1H), 8.39 (s, 1H), 8.32 (s, 1H), 5.16 (s, 2H); MS (ES+) 194.2 (M+1).

[0790] Step 3: Preparation of 2-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-N-(2-((6-bromopyrazin-2-yl)amino)-2-oxoethyl)-N-cyclopropylacetamide (66d)

[0791] N-(6-bromopyrazin-2-yl)-2-(cyclopropylamino)acetamide (49c) (70 mg, 0.26 mmol) and 2-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acetic acid (66c) (50 mg, 0.26 mmol) were reacted according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 40%], 2-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-N-(2-((6-bromopyrazin-2-yl)amino)-2-oxoethyl)-N-cyclopropylacetamide (66d) (62 mg, 0.14 mmol, 54% yield) were obtained as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ11.27(s,1H),9.25(s,1H),8.54(s,1H),8.15(s,1H),8.08(s,1H),7.87- 7.54(m,2H),5.45(s,2H),4.19(s,2H),3.14-3.02(m,1H),1.02-0.88(m,4H); MS(ES+): 446.4&448.4(M+1),468.4&470.4(M+Na).

[0792] Process 67

[0793]

[0794] Preparation of 2-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-N-(2-((6-bromopyridin-2-yl)amino)-2-oxoethyl)-N-cyclopropylacetamide (67a)

[0795] N-(6-bromopyrazin-2-yl)-2-(cyclopropylamino)acetamide (7c) (70 mg, 0.26 mmol) and 2-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acetic acid (66c) (50 mg, 0.26 mmol) were reacted according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 40%], 2-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-N-(2-((6-bromopyridin-2-yl)amino)-2-oxoethyl)-N-cyclopropylacetamide (67a) (68 mg, 0.153 mmol, 59% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ10.93(s,1H),8.15(s,1H),8.08(s,1H),8.02(d,J=8.1Hz,1H),7.86- 7.53(m,3H),7.33(dd,J=7.7,0.7Hz,1H),5.43(s,2H),4.15(s,2H),3.12-3.00(m,1H), 1.01-0.86(m,4H); MS(ES+); 445.4&447.4(M+1), 467.4&469.5(M+Na), MS(ES-): 443.4&445.4(M-1).

[0796] Process 68

[0797]

[0798] Preparation of 2-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-cyclopropylacetamide (68a)

[0799] N-(3-chloro-2-fluorobenzyl)-2-(cyclopropylamino)acetamide (10b) (70 mg, 0.27 mmol) was reacted with 2-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acetic acid (66c) (53 mg, 0.27 mmol) according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 40%], 2-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-cyclopropylacetamide (68a) (85 mg, 0.2 mmol, 72% yield) as a white solid. 1 H NMR (300MHz, DMSO-d6)δ8.45(t,J=5.8Hz,1H),8.14(s,1H),8.08(s,1H),7.88-7.52(m, 2H),7.47(td,J=7.6,1.8Hz,1H),7.27-7.19(m,1H),7.19-7.10(m,1H),5.42(s ,2H),4.32(d,J=5.7Hz,2H),3.95(s,2H),3.09-2.95(m,1H),0.99-0.82(m,4H); 19F NMR(282 MHz, DMSO-d6)δ-121.62; MS(ES+): 432.5&433.5(M+1), 454.4(M+23), MS(ES-): 430.4&432.4(M-1).

[0800] Process 69

[0801]

[0802] Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(methyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (69d)

[0803] Step 1: Preparation of 2-bromo-N-(3-chloro-2-fluorobenzyl)acetamide (69b)

[0804] 2-Bromoacetic acid (69a) (2.09 g, 15.04 mmol) was reacted with 3-chloro-2-fluorobenzylmethylamine (9d) (2.0 g, 12.53 mmol) according to the procedure reported in Procedure 32. After treatment and purification by rapid column chromatography [silica gel (40 g), eluted with EtOAc / hexane 0-100%], 2-bromo-N-(3-chloro-2-fluorobenzylmethyl)acetamide (69b) (2.58 g, 9.21 mmol, 74% yield) was obtained as a yellow solid. 1 ¹H NMR (300MHz, DMSO-d⁶) δ 8.86 (t, J = 5.9Hz, 1H, D₂O exchangeable), 7.51 (ddd, J = 7.9, 7.2, 1.8Hz, 1H), 7.36–7.27 (m, 1H), 7.26–7.16 (m, 1H), 4.44–4.27 (m, 2H), 3.91 (s, 2H); 19 F NMR(282MHz, DMSO-d6)δ-121.04; MS(ES+): 280.2,282.2(M+2); (ES-): 278.2,280.2(M-2).

[0805] Step 2: Preparation of N-(3-chloro-2-fluorobenzyl)-2-(methylamino)acetamide (69c)

[0806] 2-Bromo-N-(3-chloro-2-fluorobenzyl)acetamide (69b) (300 mg, 1.07 mmol) was reacted with methylamine (2 M, in MeOH) (0.962 mL, 1.925 mmol) in ethanol (20 mL) according to the procedure reported in step-2 of process 35. After treatment, N-(3-chloro-2-fluorobenzyl)-2-(methylamino)acetamide (69c) (217 mg, 0.94 mmol, 88% yield) as a yellow oil was used as is in the next step; MS (ES-): 229.2 (M-1).

[0807] Step 3: Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(methyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (69d)

[0808] N-(3-chloro-2-fluorobenzyl)-2-(methylamino)acetamide (69c) (217 mg, 0.94 mmol) and 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (572 mg, 2.61 mmol) were reacted according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by rapid column chromatography [silica gel (24 g), eluted with MeOH / CHCl 30-50%], 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(methyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (69d) (139 mg, 34% yield) as a pale yellow solid were obtained. 1 H NMR(300MHz, DMSO-d6)δ8.93 -8.78&8.59-8.45(2m,1H),8.18(d,J=8.1Hz,1H),7.79-7.58(m,2H),7.58-7.33(m, 3H),7.34-7.05(m,3H),5.57&5.44(2s,2H),4.46(d,J=5.1Hz)&4.35(d,J=5.6Hz) (2d,2H),4.25&4.00(2s,2H),3.19&2.81(s,3H) 19 F NMR (282MHz, DMSO-d6) δ -121.40, -121.64 [Based on NMR, the compound is a mixture of two rotational isomers in a ratio of approximately 2:3]; MS (ES+): 432.5 (M+1).

[0809] Process 70

[0810]

[0811] Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(4-hydroxybut-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (70b)

[0812] Step 1: Preparation of N-(3-chloro-2-fluorobenzyl)-2-((4-hydroxybut-2-yl)amino)acetamide (70a)

[0813] 2-Chloro-N-(3-chloro-2-fluorobenzyl)acetamide (35b) (494 mg, 2.09 mmol) was reacted with 3-aminobut-1-ol (378 mg, 4.24 mmol) according to the procedure reported in step-2 of procedure 35. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with EtOAc / MeOH (9:1) / hexane 0 to 60%], N-(3-chloro-2-fluorobenzyl)-2-((4-hydroxybut-2-yl)amino)acetamide (70a) (200 mg, 0.69 mmol, 33%) was obtained as a clear oil; MS (ES+) 289.4 (M+1); (ES-) 287.3 (M-1).

[0814] Step 2: Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(4-hydroxybut-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (70b)

[0815] N-(3-chloro-2-fluorobenzyl)-2-((4-hydroxybut-2-yl)amino)acetamide (70a) (200 mg, 0.69 mmol) and 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (167 mg, 0.76 mmol) were reacted according to the procedure reported in steps 3 of Procedure 2. After treatment and subsequent purification by rapid column chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 60%] and preparative HPLC [C18 column, MeOH / water 0-100%], 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(4-hydroxybut-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (70b) (102 mg, 0.21 mmol, 30% yield) as a white solid were obtained. 1H NMR (300MHz, DMSO-d6) δ8.83 (t,J=5.5Hz) and 8.40(t,J=5.8Hz)(2t,1H),8.18(d,J=7.9Hz,1H),7.72(d,J=6.5Hz, 1H),7.58-7.00(m,7H),5.79-5.40(m,2H),4.57-3.41(m,7H),,3.31(t,J=6 .5Hz,1H),1.80-1.41(m,2H),1.25(d,J=6.5Hz)&0.98(d,J=6.8Hz)(2d,3H); 19 F NMR (282MHz, DMSO) δ-74.30 (TFA peak), -121.26, -121.77; MS (ES + 490.5(M+1); MS(ES) - ), 488.4 (M-1); [Based on NMR, this compound is a mixture of two rotational isomers in a ratio of 4:5].

[0816] Process 71

[0817]

[0818] Preparation of 1-(2-(sec-butyl(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (71b)

[0819] Step 1: Preparation of 2-(sec-butylamino)-N-(3-chloro-2-fluorobenzyl)acetamide (71a)

[0820] 2-Chloro-N-(3-chloro-2-fluorobenzyl)acetamide (35b) (500 mg, 2.12 mmol) was reacted with butyl-2-amine (775 mg, 10.59 mmol) according to the procedure reported in step-2 of procedure 35. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with EtOAc / MeOH (9:1) / hexane 0 to 60%], 2-(sec-butylamino)-N-(3-chloro-2-fluorobenzyl)acetamide (71a) (170 mg, 0.62 mmol, 29%) was obtained as a yellow oil; MS (ES+): 273.4 (M+1); MS (ES-): 271.3 (M-1).

[0821] Step 2: Preparation of 1-(2-(sec-butyl(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (71b)

[0822] 2-(sec-butylamino)-N-(3-chloro-2-fluorobenzyl)acetamide (71a) (170 mg, 0.62 mmol) and 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (150 mg, 0.69 mmol) were reacted according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 60%], 1-(2-(sec-butyl(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (71b) (178 mg, 0.38 mmol, 60% yield) was obtained as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ8.82 (t, J = 5.7Hz) and 8.36 (t, J = 5.9Hz) (2t, 1H), 8.18 (d, J = 8.1Hz, 1H),7.77-7.67(m,1H),7.60-7.02(m,7H),5.66-5.39(m,2H),4.57-3.71(m,5H),1.69-1.28(m,2H),1.26-0.61(m,6H); 19 F NMR(282MHz,DMSO-d6)δ-121.19,-121.76; MS (ES + 474.5(M+1); MS(ES) - ), 472.5 (M-1); [Based on NMR, this compound is a mixture of two rotational isomers in a ratio of 2:1].

[0823] Process 72

[0824]

[0825] Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(2-hydroxycyclopentyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (72b)

[0826] Step 1: Preparation of N-(3-chloro-2-fluorobenzyl)-2-((2-hydroxycyclopentyl)amino)acetamide (72a)

[0827] 2-Chloro-N-(3-chloro-2-fluorobenzyl)acetamide (35b) (350 mg, 1.48 mmol) was reacted with 2-aminocyclopentanol (375 mg, 3.71 mmol) according to the procedure reported in step-2 of procedure 35. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with EtOAc / MeOH (9:1) / hexane 0 to 60%], N-(3-chloro-2-fluorobenzyl)-2-((2-hydroxycyclopentyl)amino)acetamide (72a) (158 mg, 0.53 mmol, 36%) was obtained as a yellow oil; MS (ES+): 301.3; (ES-): 299.3 (M-1).

[0828] Step 2: Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(2-hydroxycyclopentyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (72b)

[0829] N-(3-chloro-2-fluorobenzyl)-2-((2-hydroxycyclopentyl)amino)acetamide (72a) (158 mg, 0.53 mmol) reacted with 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (127 mg, 0.58 mmol) according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 60%], 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(2-hydroxycyclopentyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (72b) (128 mg, 0.26 mmol, 49% yield) as a grayish-white solid. 1 ¹H NMR (300MHz, DMSO-d⁶) δ 8.87 (t, J = 5.7Hz) and 8.47 (t, J = 5.9Hz) (2t, 1H), 8.18 (d, J = 8.1Hz, 1H), 7.77–7.64 (m, 1H), 7.60–6.99 (m, 7H), 5.69 and 5.43 (2s, 1H), 5.36 (d, J = 4.7Hz) and 4.75 (d, J = 4.8Hz) (2d, 2H), 4.50–3.70 (m, 6H), 2.04–1.28 (m, 6H); 19 F NMR (282MHz, DMSO-d6)δ-121.22,-121.68; MS(ES + 502.6(M+1); MS(ES) - ):500.5(M-1); [Based on NMR, this compound is a mixture of two rotational isomers in a ratio of 1:3].

[0830] Process 73

[0831]

[0832] Preparation of (R)-1-(2-(sec-butyl(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (73b)

[0833] Step 1: Preparation of (R)-2-(sec-butylamino)-N-(3-chloro-2-fluorobenzyl)acetamide (73a)

[0834] 2-Chloro-N-(3-chloro-2-fluorobenzyl)acetamide (35b) (200 mg, 0.85 mmol) reacted with (R)-but-2-amine (155 mg, 2.12 mmol) according to the procedure reported in step-2 of procedure 35. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with EtOAc / MeOH (9:1) / hexane 0 to 60%], (R)-2-(sec-butylamino)-N-(3-chloro-2-fluorobenzyl)acetamide (73a) (100 mg, 0.37 mmol, 43%) was obtained as a yellow oil; MS (ES+): 273.3 (M+1); MS (ES-): 271.3 (M-1).

[0835] Step 2: Preparation of (R)-1-(2-(sec-butyl(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (73b)

[0836] (R)-2-(sec-butylamino)-N-(3-chloro-2-fluorobenzyl)acetamide (73a) (100 mg, 0.37 mmol) reacted with 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (88 mg, 0.4 mmol) according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 60%], (R)-1-(2-(sec-butyl(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (73b) (101 mg, 0.21 mmol, 58% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ8.82 (t, J = 5.5Hz) and 8.36 (t, J = 5.7Hz) (2t, 1H), 8.19 (d, J = 8.1Hz, 1H),7.82-7.65(m,1H),7.59-7.01(m,7H),5.68-5.39(m,2H),4.55-3.71(m,5H),1.67-1.28(m,2H),1.26-0.65(m,6H); 19 F NMR (282 MHz, DMSO-d6) δ -121.19, -121.76; MS (ES+) 474.6 (M+1); 496.5 (M+Na); MS (ES-) 472.5 (M-1); [Based on NMR, this compound is a mixture of 1:3 rotational isomers].

[0837] Process 74

[0838]

[0839] Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)((1R,2R)-2-hydroxycyclopentyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (74b)

[0840] Step 1: Preparation of N-(3-chloro-2-fluorobenzyl)-2-(((1R,2R)-2-hydroxycyclopentyl)amino)acetamide (74a)

[0841] 2-Chloro-N-(3-chloro-2-fluorobenzyl)acetamide (35b) (350 mg, 1.48 mmol) reacted with (1R,2R)-2-aminocyclopentanol (510 mg, 3.71 mmol) according to the procedure reported in step-2 of procedure 35. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with EtOAc / MeOH (9:1) / hexane 0 to 60%], N-(3-chloro-2-fluorobenzyl)-2-(((1R,2R)-2-hydroxycyclopentyl)amino)acetamide (74a) (312 mg, 1.04 mmol, 70%) was obtained as a yellow oil; MS (ES+): 301.3 (M+1); MS (ES-): 299.3 (M-1).

[0842] Step-2: Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)((1R,2R)-2-hydroxycyclopentyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (74b)

[0843] N-(3-chloro-2-fluorobenzyl)-2-(((1R,2R)-2-hydroxycyclopentyl)amino)acetamide (74a) (135 mg, 0.55 mmol) reacted with 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (132 mg, 0.6 mmol) according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with CMA80 / CHCl30 to 60%], 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)((1R,2R)-2-hydroxycyclopentyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (74b) (95 mg, 0.189 mmol, 34.5% yield) as a white solid. 1 ¹H NMR (300MHz, DMSO-d⁶) δ 8.87 (t, J = 5.8 Hz) and 8.47 (t, J = 5.9 Hz) (2t, 1H), 8.18 (d, J = 8.1 Hz, 1H), 7.71 (d, J = 6.5 Hz, 1H), 7.58–7.00 (m, 7H), 5.69 and 5.43 (2s, 2H), 5.37 (d, J = 4.7 Hz) and 4.76 (d, J = 4.8 Hz) (2d, 1H), 4.52–3.71 (m, 6H), 2.03–1.37 (m, 6H); 19 F NMR (282MHz, DMSO-d6) δ -121.22, -121.68; MS (ES+) 502.6 (M+1); 524.5 (M+Na); [Based on NMR, this compound is a mixture of two rotational isomers in a ratio of 2:7].

[0844] Process 75

[0845]

[0846] Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)((1S,2S)-2-hydroxycyclopentyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (75b)

[0847] Step 1: Preparation of N-(3-chloro-2-fluorobenzyl)-2-(((1S,2S)-2-hydroxycyclopentyl)amino)acetamide (75a)

[0848] 2-Chloro-N-(3-chloro-2-fluorobenzyl)acetamide (35b) (350 mg, 1.48 mmol) reacted with (1S,2S)-2-aminocyclopentanol (510 mg, 3.71 mmol) according to the procedure reported in step-2 of procedure 35. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with EtOAc / MeOH (9:1) / hexane 0 to 60%], N-(3-chloro-2-fluorobenzyl)-2-(((1S,2S)-2-hydroxycyclopentyl)amino)acetamide (75a) (285 mg, 0.95 mmol, 64%) was obtained as a yellow oil; MS (ES+): 301.4 (M+1); MS (ES-): 299.4 (M-1).

[0849] Step 2: Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)((1S,2S)-2-hydroxycyclopentyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (75b)

[0850] N-(3-chloro-2-fluorobenzyl)-2-(((1S,2S)-2-hydroxycyclopentyl)amino)acetamide (75a) (165 mg, 0.55 mmol) reacted with 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (132 mg, 0.6 mmol) according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with CMA80 / CHCl30 to 60%], 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)((1S,2S)-2-hydroxycyclopentyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (75b) (185 mg, 0.369 mmol, 67.2% yield) as a white solid. 1 ¹H NMR (300MHz, DMSO-d⁶) δ 8.88 (t, J = 5.6 Hz) and 8.48 (t, J = 5.7 Hz) (2s, 1H), 8.18 (d, J = 8.1 Hz, 1H), 7.78–7.63 (m, 1H), 7.57–6.99 (m, 7H), 5.69 and 5.44 (2s, 2H), 5.37 (d, J = 4.6 Hz) and 4.76 (d, J = 4.7 Hz) (2d, 1H), 4.51–3.72 (m, 6H), 2.03–1.45 (m, 6H); 19F NMR (282MHz, DMSO-d6) δ -121.21, -121.67; MS (ES+): 524.5 (M+Na); (ES-): 500.5 (M-1); [Based on NMR, this compound is a mixture of two rotational isomers in a ratio of 2:7].

[0851] Process 76

[0852]

[0853] Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(cyclohexyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (76b)

[0854] Step 1: Preparation of N-(3-chloro-2-fluorobenzyl)-2-(cyclohexylamino)acetamide (76a)

[0855] 2-Chloro-N-(3-chloro-2-fluorobenzyl)acetamide (35b) (400 mg, 1.69 mmol) was reacted with cyclohexylamine (840 mg, 8.87 mmol) according to the procedure reported in step-2 of procedure 35. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with EtOAc / MeOH (9:1) / hexane 0 to 60%], N-(3-chloro-2-fluorobenzyl)-2-(cyclohexylamino)acetamide (76a) (331 mg, 1.11 mmol, 65%) was obtained as a yellow oil; MS (ES+): 299.4 (M+1); MS (ES-): 297.3 (M-1).

[0856] Step 2: Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(cyclohexyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (76b)

[0857] N-(3-chloro-2-fluorobenzyl)-2-(cyclohexylamino)acetamide (76a) (145 mg, 0.49 mmol) and 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (117 mg, 0.53 mmol) were reacted according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 60%], 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(cyclohexyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (76b) (176 mg, 0.352 mmol, 72.5% yield) as a white solid; 1¹H NMR (300MHz, DMSO-d⁶) δ 8.82 (t, J = 5.7 Hz) and 8.33 (t, J = 5.8 Hz) (2t, 1H), 8.18 (d, J = 8.1 Hz, 1H), 7.76–7.65 (m, 1H), 7.64–7.02 (m, 7H), 5.60 and 5.47 (2s, 2H), 4.46 (d, J = 5.5 Hz) and 4.32 (d, J = 5.7 Hz) (2d, 2H), 4.24–3.70 (m, 3H), 1.90–0.93 (m, 10H); 19 F NMR (282 MHz, DMSO-d6) δ -121.11, -121.68; MS (ES+): 500.5 (M+1); MS (ES-): 498.5 (M-1); [Based on NMR, this compound is a mixture of two rotational isomers in a 1:1 ratio].

[0858] Process 77

[0859]

[0860] Preparation of 1-(2-(tert-butyl(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (77b)

[0861] Step 1: Preparation of 2-(tert-butylamino)-N-(3-chloro-2-fluorobenzyl)acetamide (77a)

[0862] 2-Bromo-N-(3-chloro-2-fluorobenzyl)acetamide (69b) (300 mg, 1.07 mmol) and 2-methylpropyl-2-amine (0.2 mL, 1.93 mmol) were reacted according to the procedure reported in step-2 of process 35, and after treatment, 2-(tert-butylamino)-N-(3-chloro-2-fluorobenzyl)acetamide (77a) (226 mg, 0.83 mmol, 77%) was obtained as a yellow oil, which was used as is without further purification; 1 H NMR (300MHz, DMSO-d6) δ8.38 (t, J=5.9Hz, 1H), 7.51-7.43(m,1H),7.30-7.23(m,1H),7.22-7.15(m,1H),4.36(d,J=6.1Hz,2H),3.09(s,2H),2.28(s,1H),1.00(s,9H); 19 F NMR(282MHz, DMSO-d6)δ-121.72; MS(ES+): 273.4(M+1); MS(ES-): 271.3(M-1).

[0863] Step 2: Preparation of 1-(2-(tert-butyl(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (77b)

[0864] 2-(tert-butylamino)-N-(3-chloro-2-fluorobenzyl)acetamide (77a) (210 mg, 0.77 mmol) reacted with 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (203 mg, 0.92 mmol) according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with MeOH / CHCl 30 to 50%], 1-(2-(tert-butyl(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (77b) (37 mg, 0.078 mmol, 10% yield) as a white solid. 1 ¹H NMR (300 MHz, DMSO-d⁶) δ 8.81 (t, J = 5.7 Hz, ¹H, D₂O exchangeable), 8.18 (dt, J = 8.3, 1.0 Hz, ¹H), 7.76 (s, ¹H, D₂O exchangeable), 7.60–7.48 (m, 2H), 7.47–7.33 (m, 3H), 7.31–7.16 (m, 2H), 5.39 (s, 2H), 4.47 (d, J = 5.5 Hz, 2H), 4.25 (s, 2H), 1.29 (s, 9H); 19 F NMR (282MHz, DMSO-d6) δ-121.23; MS (ES+): 474.5 (M+1), 496.4 (M+Na); MS (ES-): 508.6 (M+Cl).

[0865] Process 78

[0866]

[0867] Preparation of 1-(2-(cyclopropyl(2-oxo-2-((6-vinylpyridin-2-yl)amino)ethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (78a)

[0868] A degassed solution of 1-(2-((2-(((6-bromopyridin-2-yl)amino)-2-oxoethyl)(cyclopropyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (170 mg, 0.36 mmol) in dioxane (5 mL) was added to a degassed solution of potassium vinyltrifluoroborate (97 mg, 0.72 mmol), tetrakis(triphenylphosphine)palladium(O) (42 mg, 0.036 mmol), and potassium carbonate (100 mg, 0.72 mmol) in water (0.5 mL). The reaction mixture was stirred for 16 hours under an argon atmosphere and quenched with water (30 mL) and EtOAc (40 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (20 mL). The organic layers were combined, washed with brine, dried, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography [silica gel (12 g), eluted with EtOAc-MeOH (9:1) / hexane 0 to 100%] to give 1-(2-(cyclopropyl(2-oxo-2-((6-vinylpyridin-2-yl)amino)ethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (78a) (80 mg, 0.191 mmol, 53% yield) as a grayish-white solid; 1 H NMR (300MHz, DMSO-d6) δ10.57(s,1H),8.17 (d,J=8.1Hz,1H),7.91(d,J=8.2Hz,1H),7.81-7.70(m,2H),7.67(d,J=8.5Hz,1H), 7.50-7.33(m,2H),7.31-7.13(m,2H),6.72(dd,J=17.4,10.8Hz,1H),6.19(dd,J=17.5, 1.8Hz,1H),5.70(s,2H),5.46(dd,J=10.7,1.7Hz,1H),4.21(s,2H),3.20-3.05(m,1H), 1.10-0.84(m,4H); MS(ES+):419.5(M+1); (ES-)453.4.5(M+Cl).

[0869] Process 79

[0870]

[0871] Preparation of 1-(2-(cyclopropyl(2-((6-ethylpyridin-2-yl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (79a)

[0872] 1-(2-(cyclopropyl(2-oxo-2-((6-vinylpyridin-2-yl)amino)ethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (78a) (35 mg, 0.084 mmol) was hydrogenated in EtOAc (5 mL) with a solution containing PdOH2 (12 mg, 0.084 mmol) for 16 h at atmospheric pressure. The reaction mixture was filtered through a diatomaceous earth pad to remove the catalyst and the filtrate was concentrated under vacuum. The residue was purified by rapid chromatography [silica gel (4 g), eluted with CMA80 / CHCl 30 to 40%] to give 1-(2-(cyclopropyl(2-((6-ethylpyridin-2-yl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (79a) (18 mg, 0.043 mmol, 51% yield) as a white solid; 1 H NMR (300MHz, DMSO-d6) δ10.53(s,1H),8.17(d,J=8.1,1.0Hz,1H),7.83(d,J=8.5Hz,1H),7.76(s, 1H),7.72-7.62(m,2H),7.48-7.35(m,2H),7.30-7.20(m,1H),6.96(d,J=7.5Hz,1H), 5.70(s,2H),4.19(s,2H),3.17-3.05(m,1H),2.65(q,J=7.6Hz,2H),1.19(t,J=7.6Hz, 3H), 1.07-0.87 (m, 4H); MS (ES+): 421.5 (M+1); (ES-): 419.5 (M-1).

[0873] Process 80

[0874]

[0875] Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(2,2-dimethylcyclopropyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (80b)

[0876] Step 1: Preparation of N-(3-chloro-2-fluorobenzyl)-2-((2,2-dimethylcyclopropyl)amino)acetamide (80a)

[0877] 2-Bromo-N-(3-chloro-2-fluorobenzyl)acetamide (69b) (300 mg, 1.07 mmol) was reacted with 2,2-dimethylcyclopropylamine (182 mg, 2.14 mmol) according to the procedure reported in step-2 of process 35. After treatment, N-(3-chloro-2-fluorobenzyl)-2-((2,2-dimethylcyclopropyl)amino)acetamide (80a) (305 mg, 1.07 mmol, 100%) was obtained as a yellow oil and used as is without further purification; MS (ES+): 285.4 (M+1); MS (ES-): 283.3 (M-1).

[0878] Step 2: Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(2,2-dimethylcyclopropyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (80b)

[0879] N-(3-chloro-2-fluorobenzyl)-2-((2,2-dimethylcyclopropyl)amino)acetamide (80a) (305 mg, 1.07 mmol) and 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (282 mg, 1.29 mmol) were reacted according to the procedure reported in step 3 of procedure 2. After treatment and purification by rapid column chromatography [silica gel (24 g), eluted with MeOH / CHCl 30 to 50%], 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(2,2-dimethylcyclopropyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (80b) (68 mg, 0.14 mmol, 1% yield) in the form of a white solid in the form of a mixture of two rotational isomers. 1 ¹H NMR (300MHz, DMSO-d6) (mixture of two rotational isomers) δ 8.83 (J = 5.7Hz) & 8.50 (J = 5.8Hz (2t, 1H), 8.22-8.16 (m, 1H), 7.73 & 7.70 (2s, 1H), 7.58-7.36 (m, 4H), 7.32-7.19 (m, 2H), 7.11 (td, J = 7.8, 1.0Hz, 1H), 5.74-5.25 (m, 2H), 4.37-4.30 (m, 2H), 4.17-3.81 (m, 2H), 2.96 (dd, J = 8.0, 4.5Hz, 1H), 1.28 & 0.96 (2s,3H),1.18&0.91(2s,3H),0.87-0.74(m,2H); 19F NMR (282MHz, DMSO-d6) δ -121.23, -121.56; MS (ES+): 486.5 (M+1), 508.5 (M+Na); MS (ES-): 484.5 (M-1), 520.5 (M+Cl).

[0880] Process 81

[0881]

[0882] Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(tetrahydrofuran-3-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (81b)

[0883] Step 1: Preparation of N-(3-chloro-2-fluorobenzyl)-2-((tetrahydrofuran-3-yl)amino)acetamide (81a)

[0884] 2-Chloro-N-(3-chloro-2-fluorobenzyl)acetamide (35b) (300 mg, 1.27 mmol) reacted with tetrahydrofuran-3-amine (332 mg, 3.81 mmol) according to the procedure reported in step-2 of procedure 35. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with EtOAc / MeOH (9:1) / hexane 0 to 60%], N-(3-chloro-2-fluorobenzyl)-2-((tetrahydrofuran-3-yl)amino)acetamide (81a) (152 mg, 0.53 mmol, 42% yield) was obtained as a clear oil. 1 HNMR (300MHz, DMSO-d6)δ 1 ¹H NMR (300MHz, DMSO-d⁶) δ 8.37 (t, J = 6.0 Hz, 1H, D₂O exchangeable), 7.48 (td, J = 7.8, 1.8Hz, 1H), 7.33–7.24 (m, 1H), 7.24–7.12 (m, 1H), 4.36 (d, J = 6.0Hz, 2H), 3.83–3.55 (m, 3H), 3.46–3.36 (m, 1H), 3.30–3.18 (m, 1H), 3.14 (s, 2H), 2.35 (s, 1H, D₂O exchangeable), 1.95–1.80 (m, 1H), 1.72–1.55 (m, 1H); MS (ES⁺): 287.3 (M⁺¹); (ES⁻): 285.3 (M⁻¹).

[0885] Step 2: Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(tetrahydrofuran-3-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (81b)

[0886] N-(3-chloro-2-fluorobenzyl)-2-((tetrahydrofuran-3-yl)amino)acetamide (81a) (110 mg, 0.38 mmol) reacted with 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (93 mg, 0.42 mmol) according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 60%], 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(tetrahydrofuran-3-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (81b) (136 mg, 0.28 mmol, 73% yield) as a white solid; 1 ¹H NMR (300MHz, DMSO-d⁶) δ 8.89 (t, J = 5.6Hz) and 8.49 (t, J = 5.8Hz) (2t, 1H), 8.25–8.09 (m, 1H), 7.70 (s, 1H), 7.61–7.00 (m, 7H), 5.75–5.56 (m) and 5.40 (s) (2H), 4.95–4.71 (m, 1H), 4.47 (d, J = 5.6Hz) and 4.31 (d, J = 5.5Hz) (2d, 2H), 4.25 (s) and 4.03–3.73 (m) (4H), 3.63–3.48 (m, 2H), 2.17–1.62 (m, 2H); 19 F NMR (282MHz, DMSO-d6) δ -121.27, -121.73; MS (ES+) 488.5 (M+1); 510.5 (M+Na); MS (ES-) 486.5 (M-1); [Based on NMR, this compound is a mixture of two rotational isomers in a 1:1 ratio].

[0887] Process 82

[0888]

[0889] Preparation of 3-((2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(isopropyl)amino)-2-oxoethyl)(phenyl)amino)propionamide (82e)

[0890] Step 1: Preparation of tert-butyl 2-((2-cyanoethyl)(phenyl)amino)acetate (82b)

[0891] 3-(phenylamino)propionitrile (82a) (1.0 g, 6.84 mmol) reacted with tert-butyl 2-bromoacetate (1.11 mL, 7.52 mmol) using sodium hydride (0.274 g, 6.84 mmol) as a base, according to the procedure reported in step-1 of process 57. After treatment and purification by rapid column chromatography [silica gel (40 g), eluted with EtOAc / hexane 0 to 50%], tert-butyl 2-((2-cyanoethyl)(phenyl)amino)acetate (82b) (148 mg, 0.57 mmol, 8% yield) was obtained as a colorless oil. 1 H NMR(300MHz,DMSO-d6)δ7.24-7.11(m,2H),6.76-6.51(m,3H),4.09(s,2H), 3.70 (t, J=6.9Hz, 2H), 2.74 (t, J=6.8Hz, 2H), 1.39 (s, 9H); MS (ES+): 283.5 (M+Na).

[0892] Step 2: Preparation of 2-((2-cyanoethyl)(phenyl)amino)acetic acid (82c)

[0893] 2-((2-cyanoethyl)(phenyl)amino)acetic acid tert-butyl ester (82b) (141 mg, 0.542 mmol) was reacted with TFA (0.42 mL, 5.42 mmol) according to the procedure reported in step-2 of process 2, and after treatment, 2-((2-cyanoethyl)(phenyl)amino)acetic acid (82c) was obtained, which was used as is in the next step; MS (ES+): 205.3 (M+1); MS (ES-): 203.3 (M-1).

[0894] Step 3: Preparation of N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-2-((2-cyanoethyl)(phenyl)amino)-N-isopropylacetamide (82d)

[0895] 2-((2-cyanoethyl)(phenyl)amino)acetic acid (82c) (110 mg, 0.544 mmol) and N-(3-chloro-2-fluorobenzyl)-2-(isopropylamino)acetamide (35b) (141 mg, 0.54 mmol) were reacted according to the procedure reported in step 3 of process 2, and after treatment, N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-2-((2-cyanoethyl)(phenyl)amino)-N-isopropylacetamide (82d) was used as is in the next step; MS (ES-): 443.5 (M-1).

[0896] Step 4: Preparation of 3-((2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(isopropyl)amino)-2-oxoethyl)(phenyl)amino)propionamide (82e)

[0897] N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-2-((2-cyanoethyl)(phenyl)amino)-N-isopropylacetamide (82d) (242 mg, 0.54 mmol) was reacted in ethanol (5 mL) with NH4OH aqueous solution (2.12 mL, 54.4 mmol) and H2O2 (35% aqueous solution, 0.95 mL, 10.88 mmol) according to the procedure reported in Procedure 65. After treatment and purification by rapid column chromatography [first column: silica gel (24 g), eluted with MeOH / CHCl 30-30%; second column: silica gel (12 g), eluted with MeOH / CHCl 30-10%], 3-((2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(isopropyl) was obtained as a grayish-white solid in the form of a mixture of two rotational isomers. (amino)-2-oxoethyl)(phenyl)amino)propionamide (82e) (53 mg, 0.11 mmol, 21% yield); 1 ¹H NMR (300 MHz, DMSO-d⁶) δ 8.70 (t, J = 5.8 Hz) and 8.28 (t, J = 6.0 Hz) (2t, 1H), 7.56–7.31 (m, 3H), 7.30–7.15 (m, 1H), 7.15–7.03 (m, 2H), 6.82 (bs, 1H), 6.70–6.49 (m, 3H), 4.67–4.52 and 4.19–4.05 (m, 1H), 4.46–4.30 (m, 2H), 4.30 and 4.14 (2s, 2H), 4.01 and 3.79 (2s, 2H), 3.57– 3.44(m,2H),2.41-2.31(m,2H),1.18(d,J=6.4Hz) and 0.97(d,J=6.8Hz)(2d,6H); 19 F NMR (282MHz, DMSO-d6) δ-121.30, -121.90; MS (ES+): 463.5 (M+1), 485.5 (M+Na); MS (ES-): 461.5 (M-1), 497.5 (M+Cl).

[0898] Process 83

[0899]

[0900] Preparation of 7-(2-((2-((6-bromopyridin-2-yl)amino)-2-oxoethyl)(cyclopropyl)amino)-2-oxoethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-carboxamide (83d)

[0901] Step 1: Preparation of tert-butyl 2-(4-cyano-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (83a)

[0902] Add zinc dicyandiamide (237 mg, 2.02 mmol), 1,1'-binaphthyl-2-yldi-tert-butylphosphine (80 mg, 0.20 mmol), palladium(II) trifluoroacetate (34 mg, 0.10 mmol), and Zn (66 mg, 1.01 mmol) to a degassed solution of 2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (56b) in DMA (10 mL) and heat at 95 °C for 16 hours. Cool the mixture to room temperature, dilute with EtOAc (20 mL), filter through a diatomaceous earth mat and wash with EtOAc (2 × 15 mL). Wash the combined filtrate with water (2 × 40 mL) and brine, dry, filter and concentrate under vacuum. The residue obtained by rapid column chromatography [silica gel (24 g), eluted with EtOAc / hexane 0 to 100%] yielded tert-butyl 2-(4-cyano-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (83a) as a white solid (80 mg, 0.31 mmol, 15% yield); 1 H NMR (300MHz, DMSO-d6) δ9.00 (s, 1H), 8.01 (d, J = 3.7Hz, 1H), 6.90 (d, J = 3.7Hz, 1H), 5.14 (s, 2H), 1.41 (s, 9H); MS (ES-): 257.3 (M-1).

[0903] Step 2: Preparation of tert-butyl 2-(4-carbamoyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (83b)

[0904] 2-(4-cyano-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tert-butyl acetate (83a) (350 mg, 1.36 mmol) was reacted in ethanol (10 mL) with aqueous NH4OH (1.06 mL, 27.1 mmol) and H2O2 (35% aqueous solution, 0.42 mL, 13.55 mmol) according to the procedure reported in Procedure 65. After treatment, 2-(4-carbamoyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tert-butyl acetate (83b) (360 mg, 1.30 mmol, 96% yield) as a white solid.1 HNMR(300MHz,DMSO-d6)δ8.87(s,1H),8.33(s,1H),7.88(s,1H),7.76(d,J= 3.6Hz, 1H), 7.07 (d, J = 3.5Hz, 1H), 5.09 (s, 2H), 1.41 (s, 9H); MS (ES+): 277.4 (M+1): MS (ES-): 275.3 (M-1).

[0905] Step 3: Preparation of 2-(4-carbamoyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (83c)

[0906] 2-(4-carbamoyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid tert-butyl ester (83b) (340 mg, 1.23 mmol) was reacted with TFA (0.95 mL, 12.31 mmol) according to the procedure reported in step 2 of process 2, and after treatment, 2-(4-carbamoyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (83c) was used as is in the next step; MS(ES+): 221.3 (M+1); MS(ES-): 219.2 (M-1).

[0907] Step 4: Preparation of 7-(2-((2-((6-bromopyridin-2-yl)amino)-2-oxoethyl)(cyclopropyl)amino)-2-oxoethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-carboxamide (83d)

[0908] N-(6-bromopyridin-2-yl)-2-(cyclopropylamino)acetamide (7c) (70 mg, 0.26 mmol) and 2-(4-carbamoyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (83c) (57 mg, 0.26 mmol) were reacted according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 40%], 7-(2-((2-((6-bromopyridin-2-yl)amino)-2-oxoethyl)(cyclopropyl)amino)-2-oxoethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-carboxamide (83d) (60 mg, 0.13 mmol, 49% yield) were obtained as a white solid. 1HNMR(300MHz,DMSO-d6)δ10.94(s,1H),8.86(s,1H),8.31(s,1H),8.01(d,J= 8.1Hz,1H),7.86(s,1H),7.77-7.65(m,2H),7.32(dd,J=7.7,0.7Hz,1H),7.05(d,J=3.5 Hz,1H),5.50(s,2H),4.17(s,2H),3.14-3.02(m,1H),1.04-0.89(m,4H); MS(ES+): 472.5,474.5(M+1); MS(ES-); 470.4,472.4(M-1).

[0909] Process 84

[0910]

[0911] Preparation of 7-(2-((2-((6-bromopyrazin-2-yl)amino)-2-oxoethyl)(cyclopropyl)amino)-2-oxoethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-carboxamide (84a)

[0912] N-(6-bromopyrazin-2-yl)-2-(cyclopropylamino)acetamide (49c) (70 mg, 0.26 mmol) and 2-(4-carbamoyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (83c) (57 mg, 0.26 mmol) were reacted according to the procedure reported in step 3 of Procedure 2. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 40%], 7-(2-((2-((6-bromopyrazin-2-yl)amino)-2-oxoethyl)(cyclopropyl)amino)-2-oxoethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-carboxamide (84a) (55 mg, 0.12 mmol, 45% yield) as a white solid; 1 HNMR(300MHz,DMSO-d6)δ11.28(s,1H),9.24(s,1H),8.86(s,1H),8.54(s, 1H),8.31(s,1H),7.85(s,1H),7.72(d,J=3.5Hz,1H),7.05(d,J=3.5Hz,1H),5.51(s, 2H),4.22(s,2H),3.15-3.05(m,1H),1.06-0.92(m,4H); MS(ES+):473.4 and 475.4(M+1); MS(ES-):471.3 and 473.3(M-1).

[0913] Process 85

[0914]

[0915] Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(cycloheptyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (85b)

[0916] Step 1: Preparation of N-(3-chloro-2-fluorobenzyl)-2-(cycloheptylamino)acetamide (85a)

[0917] 2-Bromo-N-(3-chloro-2-fluorobenzyl)acetamide (69b) (313 mg, 1.12 mmol) was reacted with cycloheptanamine (0.17 mL, 1.34 mmol) according to the procedure reported in step-2 of process 35. After treatment, N-(3-chloro-2-fluorobenzyl)-2-(cycloheptanylamino)acetamide (85a) was obtained as a yellow oil, which was used as is without further purification; MS (ES+): 313.4 (M+1); MS (ES-): 311.4 (M-1), 347.4 (M+Cl).

[0918] Step 2: Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(cycloheptyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (85b)

[0919] N-(3-chloro-2-fluorobenzyl)-2-(cycloheptylamino)acetamide (85a) (347 mg, 1.12 mmol) and 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (365 mg, 1.66 mmol) were reacted according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by rapid column chromatography [silica gel (40 g), eluted with MeOH / CHCl 30 to 10%], 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(cycloheptyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (85b) (136 mg, 0.27 mmol, 24% yield) in the form of a mixture of two rotational isomers as a grayish-white solid. 1H NMR(300MHz, DMSO-d6)δ8.85(t,J=5.8Hz)&8.37 (t,J=5.9Hz)(2t,1H),8.23-8.13(m,1H),7.70(s,1H),7.65-7.35(m,5H),7.32-6.96(m, 2H),5.59&5.46(s,2H),4.46(d,J=5.6Hz)&4.31(d,J=5.7Hz)(2d,2H),4.27-4.2 1&3.98-3.87(m,1H),4.19&3.82(2s,2H),1.69-1.40(m,11H),1.36-1.23(m,1H); 19 F NMR (282MHz, DMSO-d6) δ -121.10, -121.72; MS (ES+): 514.8 and 516.7 (M+1), 536.7 and 538.6 (M+Na); MS (ES-): 512.3, 514.6 (M-1), 548.5 (M+Cl).

[0920] Process 86

[0921]

[0922] Preparation of 2-(4-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-cyclopropylacetamide (86d)

[0923] Step 1: Preparation of tert-butyl 2-(4-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)acetate (86b)

[0924] 4-Chloro-1H-pyrrolo[2,3-b]pyridine (86a) (2.0 g, 13.11 mmol) was reacted with tert-butyl 2-bromoacetate (2.32 mL, 15.73 mmol) according to the procedure reported in step-1 of procedure 56. After treatment and purification by rapid column chromatography [silica gel (40 g), eluted with EtOAc / hexane 0 to 50%], tert-butyl 2-(4-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)acetate (86b) (3 g, 11.25 mmol, 86% yield) was obtained as a colorless oil. 1 H NMR (300MHz, DMSO-d6) δ8.21 (d, J = 5.2 Hz, 1H), 7.66 (d, J = 3.6 Hz, 1H), 7.26 (d, J = 5.2 Hz, 1H), 6.56 (d, J = 3.6 Hz, 1H), 5.05 (s, 2H), 1.40 (s, 9H).

[0925] Step 2: Preparation of 2-(4-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)acetic acid (86c)

[0926] 2-(4-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)acetic acid tert-butyl ester (86b) (1.5 g, 5.62 mmol) was reacted with TFA (4.33 mL, 56.2 mmol) according to the procedure reported in step 2 of process 2, and after treatment, 2-(4-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)acetic acid (86c) (940 mg, 4.46 mmol, 79% yield) as a pale orange solid. 1 HNMR(300MHz,DMSO-d6)δ13.08(s,1H),8.20(d,J=5.2Hz,1H),7.67(d,J= 3.6Hz, 1H), 7.26 (d, J = 5.2Hz, 1H), 6.56 (d, J = 3.6Hz, 1H), 5.06 (s, 2H); MS (ES+): 211.2 (M+1); (ES-) 209.1 (M-1).

[0927] Step 3: Preparation of 2-(4-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-cyclopropylacetamide (86d)

[0928] 2-(4-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)acetic acid (86c) (330 mg, 1.57 mmol) was reacted with N-(3-chloro-2-fluorobenzyl)-2-(cyclopropylamino)acetamide (10b) (402 mg, 1.57 mmol) according to the procedure reported in step 3 of process 2. After treatment and purification by rapid column chromatography [silica gel (24 g), eluted with MeOH-EtOAc (1:9) / hexane 0 to 70%], 2-(4-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-cyclopropylacetamide (86d) (580 mg, 1.29 mmol, 82% yield) as a white solid. 1HNMR (300MHz, DMSO-d6) δ8.45(t,J=5.8Hz,1H),8.18(d,J=5.2 Hz,1H),7.61(d,J=3.6Hz,1H),7.47(td,J=7.6,1.8Hz,1H),7.29-7.18(m,2H),7.18- 7.10(m,1H),6.56(d,J=3.5Hz,1H),5.44(s,2H),4.33(d,J=5.7Hz,2H),3.97(s,2H),3.09-2.98(m,1H),1.05-0.87(m,4H); 19 F NMR (282MHz, DMSO-d6) δ-121.61; MS (ES-): 447.3 and 449.5 (M-1), 483.4 and 485.4 (M+Cl).

[0929] Process 87

[0930]

[0931] Preparation of 2-(4-acetamido-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-cyclopropylacetamide (87a)

[0932] Cesium carbonate (326 mg, 1.0 mmol), acetamide (79 mg, 1.34 mmol), dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (32 mg, 0.067 mmol), and Pd2(dba)3 (31 mg, 0.033 mmol) were added to a degassed solution of 2-(4-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-cyclopropylacetamide (86d) (300 mg, 0.67 mmol) in dioxane (10 mL), and the mixture was heated at 80 °C for 16 hours. The mixture was cooled to room temperature, diluted with EtOAc (5 mL), filtered through a diatomaceous earth mat, and washed with EtOAc (2 × 5 mL). The filtrate was washed with water (2 × 30 mL) and brine, dried, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 40%] to give 2-(4-acetamido-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-cyclopropylacetamide (87a) (105 mg, 0.22 mmol, 33% yield) as a white solid; 1H NMR (300MHz, DMSO-d6) δ10.05(s,1H),8.44(t,J=5.9Hz,1H),8.06(d,J=5.4Hz,1H),7.83(d,J=5.4 Hz,1H),7.51-7.41(m,1H),7.35(d,J=3.6Hz,1H),7.27-7.07(m,2H),6.82(d,J=3.6 Hz,1H),5.37(s,2H),4.33(d,J=5.8Hz,2H),3.97(s,2H),3.09-2.97(m,1H),2.20(s,3H),1.03-0.84(m,4H); 19 F NMR (282MHz, DMSO-d6) δ-121.62; MS (ES+) 472.5 (M+1); MS (ES-): 470.5 (M-1), 506.5 (M+Cl).

[0933] Process 88

[0934]

[0935] Preparation of tert-butyl 4-(2-(3-carbamoyl-1H-indazole-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)acetamyl)piperidine-1-carboxylic acid (88b)

[0936] Step 1: Preparation of tert-butyl 4-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)amino)piperidine-1-carboxylic acid (88a)

[0937] 2-Chloro-N-(3-chloro-2-fluorobenzyl)acetamide (35b) (500 mg, 5.3 mmol) was reacted with tert-butyl 4-aminopiperidine-1-carboxylate (1.06 g, 5.3 mmol) according to the procedure reported in step-2 of procedure 35. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with EtOAc / MeOH (9:1) / hexane 0 to 60%], tert-butyl 4-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)amino)piperidine-1-carboxylate (88a) (762 mg, 1.91 mmol, 90%) was obtained as a clear oil. 1H NMR (300MHz, DMSO-d6) δ8.38 (t, J=6.1Hz, 1H), 7.53 -7.40(m,1H),7.34-7.23(m,1H),7.23-7.14(m,1H),4.36(d,J=6.0Hz,2H),3.79(d,J=1 3.1Hz,2H),3.16(s,2H),2.87-2.63(m,2H),2.48-2.40(m,1H),2.27(s,1H),1.79-1.64 (m,2H),1.38(s,9H),1.20-1.01(m,2H);MS(ES+):400.5(M+1);MS(ES-):398.4(M-1).

[0938] Step 2: Preparation of tert-butyl 4-(2-(3-carbamoyl-1H-indazole-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)acetamyl)piperidine-1-carboxylic acid (88b)

[0939] 4-((2-(((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)amino)piperidin-1-carboxylic acid tert-butyl ester (88a) (660 mg, 1.65 mmol) reacted with 2-(3-carbamoyl-1H-indazol-1-yl)acetic acid (2e) (398 mg, 1.82 mmol) according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 60%], 4-(2-(((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)acetamyl)piperidin-1-carboxylic acid tert-butyl ester (88b) (442 mg, 0.74 mmol, 45% yield) was obtained as a white solid. 1 ¹H NMR (300MHz, DMSO-d⁶) δ 8.78 (t, J = 5.7Hz) and 8.36 (t, J = 5.8Hz) (2t, 1H), 8.18 (m, 1H), 7.71 (m, 1H), 7.60–7.06 (m, 7H), 5.67 and 5.48 (2s, 2H), 4.46 (d, J = 3.7Hz) and 4.31 (d, J = 4.9Hz) (2d, 2H), 4.21 and 3.86 (2s, 2H), 4.37–3.90 (m, 3H), 2.77 (m, 2H), 1.40 (m, 13H); 19F NMR (282MHz, DMSO) δ -121.12, -121.67; MS (ES+): 623.6 & 625.7 (M+Na); [Based on NMR, this compound is a mixture of 2:1 rotational isomers].

[0940] Process 89

[0941]

[0942] Preparation of (R)-1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(piperidin-3-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (89c)

[0943] Step 1: Preparation of (R)-3-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)amino)piperidine-1-carboxylic acid tert-butyl ester (89a)

[0944] 2-Chloro-N-(3-chloro-2-fluorobenzyl)acetamide (35b) (500 mg, 5.3 mmol) reacted with (R)-3-aminopiperidine-1-carboxylic acid tert-butyl ester (1.06 g, 5.3 mmol) according to the procedure reported in step-2 of procedure 35. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with EtOAc / MeOH (9:1) / hexane 0 to 60%], (R)-3-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)amino)piperidine-1-carboxylic acid tert-butyl ester (89a) (850 mg, 2.13 mmol, 100%) was obtained as a yellow oil; MS (ES+): 400.5 (M+1); MS (ES-): 398.4 (M-1).

[0945] Step 2: Preparation of (R)-3-(2-(3-carbamoyl-1H-indazole-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)acetamyl)piperidine-1-carboxylic acid tert-butyl ester (89b)

[0946] (R)-3-((2-(((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)amino)piperidine-1-carboxylic acid tert-butyl ester (89a) (710 mg, 1.78 mmol) reacted with 2-(3-carbamoyl-1H-indazol-1-yl)acetic acid (2e) (428 mg, 1.95 mmol) according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 60%], (R)-3-(2-(3-carbamoyl-1H-indazol-1-yl)-N-(2-(((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)acetamyl)piperidine-1-carboxylic acid tert-butyl ester (89b) (520 mg, 0.87 mmol, 49% yield) as a white solid. MS(ES+):602.6(M+1).

[0947] Step 3: Preparation of (R)-1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(piperidin-3-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (89c)

[0948] (R)-3-(2-(3-carbamoyl-1H-indazole-1-yl)-N-(2-(((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)acetamyl)piperidin-1-carboxylic acid tert-butyl ester (89b) (495 mg, 0.82 mmol) reacted with TFA (0.32 mL, 4.12 mmol) according to the procedure reported in step 2 of process 2. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 60%], (R)-1-(2-((2-(((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(piperidin-3-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (89c) (300 mg, 0.6 mmol, 73% yield) was obtained as a white solid. 1H NMR (300MHz, DMSO-d6) δ8.82 (t, J = 5.6 Hz) and 8.37 (t, J = 5.9 H) (2t, 1H), 8.18 (d, J = 8.1 Hz, 1H), 7.78-7.64 (m, 1H), 7.63-7.03 (m, 7H), 5.75-5.51 (m) 5.45(s)(2H), 4.52-4.38(m,1H), 4.31(d,J=5.7Hz) and 4.22(d,J=4.6Hz)(2d,2H), 4.17-4.04 and 3.85-3.75(2m,1H), 3.89 and 3.17(2s,2H), 3.12-2.65(m,2H), 2.45-2.18(m,2H), 1.96-1.25(m,4H); 19 F NMR (282MHz, DMSO-d6) δ-73.45 (TFA peak), -121.17, -121.70; MS (ES + 501.5 (M+1); 499.5 (M-1); [Based on NMR, this compound is a mixture of rotational isomers in a ratio of 2:1].

[0949] Process 90

[0950]

[0951] Preparation of 2-(3-acetyl-5-bromo-1H-indol-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-isopropylacetamide (90d)

[0952] Step 1: Preparation of tert-butyl 2-(3-acetyl-5-bromo-1H-indole-1-yl)acetate (90b)

[0953] 1-(5-bromo-1H-indol-3-yl)acetone (90a) (prepared according to the procedure reported by Denis, Jean-Noeel et al. in PCT International Application WO 2013 / 014102, 8.24 g, 34.6 mmol) and 2-bromoacetate tert-butyl ester (6.14 mL, 41.5 mmol) were reacted according to the procedure reported in step-1 of procedure 56, and after treatment, 2-(3-acetyl-5-bromo-1H-indol-1-yl)acetate tert-butyl ester (90b) (11.26 g, 32.0 mmol, 92% yield) was obtained as a grayish-white solid. 1HNMR(300MHz,DMSO-d6)δ8.38(s,1H),8.35-8.29(m,1H),7.54-7.36(m,2H),5.14 (s,2H),2.44(s,3H),1.43(s,9H); MS(ES+):352.2,354.3(M+2),374.4,376.3(M+Na); (ES-):350.3,352.3(M-2),386.3,388.3(M+Cl).

[0954] Step 2: Preparation of 2-(3-acetyl-5-bromo-1H-indol-1-yl)acetic acid (90c)

[0955] 2-(3-acetyl-5-bromo-1H-indol-1-yl)acetic acid tert-butyl ester (90b) (11.15 g, 31.7 mmol) reacted with TFA (48.8 mL, 633 mmol) according to the procedure reported in step 2 of process 2, and after treatment, 2-(3-acetyl-5-bromo-1H-indol-1-yl)acetic acid (90c) (11.38 g, 38.4 mmol, 88% yield) in the form of a pink solid as a TFA adduct; 1 ¹H NMR (300MHz, DMSO-d⁶) δ 13.33 (bs, ¹H, D₂O exchangeable), 8.40 (s, ¹H), 8.32 (d, J = 2.0Hz, ¹H), 7.54 (d, J = 8.8, ¹H), 7.40 (dd, J = 8.7, 2.0Hz, ¹H), 5.15 (s, 2H), 2.44 (s, 3H); MS (ES⁺): 296.2, 298.2 (M⁺²); (ES⁻) 294.2, 296.2 (M⁻²).

[0956] Step 3: Preparation of 2-(3-acetyl-5-bromo-1H-indol-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-isopropylacetamide (90d)

[0957] 2-(3-acetyl-5-bromo-1H-indol-1-yl)acetic acid (90c) (1.6 g, 5.4 mmol) and N-(3-chloro-2-fluorobenzyl)-2-(isopropylamino)acetamide (19c) (1.4 g, 5.4 mmol) were reacted according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by rapid column chromatography [silica gel (40 g), eluted with MeOH / CHCl 30-100%], 2-(3-acetyl-5-bromo-1H-indol-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-isopropylacetamide (90d) (1.67 g, 3.11 mmol, 58% yield) were obtained as a pale yellow solid in the form of a mixture of two rotational isomers. 1 ¹H NMR (300MHz, DMSO-d⁶) δ 8.83 (t, J = 5.7 Hz, 1H), 8.36–8.28 (m, 2H, with another triplet overlapping in this region for the amide proton of one of the two rotational isomers), 7.56–7.29 (m, 4H), 7.22 (td, J = 7.9, 1.1 Hz) & 6.99 (td, J = 7.9, 1.1 Hz) (2td, 1H), 5.37 & 5.18 (2s, 2H), 4.65–4.51 & 4.27–4.18 (2m, 1H), 4.47 (d, J = 5.6 Hz) & 4.33 (d, J = 5.8 Hz) (2d, 2H). 4.17&3.84(2s,2H),2.44&2.42(2s,3H),1.25(d,J=6.4Hz)&0.99(d,J=6.8Hz)(2d, 6H); 19 F NMR (282MHz, DMSO-d6) δ -121.19, -121.76; MS (ES+): 536.49 and 538.49 (M+1), 558.5 and 560.5 (M+Na); (ES-): 534.36 and 536.41 (M-1), 570.4 and 572.4 (M+Cl).

[0958] Process 91

[0959]

[0960] Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(piperidin-4-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (91a)

[0961] 4-(2-(3-carbamoyl-1H-indazole-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)acetamyl)piperidin-1-carboxylic acid tert-butyl ester (88b) (500 mg, 0.92 mmol) reacted with TFA (0.35 mL, 4.58 mmol) according to the procedure reported in step 2 of process 2. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with CMA80 / CHCl30 to 60%], 1-(2-((2-(((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(piperidin-4-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (91a) (386 mg, 0.77 mmol, 84% yield) as a white solid; 1 ¹H NMR (300MHz, DMSO-d⁶) δ 8.89 (t, J = 5.6Hz) and 8.42 (t, J = 5.9Hz) (2t, 1H), 8.23–8.12 (m, 1H), 7.77–7.64 (m, 1H), 7.64–7.04 (m, 7H), 5.65 and 5.44 (s, 2H). 4.47 (d, J = 5.4 Hz) and 4.32 (d, J = 5.7 Hz) (2d, 2H), 4.21 and 3.84 (2s, 2H), 4.32-4.30 and 4.12-3.95 (2m, 1H), 3.22-3.01 (m, 2H), 2.85-2.69 and 2.69-2.56 (2m, 2H), 1.94-1.40 (m, 4H); 19 F NMR (282MHz, DMSO) δ -73.53 (TFA peak), -121.18, -121.66; MS (ES+): 501.6 (M+1); 499.5 (M-1); [Based on NMR, this compound is a mixture of rotational isomers in a 3:2 ratio].

[0962] Process 92

[0963]

[0964] Preparation of 2-(3-acetyl-5-(phenylethynyl)-1H-indol-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-isopropylacetamide (92a)

[0965] A solid mixture of 2-(3-acetyl-5-bromo-1H-indol-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-isopropylacetamide (90d) (113 mg, 0.21 mmol), Cs₂CO₃ (69 mg, 0.21 mmol), dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (X-PHOS, 20 mg, 0.04 mmol), and Pd₂(dba)₃ (19 mg, 0.02 mmol) was purified with a positive nitrogen stream for 10 min, and then phenylacetylene (0.023 mL, 0.21 mmol) and anhydrous toluene (10 mL) were added under a positive nitrogen stream. The reaction flask was heated at 90 °C for 8 h. The reaction mixture was diluted with EtOAc (50 mL), filtered through a diatomaceous earth pad, and then the diatomaceous earth pad was rinsed with EtOAc (3 × 20 mL). The filtrate was washed with brine, dried, filtered, and evaporated to dryness. The residue was purified by rapid column chromatography [silica gel (24 g), eluted with MeOH / CHCl 30 to 20%] to give 2-(3-acetyl-5-(phenylethynyl)-1H-indol-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-isopropylacetamide (92a) (63 mg, 54% yield) as a brown solid in the form of a mixture of two rotational isomers. 1 H NMR (300MHz, DMSO-d6) δ8.84 (t,J=5.7Hz) and 8.43-8.26(m)(3H),7.63-7.34(m,9H),7.30-6.96(m,1H),5.39&5.21 (2s,2H),4.67-4.53&4.32-4.19(2m,1H),4.48(d,J=5.9Hz)&4.34(d,J=5.8Hz)(2d, 2H),4.19&3.86(2s,2H),2.46&2.44(2s,3H),1.26(d,J=6.4Hz)&1.01(d,J=6.8Hz) (2d,6H); 19 F NMR (282MHz, DMSO-d6) δ-121.18,-121.77; MS (ES+): 558.7&560.6 (M+1); (ES-): 556.6&558.6 (M-1).

[0966] Process 93

[0967]

[0968] Preparation of (S)-3-(2-(3-carbamoyl-1H-indazole-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)acetamyl)pyrrolidine-1-carboxylic acid tert-butyl ester (93b)

[0969] Step 1: Preparation of (S)-3-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (93a)

[0970] 2-Chloro-N-(3-chloro-2-fluorobenzyl)acetamide (35b) (350 mg, 1.48 mmol) reacted with (S)-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (690 mg, 3.71 mmol) according to the procedure reported in step-2 of procedure 35. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with EtOAc / MeOH (9:1) / hexane 0 to 60%], (S)-3-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (93a) (500 mg, 1.3 mmol, 87%) was obtained as a yellow oil; MS (ES+): 386.5 (M+1).

[0971] Step 2: Preparation of (S)-3-(2-(3-carbamoyl-1H-indazole-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)acetamyl)pyrrolidine-1-carboxylic acid tert-butyl ester (93b)

[0972] (S)-3-((2-(((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (93a) (300 mg, 0.78 mmol) reacted with 2-(3-carbamoyl-1H-indazol-1-yl)acetic acid (2e) (187 mg, 0.86 mmol) according to the procedure reported in step 3 of process 2. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 60%], (S)-3-(2-(3-carbamoyl-1H-indazol-1-yl)-N-(2-(((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)acetamyl)pyrrolidine-1-carboxylic acid tert-butyl ester (93b) (352 mg, 0.6 mmol, 77% yield) as a white solid. 1¹H NMR (300MHz, DMSO-d⁶) δ 8.83 (t, J = 5.6Hz) and 8.44 (t, J = 5.0Hz) (2t, 1H), 8.22–8.13 (m, 1H), 7.77–7.65 (m, 1H), 7.64–7.01 (m, 7H), 5.70 and 5.42 (2s, 2H), 4.84–4.63 (m, 1H), 4.47 (d, J = 5.1Hz) and 4.31 (d, J = 5.7Hz) (2d, 2H), 4.26 and 3.91 (2s, 2H), 3.46–2.95 (m, 2H), 2.19–1.80 (m, 2H), 1.41 and 1.37 (2s, 9H), 0.89–0.77 (m, 2H); 19 F NMR (282MHz, DMSO-d6) δ -121.24, -121.68; MS (ES+): 587.6 (M+1); MS (ES-): 585.6 (M-1); [Based on NMR, this compound is a mixture of rotational isomers].

[0973] Process 94

[0974]

[0975] Preparation of (S)-1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(1-hydroxypropyl-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (94b)

[0976] Step 1: Preparation of (S)-N-(3-chloro-2-fluorobenzyl)-2-((1-hydroxypropyl-2-yl)amino)acetamide (94a)

[0977] 2-Chloro-N-(3-chloro-2-fluorobenzyl)acetamide (35b) (350 mg, 1.48 mmol) reacted with (S)-2-aminoprop-1-ol (278 mg, 3.71 mmol) according to the procedure reported in step 2 of process 35. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with EtOAc / MeOH (9:1) / hexane 0 to 60%], (S)-N-(3-chloro-2-fluorobenzyl)-2-((1-hydroxyprop-2-yl)amino)acetamide (94a) (200 mg, 0.73 mmol, 49%) was obtained as a yellow oil; MS (ES). + ):275.4,277.4(M+1,M+3).

[0978] Step 2: Preparation of (S)-1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(1-hydroxypropyl-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (94b)

[0979] (S)-N-(3-chloro-2-fluorobenzyl)-2-((1-hydroxypropyl-2-yl)amino)acetamide (94a) (200 mg, 0.73 mmol) reacted with 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (176 mg, 0.8 mmol) according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 60%], (S)-1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(1-hydroxypropyl-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (94b) (210 mg, 0.44 mmol, 61% yield) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ8.90-8.46(m,1H),8.25-8.12(m,1H),7.72 (s,1H),7.60-6.89(m,7H),5.83-5.31(m,3H),4.86-4.11(m,4H),4.00 -3.72(m,1H),3.55-3.39(m,1H),3.32-3.13(m,1H),1.17-0.88(m,3H); 19 F NMR (282MHz, DMSO) δ -121.26, -121.65; MS (ES+): 476.5 (M+1); (ES-): 474.5 (M-1); [Based on NMR, this compound is a mixture of rotational isomers].

[0980] Process 95

[0981]

[0982] Preparation of (R)-1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(4-hydroxybut-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (95b)

[0983] Step 1: Preparation of (R)-N-(3-chloro-2-fluorobenzyl)-2-((4-hydroxybut-2-yl)amino)acetamide (95a)

[0984] 2-Chloro-N-(3-chloro-2-fluorobenzyl)acetamide (35b) (500 mg, 2.12 mmol) reacted with (R)-3-aminobut-1-ol (378 mg, 4.24 mmol) according to the procedure reported in step-2 of procedure 35. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with EtOAc / MeOH (9:1) / hexane 0 to 60%], (R)-N-(3-chloro-2-fluorobenzyl)-2-((4-hydroxybut-2-yl)amino)acetamide (95a) (150 mg, 0.52 mmol, 25%) was obtained as a yellow oil; MS (ES+): 289.4 (M+1); MS (ES-): 287.3 (M-1).

[0985] Step 2: Preparation of (R)-1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(4-hydroxybut-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (95b)

[0986] (R)-N-(3-chloro-2-fluorobenzyl)-2-((4-hydroxybut-2-yl)amino)acetamide (95a) (150 mg, 0.52 mmol) reacted with 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (125 mg, 0.57 mmol) according to the procedure reported in step 3 of process 2. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 60%], (R)-1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(4-hydroxybut-2-yl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (95b) (43 mg, 0.088 mmol, 17% yield) as a white solid. 1 ¹H NMR (300MHz, DMSO-d6) δ 8.90–8.46 (m, 1H), 8.25–8.12 (m, 1H), 7.72 (s, 1H), 7.60–6.89 (m, 7H), 5.83–5.31 and 4.86–4.11 and 4.00–3.72 (3m, 8H), 3.55–3.39 and 3.32–3.13 (2m, 2H), 1.17–0.88 (m, 3H); 19 F NMR (282MHz, DMSO) δ -121.26, -121.77; MS (ES+): 490.5 (M+1); (ES-): 488.5 (M-1); [Based on NMR, this compound is a mixture of 1:1 rotational isomers].

[0987] Process 96

[0988]

[0989] Preparation of 2-(3-acetyl-5-bromo-1H-indol-1-yl)-N-(2-((6-bromopyridin-2-yl)amino)-2-oxoethyl)-N-isopropylacetamide (96a)

[0990] N-(6-bromopyridin-2-yl)-2-(isopropylamino)acetamide (28b) (1.1 g, 4.05 mmol) and 2-(3-acetyl-5-bromo-1H-indol-1-yl)acetic acid (90c) (1.2 g, 4.05 mmol) were reacted according to the procedure reported in step 3 of process 2, and after treatment, 2-(3-acetyl-5-bromo-1H-indol-1-yl)-N-(2-((6-bromopyridin-2-yl)amino)-2-oxoethyl)-N-isopropylacetamide (96a) (1.5 g, 2.73 mmol, 67% yield) was obtained as a white solid. 1 ¹H NMR (300MHz, DMSO-d6) (as a mixture of rotational isomers): δ 11.20 and 10.81 (2s, 1H), 8.36–8.28 (m, 2H), 8.17 and 8.01 (2d, J = 8.1Hz, 1H), 7.81 and 7.70 (2t, J = 8.0Hz, 1H), 7.48–7.27 (m, 3H), 5.41 and 5.20 (2s, 2H), 4.69–4.55 and 4.32–4.20 (2m, 1H), 4.42 and 4.04 (2s, 2H), 2.44 and 2.43 (2s, 3H), 1.26 and 1.03 (2d, J = 6.4Hz, 6H); MS (ES+): 551.4, 553.4 (M+1); MS (ES-): 583.4, 585.4 (M+Cl).

[0991] Process 97

[0992]

[0993] Preparation of 2-(3-acetyl-5-(pyrimidin-5-ylamino)-1H-indol-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-isopropylacetamide (97c)

[0994] Step 1: Preparation of tert-butyl 2-(3-acetyl-5-(pyrimidin-5-ylamino)-1H-indole-1-yl)acetate (97a)

[0995] Add tert-butyl 2-(3-acetyl-5-bromo-1H-indol-1-yl)acetate (90b) (1.05 g, 2.98 mmol), cesium carbonate (1.94 g, 5.96 mmol), pyrimidine-5-amine (340 mg, 3.58 mmol), Pd2(dba)3 (273 mg, 0.3 mmol), and (9,9-dimethyl-9H-xanthon-4,5-diyl)bis(diphenylphosphine) (Xanthphos, 172 mg, 0.3 mmol) to a sealed reactor of degassed DMF (12 mL), and heat at 100 °C for 16 hours with stirring. Cool the mixture to room temperature, dilute with EtOAc (30 mL), and filter through a diatomaceous earth mat. The diatomaceous earth pad was washed with EtOAc (2 × 15 mL) and the combined filtrates were concentrated to obtain a crude residue, which was purified by rapid column chromatography [silica gel (40 g), eluted with CMA80 / CHCl 30 to 20%] to give 2-(3-acetyl-5-(pyrimidin-5-ylamino)-1H-indol-1-yl)tert-butyl acetate (97a) (0.34 g, 0.93 mmol, 31% yield) as a pale yellow solid; MS (ES+): 367.5 (M+1), MS (ES-): 401.4 (M+Cl).

[0996] Step 2: Preparation of 2-(3-acetyl-5-(pyrimidin-5-ylamino)-1H-indol-1-yl)acetic acid (97b)

[0997] 2-(3-acetyl-5-(pyrimidin-5-ylamino)-1H-indol-1-yl)acetic acid tert-butyl ester (97a) (340 mg, 0.93 mmol) was reacted with TFA (1.43 mL, 18.56 mmol) according to the procedure reported in step 2 of process 2, and after treatment, 2-(3-acetyl-5-(pyrimidin-5-ylamino)-1H-indol-1-yl)acetic acid (97b) (250 mg, 0.81 mmol, 87% yield) was given as a pale orange solid. 1 HNMR showed that the product was a mixture of rotational isomers and the data corresponded to the major rotational isomer; 1 ¹H NMR (300MHz, DMSO-d⁶) δ 13.7–13.1 (bs, 1H, D₂O exchangeable), 8.67–8.51 (m, 2H), 8.48 (s, 2H), 8.31 (s, 1H), 8.01 (d, J = 2.2 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.18–7.07 (m, 1H), 5.11 (s, 2H), 2.41 (s, 3H); MS (ES⁺) 311.4 (M⁺), MS (ES⁻) 309.3 (M⁻).

[0998] Step 3: Preparation of 2-(3-acetyl-5-(pyrimidin-5-ylamino)-1H-indol-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-isopropylacetamide (97c)

[0999] 2-(3-acetyl-5-(pyrimidin-5-ylamino)-1H-indol-1-yl)acetic acid (97b) (80 mg, 0.26 mmol) was reacted with N-(3-chloro-2-fluorobenzyl)-2-(isopropylamino)acetamide (19c) (67 mg, 0.26 mmol) according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with CMA-80 / CHCl 30-100%], 2-(3-acetyl-5-(pyrimidin-5-ylamino)-1H-indol-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-isopropylacetamide (97c) (68 mg, 0.12 mmol, 48% yield) as a grayish-white solid. 1 ¹H NMR (300MHz, DMSO-d6) (as a mixture of two rotational isomers) δ 8.83 and 8.35 (2t, J = 5.8Hz, 1H), 8.57 and 8.56 (2s, 1H), 8.49 (s, 1H), 8.47 (s, 2H), 8.25 and 8.20 (2s, 1H), 8.00 (d, J = 2.2Hz, 1H), 7.57–7.34 (m, 3H), 7.25–6.96 (m, 2H), 5.34 and 5.15 (2s, 2H), 4.69–4.51 and 4.28–4.21 (2m, 1H), 4.47 and 4.34 (2d, J = 5.6Hz, 2H), 4.18 and 3.85 (2s, 3H). 2H), 2.41 and 2.40 (2s, 3H), 1.25 and 1.00 (2d, J = 6.8 Hz, 6H); 19 F NMR (282MHz, DMSO-d6) (in the form of a mixture of two rotational isomers) δ -121.18 and -121.77; MS (ES+): 551.6 (M+1), MS (ES-): 549.5 (M-1).

[1000] Process 98

[1001]

[1002] Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(1-cyclopropylethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (98b)

[1003] Step 1: Preparation of N-(3-chloro-2-fluorobenzyl)-2-((1-cyclopropylethyl)amino)acetamide (98a)

[1004] 2-Bromo-N-(3-chloro-2-fluorobenzyl)acetamide (69b) (307 mg, 1.09 mmol) was reacted with 1-cyclopropylethylamine (93 mg, 1.09 mmol) according to the procedure reported in step-2 of process 35, and after treatment, N-(3-chloro-2-fluorobenzyl)-2-((1-cyclopropylethyl)amino)acetamide (98a) was obtained as a yellow oil, which was used as is without further purification; MS (ES+): 285.4 (M+1); MS (ES-): 283.3 (M-1).

[1005] Step 2: Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(1-cyclopropylethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (98b)

[1006] N-(3-chloro-2-fluorobenzyl)-2-((1-cyclopropylethyl)amino)acetamide (98a) (312 mg, 1.1 mmol) and 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (288 mg, 1.32 mmol) were reacted according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by rapid column chromatography [silica gel (40 g), eluted with MeOH / CHCl 30 to 10%], 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)(1-cyclopropylethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (98b) (115 mg, 0.24 mmol, 22% yield) in the form of a mixture of two rotational isomers as a pale yellow solid. 1 ¹H NMR (300MHz, DMSO-d⁶) δ 8.82 (t, J = 5.7Hz) and 8.30 (t, J = 5.9Hz) (2t, 1H), 8.22–8.13 (m, 1H), 7.74 and 7.70 (2s, 1H), 7.61–7.33 (m, 5H), 7.30–7.00 (m, 2H), 5.76–5.35 (m, 2H), 4.54–4.21 (m) and 3.96 (s) (4H), 3.80–3.46 (m, 1H), 1.27 (d, J = 6.4 Hz) and 1.02 (d, J = 6.8 Hz) (2d, 3H), 0.93-0.76 (m) and 0.64-0.37 (m) and 0.31-0.14 (m) and 0.13-0.02 (m) (5H); 19F NMR (282MHz, DMSO-d6) δ-121.19,-121.75; MS (ES+): 486.5 (M+1), 508.5 (M+Na); (ES-) 484.5 (M-1), 520.5 (M+Cl).

[1007] Process 99

[1008]

[1009] Preparation of 2-(3-acetyl-5-((trimethylsilyl)ethynyl)-1H-indol-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-isopropylacetamide (99a)

[1010] 2-(3-acetyl-5-bromo-1H-indol-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-isopropylacetamide (90d) (504mg, 0.94mmol) reacted with ethynyltrimethylsilane (0.13mL, 0.94mmol) according to the procedure reported in Procedure 92, after treatment and by rapid column chromatography [silica gel (40g), eluted with MeOH / CHCl 30 to 100%; second column: silica gel (12g), eluted with MeOH / EtOAc (9:1) / hexane 0 to 100%]. After purification, 2-(3-acetyl-5-((trimethylsilyl)ethynyl)-1H-indol-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-isopropylacetamide (99a) (21 mg, 0.038 mmol, 4% yield) was obtained as a yellow solid in the form of a mixture of two rotational isomers. 1 ¹H NMR (300MHz, DMSO-d⁶) δ 8.84 (t, J = 5.8Hz) and 8.42–8.22 (m) (3H), 7.62–6.96 (m, 5H), 5.37 and 5.19 (2s, 2H), 4.65–4.52 and 4.26–4.21 (2m, 1H), 4.47 (d, J = 5.6Hz) and 4.32 (d, J = 5.7Hz) (2d, 2H), 4.17 and 3.84 (2s, 2H), 2.44 and 2.42 (2s, 3H), 1.25 (d, J = 6.4Hz) and 0.99 (d, J = 6.8Hz) (2d, 6H), 0.40–0.08 (m, 9H); 19F NMR (282MHz, DMSO-d6) δ-121.20, -121.77 (d, J=4.0Hz); MS (ES+): 554.6&556.6 (M+1), 576.6&578.7 (M+Na); MS (ES-): 588.5&590.6 (M+Cl).

[1011] Process 100

[1012]

[1013] Preparation of 2-(3-acetyl-5-(1-methyl-1H-pyrazol-3-yl)-1H-indol-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-isopropylacetamide (100a)

[1014] A solution of 2-(3-acetyl-5-bromo-1H-indol-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-isopropylacetamide (90d) (150 mg, 0.28 mmol), a solution of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)-1H-pyrazole (70 mg, 0.335 mmol) in dioxane (4 mL) and degassed solutions of K₂CO₃ (1.12 mL, 0.56 mmol) in water (1 mL), and tetrakis(triphenylphosphine)palladium (0) (32 mg, 0.028 mmol) were successively added to the degassed solution of 2-(3-acetyl-5-bromo-1H-indol-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-isopropylacetamide (90d) (150 mg, 0.28 mmol), and heated at 80 °C for 4 hours. The mixture was cooled to room temperature and diluted with EtOAc (50 mL) and water (60 mL). The organic layer was separated, washed with brine, dried, filtered, and concentrated under vacuum. The residue obtained by rapid column chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 30%] yielded 2-(3-acetyl-5-(1-methyl-1H-pyrazol-3-yl)-1H-indol-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-isopropylacetamide (100a) (85 mg, 0.16 mmol, 57% yield) as a white solid. 1¹H NMR (300MHz, DMSO-d6) (a mixture of two rotational isomers in a 2:1 ratio) δ 8.83 and 8.35 (2t, J = 6.0 Hz, 1H), 8.31–8.27 (m, 1H), 8.24 and 8.19 (2s, 1H), 8.10 (s, 1H), 7.83–7.76 (m, 1H), 7.55–7.35 (m, 4H), 7.26–7.17 7.05-6.96 (2m, 1H), 5.34 and 5.16 (2s, 2H), 4.65-4.52 and 4.30-4.21 (2m, 1H), 4.48 and 4.34 (2d, J = 5.6Hz, 2H), 4.18 and 3.85 (2s, 2H), 3.88 and 3.87 (2s, 3H), 2.44 and 2.42 (2s, 3H), 1.25 and 1.00 (2d, J = 6.4Hz, 6H); r FNMR (282MHz, DMSO-d6) (a mixture of two rotational isomers) δ -121.19 and -121.79; MS (ES+): 538.6 (M+1), 560.6 (M+Na); MS (ES): 536.6 (M-1).

[1015] Process 101

[1016]

[1017] Preparation of 2-(3-acetyl-5-(2-(dimethylamino)pyrimidin-5-yl)-1H-indol-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-isopropylacetamide (101a)

[1018] 2-(3-acetyl-5-bromo-1H-indol-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-isopropylacetamide (90d) (150mg, 0.28mmol) and (2-(dimethylamino)pyrimidin-5-yl)boronic acid (56mg, 0.34mmol) Following the procedural reaction reported in Procedure 100, after processing and purification by rapid column chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 30%], 2-(3-acetyl-5-(2-(dimethylamino)pyrimidin-5-yl)-1H-indol-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-isopropylacetamide (101a) (26 mg, 0.045 mmol, 16% yield) was obtained as a white solid. 1¹H NMR (300MHz, DMSO-d6) (mixture of rotational isomers): 8.83 and 8.35 (2t, J = 5.2Hz, 1H), 8.65 and 8.646 (2s, 2H), 8.31 and 8.26 (2s, 1H), 7.60–7.47 (m, 2H), 7.47–7.36 (m, 2H), 7.28–7.16 and 7.07–6.95 (2m, 2H), 5.38 and 5.20 (2s, 1H). 2H), 4.65-4.53 and 4.29-4.22 (2m, 1H), 4.48 and 4.33 (2d, J = 5.6Hz, 2H), 4.19 and 3.85 (2s, 2H), 3.25-3.10 (m, 6H), 2.45 and 2.44 (2s, 3H), 1.26 and 1.00 (d, J = 6.8Hz, 6H); 19 F NMR (282 MHz, DMSO-d6) (a mixture of two rotational isomers) δ -121.18 and -121.78; MS (ES+): 579.7 (M+1), 601.7 (M+Na), MS (ES-): 577.6 (M-1).

[1019] Process 102

[1020]

[1021] Preparation of 1-(2-((3-amino-3-oxopropyl)(2-(((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (102b)

[1022] Step 1: Preparation of 3-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)amino)propionamide (102a)

[1023] 2-Chloro-N-(3-chloro-2-fluorobenzyl)acetamide (35b) (350 mg, 1.48 mmol) reacted with 3-aminopropionamide hydrochloride (462 mg, 3.71 mmol) according to the procedure reported in step-2 of procedure 35. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with EtOAc / MeOH (9:1) / hexane 0 to 60%], 3-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)amino)propionamide (102a) (168 mg, 0.77 mmol, 52%) was obtained as a yellow oil; MS (ES+): 288.4 (M+1), 310.3 (M+Na); (ES-): 286.3 (M-1).

[1024] Step 2: Preparation of 1-(2-((3-amino-3-oxopropyl)(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (102b)

[1025] 3-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)amino)propionamide (102a) (168 mg, 0.77 mmol) was reacted with 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (200 mg, 0.7 mmol) according to the procedure reported in step 3 of process 2. After treatment and wet milling of the residue with MeOH (5 mL), 1-(2-((3-amino-3-oxopropyl)(2-(((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (102b) (158 mg, 0.32 mmol, 47% yield) as a white solid. 1 ¹H NMR (300MHz, DMSO-d⁶) δ 8.89 (t, J = 5.5Hz) and 8.56 (t, J = 5.8Hz) (2t, 1H), 8.24–8.08 (m, 1H), 7.78–7.65 (m, 1H), 7.64–6.85 (m, 9H), 5.70 and 5.412 (s, 2H), 4.47 (d, J = 5.5Hz) and 4.38–4.24 (m) and 3.95 (s) (4H), 3.74 (t, J = 6.3Hz) and 3.41 (t, J = 7.0Hz) (2t, 2H), 2.28 (t, J = 7.1Hz, 1H); 19 F NMR (282MHz, DMSO-d6) δ -121.36, -121.65; MS (ES+) 489.5 (M+1); (ES-) 487.4 (M-1); [Based on NMR, this compound is a mixture of two rotational isomers in a 4:5 ratio].

[1026] Process 103

[1027]

[1028] Preparation of 2-(3-acetyl-5-(pyrimidin-5-ylamino)-1H-indol-1-yl)-N-(2-((6-bromopyridin-2-yl)amino)-2-oxoethyl)-N-isopropylacetamide (103a)

[1029] N-(6-bromopyridin-2-yl)-2-(isopropylamino)acetamide (28b) (61 mg, 0.23 mmol) and 2-(3-acetyl-5-(pyrimidin-5-ylamino)-1H-indol-1-yl)acetic acid (97b) (70 mg, 0.23 mmol) were reacted according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 30%], 2-(3-acetyl-5-(pyrimidin-5-ylamino)-1H-indol-1-yl)-N-(2-((6-bromopyridin-2-yl)amino)-2-oxoethyl)-N-isopropylacetamide (103a) (45 mg, 0.080 mmol, 35% yield) were obtained as a mixture of grayish-white solids in rotational isomers. 1 ¹H NMR (300MHz, DMSO-d⁶) δ 11.20 and 10.83 (2s, 1H), 8.56 and 8.55 (2s, 1H), 8.50 and 8.49 (2s, 1H), 8.47 and 8.46 (2s, 2H), 8.25 and 8.24 (2s, 1H), 8.21–7.97 (m, 2H), 7.81 and 7.70 (2t, J = 8.0Hz, 1H), 7.48–7.27 (m, 2H), 7.17–7.07 (m, 1H), 5.37 and 5.18 (2s, 2H), 4.71–4.59 and 4.36–4.23 (2m, 1H), 4.43 and 4.05 (2s, 1H). 2H), 2.42 and 2.40 (2s, 3H), 1.26 and 1.04 (2d, J = 6.8 Hz, 6H); MS(ES+): 564.5, 566.5 (M+1), MS(ES-): 562.5, 564.5 (M-1), 598.5, 600.5 (M+Cl).

[1030] Process 104

[1031]

[1032] Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)((cis)-3-hydroxycyclobutyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (104b)

[1033] Step 1: Preparation of N-(3-chloro-2-fluorobenzyl)-2-(((cis)-3-hydroxycyclobutyl)amino)acetamide (104a)

[1034] 2-Chloro-N-(3-chloro-2-fluorobenzyl)acetamide (35b) (350 mg, 1.48 mmol) reacted with (cis)-3-aminocyclobutanol hydrochloride (458 mg, 3.71 mmol) according to the procedure reported in step-2 of procedure 35. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with EtOAc / MeOH (9:1) / hexane 0 to 60%], N-(3-chloro-2-fluorobenzyl)-2-(((cis)-3-hydroxycyclobutyl)amino)acetamide (104a) (250 mg, 0.87 mmol, 59%) was obtained as a yellow oil; MS (ES+): 287.3 (M+1); MS (ES-): 285.3 (M-1).

[1035] Step 2: Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)((cis)-3-hydroxycyclobutyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (104b)

[1036] N-(3-chloro-2-fluorobenzyl)-2-(((cis)-3-hydroxycyclobutyl)amino)acetamide (104a) (250 mg, 0.87 mmol) reacted with 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (210 mg, 0.96 mmol) according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with CMA-80 / CHCl 30 to 60%], 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)((cis)-3-hydroxycyclobutyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (104b) (245 mg, 0.5 mmol, 58% yield) as a white solid; 1 ¹H NMR (300MHz, DMSO-d⁶) δ 8.88 (t, J = 5.7Hz) and 8.44 (t, J = 5.9Hz) (2t, 1H), 8.24–8.09 (m, 1H), 7.70 (s, 1H), 7.59–7.04 (m, 7H), 5.53 and 5.40 (2s, 2H), 5.20– 5.06 (m, 1H), 4.47 (d, J = 5.5 Hz) and 4.34 (d, J = 5.7 Hz) (2d, 2H), 4.30 and 4.04 (2s, 2H), 4.19-4.05 (m, 1H), 3.88-3.68 (m, 1H), 2.70-2.55 (m, 1H), 2.39-2.25 (m, 1H), 2.13-1.90 (m, 1H), 1.85-1.70 (m, 1H); 19F NMR (282 MHz, DMSO-d6) δ -121.26, -121.59; MS (ES+): 488.5 (M+1); (ES-): 486.5 (M-1); [Based on NMR, this compound is a mixture of 4:5 rotational isomers.]

[1037] Process 105

[1038]

[1039] Preparation of 2-(3-acetyl-5-(pyridin-3-yl)-1H-indol-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-isopropylacetamide (105a)

[1040] 2-(3-acetyl-5-bromo-1H-indol-1-yl)-N-(2-(((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-isopropylacetamide (90d) (150 mg, 0.28 mmol) was reacted with pyridin-3-ylboronic acid (34 mg, 0.28 mmol) according to the procedure reported in Procedure 100. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 30%], 2-(3-acetyl-5-(pyridin-3-yl)-1H-indol-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-isopropylacetamide (105a) (75 mg, 0.14 mmol, 50% yield) was obtained as a white solid in the form of a mixture of rotational isomers in a ratio of 2:1. 1 ¹H NMR (300MHz, DMSO-d⁶) δ 8.91–8.87 (m, ¹H), 8.84 (t, J = 5.7Hz) and 8.39–8.27 (m)(2H), 8.61–8.53 (m, ¹H), 8.45 (s, ¹H), 8.14–8.05 (m, ¹H), 7.67–7.57 (m, 2H), 7.57–7.47 (m, 2H), 7.46–7.36 (m, ¹H), 7.26–6.94 (m, ¹H), 5.41 and 5.22 (s, 2H), 4.66–4.53 and 4.32–4.21 (m, ¹H), 4.49 and 4.34 (d, J = 5.7Hz) 5.8 Hz, 2H), 4.20 and 3.86 (s, 2H), 2.47 and 2.45 (s, 3H), 1.27 and 1.01 (2d, J = 6.4 Hz, 6H); 19F NMR (282MHz, DMSO-d6) δ-121.18, -121.77; MS (ES+) 535.6 (M+1), MS (ES-): 569.5, 571.5 (M+Cl).

[1041] Process 106

[1042]

[1043] Preparation of 2-(3-acetyl-5-(2-fluoropyridin-4-yl)-1H-indol-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-isopropylacetamide (106a)

[1044] 2-(3-acetyl-5-bromo-1H-indol-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-isopropylacetamide (90 d) (150 mg, 0.28 mmol) reacted with 2-fluoropyridin-4-ylboronic acid (39 mg, 0.28 mmol) according to the procedure reported in Procedure 100, after treatment and by rapid column chromatography [silica gel (12 g), with CM] After purification [A80 / CHCl 30 to 30% elution], 2-(3-acetyl-5-(2-fluoropyridin-4-yl)-1H-indol-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-isopropylacetamide (106a) (52 mg, 0.094 mmol, 34% yield) was obtained as a white solid in the form of a mixture of 2:1 rotational isomers. 1 ¹H NMR (300 MHz, DMSO-d⁶) δ 8.84 (t, J = 5.7 Hz) and 8.42–8.23 (m) (3H), 8.58 (bs, 1H), 7.81–6.89 (m, 7H), 5.42 and 5.23 (2s, 2H), 4.66–4.53 and 4.30–4.22 (m, 1H), 4.49 and 4.34 (2d, J = 5.8 Hz, 2H), 4.20 and 3.86 (s, 2H), 2.48 and 2.46 (s, 3H), 1.27 and 1.00 (2d, J = 6.8 Hz, 6H); 19 F NMR (282MHz, DMSO-d6) δ-69.06, -69.09, -121.18, -121.77; MS (ES+): 553.6 (M+1), MS (ES-): 587.5 (M+Cl).

[1045] Process 107

[1046]

[1047] Preparation of 2-(3-acetyl-5-(pyridin-3-ylamino)-1H-indol-1-yl)-N-(2-((6-bromopyridin-2-yl)amino)-2-oxoethyl)-N-isopropylacetamide (107c)

[1048] Step 1: Preparation of tert-butyl 2-(3-acetyl-5-(pyridin-3-ylamino)-1H-indole-1-yl)acetate (107a)

[1049] 2-(3-acetyl-5-bromo-1H-indol-1-yl)tert-butyl acetate (90b) (1.05 g, 2.98 mmol) was reacted with pyridine-3-amine (310 mg, 3.28 mmol) according to the procedure reported in step-1 of procedure 97. After treatment and purification by column chromatography [silica gel (40 g), eluted with CMA80 / CHCl30 to 20%], 2-(3-acetyl-5-(pyridine-3-ylamino)-1H-indol-1-yl)tert-butyl acetate (107a) (250 g, 0.7 mmol, 23% yield) was obtained as a pale yellow solid. 1 HNMR(300MHz,DMSO-d6)δ8.35-8.23(m,3H),8.02-7.91(m,2H),7.43-7.31 (m,2H),7.18(dd,J=8.3,4.6Hz,1H),7.07(dd,J=8.8,2.2Hz,1H),5.08(s,2H),2.41(s, 3H), 1.44(s,9H); MS(ES+): 366.5(M+1), MS(ES-): 400.4(M+Cl).

[1050] Step 2: Preparation of 2-(3-acetyl-5-(pyridin-3-ylamino)-1H-indol-1-yl)acetic acid (107b)

[1051] 2-(3-acetyl-5-(pyridin-3-ylamino)-1H-indol-1-yl)acetic acid tert-butyl ester (107a) (250 mg, 0.68 mmol) was reacted with TFA (1.58 mL, 20.52 mmol) according to the procedure reported in step 2 of process 2. After treatment and wet milling of the crude product with EtOAc-hexane (10 mL), 2-(3-acetyl-5-(pyridin-3-ylamino)-1H-indol-1-yl)acetic acid (107b) (0.2 g, 0.647 mmol, 95% yield) as a pale orange solid. 1¹H NMR (300MHz, DMSO-d⁶) δ 13.31 (bs, 1H, D₂O exchangeable), 9.09 (s, 1H), 8.36 (s, 1H), 8.28 (s, 1H), 8.14 (s, 1H), 8.05 (s, 1H), 7.82 (s, 1H), 7.70 (s, 1H), 7.55 (d, J = 8.7Hz, 1H), 7.18 (d, J = 8.6Hz, 1H), 5.14 (s, 2H), 2.42 (s, 3H); MS (ES⁻): 308.3 (M⁻¹).

[1052] Step 3: Preparation of 2-(3-acetyl-5-(pyridin-3-ylamino)-1H-indol-1-yl)-N-(2-((6-bromopyridin-2-yl)amino)-2-oxoethyl)-N-isopropylacetamide (107c)

[1053] 2-(3-acetyl-5-(pyridin-3-ylamino)-1H-indol-1-yl)acetic acid (107b) (60 mg, 0.19 mmol) and N-(6-bromopyridin-2-yl)-2-(isopropylamino)acetamide (28b) (53 mg, 0.19 mmol) were reacted according to the procedure reported in step 3 of process 2. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with CMA-80 / CHCl 30-100%], 2-(3-acetyl-5-(pyridin-3-ylamino)-1H-indol-1-yl)-N-(2-((6-bromopyridin-2-yl)amino)-2-oxoethyl)-N-isopropylacetamide (107c) (57 mg, 0.101 mmol, 52% yield) were obtained as a mixture of grayish-white solids in a ratio of 2:1 of the rotational isomers. 1 ¹H NMR (300MHz, DMSO-d6) (mixture of two rotational isomers) δ 11.20 and 10.82 (2s, 1H), 8.33–8.24 (m, 2H), 8.22 and 8.21 (2s, 1H), 8.05–7.91 (m, 3H), 7.81 and 7.70 (2t, J = 8.0Hz, 1H), 7.44–7.28 (m, 3H), 7.23–7.11 (m, 1H), 7.12–7.01 (m, 1H), 5.35 and 5.16 (2s, 2H), 4.72–4.57 and 4.47–4.20 (2m, 1H), 4.43 4.05 (2s, 2H), 2.41 and 2.40 (2s, 3H), 1.26 and 1.04 (2d, J = 6.8 Hz, 6H); MS(ES+): 563.5, 565.5 (M+1); MS(ES-): 561.5, 563.5 (M-1), 597.5, 599.5 (M+Cl).

[1054] Process 108

[1055]

[1056] Preparation of 2-(3-acetyl-5-(pyrimidin-5-yl)-1H-indol-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-isopropylacetamide (108a)

[1057] 2-(3-acetyl-5-bromo-1H-indol-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-isopropylacetamide (90 d) (150 mg, 0.28 mmol) reacted with pyrimidin-5-ylboronic acid (35 mg, 0.28 mmol) according to the procedure reported in Procedure 100. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 30%], 2-(3-acetyl-5-(pyrimidin-5-yl)-1H-indol-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N- Isopropylacetamide (108a) (85 mg, 0.159 mmol, 57% yield); 1 ¹H NMR (300MHz, DMSO-d6) (mixture of two rotational isomers) δ 9.19 and 9.18 (2s, 1H), 9.12 and 9.11 (2s, 2H), 8.89–8.79 and 8.40–8.28 (2m, 2H), 8.48 (s, 1H), 7.71–6.95 (m, 5H), 5.42 and 5.23 (2s, 2H), 4.65–4.54 and 4.32–4.21 (2m, 1H), 4.49 and 4.34 (2d, J = 5.6Hz, 2H), 4.20 and 3.86 (2s, 2H), 2.48 and 2.46 (2s, 3H), 1.27 and 1.01 (d, J = 6.8Hz, 6H); 19 F NMR (282MHz, DMSO-d6) (a mixture of two rotational isomers) δ -121.18 and -121.79; MS (ES+): 536.5 (M+1), MS (ES-): 534.5 (M-1), 570.5 (M+Cl).

[1058] Process 109

[1059]

[1060] Preparation of 2-(3-acetyl-5-(3-acetylphenyl)-1H-indol-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-isopropylacetamide (109a)

[1061] 2-(3-acetyl-5-bromo-1H-indol-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-isopropylacetamide (90 d) (150 mg, 0.28 mmol) and 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)phenyl)acetone (70 mg, 0.28 mmol) were reacted according to the procedure reported in Procedure 100. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with CMA80 / CHCl30 to 30%], 2-(3-acetyl-5-(3-acetylphenyl)-1H-indol-1-yl) was given as a white solid in the form of a mixture of rotational isomers in a ratio of 2:1. 2-(((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-isopropylacetamide (109a) (80 mg, 0.14 mmol, 50% yield); 1 ¹H NMR (300MHz, DMSO-d⁶) δ 8.84 and 8.35 (2t, J = 5.7Hz, 1H), 8.47 (bs, 1H), 8.35 and 8.34 (s, 1H), 8.21–8.13 (m, 1H), 8.01–7.88 (m, 2H), 7.70–6.95 (m, 6H), 5.41 and 5.22 (s, 2H), 4.68–4.51 and 4.32–4.20 (m, 1H), 4.49 and 4.34 (d, J = 5.8Hz, 2H), 4.20 and 3.86 (s, 2H), 2.668 and 2.666 (2s, 3H), 2.47 and 2.45 (s, 3H), 1.27 and 1.01 (2d, J = 6.8Hz, 6H); 19 F NMR (282MHz, DMSO-d6) δ-121.18, -121.76; MS (ES+): 576.6 (M+1), 598.6 (M+Na); MS (ES-): 574.6 (M-1).

[1062] Process 110

[1063]

[1064] Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)((trans)-3-hydroxycyclobutyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (110b)

[1065] Step 1: Preparation of N-(3-chloro-2-fluorobenzyl)-2-(((trans)-3-hydroxycyclobutyl)amino)acetamide (110a)

[1066] 2-Chloro-N-(3-chloro-2-fluorobenzyl)acetamide (35b) (350 mg, 1.48 mmol) reacted with (trans)-3-aminocyclobutanol hydrochloride (458 mg, 3.71 mmol) according to the procedure reported in step-2 of procedure 35. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with EtOAc / MeOH (9:1) / hexane 0 to 60%], N-(3-chloro-2-fluorobenzyl)-2-(((trans)-3-hydroxycyclobutyl)amino)acetamide (110a) (200 mg, 0.7 mmol, 47%) was obtained as a yellow oil; MS (ES+): 287.4 (M+1); (ES-): 285.3 (M-1).

[1067] Step 2: Preparation of 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)((trans)-3-hydroxycyclobutyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (110b)

[1068] N-(3-chloro-2-fluorobenzyl)-2-(((trans)-3-hydroxycyclobutyl)amino)acetamide (110a) (200 mg, 0.7 mmol) was reacted with 2-(3-carbamoyl-1H-indazole-1-yl)acetic acid (2e) (168 mg, 0.77 mmol) according to the procedure reported in step 3 of process 2. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with CMA-80 / CHCl 30 to 60%], 1-(2-((2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)((trans)-3-hydroxycyclobutyl)amino)-2-oxoethyl)-1H-indazole-3-carboxamide (110b) (92 mg, 27%) was obtained as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.86 (t, J = 5.5 Hz) and 8.43 (t, J = 5.7 Hz) (2t, 1H), 8.18 (d, J = 8.1 Hz, 1H), 7.78–7.64 (m, 1H), 7.63–7.00 (m, 7H), 5.53 and 5.42 (2s, 2H), 5.12 (d, J = 4.0 Hz) and 5.00 (d, J = 4.3 Hz) (2d, 1H), 4.96–4.79 (m, 1H), 4.47 (d, J = 5.2 Hz) and 4.33 (d, J = 5.2 Hz) 5.5Hz (2d, 2H), 4.28 and 4.00 (2s, 2H), 4.23-4.05 (m, 1H), 2.46-2.30 (m, 1H), 2.28-2.09 (m, 2H), 2.02-1.85 (m, 1H); 19 F NMR (282 MHz, DMSO-d6) δ -121.23, -121.62; MS (ES+): 488.5 (M+1); (ES-): 486.5 (M-1); [Based on NMR, this compound is a mixture of 4:5 rotational isomers].

[1069] Process 111

[1070]

[1071] Preparation of 2-(3-acetyl-5-(pyridin-3-ylamino)-1H-indol-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-isopropylacetamide (111a)

[1072] N-(3-chloro-2-fluorobenzyl)-2-(isopropylamino)acetamide (19c) (50 mg, 0.19 mmol) and 2-(3-acetyl-5-(pyridin-3-ylamino)-1H-indol-1-yl)acetic acid (107b) (60 mg, 0.19 mmol) were reacted according to the procedure reported in steps 3 of Procedure 2. After treatment and purification by rapid column chromatography [silica gel (12 g), eluted with CMA80 / CHCl 30 to 30%], 2-(3-acetyl-5-(pyridin-3-ylamino)-1H-indol-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-isopropylacetamide (111a) (40 mg, 0.073 mmol, 38% yield) were obtained as a grayish-white solid in the form of a mixture of rotational isomers in a ratio of 2:1. 1¹H NMR (300MHz, DMSO-d6) (mixture of two rotational isomers) δ 8.82 and 8.34 (2t, J = 5.7 Hz, 1H), 8.32–8.23 (m, 2H), 8.21 and 8.16 (2s, 1H), 7.98 (d, J = 2.2 Hz, 1H), 7.96–7.90 (m, 1H), 7.56–6.96 (m, 7H), 5.32 and 5.13 (2s, 2H), 4.67–4.51 and 4.31–4.18 (2m, 1H), 4.47 and 4.34 (2d, J = 5.8 Hz, 2H). 4.18 and 3.85 (2s, 2H), 2.40 and 2.39 (2s, 3H), 1.25 and 1.00 (2d, J = 6.8 Hz, 6H); 19 F NMR (282 MHz, DMSO-d6) (mixture of two rotational isomers) δ -121.18, -121.77; MS (ES+): 550.6 (M+1); MS (ES-): 584.6 (M+Cl).

[1073] Process 112

[1074]

[1075] Preparation of 2-(3-acetyl-5-(pyrimidin-5-ylethynyl)-1H-indol-1-yl)-N-(2-((3-chloro-2-fluorobenzyl)amino)-2-oxoethyl)-N-isopropylacetamide (112a)

[1076] 2-(3-acetyl-5-bromo-1H-indol-1-yl)-N-(2-((3-chloro-2-fl...

Claims

1. A compound represented by formula (I), or a pharmaceutically acceptable salt thereof: in, Independently each time it appears: R 1 Represents pyridine, phenyl, or pyrimidine, wherein the pyridine, phenyl, or pyrimidine is substituted by one or more substituents independently selected from the group consisting of: halogen, -CN, (C1-C2). 10 )alkoxy, halogen (C1-C) 10 )alkoxy, (C1-C 10 alkyl, halogenated (C1-C) 10 )alkyl, (C2-C 10 )alkenyl, di(C1-C 10 )alkylamino and heterocyclic alkyl; R 2 and R 3 Each represents H independently; R 4 Indicates H or (C1-C) which is optionally substituted. 10 )alkyl, optionally substituted (C2-C 10 )alkenyl, optionally substituted (C2-C 10 ) alkynyl, optionally substituted (C3-C7)cycloalkyl or optionally substituted heterocycloalkyl; X represents NH, CH2, CHF, CF2, CH(C1-C6)alkyl or C((C1-C6)alkyl)2; Y does not exist or indicates CR 15 R 16 Or optionally substituted phenylene; R a H represents (C1-C6) alkyl groups or (heterocyclic alkyl groups) that are optionally substituted. 10 )alkyl or (C3-C7)cycloalkyl; m is an integer from 1 to 2; n is 1; R 15 and R 16 Each independently selects from the following groups: H and (C1-C 10 )alkyl; express Z 1 and Z 3 Each can be represented independently as C or N; Z 2 Indicates N, CH, or CF; Z 4 Indicates N or CR 8 ; Z 5 Indicates N or CR 5 ; Z 6 Indicates N or CR 6 ; Z 7 Indicates N or CR 9 ; Z 8 and Z 9 Each can be represented independently as N or CR. 19 ; R 5 and R 6 Each can be independently represented as H, halogen, -CN, -NO2, or -OR. 13 -NR 13 R 14 -C(O)R 13 -C(O)OR 13 -C(O)NR 13 R 14 -OC(O)R 13 -NR 13 C(O)R 14 -OC(O)NR 13 R 14 -OC(O)OR 13 -NR 13 C(O)OR 14 -NR 13 C(O)NR 13 R 14 -OS(O) p (R 13 -NR 13 S(O) p (R 14 ), or optionally replaced (C1-C 10 )alkyl, optionally substituted (C2-C 10 )alkenyl, optionally substituted (C2-C 10 ) alkynyl, optionally substituted heteroaryl, optionally substituted (C6-C 10 ) aryl, optionally substituted (C3-C7) cycloalkyl or optionally substituted heterocyclic alkyl; L represents -H, -CN, -C(O)R 7 -CH(OH)R 7 or -S(O) p ((C1-C 10 )alkyl); R 7 Each time it appears, it independently represents H, NH2, CH3, OH, CF3, CH2OH, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, halogen(C1-C6)alkyl, NH(C1-C6)alkyl, N((C1-C6)alkyl)2; R 8 and R 9 Each can be used independently to represent H, halogen, and -OR. 13 -NR 13 R 14 -C(O)R 13 -C(O)OR 13 -C(O)NR 13 R 14 -OC(O)R 13 -NR 13 C(O)R 14 -OC(O)NR 13 R 14 -OC(O)OR 13 -NR 13 C(O)OR 14 -NR 13 C(O)NR 13 R 14 -OS(O) p (R 13 -NR 13 S(O) p (R 14 ), or optionally replaced (C1-C 10 )alkyl, optionally substituted (C2-C 10 )alkenyl, optionally substituted (C2-C 10 ) alkynyl, optionally substituted heteroaryl, or optionally substituted (C6-C) 10 aryl; or R 5 and R 8 、or R 5 and R 6 、or R 6 and R 9 It can form, together with the intermediate atom, optional substituted heterocycles or (C3-C7) carbon rings; R 13 and R 14 Each occurrence independently represents H or optionally substituted (C1-C). 10 )alkyl, optionally substituted (C2-C 10 )alkenyl, optionally substituted (C2-C 10 ) ynyl group, optionally substituted (C6-C 10 ) aryl, optionally substituted heteroaryl, optionally substituted (C3-C7)cycloalkyl, or optionally substituted heterocycloalkyl; or, when R 13 and R 14 When attached to the same atom, R 13 and R 14 Together with the aforementioned atoms, they can form optionally substituted heterocycles; R 19 Each occurrence is independently represented by H, F, CN, -C(O)R. 7 -CH(OH)R 7 or -S(O) p ((C1-C 10 )alkyl); J represents H or NH2; and p is 0, 1, or 2; Where Z 1 Is it N, or if express So X represents CH2; When the group is optionally substituted, the optional substituent is selected from the group consisting of: halogen, azido, (C1-C2) group, etc. 10 )alkyl, (C6-C 10 )Aryl(C1-C 10 )alkyl, (C2-C 10 )alkenyl, (C2-C 10 ) alkynyl, (C3-C7)cycloalkyl, hydroxyl, (C1-C 10 )alkoxy, halogen (C1-C) 10 )alkoxy, halogen (C1-C) 10 )alkyl, (C1-C 10 )alkoxy (C1-C 10 )alkyl, amino (-NH2), amide, nitro, mercapto, imino, (C1-C 10 )alkylamide group, carboxyl group, -Si((C1-C 10 )alkyl)3, (C1-C 10 ) alkylthioyl, aldehyde (-C(O)H), -C(O)(C1-C 10 (alkyl), heterocyclic alkyl, (C6-C) 10 )Aryl, heteroaryl, fluorinated (C1-C 10 )alkyl and cyano groups; "Heteroaryl" is a monocyclic, bicyclic, or polycyclic aromatic group having a total of 3 to 12 ring atoms, including one or more heteroatoms selected from N, O, and S; and "Heterocyclic alkyl" and "heterocyclic" each refer to a non-aromatic group having 3 to 12 atoms, including one or more heteroatoms selected from N, O and S, and consisting of a monocyclic, bicyclic or tricyclic ring.

2. The compound according to claim 1, wherein R 1 This indicates a pyridine, phenyl, or pyrimidine substituted with one or more substituents, at least one of which is a halogen.

3. The compound according to claim 1, wherein Y is absent.

4. The compound according to claim 1, wherein Y is CH2.

5. The compound according to claim 1, wherein Y is CR 15 R 16 .

6. The compound according to claim 1, wherein R 4 Indicates H or (C1-C) which is optionally substituted. 10 Alkyl, optionally substituted (C3-C7) cycloalkyl, or optionally substituted heterocyclic alkyl.

7. The compound according to claim 1, wherein R 4 Indicates H or (C1-C) which is optionally substituted. 10 )alkyl or (C3-C7)cycloalkyl.

8. The compound according to claim 1, wherein R 4 Indicates that (C1-C) are optionally replaced 10 Alkyl, optionally substituted (C3-C7) cycloalkyl, or optionally substituted heterocyclic alkyl.

9. The compound according to claim 1, wherein R 4 It represents ((C3-C7)cycloalkyl)(C1-C 10 )alkyl, (heterocyclic alkyl) (C1-C 10 )alkyl, (C6-C 10 )Aryl(C1-C 10 )alkyl, heteroaryl (C1-C 10 )alkyl, hydroxyl (C1-C 10 )alkyl or halogenated (C1-C 10 )alkyl.

10. The compound according to claim 1, wherein R 4 It represents ((C3-C7)cycloalkyl)(C1-C 10 )alkyl, (C6-C 10 )Aryl(C1-C 10 )alkyl, hydroxyl (C1-C 10 )alkyl or halogenated (C1-C 10 )alkyl.

11. The compound according to claim 1, wherein R a It's H.

12. The compound according to claim 1, wherein m is 1.

13. The compound according to any one of claims 1 to 12, wherein express 14. The compound according to claim 13, wherein... express 15. The compound according to claim 14, wherein L represents -C(O)R 7 .

16. The compound according to any one of claims 1 to 12, wherein X represents NH or CH2.

17. The compound according to any one of claims 1 to 12, having the structure of formula (Ia):

18. The compound according to any one of claims 1 to 12, having the structure of formula (Ib):

19. The compound according to any one of claims 1 to 12, having the structure of formula (Ic):

20. The compound according to any one of claims 1 to 12, having the structure of formula (Id):

21. The compound according to claim 19, wherein X is NH.

22. The compound according to claim 17, wherein: Z 4 Indicates CR 8 ; Z 5 Indicates CR 5 ; Z 6 Indicates CR 6 ;and Z 7 Indicates CR 9 .

23. The compound according to claim 22, wherein R 8 and R 9 Each independently represents a halogenation (C1-C). 10 )alkyl, (C6-C 10 )Aryl(C1-C 10 )alkyl or heteroaryl (C1-C 10 )alkyl.

24. The compound according to claim 17, wherein Z 4 and Z 7 Each represents CH.

25. The compound according to claim 17, wherein Z 5 Indicates CR 5 And Z 6 Indicates CR 6 ;and R 5 and R 6 Each can be independently represented by H, halogen, and -NR. 13 R 14 -C(O)R 13 -C(O)OR 13 -C(O)NHR 14 -NHC(O)NR 13 R 14 -NHS(O)2(R 14 ), or optionally replaced (C1-C 10 )alkyl, (C2-C 10 alkenyl, (C2-C 10 ) ynyl, heteroaryl or (C6-C 10 Aryl.

26. The compound according to claim 25, wherein R 5 and R 6 Each independently represents H or optionally substituted by one or more substituents selected from the group consisting of (C1-C). 10 )alkyl, (C2-C 10 )alkenyl, (C2-C 10 ) ynyl, heteroaryl or (C6-C 10 )Aryl: (C6-C 10 )Aryl, heteroaryl, -Si((C1-C 10 )alkyl)3, (C1-C 10 )alkyl, amino (-NH2), (C1-C 10 )alkylamino, di(C1-C 10 )alkylamino, -C(O)((C1-C 10 Alkyl groups and halogens.

27. The compound according to claim 25, wherein R 5 and R 6 Each independently represents a halogenation (C1-C). 10 )alkyl, (C6-C 10 )Aryl(C1-C 10 )alkyl, heteroaryl (C1-C 10 )alkyl, (heterocyclic alkyl) (C1-C 10 )alkyl or ((C3-C7)cycloalkyl)(C1-C 10 )alkyl.

28. The compound according to claim 25, wherein R 13 and R 14 Each occurrence independently represents H or optionally substituted (C6-C) 10 ) aryl, optionally substituted heteroaryl or optionally substituted (C3-C7) cycloalkyl.

29. The compound according to claim 25, wherein R 13 and R 14 Represented independently each time it appears (C6-C) 10 )Aryl(C1-C 10 )alkyl, heteroaryl (C1-C 10 )alkyl, ((C3-C7)cycloalkyl)(C1-C 10 )alkyl or (heterocyclic alkyl) (C1-C 10 )alkyl.

30. The compound according to claim 15, wherein R 7 It represents NH2, CH3, or CF3.

31. The compound according to claim 15, wherein R 7 It represents NH2.

32. A pharmaceutical composition comprising a compound according to any one of claims 1 to 31; and a pharmaceutically acceptable carrier.

33. Use of the compound according to any one of claims 1 to 31 in the preparation of a medicament for treating or preventing a disease or condition characterized by abnormal complement system activity.

34. The use according to claim 33, wherein the disease or condition characterized by abnormal complement system activity is an immune disorder.

35. The use according to claim 33, wherein the disease or condition characterized by abnormal complement system activity is a central nervous system disease.

36. The use according to claim 33, wherein the disease or condition characterized by abnormal complement system activity is a neurological disease.

37. The use according to claim 36, wherein the disease or condition characterized by abnormal complement system activity is a neurodegenerative disease.

38. The use according to claim 33, wherein the disease or condition characterized by abnormal complement system activity is kidney disease.

39. The use according to claim 33, wherein the disease or condition characterized by abnormal complement system activity is a cardiovascular disease.

40. The use according to claim 33, wherein the disease or condition characterized by abnormal complement system activity is selected from the group consisting of: paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, organ transplant rejection, myasthenia gravis, neuromyelitis optica, membranoproliferative glomerulonephritis, dense deposit disease, cold agglutinin disease, and catastrophic antiphospholipid syndrome.

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