BCL-2 inhibitors

Abstract

The present invention relates generally to inhibitors of the BCL-2 protein, which are useful in the treatment of diseases and disorders regulated by said enzyme, and have the formula (I): JPEG2025502899000430.jpg64170.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 294,646, filed December 29, 2021, entitled "BCL-2 Inhibitors," and U.S. Provisional Patent Application No. 63 / 415,203, filed October 11, 2022, entitled "BCL-2 Inhibitors," the disclosures of which are incorporated herein by reference in their entireties for all purposes.

[0002] FIELD OF THE INVENTION The present invention relates to inhibitors of B-cell lymphoma 2 (BCL-2) protein. The inhibitors described herein may be useful in treating diseases or disorders associated with BCL-2. In particular, the present invention relates to compounds and pharmaceutical compositions that inhibit BCL-2, methods of treating diseases or disorders associated with BCL-2, and methods of synthesizing these compounds. [Background technology]

[0003] BACKGROUND OF THE INVENTION Apoptosis, or programmed cell death, is a physiological process important for embryonic development and the maintenance of tissue homeostasis (US Pat. No. 9,120,791).

[0004] Deregulation of apoptosis is involved in certain pathologies. Increased apoptosis is associated with neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and ischemia (ibid.). Conversely, defects in apoptosis execution play an important role in the development of cancer and its resistance to chemotherapy in autoimmune diseases, inflammatory diseases, and viral infections. Therefore, lack of apoptosis is one of the phenotypic characteristics of cancer (Hanahan, D. et al., Cell, 2000, 100, 57-70).

[0005] BCL-2 family proteins play a key role in tumorigenesis (WO2018 / 102,766). BCL-2 proteins are characterized based on the presence of Bcl-2 homology (BH) domains. Anti-apoptotic proteins contain all four BH domains. Pro-apoptotic proteins contain only the BH3 domain or multiple BH domains. The BH3 domain is required for the pro-apoptotic function of these proteins. In anti-apoptotic proteins, the BH3 domain remains hidden or buried within other BH domains, and therefore they function exclusively as protectors of cell survival. BCL-2 proteins interact with each other using their BH domains. Anti-apoptotic BCL-2 proteins interact with pro-apoptotic members and inhibit their function to maintain cellular homeostasis. The altered balance between anti- and pro-apoptotic BCL-2 proteins may determine the fate of cancer cells.

[0006] Cancer therapeutics targeting the BCL-2 family have primarily focused on neutralizing one or more anti-apoptotic members by inhibiting their function using small molecule inhibitors or suppressing their expression using antisense oligonucleotides (WO 2018 / 102,766). The concept was to inhibit the function of anti-apoptotic Bcl-2 members and allow pro-apoptotic members to induce cell death in cancer cells. (Ibid.) However, cancer cells treated with Bcl-2 inhibitors were found to upregulate other anti-apoptotic BCL-2 or non-BCL-2 family proteins involved in cell survival, resulting in treatment resistance.

[0007] There is a need for therapeutic agents that can induce cell death in tumors or cancers that have increased expression of Bcl-2. The present invention is intended to fulfill this unmet need associated with current BCL-2 inhibitory therapies. (Summary of the Invention)

[0008] A first aspect of the present invention is a compound of formula (I): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug or tautomer thereof, wherein: R 1 is selected from halogen, —OH, —CN, and —CONH2; R 1a is H; Or, R 1 and R 1a together with the atoms to which they are attached form a 3- to 10-membered heteroaryl ring further containing 1, 2, or 3 heteroatoms selected from N, O, and S; R 2 and R 3 are each independently selected from C1-C6 alkyl; Or, R2 and R 3 together with the atoms to which they are attached form a 3- to 10-membered heterocyclyl ring further containing 1, 2, or 3 heteroatoms selected from N, O, and S; Each R 4 are halogens, -OH, -CN, -NO2, -COOH, -CH2CN, CH2N(R 8 )2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogen alkyl, C1-C6 halogen alkoxy, -O-(C2-C6 alkenyl), -O-(C2-C6 alkynyl), C2-C6 alkenyl, C2-C6 alkynyl, -OH, -OP(O)(OH)2, -OC(O)(C1-C6 alkyl), -C(O)(C1-C6 alkyl), -OC(O )O(C-C alkyl), -NH, -NH(C-C alkyl), -N(C-C alkyl), -NHC(O)(C-C alkyl), -C(O)NH, -C(O)NH(C-C alkyl), -S(O)(C-C alkyl), -S(O)NH(C-C alkyl), and S(O)N(C-C alkyl); R5 teeth, [ka] Selected from; Each R 6 are halogens, -OH, -CN, -COOH, -CHCN, -CHN(R 8 )2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogenalkyl, C1-C6 halogenalkoxy, —O—(C2-C6)alkenyl, —O—(C2-C6)alkynyl, C2-C6 alkenyl, C2-C6 alkynyl, —OH, —O—P(O)(OH)2, —OC(O)(C1-C6)alkyl, —C(O)(C1-C6)alkyl, —OC(O)O(C1-C6)alkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —NHC(O)(C1-C6)alkyl, —C(O)NH(C1-C6)alkyl, —S(O)2(C1-C6)alkyl, —S(O)NH(C1-C6)alkyl, and S(O)N(C1-C6 alkyl)2; Each R 7 is H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 independently selected from alkynyl, aryl; Alkyl or aryl is not a halogen, -OH, -CN, -COOH, -CHCN, -CHN(R 8 )2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogen alkyl, C1-C6 halogen alkoxy, -O-(C2-C6) alkenyl, -O-(C2-C6) alkynyl, C2-C6 alkenyl, C2-C6 alkynyl, -OH, -OP(O)(OH)2, -OC(O)(C1-C6) alkyl, -C(O)(C1-C6) alkyl, -OC(O)O(C1- optionally substituted with one or more substituents independently selected from: —C6)alkyl, —NH, —NH(C1-C6 alkyl), —N(C1-C6 alkyl), —NHC(O)(C1-C6)alkyl, —C(O)NH(C1-C6)alkyl, —S(O)2(C1-C6)alkyl, —S(O)NH(C1-C6)alkyl, and S(O)N(C1-C6 alkyl); Or two R's 7 are halogens, -OH, -CN, -COOH, -CHCN, -CHN(R), together with the nitrogen atom to which they are attached and any intervening atoms. 8 )2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogen alkyl, C1-C6 halogen alkoxy, -O-(C2-C6) alkenyl, -O-(C2-C6) alkynyl, C2-C6 alkenyl, C2-C6 alkynyl, -OH, -OP(O)(OH)2, -OC(O)(C1-C6) alkyl, -C(O)(C1-C6) alkyl, -OC(O)O(C1-C6) alkenyl forming a heterocycle optionally substituted with one or more substituents independently selected from alkyl, -NH, -NH(C-C alkyl), -N(C-C alkyl), -NHC(O)(C-C) alkyl, -C(O)NH(C-C) alkyl, -S(O)(C-C) alkyl, -S(O)NH(C-C) alkyl, and S(O)N(C-C alkyl); R 8 is H, C 1-6 Alkyl, C 3-8 Cycloalkyl, aryl, C 1-6 selected from halogen alkyl; R 9 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) 1-6 OR 8 , C 3-8cycloalkyl, aryl, and heterocyclyl, wherein said alkyl, cycloalkyl, aryl, or heterocyclyl is selected from halogen, —OH, —CN, —COOH, —CHCN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogenalkyl, C1-C6 halogenalkoxy, —O—(C2-C6)alkenyl, —O—(C2-C6)alkynyl, C2-C6 alkenyl, C2-C6 alkynyl, —OH, —O—P(O)(OH), —OC(O )(C-C)alkyl, —C(O)(C-C)alkyl, —OC(O)O(C-C)alkyl, —NH, —NH(C-C alkyl), —N(C-C alkyl), —NHC(O)(C-C)alkyl, —C(O)NH(C-C)alkyl, —S(O)(C-C)alkyl, —S(O)NH(C-C)alkyl, and S(O)N(C-C alkyl); x is an integer selected from 0, 1, 2, and 3; y is an integer selected from 0, 1, 2, and 3; m is an integer selected from 0, 1, and 2; each n is an integer independently selected from 1, 2, and 3; Aryl is a cyclic aromatic hydrocarbon group having 1 to 3 aromatic rings; Heterocycles are saturated or partially unsaturated 3- to 10-membered monocyclic, 7- to 12-membered bicyclic (fused, bridged, or spiro) or 11- to 14-membered tricyclic ring systems (fused, bridged, or spiro) having one or more heteroatoms selected from O, N, S, P, Se, and B.

[0009] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, which may further comprise an excipient, diluent, or surfactant.

[0010] Another aspect of the present invention relates to a method of treating a disease or disorder associated with the regulation of BCL-2 proteins, such as isoform 1 and isoform 2. The method comprises administering to a patient in need of treatment for a disease or disorder associated with the regulation of BCL-2 proteins an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0011] Another aspect of the present invention relates to a method of inhibiting BCL-2 proteins, including but not limited to isoform 1 and isoform 2. The method comprises administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0012] Another aspect of the present invention relates to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, the method comprising administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0013] Another aspect of the present invention relates to compounds of formula (I), and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting BCL-2 proteins, such as isoform 1 and isoform 2.

[0014] Another aspect of the present invention pertains to compounds of formula (I) and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof for use in the manufacture of a medicament for the treatment or prevention of a disease or disorder disclosed herein.

[0015] Another aspect of the present invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, in the treatment of diseases associated with inhibiting BCL-2 proteins, such as isoform 1 and isoform 2.

[0016] Another aspect of the present invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, in the treatment of a disease or disorder disclosed herein.

[0017] The present invention further provides methods for treating diseases or disorders associated with the regulation of BCL-2 protein, including cancer and metastasis, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0018] The present invention provides inhibitors of the BCL-2 protein that are therapeutic agents in the treatment of diseases such as cancer and metastasis.

[0019] The present invention further provides compounds and compositions with improved efficacy and safety profiles compared to known BCL-2 protein inhibitors. The present disclosure also provides agents with novel mechanisms of action against BCL-2 protein in the treatment of various types of diseases, including cancer and metastasis.

[0020] In some aspects, the disclosure provides compounds obtainable by or obtained by a method for preparing a compound described herein (e.g., a method comprising one or more steps described in the general procedures).

[0021] In some aspects, the present disclosure provides intermediates described herein that are suitable for use in the methods for preparing the compounds described herein (e.g., the intermediates are selected from the intermediates described in Preparations 1-168).

[0022] In some aspects, the disclosure provides methods of preparing the compounds of the disclosure.

[0023] In some aspects, the disclosure provides methods for preparing compounds comprising one or more of the steps described herein.

[0024] 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 disclosure belongs. As used herein, the singular also includes the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. No reference cited herein is admitted to be prior art to the claimed invention. In case of conflict, the present specification, including definitions, will control. Furthermore, the materials, methods, and examples are illustrative only and not intended to be limiting. In the event of a conflict between the chemical structure and name of a compound disclosed herein, the chemical structure will control.

[0025] Other features and advantages of the present disclosure will become apparent from the following detailed description and claims. Detailed Description of the Invention

[0026] The present disclosure relates to compounds and compositions capable of inhibiting the activity of BCL-2 proteins, including, but not limited to, isoform 1 and isoform 2. The present disclosure features methods for treating, preventing, or ameliorating diseases or disorders in which BCL-2 plays a role by administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, to a patient in need thereof. The methods of the present invention can be used to treat various BCL-2-mediated diseases and disorders by inhibiting the activity of BCL-2 proteins. Inhibition of BCL-2 can be an effective approach to treating, preventing, or ameliorating diseases, including, but not limited to, cancer and metastasis. Reducing BCL-2 activity can suppress cancer mutagenesis, inhibit tumor evolution, and / or reduce the probability of adverse outcomes such as drug resistance and / or metastasis.

[0027] In a first aspect of the present invention, there is provided a compound of formula (I): [ka] , and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers and tautomers thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , x and y are as described herein.

[0028] For compounds of formula (I), R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , x and y may each be selected from groups described herein, where applicable; R 1 , R 2 , R 3 , R 4 , R 5 , R 6, any group described herein for any of x and y, where applicable, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 It is understood that one or more of the remaining x and y may be combined with any group described herein.

[0029] Details of the present invention are described in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, exemplary methods and materials are described herein. Other features, objects, and advantages of the present invention will become apparent from the specification and claims. In this specification and the appended claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. 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 belongs. All patents and publications cited herein are incorporated herein by reference in their entirety. definition

[0030] The articles "a" and "an" are used in this disclosure to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0031] In this disclosure, the term "and / or" means either "and" or "or" unless otherwise stated.

[0032] The term "optionally substituted" is understood to mean that a given chemical moiety (e.g., an alkyl group) can (but need not) be bonded to other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group can be a fully saturated alkyl chain (i.e., pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents other than hydrogen. For example, at any point along the chain, it can be bonded to a halogen atom, a hydroxyl group, or other substituents described herein. Thus, the term "optionally substituted" means that a given chemical moiety has the potential to include other functional groups, but does not necessarily have any additional functional groups. Suitable substituents for use in any substitution of the described groups include, but are not limited to, halogen, oxo, —OH, —CN, —COOH, —CHCN, —O—(C-C)alkyl, (C-C)alkyl, (C-C)alkoxy, (C-C)haloalkyl, (C-C)haloalkoxy, —O—(C-C)alkenyl, —O—(C-C)alkynyl, (C-C)alkenyl, (C-C)alkynyl, —OH, —OP(O )(OH), —OC(O)(C-C)alkyl, —C(O)(C-C)alkyl, —OC(O)O(C-C)alkyl, —NH, —NH((C-C)alkyl), —N((C-C)alkyl), —NHC(O)(C-C)alkyl, —C(O)NH(C-C)alkyl, —S(O)(C-C)alkyl, —S(O)NH(C-C)alkyl, and S(O)N((C-C)alkyl). Substituents may themselves be optionally substituted. As used herein, “optionally substituted” means substituted or unsubstituted, the meaning of which is described below.

[0033] As used herein, the term "substituted" means that a particular group or moiety has one or more suitable substituents, and the substituents may be linked to the particular group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl indicates that the cycloalkyl is linked to one atom of the aryl by a bond or by being fused to the aryl and sharing two or more common atoms.

[0034] As used herein, the term "unsubstituted" means that the particular group bears no substituents.

[0035] Unless otherwise defined, the term "aryl" refers to a cyclic, aromatic hydrocarbon group having one to three aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. When containing two aromatic rings (such as bicyclic), the aromatic rings of the aryl group can be attached at a single point (e.g., biphenyl) or fused (e.g., naphthyl). The aryl group can be optionally substituted at any point of attachment with one or more substituents, e.g., 1 to 5 substituents. Exemplary substituents include, but are not limited to, -H, -halogen, -O-(C-C)alkyl, (C-C)alkyl, -O-(C-C)alkenyl, -O-(C-C)alkynyl, (C-C)alkenyl, (C-C)alkynyl, -OH, -O-P(O)(OH), -OC(O)(C-C)alkyl, -C(O)(C-C)alkyl, -OC(O)O(C-C)alkyl, -NH, NH((C-C)alkyl), N((C-C)alkyl), -S(O)-(C-C)alkyl, -S(O)NH(C-C)alkyl, and -S(O)N((C-C)alkyl). Substituents may themselves be optionally substituted. Additionally, when containing two fused rings, aryl groups as defined herein may have a saturated or partially unsaturated ring fused to a fully unsaturated aromatic ring. Examples of ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannurenyl, and the like.

[0036] Unless otherwise defined, "heteroaryl" means a monovalent monocyclic or polycyclic aromatic radical of 5 to 24 ring atoms containing one or more ring heteroatoms selected from N, O, S, P, Se, or B, with the remaining ring atoms being C. Heteroaryl, as defined herein, also means bicyclic heteroaromatic groups in which the heteroatoms are selected from N, O, S, P, Se, or B. Heteroaryl, as defined herein, also means tricyclic heteroaromatic groups containing one or more ring heteroatoms selected from N, O, S, P, Se, or B. The aromatic radicals may be optionally substituted independently with one or more substituents described herein. Examples include furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolinyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triphenylmethane, and the like. Azinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl , indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl yl, tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1λ 2-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzoxazolyl, benzisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[ 4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl, and derivatives thereof. Furthermore, when containing two or more fused rings, heteroaryl groups as defined herein may have one or more saturated or partially unsaturated rings, such as a 5-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O, S, P, Se, or B, or a 6-membered heteroaromatic ring containing 1 to 3 nitrogen atoms, fused to a fully unsaturated aromatic ring, wherein the saturated or partially unsaturated ring contains 0 to 4 heteroatoms selected from N, O, S, P, Se, or B, and is optionally substituted with one or more oxo. In heteroaryl ring systems containing more than two fused rings, the saturated or partially unsaturated ring may be further fused to a saturated or partially unsaturated ring as described herein.Exemplary ring systems of these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranonyl, indolinyl, oxindolyl, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-1H-isoquinolinyl, 1,6-dihydro-2H-pyrazolo[3,4-c]pyridin-7-on ... hydro-6H-pyrido[3,2-b]pyrrolidinyl, 8H-pyrido[3,2-b]pyrrolidinyl, 1,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3-e]pyridinyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolidine, pyrazolo[1,5-a]pyrimidin-7(4H)-onyl, 3,4-dihydropyrazino[1,2-a]indol-1(2H)-onyl, or benzo[c][1,2]oxaborol-1(3H)-olyl.

[0037] "Halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0038] "Alkyl" refers to a straight or branched chain saturated hydrocarbon containing 1 to 12 carbon atoms. Examples of (C1-C6) alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

[0039] "Alkoxy" refers to a straight or branched chain saturated hydrocarbon containing 1 to 12 carbon atoms including a terminal "O" in the chain, i.e., -O(alkyl). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

[0040] "Alkenyl" refers to a straight- or branched-chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "alkenyl" group contains at least one double bond in the chain. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl. An alkenyl group can be unsubstituted or substituted. As defined herein, alkenyl can be straight-chain or branched.

[0041] "Alkynyl" refers to a straight or branched chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "alkynyl" group contains at least one triple bond in the chain. Examples of alkenyl groups include ethynyl, propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl. Alkynyl groups can be unsubstituted or substituted.

[0042] The term "alkylene" or "alkylenyl" refers to a divalent alkyl radical. Any of the above monovalent alkyl groups can be alkylene by abstraction of a second hydrogen atom from the alkyl. As defined herein, alkylene can be a C1-C6 alkylene. Alkylene can further be a C1-C4 alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, and -CH2CH2CH2CH2-, and the like.

[0043] "Cycloalkyl" means a group having 3 to 30 carbon atoms (e.g., C3-C 12 , C3-C 10, or C3-C8). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, bicyclo[2.2.2]octanyl, bicyclo[2.2.2]octenyl, decahydronaphthalenyl, octahydro-1H-indenyl, cyclopentenyl, cyclohexenyl, cyclohexa-1,4-dienyl, cyclohexa-1,3-dienyl, 1,2,3,4-tetrahydronaphthalenyl, octahydropentalenyl, 3a,4,5,6 Examples of cycloalkyls include, but are not limited to, 7,7a-hexahydro-1H-indenyl, 1,2,3,3a-tetrahydropentalenyl, bicyclo[3.1.0]hexanyl, bicyclo[2.1.0]pentanyl, spiro[3.3]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]hept-2-enyl, bicyclo[2.2.2]octanyl, 6-methylbicyclo[3.1.1]heptanyl, 2,6,6-trimethylbicyclo[3.1.1]heptanyl, adamantyl, and derivatives thereof. In the case of polycyclic cycloalkyls, only one of the rings of the cycloalkyl need be non-aromatic.

[0044] "Heterocyclyl," "heterocycle," or "heterocycloalkyl," unless otherwise specified, refers to a saturated or partially unsaturated 3- to 10-membered monocyclic, 7- to 12-membered bicyclic (fused, bridged, or spiro) or 11- to 14-membered tricyclic ring system (fused, bridged, or spiro) having one or more heteroatoms (such as O, N, S, P, Se, or B) independently selected from the group consisting of nitrogen, oxygen, and sulfur.Examples of heterocycloalkyl groups are piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-diaze ... -oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, 1-oxaspiro[4.5]decanyl, 1-azaspiro[4.5]decanyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl, 7'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl, 'H-spiro[cyclohexane-1,5'-furo[3,4-b]pyridin]-yl, 3'H-spiro[cyclohexane-1,1'-furo[3,4-c]pyridin]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl , 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa-azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, and the like.

[0045] The term "haloalkyl," as used herein, refers to an alkyl group, as defined herein, that is substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, and the like.

[0046] The term "haloalkoxy," as used herein, refers to an alkoxy group, as defined herein, that is substituted with one or more halogens. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, and the like.

[0047] As used herein, the term "cyano" refers to a substituent having a carbon atom attached to a nitrogen atom by a triple bond, i.e., C≡N.

[0048] As used herein, the term "amine" refers to primary (R-NH, where R is not H), secondary (R-NH, where R is not H), and tertiary (R-N, where R is not H) amines. A substituted amine is intended to mean an amine in which at least one hydrogen atom is replaced with a substituent.

[0049] As used herein, the term "amino" refers to a substituent containing at least one nitrogen atom. Specifically included within the term "amino" are -NH, -NH(alkyl) or alkylamino, -N(alkyl) or dialkylamino, amido, carbamido, urea, and sulfamido substituents.

[0050] The term "solvate" refers to a complex of varying stoichiometry formed by a solute and a solvent. For the purposes of the present invention, such a solvent may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates in which water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water as well as compositions containing variable amounts of water.

[0051] The term "isomer" refers to compounds that have the same composition and molecular weight but different physical and / or chemical properties. The structural differences may be in constitution (geometric isomers) or in ability to rotate the plane of polarized light (stereoisomers). With respect to stereoisomers, compounds of formula (I) may have one or more asymmetric carbon atoms and may occur as racemates, racemic mixtures, and individual enantiomers or diastereomers.

[0052] The present invention also provides isotopically labeled compounds of formula I, such as 2 H and 14 C) are intended to be deuterated (i.e., 2 H or D) isotopes and carbon-14 (i.e., 14 C) Isotopes are particularly preferred for their ease of preparation and detectability. Furthermore, substitution with heavier isotopes, such as deuterium, may offer certain therapeutic advantages due to higher metabolic stability (e.g., increased in vivo half-life or reduced required dose), and therefore may be preferred in some circumstances. Isotopically labeled compounds of Formula I can generally be prepared by replacing non-isotopically labeled reagents with appropriate isotopically labeled reagents in accordance with procedures similar to those disclosed in the following schemes and / or examples.

[0053] The present disclosure also includes pharmaceutical compositions comprising an effective amount of the disclosed compounds and a pharmaceutically acceptable carrier. Representative "pharmaceutically acceptable salts" include, for example, water soluble salts and water insoluble salts, such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, and the like. The salts include, but are not limited to, isethionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, embonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, diacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate.

[0054] A "patient" or "subject" is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, e.g., a monkey, chimpanzee, baboon, or rhesus monkey.

[0055] An "effective amount," when used in connection with a compound, is an amount effective to treat or prevent a disease or disorder in a subject as described herein.

[0056] The term "carrier" as used in this disclosure encompasses carriers, excipients, and diluents and means a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting a pharmaceutical agent from one organ or part of the body of a subject to another organ or part of the body.

[0057] The term "treating" with respect to a subject refers to improving at least one symptom of the subject's disorder. Treating includes curing, ameliorating, or at least partially ameliorating the disorder.

[0058] In this disclosure, the term "disorder" is used to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise specified.

[0059] The terms "administer," "administering," or "administration," as used in this disclosure, refer to either administering a disclosed compound, or a pharmaceutically acceptable salt or composition of a disclosed compound, directly to a subject, or administering a prodrug derivative or analog of the compound, or a pharmaceutically acceptable salt or composition of the compound, to a subject, allowing an equivalent amount of active compound to form in the subject's body.

[0060] The term "prodrug," as used in this disclosure, means a compound that is convertible in vivo by metabolic means (e.g., hydrolysis) to a disclosed compound.

[0061] The present invention relates to compounds, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, that can inhibit BCL-2 proteins, such as isoform 1 and isoform 2, and that are useful in treating diseases and disorders associated with the modulation of BCL-2 proteins. The present invention further relates to compounds, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, that are useful for inhibiting BCL-2.

[0062] In some embodiments, the compound of formula (I) has the structure of formula (I'): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0063] In some embodiments, the compound of Formula (I) has the structure of Formula (II): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0064] In some embodiments, the compound of formula (I) has the structure of formula (II'): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0065] In some embodiments, the compound of Formula (I) has the structure of Formula (III-XI): [ka] [ka] [ka] wherein each n is independently selected from 1, 2, and 3; and X is NR 9 , O, S), and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, stereoisomers, or tautomers thereof.

[0066] In some embodiments, the compound of formula (I) has the structure of formula (III):

[0067] In some embodiments, the compound of formula (I) has the structure of formula (IV):

[0068] In some embodiments, the compound of formula (I) has the structure of formula (V):

[0069] In some embodiments, the compound of formula (I) has the structure of formula (VI):

[0070] In some embodiments, the compound of formula (I) has the structure of formula (VII):

[0071] In some embodiments, the compound of formula (I) has the structure of formula (VIII):

[0072] In some embodiments, the compound of formula (I) has the structure of formula (IX):

[0073] In some embodiments, the compound of formula (I) has the structure of formula (X):

[0074] In some embodiments, the compound of formula (I) has the structure of formula (XI):

[0075] In some embodiments, the compound of formula (I) has the structure of formula (III'-XI'): [ka] [ka] [ka] wherein each n is independently selected from 1, 2, and 3; and X is NR 9 , O, S), and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, stereoisomers, or tautomers thereof.

[0076] In some embodiments, the compound of formula (I) has the structure of formula (III').

[0077] In some embodiments, the compound of formula (I) has the structure of formula (IV').

[0078] In some embodiments, the compound of formula (I) has the structure of formula (V').

[0079] In some embodiments, the compound of formula (I) has the structure of formula (VI').

[0080] In some embodiments, the compound of formula (I) has the structure of formula (VII').

[0081] In some embodiments, the compound of formula (I) has the structure of formula (VIII').

[0082] In some embodiments, the compound of formula (I) has the structure of formula (IX').

[0083] In some embodiments, the compound of formula (I) has the structure of formula (X').

[0084] In some embodiments, the compound of formula (I) has the structure of formula (XI').

[0085] In some embodiments, the compound of formula (I) has the structure of formula (I-1): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0086] In some embodiments, the compound of Formula (I) has the structure of Formula (I-1′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0087] In some embodiments, the compound of formula (I) has the structure of formula (I-2): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0088] In some embodiments, the compound of Formula (I) has the structure of Formula (I-2'): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0089] In some embodiments, the compound of Formula (I) has the structure of Formula (I-3): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0090] In some embodiments, the compound of Formula (I) has the structure of Formula (I-3'): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0091] In some embodiments, the compound of Formula (I) has the structure of Formula (I-4): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0092] In some embodiments, the compound of Formula (I) has the structure of Formula (I-4'): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0093] In some embodiments, the compound of formula (I) has the structure of formula (II-1): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0094] In some embodiments, the compound of formula (I) has the structure of formula (II-1′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0095] In some embodiments, the compound of formula (I) has the structure of formula (II-2): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0096] In some embodiments, the compound of formula (I) has the structure of formula (II-2'): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0097] In some embodiments, the compound of formula (I) has the structure of formula (II-3): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0098] In some embodiments, the compound of formula (I) has the structure of formula (II-3'): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0099] In some embodiments, the compound of formula (I) has the structure of formula (II-4): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0100] In some embodiments, the compound of formula (I) has the structure of formula (II-4'): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0101] In some embodiments, the compound of formula (I) has the structure of formula (II-A): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0102] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-1): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0103] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-1′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0104] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0105] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0106] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-3): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0107] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-3′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0108] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-4): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0109] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-4'): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0110] In some embodiments, the compound of formula (I) has the structure of formula (II-B): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0111] In some embodiments, the compound of Formula (I) has the structure of Formula (II-B-1): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0112] In some embodiments, the compound of Formula (I) has the structure of Formula (II-B-1′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0113] In some embodiments, the compound of Formula (I) has the structure of Formula (II-B-1): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0114] In some embodiments, the compound of Formula (I) has the structure of Formula (II-B-2'): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0115] In some embodiments, the compound of Formula (I) has the structure of Formula (II-B-3): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0116] In some embodiments, the compound of Formula (I) has the structure of Formula (II-B-3′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0117] In some embodiments, the compound of Formula (I) has the structure of Formula (II-B-4): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0118] In some embodiments, the compound of Formula (I) has the structure of Formula (II-B-4'): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0119] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-1-A): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0120] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-1-A): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0121] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-1-A'): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0122] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0123] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A'): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0124] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-3-A): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0125] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-3-A'): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0126] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-4-A): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0127] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-4-A'): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0128] In some embodiments, the compound of Formula (I) has the structure of Formula (II-BA): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0129] In some embodiments, the compound of Formula (I) has the structure of Formula (II-B-1-A): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0130] In some embodiments, the compound of Formula (I) has the structure of Formula (II-B-1-A'): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0131] In some embodiments, the compound of Formula (I) has the structure of Formula (II-B-2-A): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0132] In some embodiments, the compound of Formula (I) has the structure of Formula (II-B-2-A'): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0133] In some embodiments, the compound of Formula (I) has the structure of Formula (II-B-3-A): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0134] In some embodiments, the compound of Formula (I) has the structure of Formula (II-B-3-A'): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0135] In some embodiments, the compound of Formula (I) has the structure of Formula (II-B-4-A): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0136] In some embodiments, the compound of Formula (I) has the structure of Formula (II-B-4-A'): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0137] In some embodiments, the compound of Formula (I) has the structure of Formula (II-AB): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0138] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-1-B): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0139] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-1-B'): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0140] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-B): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0141] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-B'): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0142] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-3-B): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0143] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-3-B'): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0144] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-4-B): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0145] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-4-B'): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0146] In some embodiments, the compound of Formula (I) has the structure of Formula (II-BB): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0147] In some embodiments, the compound of Formula (I) has the structure of Formula (II-B-1-B): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0148] In some embodiments, the compound of Formula (I) has the structure of Formula (II-B-1-B'): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0149] In some embodiments, the compound of Formula (I) has the structure of Formula (II-B-2-B): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0150] In some embodiments, the compound of Formula (I) has the structure of Formula (II-B-2-B'): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0151] In some embodiments, the compound of Formula (I) has the structure of Formula (II-B-3-B): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0152] In some embodiments, the compound of Formula (I) has the structure of Formula (II-B-3-B'): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0153] In some embodiments, the compound of Formula (I) has the structure of Formula (II-B-4-B): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0154] In some embodiments, the compound of Formula (I) has the structure of Formula (II-B-4-B'): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0155] In some embodiments, the compound of Formula (I) has the structure of Formula (II-AC): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0156] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-1-C): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0157] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-1-C'): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0158] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-C): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0159] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-C'): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0160] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-3-C): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0161] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-3-C'): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0162] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-4-C): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0163] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-4-C'): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0164] In some embodiments, the compound of formula (I) has the structure of formula (II-BC): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0165] In some embodiments, the compound of Formula (I) has the structure of Formula (II-B-1-C): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0166] In some embodiments, the compound of Formula (I) has the structure of Formula (II-B-1-C'): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0167] In some embodiments, the compound of Formula (I) has the structure of Formula (II-B-2-C): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0168] In some embodiments, the compound of Formula (I) has the structure of Formula (II-B-2-C'): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0169] In some embodiments, the compound of Formula (I) has the structure of Formula (II-B-3-C): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0170] In some embodiments, the compound of Formula (I) has the structure of Formula (II-B-3-C'): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0171] In some embodiments, the compound of Formula (I) has the structure of Formula (II-B-4-C): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0172] In some embodiments, the compound of Formula (I) has the structure of Formula (II-B-4-C'): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0173] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-1-A-1): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0174] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-1-A'): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0175] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-1-Aa): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof, wherein Hal is a halogen and all other variables are as defined herein.

[0176] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-1-A-a′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof, wherein Hal is a halogen and all other variables are as defined herein.

[0177] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-1-A-2): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0178] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-1-A-2′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0179] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-1-A-3): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0180] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-1-A-3′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0181] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-1-A-4): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0182] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-1-A-4′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0183] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-1-A-5): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0184] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-1-A-5′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0185] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-1-A-6): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0186] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-1-A-6′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0187] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-1-A-7): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0188] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-1-A-7′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0189] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-1-A-8): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0190] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-1-A-8′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0191] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-1-A-9): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0192] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-1-A-9′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0193] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-1): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0194] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-1′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0195] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-2): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0196] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-2′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0197] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-3): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0198] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-3′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0199] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-4): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0200] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-4′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0201] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-5): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0202] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-5′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0203] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-6): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0204] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-6′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0205] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-7): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0206] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-7′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0207] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-8): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0208] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-8′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0209] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-9): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0210] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-9′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0211] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-10): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0212] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-10′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0213] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-11): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0214] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-11′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0215] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-12): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0216] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-12′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0217] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-13): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0218] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-13′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0219] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-14): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0220] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-14'): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0221] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-15): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0222] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-15′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0223] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-16): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0224] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-16'): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0225] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-17): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0226] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-17'): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0227] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-18): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0228] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-18'): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0229] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-19): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0230] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-19′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0231] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-20): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0232] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-20′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0233] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-21): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0234] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-2-A-21′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0235] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-3-A-1): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0236] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-3-A-1′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0237] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-4-A-1): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0238] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-4-A-1′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0239] In some embodiments, the compound of Formula (I) has the structure of Formula (II-B-1-A-1): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0240] In some embodiments, the compound of Formula (I) has the structure of Formula (II-B-1-A-1′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0241] In some embodiments, the compound of Formula (I) has the structure of Formula (II-B-1-A-2): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0242] In some embodiments, the compound of Formula (I) has the structure of Formula (II-B-1-A-2′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0243] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-1-B-1): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0244] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-1-B-1′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0245] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-1-B-2): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0246] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-1-B-2′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0247] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-1-C-1): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0248] In some embodiments, the compound of Formula (I) has the structure of Formula (II-A-1-C-1′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0249] In some embodiments, the compound of Formula (I) has the structure of Formula (II-AA-1′) or Formula (II-BA-1′): [ka] [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0250] In some embodiments, the compound of Formula (I) has the structure of Formula (II-AA-2′) or Formula (II-BA-2′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0251] In some embodiments, the compound of Formula (I) has the structure of Formula (II-AA-3′) or Formula (II-BA-3′): [ka] or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0252] In some embodiments, the compound of Formula (I) has the structure of Formula (II-AA-4′) or Formula (II-BA-4′): [ka] , [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0253] In some embodiments, the compound of Formula (I) has the structure of Formula (II-AA-5′) or Formula (II-BA-5′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0254] In some embodiments, the compound of Formula (I) has the structure of Formula (II-AA-5-1′) or Formula (II-BA-5-1′): [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0255] In some embodiments, the compound of Formula (I) has the structure of Formula (II-AA-6′) or Formula (II-BA-6′): [ka] [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0256] In some embodiments, the compound of Formula (I) has the structure of Formula (VA), the structure of Formula (VI-A), or the structure of Formula (XI-A): [ka] [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0257] In some embodiments, the compound of Formula (I) has the structure of Formula (V-A'), the structure of Formula (VI-A'), or the structure of Formula (XI-A'): [ka] [ka] , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof.

[0258] In some embodiments, R 1 is a halogen, —OH, —CN, or —CONH2.

[0259] In some embodiments, R 1 is a halogen.

[0260] In some embodiments, R 1 is fluoro.

[0261] In some embodiments, R 1 is chloro.

[0262] In some embodiments, R 1 is -OH.

[0263] In some embodiments, R 1 is -CN.

[0264] In some embodiments, R 1a is H.

[0265] In some embodiments, R 1 and R 1a together with the atoms to which they are attached form a 3- to 10-membered heteroaryl ring further containing 1, 2, or 3 heteroatoms selected from N, O, and S.

[0266] In some embodiments, R 1 and R 1a together with the atoms to which they are attached form a 5-membered heteroaryl ring further containing 1, 2, or 3 heteroatoms selected from N, O, and S.

[0267] In some embodiments, R 1 and R 1a together with the atoms to which they are attached form a 5-membered heteroaryl ring further containing two heteroatoms selected from N, O, and S.

[0268] In some embodiments, R 1 and R 1a together with the atoms to which they are attached form a 5-membered heteroaryl ring further containing two nitrogen atoms.

[0269] In some embodiments, R 2 is C1-C6 alkyl.

[0270] In some embodiments, R 2 is -CH3.

[0271] In some embodiments, R 3 is C1-C6 alkyl.

[0272] In some embodiments, R 3 is -CH3.

[0273] In some embodiments, R 2 and R 3 together with the atoms to which they are attached form a 3- to 10-membered heterocyclyl ring further containing 1, 2, or 3 heteroatoms selected from N, O, and S.

[0274] In some embodiments, R 2 and R 3together with the atoms to which they are attached form a 5-membered heterocyclyl ring further containing one nitrogen atom.

[0275] In some embodiments, R 2 and R 3 together with the atoms to which they are attached form a 6-membered heterocyclyl ring further containing one nitrogen atom.

[0276] In some embodiments, R 2 and R 3 together with the atoms to which they are attached form a 7-membered heterocyclyl ring further containing one nitrogen atom.

[0277] In some embodiments, each R 4 are halogens, -OH, -CN, -NO2, -COOH, -CH2CN, CH2N(R 8 )2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogen alkyl, C1-C6 halogen alkoxy, -O-(C2-C6 alkenyl), -O-(C2-C6 alkynyl), C2-C6 alkenyl, C2-C6 alkynyl, -OH, -OP(O)(OH)2, -OC(O)(C1-C6 alkyl), -C(O)(C1-C6 alkyl), -OC(O) and independently selected from O(C-C alkyl), -NH, -NH(C-C alkyl), -N(C-C alkyl), -NHC(O)(C-C alkyl), -C(O)NH, -C(O)NH(C-C alkyl), -S(O)(C-C alkyl), -S(O)NH(C-C alkyl), and S(O)N(C-C alkyl).

[0278] In some embodiments, R 4 is a halogen.

[0279] In some embodiments, R 4 is F.

[0280] In some embodiments, R 4 is Cl.

[0281] In some embodiments, R 4 is -CN.

[0282] In some embodiments, R4 is NO2.

[0283] In some embodiments, R 4 is -C(O)NH2.

[0284] In some embodiments, R 4 is -C1-C6 alkyl.

[0285] In some embodiments, R 4 is -CH3.

[0286] In some embodiments, R 4 is C1-C6 halogen alkyl.

[0287] In some embodiments, R 4 is -CHF2.

[0288] In some embodiments, R 4 is C1-C6 alkoxy.

[0289] In some embodiments, R 4 is -OCH3.

[0290] In some embodiments, R 4 is C1-C6 halogenalkoxy.

[0291] In some embodiments, R 4 is -OCHF2.

[0292] In some embodiments, R 4 is —NHC(O)(C1-C6 alkyl).

[0293] In some embodiments, R 4is -NHC(O)CH3.

[0294] In some embodiments, R 4 is S(O)2(C1-C6 alkyl).

[0295] In some embodiments, R 4 is S(O)2CH3.

[0296] In some embodiments, x is an integer selected from 0, 1, 2, and 3.

[0297] In some embodiments, x is 0.

[0298] In some embodiments, x is 1.

[0299] In some embodiments, x is 2.

[0300] In some embodiments, x is 3.

[0301] In some embodiments, R 5 teeth [ka] and [ka] Selected from;

[0302] In some embodiments, R 5 teeth, [ka] is.

[0303] In some embodiments, R 5 teeth, [ka] is.

[0304] In some embodiments, R 5 teeth, [ka] is.

[0305] In some embodiments, R 5 teeth, [ka] is selected from.

[0306] In some embodiments, R 5 teeth, [ka] is selected from.

[0307] In some embodiments, R 5 teeth, [ka] is selected from.

[0308] In some embodiments, R 5 teeth, [ka] is selected from.

[0309] In some embodiments, R 5 teeth, [ka] [ka] is selected from the group consisting of:

[0310] In some embodiments, R 5 teeth, [ka] [ka] is selected from the group consisting of:

[0311] In some embodiments, R 5 teeth, [ka] [ka] is selected from the group consisting of:

[0312] In some embodiments, m is selected from 0, 1, and 2.

[0313] In some embodiments, m is 0.

[0314] In some embodiments, m is 1.

[0315] In some embodiments, m is 2.

[0316] In some embodiments, each n is an integer independently selected from 1, 2, and 3.

[0317] In some embodiments, each R 6 is halogen, -OH, -CN, -COOH, -CHCN, -CON(R 8)2, C-C alkyl, C-C alkoxy, C-C halogen alkyl, C-C halogen alkoxy, —O—(C-C alkenyl), —O—(C-C alkynyl), C-C alkenyl, C-C alkynyl, —OH, —O—P(O)(OH)2, —OC(O)(C-C alkyl), —C(O)(C-C alkyl), —OC(O)O(C-C alkyl), —NH2, —NH(C-C alkyl), —N(C-C alkyl)2, —NHC(O)(C-C alkyl), —C(O)NH(C-C alkyl), —S(O)2(C-C alkyl), —S(O)NH(C-C alkyl), and S(O)N(C-C alkyl)2.

[0318] In some embodiments, each R 6 is CN, CO(NR 8 )2, independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogenalkyl, and C1-C6 halogenalkoxy.

[0319] In some embodiments, R 6 is -CH3.

[0320] In some embodiments, R 6 is -OCH3.

[0321] In some embodiments, R 6 is -CN.

[0322] In some embodiments, R 6 is -C(O)NH2.

[0323] In some embodiments, y is an integer selected from 0, 1, 2, and 3.

[0324] In some embodiments, y is 0.

[0325] In some embodiments, y is 1.

[0326] In some embodiments, y is 2.

[0327] In some embodiments, y is 3.

[0328] In some embodiments, each R 7 is H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, and aryl.

[0329] In some embodiments, two R 7 form a heterocyclic ring together with the nitrogen atom to which they are attached and any intervening atoms.

[0330] In some embodiments, two R 7 together with the nitrogen atom to which they are attached and any intervening atoms form a 6-membered heterocyclic ring.

[0331] In some embodiments, two R 7 together with the nitrogen atom to which they are attached and any intervening atoms form a 6-membered heterocyclic ring containing N and O.

[0332] In some embodiments, R 8 is H, C 1-6 Alkyl, C 3-8 Cycloalkyl, aryl, C 1-6 halogen alkyl.

[0333] In some embodiments, R 8 is H and C 1-6 alkyl.

[0334] In some embodiments, R 9 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) 1-6 OR 8 , C3-8 It is selected from cycloalkyl, aryl, and heterocycle.

[0335] In some embodiments, R 9 is C 1-6 Alkyl, or C 1-6 It is a halogen alkyl.

[0336] In some embodiments, R 9 is C 1-4 In some embodiments, R 9 is C 1-4 It is a halogen alkyl.

[0337] In some embodiments, R 9 is -CH3. In some embodiments, R 9 is -CHF. In some embodiments, R 9 is -CHF. In some embodiments, R 9 is -CF3.

[0338] Non-limiting exemplary compounds of the present disclosure include those shown in Table 1, or a pharmaceutically acceptable salt, isomer, solvate, prodrug, or tautomer thereof.

[0339] JPEG0007772431000206.jpg197170JPEG0007772431000207.jpg191170JPEG0007772431000208.jpg191170JPE G0007772431000209.jpg205170JPEG0007772431000210.jpg205170JPEG0007772431000211.jpg205170JPEG000 7772431000212.jpg205170JPEG0007772431000213.jpg198170JPEG0007772431000214.jpg205170JPEG0007772 431000215.jpg205170JPEG0007772431000216.jpg198170JPEG0007772431000217.jpg198170JPEG00077724310 00218.jpg205170JPEG0007772431000219.jpg205170JPEG0007772431000220.jpg205170JPEG00077724310002 21.jpg198170JPEG0007772431000222.jpg191170JPEG0007772431000223.jpg185170JPEG0007772431000224.j pg185170JPEG0007772431000225.jpg198170JPEG0007772431000226.jpg178170JPEG0007772431000227.jpg18 5170JPEG0007772431000228.jpg185170JPEG0007772431000229.jpg185170JPEG0007772431000230.jpg132170

[0340] In some embodiments, the compound is a pharmaceutically acceptable salt.

[0341] In some embodiments, the compound is a hydrochloride salt.

[0342] It is to be understood that all isomers, including mixtures thereof, are included in the present invention.When a compound contains a double bond, the substituent may be in E-configuration or Z-configuration.When a compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have cis- or trans-configuration.All tautomers are also intended to be included.

[0343] Compounds of the present invention, and their pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, and prodrugs, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.

[0344] The compounds of the present invention may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention, and mixtures thereof, including racemic mixtures, are intended to form part of the present invention. Furthermore, the present invention encompasses all geometric and positional isomers. For example, if a compound of the present invention incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are encompassed within the scope of the present invention. Each compound disclosed herein includes all enantiomers that conform to the compound's general structure. The compounds may be in racemic or enantiomerically pure form, or in other stereochemical forms. Assay results may reflect data collected for racemic, enantiomerically pure, or other stereochemical forms.

[0345] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, chromatography and / or fractional crystallization. Enantiomers can also be separated by converting the enantiomeric mixture to a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereomers to the corresponding pure enantiomers (e.g., by hydrolysis). Some of the compounds of the present invention may also be atropisomers (e.g., substituted biaryls) and are considered part of the present invention. Enantiomers can also be separated using a chiral HPLC column.

[0346] It is also possible that compounds of the present invention may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.

[0347] All stereoisomers (e.g., geometric isomers, optical isomers, etc.) of the present compounds (including salts, solvates, esters, and prodrugs of the compounds, and salts, solvates, and esters of the prodrugs), including, for example, enantiomers (which may exist even when no asymmetric carbon is present), rotameric forms, atropisomers, and diastereomeric forms, which may exist due to asymmetric carbons on various substituents, are contemplated within the scope of the present invention, as are positional isomers (e.g., 4-pyridyl, 3-pyridyl, etc.). (For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention. Also, for example, keto-enol and imine-enamine forms of the compounds are all included in the invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be mixed, for example, as a racemate or with all other or selected stereoisomers. The chiral centers of the present invention may have the S or R configuration as defined by the IUPAC 1974 Recommendations. Use of the terms "salts," "solvates," "esters," "prodrugs," and the like, is intended to apply equally to enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrug salts, solvates, esters and prodrugs of the compounds of the invention.)

[0348] The compounds of formula I may form salts which are also within the scope of the present invention, and references herein to compounds of formula I are understood to include references to salts thereof, unless otherwise specified.

[0349] The present invention relates to compounds that are modulators of BCL-2 protein. In one embodiment, the compounds of the present invention are inhibitors of BCL-2 protein. In another embodiment, the BCL-2 protein is isoform 1. In another embodiment, the BCL-2 protein is isoform 2.

[0350] The present invention relates to the compounds described herein, and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, and to pharmaceutical compositions comprising one or more compounds described herein, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof. Compound synthesis method

[0351] The compounds of the invention may be made in a variety of ways, including standard chemistry. Suitable synthetic routes are illustrated in the schemes set out below.

[0352] Compounds of formula (I) can be prepared by methods known in the art of organic synthesis, as defined in part by the synthetic schemes below. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis," Third Edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods readily apparent to those skilled in the art. The presence of a stereocenter in a compound of formula (I) will be recognizable by those skilled in the art by the selection process and reaction conditions and sequences. Accordingly, the present invention (unless specified in the synthesis) encompasses both possible stereoisomers, including not only racemates but also individual enantiomers and / or diastereomers. When a compound is desired as a single enantiomer or diastereomer, it can be obtained by stereospecific synthesis or by separation of the final product or any convenient intermediate. Separation of the final product, an intermediate, or a starting material can be affected by any suitable method known in the art, see, for example, "Stereochemistry of Organic Compounds" by EL Eliel, SH Wilen, and LN Mander (Wiley-Interscience, 1994).

[0353] The compounds described herein can be made from commercially available starting materials or can be synthesized using known organic, inorganic, and / or enzymatic processes. Preparation of compounds

[0354] The compounds of the present invention can be prepared by many methods well known to those skilled in the art of organic synthesis. For example, the compounds of the present invention can be synthesized using the methods described below, along with synthetic methods known in the art of organic synthetic chemistry, or by modifications thereof that will be understood by those skilled in the art. Preferred methods include, but are not limited to, those described below. The compounds of the present invention can be synthesized according to the steps outlined in Scheme 1, including assembling intermediates or compounds of different sequences. Starting materials are commercially available or prepared by known procedures in the published literature, or as shown below. The general scheme 1 provided has only exemplary suggestions, and it is clear to those skilled in the art that it can be modified when preparing each specific compound of formula (I). General Scheme 1 [ka]

[0355] Table 2 shows non-limiting exemplary conditions for the reactions described in General Scheme 1. JPEG0007772431000232.jpg150170

[0356] It will be apparent to one skilled in the art that suitable protecting groups may be used for a given transformation. A non-limiting list of protecting groups useful in the preparation of compounds of formula I includes: acetyl (Ac), benzoyl (Bz), benzyl (Bn), methoxymethyl ether (MOM), p-methoxybenzyl ether (PMB), pivaloyl (Piv), trityl (Tr), carbobenzyloxy group (Cbz), tert-butyloxycarbonyl (Boc), tosyl (Ts).

[0357] Such an example uses the protecting groups shown in the preparation of compound 3: [ka] Methods of Use of the Disclosed Compounds

[0358] Another aspect of the present invention relates to a method for treating a disease or disorder associated with the regulation of BCL-2 protein, comprising administering to a patient in need of treatment for a disease or disorder associated with the regulation of BCL-2 protein an effective amount of a composition or compound of formula (I).

[0359] In another aspect, the present invention relates to a method for inhibiting BCL-2 protein, the method comprising administering to a patient in need thereof an effective amount of a compound of formula (I).

[0360] Another aspect of the present invention relates to a method for treating, preventing, inhibiting, or eliminating a disease or disorder in a patient associated with inhibition of BCL-2 protein, the method comprising administering to a patient in need thereof an effective amount of a compound of Formula (I). In one embodiment, the disease can be, but is not limited to, cancer and metastasis.

[0361] The present invention also relates to the use of an inhibitor of a BCL-2 protein for the preparation of a medicament for use in the treatment, prevention, inhibition or elimination of a disease or condition mediated by a BCL-2 protein, wherein the medicament comprises a compound of formula (I).

[0362] In another aspect, the invention relates to a method for the manufacture of a medicament for treating, preventing, inhibiting or eliminating a disease or condition mediated by a BCL-2 protein, wherein the medicament comprises a compound of formula (I).

[0363] Another aspect of the present invention relates to a compound of formula (I) for use in the manufacture of a medicament for the treatment of a disease associated with the inhibition of BCL-2 protein.

[0364] In another aspect, the present invention relates to the use of compounds of formula (I) in the treatment of diseases associated with the inhibition of the BCL-2 protein.

[0365] Another aspect of the present invention relates to a method for treating cancer, the method comprising administering to a patient in need thereof an effective amount of a compound of formula (I).

[0366] Another aspect of the present invention relates to a method for treating or preventing cancer, the method comprising administering to a patient in need thereof an effective amount of a compound of formula (I).

[0367] In one embodiment, the present invention relates to the use of an inhibitor of a BCL-2 protein for the preparation of a medicament for use in the treatment, prevention, inhibition or elimination of a disease or disorder related to cancer.

[0368] In another embodiment, the present invention relates to a compound of formula (I) or a pharmaceutical composition comprising a compound of this invention and a pharmaceutically acceptable carrier for use in the treatment of cancer, including but not limited to, bladder cancer, bone cancer, brain cancer, breast cancer, heart cancer, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, fibrosarcoma, stomach cancer, gastrointestinal cancer, head, spine and neck cancer, Kaposi's sarcoma, kidney cancer, leukemia, liver cancer, lymphoma, melanoma, multiple myeloma, pancreatic cancer, penile cancer, testicular germ cell cancer, thymic carcinoma, thymic carcinoma, lung cancer, ovarian cancer, and prostate cancer.

[0369] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier, which may further comprise an excipient, diluent, or surfactant.

[0370] In one embodiment, there is provided a method for treating a disease or disorder associated with the regulation of BCL-2 protein, including cancer or a cell proliferation disorder, comprising administering a compound of formula (I) to a patient suffering from at least one of said diseases or disorders.

[0371] One therapeutic use of the compounds or compositions of the invention that inhibit BCL-2 protein is to provide treatment to patients or subjects suffering from cancer or a cell proliferative disorder.

[0372] The compounds of the disclosed invention can be administered in an effective amount to treat or prevent a disorder in a subject and / or to prevent its onset.

[0373] Administration of the disclosed compounds can be via any mode of administration for therapeutic agents, including systemic or local administration, such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal, or topical modes of administration.

[0374] Depending on the intended mode of administration, the disclosed compositions can be in solid, semi-solid, or liquid dosage forms, such as, for example, injections, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, solutions, suspensions, and the like, optionally in unit dosage amounts, consistent with conventional pharmaceutical practice. Likewise, they can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous, or intramuscular form, all of which forms well known to those of ordinary skill in the pharmaceutical arts can be used.

[0375] Exemplary pharmaceutical compositions include a compound of the invention and a pharmaceutically acceptable carrier, such as a) a diluent, such as purified water, triglyceride oil, such as hydrogenated or partially hydrogenated vegetable oil or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oil, such as EPA or DHA, or esters, triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine; b) a lubricant, such as silica, talc, stearic acid, magnesium or calcium salts thereof, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and / or polyethylene glycol; also for tablets; c) binders, for example magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, waxes and / or polyvinylpyrrolidone, if desired; d) disintegrants, for example starch, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or effervescent mixtures; e) absorbents, colorants, flavors and sweeteners; f) emulsifiers or dispersants, for example Tween 80, Labrasol, HPMC, DOSS, caproyl 909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS or other acceptable emulsifier; and / or; g) an agent that enhances absorption of the compound, such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, PEG200, etc.

[0376] Liquid, particularly injectable compositions can be prepared, for example, by dissolving, dispersing, etc. For example, the disclosed compounds are dissolved or mixed in a pharmaceutically acceptable solvent, such as water, saline, aqueous dextrose, glycerol, ethanol, etc., to form an injectable isotonic solution or suspension. Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds.

[0377] The disclosed compounds can also be formulated as suppositories which can be prepared from fatty emulsions or suspensions; polyalkylene glycols such as propylene glycol are used as the carrier.

[0378] The disclosed compounds can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from various phospholipids, including cholesterol, stearylamine, or phosphatidylcholine. In some embodiments, a film of lipid components is hydrated with an aqueous solution of drug to form a lipid layer encapsulating the drug, as described in U.S. Patent No. 5,262,564, the entire contents of which are incorporated herein by reference.

[0379] The disclosed compounds can also be delivered by using monoclonal antibodies as individual carriers to which the disclosed compounds are bound. The disclosed compounds can also be bound to soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidophenol, or polyethylene oxide polylysine substituted with palmitoyl residues. Furthermore, the disclosed compounds can be bound to classes of biodegradable polymers useful for achieving controlled drug release, such as polylactic acid, polyepsiloncaprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels. In embodiments, the disclosed compounds are not covalently bound to polymers, such as polycarboxylic acid polymers or polyacrylates.

[0380] Parenteral injectable administration is generally used for subcutaneous, intramuscular or intravenous injection and infusion. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, or as solid forms suitable for dissolving in liquid prior to injection.

[0381] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further comprise an excipient, diluent, or surfactant. In some embodiments, the pharmaceutical composition may further comprise an additional pharmaceutically active agent.

[0382] The compositions can be prepared according to conventional mixing, granulating, or coating methods, respectively, and the pharmaceutical compositions of the present invention can contain about 0.1% to about 99%, about 5% to about 90%, or about 1% to about 20% of the disclosed compounds by weight or volume.

[0383] Dosage regimens utilizing the disclosed compounds are selected according to a variety of factors, including the type, species, age, weight, sex, and condition of the patient; the severity of the condition being treated; the route of administration; the patient's renal or hepatic function; and the particular disclosed compound being employed. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the agent required to prevent, counter, or arrest the progression of the condition.

[0384] Effective dosages of the disclosed compounds, when used for the indicated effects, range from about 0.5 mg to about 5,000 mg of the disclosed compounds required to treat a condition. Compositions for in vivo or in vitro use can include about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1,000, 1,250, 2,500, 3,500, or 5,000 mg of the disclosed compounds, or any range from one amount to another listed in the dosage list. In one embodiment, the composition is in the form of a scoreable tablet. [Example]

[0385] The present disclosure is further illustrated by the following examples and synthetic schemes, which should not be construed as limiting the scope or spirit of the disclosure to the specific procedures described herein. It should be understood that the examples are provided to illustrate particular embodiments and are not intended to limit the scope of the disclosure. Furthermore, it should be understood that various other embodiments, modifications, and equivalents that may be suggested to those skilled in the art can be relied upon without departing from the spirit of the present disclosure and / or the scope of the appended claims.

[0386] Abbreviations used in the following examples and elsewhere in this specification are as follows: anh. anhydrous ATM atmosphere Br. Broad aq. water-based Conc. Concentration DCM dichloromethane DIPEA N,N-Diisopropylethylamine DMEM Dulbecco's Modified Eagle's Medium DMF N,N-dimethylformamide DMSO dimethyl sulfoxide ESI electrospray ionization EtOAc Ethyl acetate EtOH ethanol h hour(s) HPLC High-Pressure (or High-Performance) Liquid Chromatography LAH Lithium aluminum hydride LCMS Liquid Chromatography Mass Spectrometry M mole m multiplet MHz Megahertz min NMR nuclear magnetic resonance ppm (parts per million) TBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate THF tetrahydrofuran TLC thin layer chromatography

[0387] Example Analysis and purification Preparative HPLC Neutral conditions were as follows: YMC-Pack ODS-AQ 250 x 20 mm, S-10 μm, pore size 12 nm, gradient water-acetonitrile.

[0388] The standard acidic conditions were as follows: YMC-Pack ODS-AQ 250 × 20 mm, S-10 μm, pore size 12 nm, gradient A solution - B solution: 1000 ml water - 226 μl trifluoroacetic acid, B: 1000 ml CH3CN - 226 μl trifluoroacetic acid. Analytical data, LCMS conditions:

[0389] C18 column 100 × 4.6 mm, 5.0 μm, pore size 100 Å, water-acetonitrile + 0.1% trifluoroacetic acid, gradient 5 to 87%, 10 min Synthesis of intermediates N-(4-chlorophenyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide (P3) [ka]

[0390] Preparation 1: Ethyl 5,6,7,8-tetrahydroindolizine-1-carboxylate P1 (as a mixture with ethyl 5,6,7,8-tetrahydroindolizine-2-carboxylate) While maintaining the temperature at 0°C, propionic anhydride (90 mL) was added to a stirred solution of piperidine-2-carboxylic acid (21 g, 162 mmol) in formic acid (70 mL). The reaction mixture was allowed to warm to ambient temperature, then stirred for 3 hours and evaporated to dryness on a rotary evaporator under reduced pressure. The residue was dissolved in propionic anhydride (150 mL), ethyl propionate (78 g, 800 mmol) was added in one portion, and the resulting mixture was stirred and heated at 100°C for 1 hour. The volatiles were removed under reduced pressure, and the residue was stirred with 20% aqueous Na2CO3 for 2 hours. The product was extracted with DCM (2 x 200 mL). The combined organic layers were washed with brine, dried over NaSO, and concentrated on a rotary evaporator under reduced pressure to give 28 g (89%) of crude product as a 5:1 mixture of isomers ethyl 5,6,7,8-tetrahydroindolizine-1-carboxylate (P1) and ethyl 5,6,7,8-tetrahydroindolizine-2-carboxylate, which was used in the next step without further purification and separation.

[0391] Preparation 2: 5,6,7,8-Tetrahydroindolizine-1-carboxylic acid P2 (as a mixture with 5,6,7,8-tetrahydroindolizine-2-carboxylic acid) A solution of KOH (31.3 g, 560 mmol) in 100 mL of water was added to a solution of the ester mixture (28 g, 140 mmol) obtained in Preparation 1 in methanol (300 mL). The resulting mixture was stirred and heated at 50° C. for 5 hours (TLC monitoring). Volatiles were removed under reduced pressure. The residue was diluted with water (400 mL) and acidified to pH=2 with concentrated HCl. The formed precipitate was filtered, washed with water, and dried by lyophilization to give 23 g (77%) of crude product as a mixture of isomers 5,6,7,8-tetrahydroindolizine-1-carboxylic acid (P2) and 5,6,7,8-tetrahydroindolizine-2-carboxylic acid, which was used in the next step without further purification and separation.

[0392] Preparation 3: N-(4-chlorophenyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide (P3) A mixture of the crude product from Preparation 2 (5.0 g, 30.3 mmol), 4-chloroaniline (3.8 g, 30.3 mmol), EtN (6.5 mL, 45.5 mmol), and TBTU (11.6 g, 36.3 mmol) in DCM (250 mL) was stirred at ambient temperature overnight and quenched with water (200 mL). The organic layer was separated, washed with brine, dried over NaSO, filtered, and the filtrate was evaporated under reduced pressure. The residue after evaporation was subjected to flash chromatography on silica eluting with a mixture of EtOAc (0 to 10%) and CCl to give 800 mg (10%) of the title compound P3. 4-chloro-2-(1-{[(4-chlorophenyl)amino]carbonyl}-5,6,7,8-tetrahydroindolizin-3-yl)benzoic acid (P5) [ka]

[0393] Preparation 4: Ethyl 4-chloro-2-(1-{[(4-chlorophenyl)amino]carbonyl}-5,6,7,8-tetrahydroindolizin-3-yl)benzoate (P4) A mixture of N-(4-chlorophenyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide P3 (800 mg, 2.9 mmol), ethyl 6-bromo-1,3-benzodioxole-5-carboxylate (1.5 g, 5.8 mmol), K3PO4 (3.08 g, 14.5 mmol), and pivalic acid (0.09 g, 0.8 mmol) in N,N-dimethylacetamide (10 mL) was stirred for 15 min at 135 °C, and then PdCl2(PPh3)2 (0.4 g, 0.58 mmol) was added. The resulting mixture was stirred for 30 min at 135 °C. Upon completion of the reaction, the mixture was diluted with water (20 mL) and EtOAc (20 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0→20%) and DCM to give 1.0 g (76%) of the title compound P4. ESI LCMS [MH] + : 457, 458.

[0394] Preparation 5: 4-chloro-2-(1-{[(4-chlorophenyl)amino]carbonyl}-5,6,7,8-tetrahydroindolizin-3-yl)benzoic acid (P5) A solution of ester P4 (11000 mg, 2.2 mmol) and NaOH (440 mg, 10.9 mol) in a mixture of EtOH (20 mL) and water (5 mL) was stirred at ambient temperature for 12 h. The volatiles were removed under reduced pressure, and water (20 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 20 mL). The combined organic layers were dried over NaSO and evaporated to dryness under reduced pressure to give 900 mg (97%) of the title compound P5, which was sufficiently pure for further use in the next step. ESI LCMS [MH] + : 429, 430. 3-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-chlorophenyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide (P6) [ka]

[0395] Preparation 6: 3-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-chlorophenyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide (P6) 4-Chloro-2-(1-{[(4-chlorophenyl)amino]carbonyl}-5,6,7,8-tetrahydroindolizin-3-yl)benzoic acid P5 (900 mg, 2.1 mmol), (3S)-3-(morpholin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (0.53 g, 2.3 mmol), DIPEA (0.55 mL, 3.1 mmol), and TBTU (0.8 g, 2.5 mmol), and DMF (10 mL) were dissolved in 60 mL of water. 0 The mixture was stirred at RT overnight. The reaction mixture was diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated, washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0->100%) and DCM to give 88 mg (65%) of the title compound P6. ESI LCMS [MH] + : 643, 645, 644. N-[4-(benzyloxy)phenyl]-5,6,7,8-tetrahydroindolizine-1-carboxamide (P7) [ka]

[0396] Preparation 7: N-[4-(benzyloxy)phenyl]-5,6,7,8-tetrahydroindolizine-1-carboxamide (P7) A mixture of crude product P2 (17.0 g, 100 mol), [4-(benzyloxy)phenyl]amine (18.0 g, 90 mmol), EtN (22 mL, 150 mmol), and TBTU (36.0 g, 110 mmol) in DCM (250 mL) was stirred overnight at ambient temperature and quenched with water (200 mL). The organic layer was separated, washed with brine, dried over NaSO, filtered, and the filtrate was evaporated under reduced pressure. The residue after evaporation was subjected to silica flash chromatography eluting with a mixture of EtOAc (0 to 10%) and DCM to give 14.5 g (41%) of the title compound P7. ESI LCMS [MH] + : 347. 2-[1-({[4-(benzyloxy)phenyl]amino}carbonyl)-5,6,7,8-tetrahydroindolizin-3-yl]-4-chlorobenzoic acid (P9) [ka]

[0397] Preparation 8: Ethyl 2-[1-({[4-(benzyloxy)phenyl]amino}carbonyl)-5,6,7,8-tetrahydroindolizin-3-yl]-4-chlorobenzoate (P8) A mixture of N-[4-(benzyloxy)phenyl]-5,6,7,8-tetrahydroindolizine-1-carboxamide (P7, 500 mg, 1.44 mmol), ethyl 2-bromo-4-chlorobenzoate (0.76 g, 2.9 mmol), KPO (1.53 g, 7.2 mmol), and pivalic acid (0.04 g, 0.4 mmol) in N,N-dimethylacetamide (10 mL) was stirred at 135 °C for 15 minutes, and then PdCl(PPh) (0.2 g, 0.29 mmol) was added. The resulting mixture was stirred for 30 minutes at 135 °C. Upon completion of the reaction, the mixture was diluted with water (20 mL) and EtOAc (20 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica eluting with a mixture of EtOAc (0→20%) and DCM to give 450 mg (59%) of the title compound P8. ESI LCMS [MH] + : 529.

[0398] Preparation 9: 2-[1-({[4-(benzyloxy)phenyl]amino}carbonyl)-5,6,7,8-tetrahydroindolizin-3-yl]-4-chlorobenzoic acid (P9) A solution of the ester (P8, 450 mg, 0.85 mmol) and NaOH (170 mg, 4.2 mol) in a mixture of EtOH (20 mL) and water (5 mL) was stirred at ambient temperature for 12 h. The volatiles were removed under reduced pressure, and water (20 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 20 mL). The combined organic layers were dried over NaSO and evaporated to dryness under reduced pressure to give 400 mg (94%) of the title compound P9, pure enough for further use in the next step. ESI LCMS [MH] + : 501. N-[4-(benzyloxy)phenyl]-3-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide (P10) [ka]

[0399] Preparation 10: N-[4-(benzyloxy)phenyl]-3-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide (P10) A mixture of 2-[1-({[4-(benzyloxy)phenyl]amino}carbonyl)-5,6,7,8-tetrahydroindolizin-3-yl]-4-chlorobenzoic acid (P9, 450 mg, 0.8 mmol), (3S)-3-(morpholin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (0.23 g, 1.0 mmol), DIPEA (0.2 mL, 1.2 mmol), and TBTU (0.3 g, 0.9 mmol), and DMF (10 mL) was stirred at 60 °C overnight. The reaction mixture was diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated, washed with brine, dried over Na SO , filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0→100%) and DCM to give 400 mg (70%) of the title compound P10. ESI LCMS [MH] + : 715. N-[4-(benzyloxy)phenyl]-3-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(2-cyanobenzyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide (P11) [ka]

[0400] Preparation 11. N-[4-(benzyloxy)phenyl]-3-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(2-cyanobenzyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide (P11) A mixture of N-[4-(benzyloxy)phenyl]-3-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide (P10, 200 mg, 0.28 mmol), tert-BuOK (125 mg, 1.1 mmol), and tert-BuOH (5 mL) was stirred at 50° C. for 30 minutes, and then 2-(bromomethyl)benzonitrile (110 mg, 0.56 mmol) was added. The reaction mixture was stirred at 60° C. for 1 hour and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0→100%) and DCM to give 180 mg (78%) of the title compound P11. ESI LCMS [MH] + : 830. N-[4-(benzyloxy)phenyl]-3-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide (P12) [ka]

[0401] Preparation 12. N-[4-(benzyloxy)phenyl]-3-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide (P12) A mixture of N-[4-(benzyloxy)phenyl]-3-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide (P10, 200 mg, 0.28 mmol), tert-BuOK (125 mg, 1.1 mmol), and tert-BuOH (5 mL) was stirred at 50° C. for 30 minutes, and then 3-methoxy-2-methylbenzyl methanesulfonate (130 mg, 0.56 mmol) was added. The reaction mixture was stirred at 60° C. for 1 hour and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica eluting with a mixture of EtOAc (0→100%) and DCM to give 200 mg (84%) of the title compound P12. ESI LCMS [MH] + : 849. N-(4-cyanophenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P13) [ka]

[0402] Preparation 13. N-(4-cyanophenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P13). To a stirred solution of P14 (1.0 g, 7.2 mmol) in pyridine (5 mL) was added neat SOCl (0.55 mL, 7.6 mmol) dropwise at 0 °C, and the reaction mixture was stirred at 0 °C for 3 h. Next, 4-aminobenzonitrile (0.85 g, 7.2 mmol) in DIPEA (1.4 mL, 7.96 mmol) was added dropwise, maintaining the temperature at 0 °C. The reaction was allowed to warm to ambient temperature and then stirred at ambient temperature for 16 h. The volatiles were removed under reduced pressure. The residue was diluted with water and EtO. The organic layer was separated, washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel flash chromatography eluting with a mixture of EtOAc (0 to 20%) and DCM to afford 850 mg (50%) of the title compound. 1 H NMR (400 MHz, DMSO-d6), δ: 9.70 (br. s, 1H), 7.95 (d, 1H, J = 8.7 Hz,), 7.7.73 (d, 1H, J = 8.7 Hz), 6.73 - 6.64 (m, 1H), 3.54 (s, 3H), 2.47 (s, 3H). LCMS (ESI+) m / z 240 [M+H] + . N-[4-(benzyloxy)phenyl]-1,2-dimethyl-1H-pyrrole-3-carboxamide (P15) [ka]

[0403] Preparation 14. 1,2-Dimethyl-1H-pyrrole-3-carboxylic acid (P14) A solution of NaOH (6.5 g, 163 mmol) in 10 mL of water was added to a solution of P13 in ethanol (50 mL). The resulting mixture was stirred and heated at 50° C. for 5 h (TLC monitoring). The volatiles were removed under reduced pressure. The residue was diluted with water (50 mL) and acidified to pH=2 with concentrated HCl. The resulting precipitate was filtered, washed with water, and lyophilized to give 4.0 g of P14 (88%). ESI+ LCMS [MH] + : 140.

[0404] Preparation 15. N-[4-(benzyloxy)phenyl]-1,2-dimethyl-1H-pyrrole-3-carboxamide (P15) A mixture of P14 (2.0 g, 14.4 mmol), [4-(benzyloxy)phenyl]amine (3.1 g, 15.58 mmol), EtN (3.1 mL, 21.5 mmol), and TBTU (5.5 g, 17.2 mmol) in DCM (250 mL) was stirred overnight at ambient temperature and quenched with water (200 mL). The organic layer was separated, washed with brine, dried over NaSO, filtered, and the filtrate was evaporated under reduced pressure. The residue after evaporation was subjected to silica flash chromatography eluting with a mixture of EtOAc (0 to 20%) and DCM to give 2.5 g (54%) of P15. ESI+ LCMS [MH] + : 321. 2-[4-({[4-(benzyloxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]-4-chlorobenzoic acid (P17) [ka]

[0405] Preparation 16. Ethyl 2-[4-({[4-(benzyloxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]-4-chlorobenzoate (P16) A mixture of N-[4-(benzyloxy)phenyl]-1,2-dimethyl-1H-pyrrole-3-carboxamide (P15, 1.0 g, 3.1 mmol), ethyl 6-bromo-1,3-benzodioxole-5-carboxylate (1.0 g, 3.1 mmol), KPO (3.3 g, 15.6 mmol), and pivalic acid (0.1 g, 0.9 mmol) in N,N-dimethylacetamide (10 mL) was stirred at 135 °C for 15 minutes, and then PdCl(PPh) (0.44 g, 0.6 mmol) was added. The resulting mixture was stirred for 30 minutes at 135 °C. Upon completion of the reaction, the mixture was diluted with water (20 mL) and EtOAc (20 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0→20%) and DCM to give 1.1 g (70%) of P16. ESI+ LCMS [MH] + : 503.

[0406] Preparation 17. 2-[4-({[4-(benzyloxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]-4-chlorobenzoic acid (P17) A solution of P16 (1100 mg, 2.2 mmol) and NaOH (440 mg, 10.9 mol) in a mixture of EtOH (20 mL) and water (5 mL) was stirred at ambient temperature for 12 h. The volatiles were removed under reduced pressure, and water (20 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 20 mL). The combined organic layers were dried over NaSO and evaporated to dryness under reduced pressure to give 900 mg (90%) of P17, pure enough for further use in the next step. ESI+ LCMS [MH] + : 475. N-[4-(benzyloxy)phenyl]-5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide [ka]

[0407] Preparation 18. N-[4-(benzyloxy)phenyl]-5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P18) A mixture of 2-[4-({[4-(benzyloxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]-4-chlorobenzoic acid (P17, 900 mg, 1.9 mmol), (3S)-3-(morpholin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (0.48 g, 2.1 mmol), DIPEA (0.5 mL, 2.8 mmol), and TBTU (0.73 g, 2.3 mmol), and DMF (10 mL) was stirred at 60 °C overnight. The reaction mixture was diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated, washed with brine, dried over Na SO , filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0->100%) and DCM to give 700 mg (54%) of P18. ESI LCMS [MH] + : 689. N-[4-(benzyloxy)phenyl]-5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(2-cyanobenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P19) [ka]

[0408] Preparation 19. N-[4-(benzyloxy)phenyl]-5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(2-cyanobenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P19) A mixture of N-[4-(benzyloxy)phenyl]-5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P18, 150 mg, 0.2 mmol), tert-BuOK (92 mg, 0.8 mmol), and tert-BuOH (5 mL) was stirred at 50° C. for 30 minutes, and then 2-(bromomethyl)benzonitrile (85 mg, 0.4 mmol) was added. The reaction mixture was stirred at 60° C. for 1 hour and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0->100%) and DCM to give 100 mg (57%) of P19. ESI LCMS [MH] + : 804. N-[4-(benzyloxy)phenyl]-5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P20) [ka]

[0409] Preparation 20. N-[4-(benzyloxy)phenyl]-5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P20). A mixture of N-[4-(benzyloxy)phenyl]-5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P18, 150 mg, 0.2 mmol), tert-BuOK (92 mg, 0.8 mmol), and tert-BuOH (5 mL) was stirred at 50° C. for 30 minutes, and then 3-methoxy-2-methylbenzyl methanesulfonate (98 mg, 0.4 mmol) was added. The reaction mixture was stirred at 60° C. for 12 hours and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica eluting with mixtures of EtOAc (0→100%) and DCM to afford 120 mg (67%) of P20. 4-Chloro-N-(3-methoxy-2-methylbenzyl)aniline (P23) [ka]

[0410] Preparation 21. 1-(Chloromethyl)-3-methoxy-2-methylbenzene (P21). To a solution of 3-methoxy-2-methylbenzoic acid (10.0 g, 60.2 mmol, 1 equiv.) in anhydrous THF (200 mL) was added lithium aluminum hydride (72.0 mL, 72.2 mmol, 1.2 equiv., 1 M THF solution) at 0 °C. The solution was stirred at room temperature for 16 h, after which the mixture was diluted with water and NaOH. (aq) (15%, 3 mL) and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to give P21 (9.0 g, 98% yield) as a white solid, which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3), δ: 7.18 (dd, J = 8.2, 7.8 Hz, 1H), 6.98 (d, J = 7.8 Hz, 1H), 6.83 (d, J = 8.2 Hz, 1H), 4.68 (s, 2H), 3.84 (s, 3H), 2.22 (s, 3H).

[0411] Preparation 22. 3-Methoxy-2-methylbenzaldehyde (P22). To a solution of pyridinium chlorochromate (10.6 g, 49.3 mmol, 1.5 equiv) in DCM (83 mL) was added a solution of P21 (5.0 g, 32.9 mmol, 1.0 equiv) in DCM (83 mL). After stirring the solution at room temperature for 6 h, the mixture was diluted with diethyl ether (80 mL) and filtered through a pad of Celite, washing with diethyl ether. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0–100% EtOAc in n-hexane) to give P22 (3.6 g, 72% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3), δ: 10.32 (s, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.30 (dd, J = 8.0, 7.8 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 3.87 (s, 3H), 2.54 (s, 3H).

[0412] Preparation 23. 4-Chloro-N-(3-methoxy-2-methylbenzyl)aniline (P23). To a solution of P22 (292 mg, 1.90 mmol, 1.0 equiv.), 4-chloroaniline (247 mg, 1.90 mmol, 1.0 equiv.), and AcOH (11 mg, 0.18 mmol, 0.1 equiv.) in DCM (213 mL) was added NaBH(OAc) (990 mg, 4.67 mmol, 2.5 equiv.) at room temperature, and the mixture was stirred for 16 h at room temperature. 3(aq)The mixture was treated with HCl and extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated. The residue was purified on a silica gel column (0-50% EtOAc in n-hexane) to give P23 (350 mg, 70% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3), δ: 7.18-7.09 (m, 3H), 6.93 (d, J = 7.8 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.54 (d, J = 8.8 Hz, 2H), 4.24 (d, J = 5.2 Hz, 2H), 3.84 (s, 4H, OMe and NH), 2.22 (s, 3H); LRMS (ESI+) m / z: 262.0 [M + H] + . (S)-5-(4-(difluoromethoxy)-5-fluoro-2-(3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1,2-dimethyl-1H-pyrrole-3-carbonyl chloride (P28) [ka]

[0413] Preparation 24. 2-Bromo-5-(difluoromethoxy)-4-fluorobenzoic acid (P24). Sodium hydroxide (511 mg, 12.8 mmol) was added to a solution of ethyl 2-bromo-5-(difluoromethoxy)-4-benzoate (800 mg, 2.56 mmol) in EtOH / HO (4:1, 25 mL), which was then stirred at room temperature for 3 hours. The mixture was diluted with 2N HCl (aq) The pH value (pH = 5) was adjusted with HCl and extracted with EtOAc. The combined organic layers were dried over MgSO, filtered, and concentrated in vacuo to give P24 (709 mg, 97%) as a white solid, which was used in the next step without purification. 1 H NMR (400 MHz, CD3OD), δ: 7.81 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 9.6 Hz, 1H), 6.93 (t, 2J H-F = 72.8 Hz, 1H); LCMS (ESI) m / z calculated for C8H4BrF3O3 283.93; found, 282.8 [M - H] - .

[0414] Preparation 25. (S)-(2-Bromo-5-(difluoromethoxy)-4-fluorophenyl)(3-(morpholinomethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (P25). To a solution of P24 (700 mg, 2.46 mmol) and (3S)-3-(morpholin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (627 mg, 2.70 mmol) in N,N-dimethylacetamide (25 mL) was added N,N-diisopropylethylamine (0.64 mL, 3.7 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (946 mg, 2.95 mmol). After stirring the reaction at room temperature for 1 h, the mixture was treated with water and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0–80% EtOAc in n-hexane) to give P25 (1.18 g, 96%) as a white solid. 1 H NMR (400 MHz, CDCl3), δ: 7.58-7.29 (m, 2H), 7.26-7.02 (m, 3H), 7.02-6.30 (m, 2H), 5.39-5.22 (m, 1H), 4.56-4.17 (m, 2H), 3.89-3.56 (m, 4H), 3.34-3.09 (m, 1H), 2.87-2.11 (m, 7H); LCMS (ESI) m / z C 22 H 22 Calculated for BrF3N2O3 498.08; Found 499.2 [M + H] + .

[0415] Preparation 26. Ethyl (S)-5-(4-(difluoromethoxy)-5-fluoro-2-(3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxylate (P26). A solution of P25 (680 mg, 1.36 mmol), ethyl 1,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrole-3-carboxylate (600 mg, 2.04 mmol), and cesium carbonate (887 mg, 2.72 mmol) in N,N-dimethylformamide (10 mL) was degassed with argon for 30 minutes. The mixture was then treated with bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (48 mg, 0.068 mmol) and then degassed again with argon. The mixture was stirred at 130 °C under microwave irradiation for 2 hours. The reaction was treated with water and extracted with EtOAc. The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-50% EtOAc in n-hexane) to give P26 (818 mg, 77%) as a yellow powder. 1 H NMR (400 MHz, CDCl3), δ: 7.52-7.31 (m, 1H), 7.22-6.17 (m, 7H), 5.29-4.81 (m, 1H), 4.36-4.02 (m, 3H), 3.82-3.50 (m, 4H), 3.45-3.21 (m, 2H), 3.06-2.42 (m, 6H), 2.42-1.84 (m, 8H), 1.29-1.25 (m, 3H); LCMS (ESI) m / z C 31 H 34 Calculated for F3N3O5 585.25; Found 586.8 [M + H] + .

[0416] Preparation 27. (S)-5-(4-(difluoromethoxy)-5-fluoro-2-(3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxylic acid (P27). Sodium hydroxide (208 mg, 5.21 mmol) was added to a solution of P26 (610 mg, 1.04 mmol) in ethanol (4.0 mL) and water (1.0 mL), which was then stirred at 80° C. for 16 h. The mixture was diluted with 2N HCl (aq) The pH value was adjusted to 5 with HCl and extracted with EtOAc. The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1% NH (aq) Purification with 0-10% MeOH in DCM gave P27 (500 mg, 86%) as a white solid. 1 H NMR (400 MHz, CDCl3), δ: 7.23-6.91 (m, 5H), 6.91-6.24 (m, 3H), 5.51-5.35 (m, 1H), 4.36-4.16 (m, 2H), 4.06-3.67 (m, 4H), 3.64-3.11 (m, 5H), 3.00 2.34 (m, 7H), 2.26-2.06 (m, 3H); LCMS (ESI) m / z C 29 H 30 Calculated for F3N3O5: 557.21; Found: 556.2 [M - H] - .

[0417] Preparation 28. (S)-5-(4-(difluoromethoxy)-5-fluoro-2-(3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1,2-dimethyl-1H-pyrrole-3-carbonyl chloride (P28). To a solution of P27 (100 mg, 0.179 mmol) in DCM (4.0 mL) was added oxalyl chloride (31 μL, 0.36 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated to remove the solvent to give P28 as a crude product, which was used in the next step without purification. 2-Cyclopropyl-6-(5-isopropoxy-1H-indazol-3-yl)-4-morpholinopyridazin-3(2H)-one (P34) [ka]

[0418] Preparation 29. Methyl 2-bromo-5-hydroxybenzoate (P29). To a solution of methyl 2-bromo-5-methoxybenzoate (20.0 g, 81.6 mmol) in anhydrous DCM (300 mL) was added boron tribromide (48 mL, 0.50 mmol) at −78° C. After the mixture was stirred at −78° C. for 6 h to room temperature, the reaction was cooled to 0° C. and quenched with MeOH. The solution was concentrated under reduced pressure. The residue was diluted with EtOAc and washed with aqueous sodium bicarbonate. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give P28 (3.20 g, 68%) as a white solid, which was used in the next step without further purification. 1 H NMR (400 MHz, CD3OD), δ: 7.45 (d, J = 8.8 Hz, 1H), 7.15 (d, J = 3.0 Hz, 1H), 6.83 (dd, J = 8.8, 3.0 Hz, 1H), 3.88 (s, 3H); LCMS (ESI) m / z calculated for C8H7BrO3 229.96; found 230.7 [M + H] + .

[0419] Preparation 30. Methyl 2-bromo-5-(difluoromethoxy)benzoate (P30). To a solution of potassium carbonate (14.2 g, 102 mmol) in anhydrous DMF (45 mL) at 95 °C was added a mixture of P29 (15.8 g, 68.4 mmol) and sodium chlorodifluoroacetate (20.9 g, 136 mmol) in anhydrous DMF (90 mL). After stirring the mixture at 95 °C for 30 min, the mixture was diluted with EtOAc and washed with HO and brine. The organic layer was dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0–50% EtOAc in n-hexane) to give P30 (8.2 g, 45%) as a white gum. 1 H NMR (400 MHz, CD3OD), δ: 7.73 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 2.8 Hz, 1H), 7.23 (dd, J = 8.8, 2.8 Hz, 1H), 6.90 (t, J H-F = 73.6 Hz, 1H), 3.92 (s, 3H).

[0420] Preparation 31. Methyl 2-(4-((4-(benzyloxy)phenyl)carbamoyl)-1,5-dimethyl-1H-pyrrol-2-yl)-5-(difluoromethoxy)benzoate (P31). A solution of P30 (200 mg, 0.624 mmol), N-(4-benzyloxyphenyl)-1,2-dimethylpyrrole-3-carboxamide (263 mg, 0.936 mmol), pivalic acid (19 mg, 0.19 mmol), and potassium phosphate (662 mg, 3.12 mmol) in N,N-dimethylacetamide (42 mL) was degassed with argon for 15 minutes. Next, bis(triphenylphosphine)palladium(II) dichloride (88 mg, 0.13 mmol) was added to the mixture, and the reaction was again degassed with argon for 15 minutes. After stirring the mixture at 135 °C for 3 hours, the mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography (0–80% MeOH in HO) to give P31 (219 mg, 59%) as a yellow solid. 1H NMR (400 MHz, CDCl3), δ: 7.74 (s, 1H), 7.50-7.27 (m, 10H), 6.94 (d, J = 8.8 Hz, 2H), 6.61 (t, J H-F LCMS (ESI) m / z C 29 H 26 Calculated for F2N2O5 520.18; Found 521.6 [M + H] + .Note: The degassing step is critical for yield.

[0421] Preparation 32. 2-(4-((4-(benzyloxy)phenyl)carbamoyl)-1,5-dimethyl-1H-pyrrol-2-yl)-5-(difluoromethoxy)benzoic acid (P32). To a solution of P31 (218 mg, 0.419 mmol) in EtOH (3.2 mL) and HO (0.80 mL) was added sodium hydroxide (84 mg, 2.1 mmol), which was then stirred at room temperature for 2 h. The mixture was then diluted with 2 N HCl. (aq) The mixture was adjusted to pH 5 with HCl and extracted with EtOAc. The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-10% MeOH in DCM) to give P32 (148 mg, 70%) as a white solid. 1 H NMR (400 MHz, CD3OD), δ: 7.70 (s, 1H), 7.51-7.26 (m, 9H), 7.17-6.74 (m, 3H), 6.49 (s, 1H), 5.07 (s, 2H), 3.30 (s, 3H, overlapping with solvent residue of d-methanol), 2.57 (s, 3H); LCMS (ESI) m / z C 28 H 24 Calculated for F2N2O5 506.17; Found 507.4 [M + H] + .

[0422] Preparation 33. (S)-N-(4-(benzyloxy)phenyl)-5-(4-(difluoromethoxy)-2-(3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P33). To a solution of P32 (145 mg, 0.286 mmol) and 4-[[(3S)-1,2,3,4-tetrahydroisoquinolin-3-yl]methyl]morpholine (72.9 mg, 0.315 mmol) in DMF (1.5 mL) was added N,N-diisopropylethylamine (0.075 mL, 0.43 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (110 mg, 0.344 mmol). After stirring the reaction at 60 °C overnight, the mixture was treated with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% EtOAc in DCM) to give P33 (105 mg, 51%) as a colorless gum. 1 H NMR (400 MHz, CDCl3), δ: 7.47-7.28 (m, 8H), 7.22-7.08 (m, 3H), 7.00-6.86 (m, 4H), 6.75-6.51 (m, 2H), 5.08-5.04 (m, 2H), 4.36-4.16 (m, 2H), 3.77-3.63 (m, 3H), 3.59-3.54 (m, 1H), 3.49 (s, 1H), 3.20 (s, 3H), 2.78-2.69 (m, 1H), 2.68-2.60 (m, 2H), 2.55-2.44 (m, 2H), 2.38-2.30 (m, 4H), 2.28-2.20 (m, 1H); LCMS (ESI) m / z C 42 H 42 Calculated for F2N4O5 720.31; Found 721.9 [M + H] + .

[0423] Preparation 34. 2-Cyclopropyl-6-(5-isopropoxy-1H-indazol-3-yl)-4-morpholinopyridazin-3(2H)-one (P34). A solution of P (100 mg, 0.139 mmol) and t-BuOK (93 mg, 0.83 mmol) in t-BuOH (3.5 mL) was stirred at 50 °C for 30 min, and then (3-methoxy-2-methyl-phenyl)methyl methanesulfonate (128 mg, 0.555 mmol) was added to the mixture. After stirring the mixture at 60 °C overnight, the mixture was cooled, diluted with EtOAc, and washed with brine. The organic layer was dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% EtOAc in 3% TEA in n-hexane) to give P34 (24 mg, 20%) as a colorless gum. 1 H NMR (400 MHz, CDCl3), δ: 7.42-7.36 (m, 1H), 7.35-7.27 (m, 3H), 7.20-6.94 (m, 8H), 6.89-6.62 (m, 5H), 6.62-6.40 (m, 3H), 5.23-5.00 (m, 2H), 4.99-4.90 (m, 2H), 4.82-4.63 (m, 1H), 4.31-3.93 (m, 1H), 3.86-3.75 (m, 3H), 3.72-3.60 (m, 3H), 3.55-3.48 (m, 1H), 3.27-3.19 (m, 1H), 3.10 (s, LCMS (ESI) m / z C 51 H 52 Calculated for F2N4O6 854.39; Found, 856.0 [M + H] + . 1-(chloromethyl)-3-methoxy-2-methylbenzene (P35) [ka]

[0424] Preparation 35. 1-(Chloromethyl)-3-methoxy-2-methylbenzene (P35). To a solution of (3-methoxy-2-methyl-phenyl)methanol (73.3 mg, 0.481 mmol) in DCM (1.5 mL) was added methanesulfonyl chloride (56.0 μL, 0.722 mmol) and triethylamine (134 μL, 0.963 mmol) at 0° C. The reaction solution was stirred at 0° C. for 2 h, then quenched with HO and extracted with EtOAc. The organic layer was filtered with MgSO 4 . 4(s) The extract was dried at 77° C., filtered, and concentrated under reduced pressure to give P35 (82.2 mg), which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3), δ: 7.20 (t, J = 7.6 Hz, 1H), 7.00-6.90 (m, 2H), 5.28 (s, 2H), 3.84 (s, 3H), 2.87 (s, 3H). (S)-N-(4-(benzyloxy)phenyl)-5-(5-chloro-4-(difluoromethoxy)-2-(3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P38) [ka]

[0425] Preparation 36. (S)-5-(5-chloro-4-(difluoromethoxy)-2-(3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1,2-dimethyl-1H-pyrrole-3-carbonyl chloride (P36). To a solution of 5-[5-chloro-4-(difluoromethoxy)-2-[(3S)-3-(morpholinomethyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]phenyl]-1,2-dimethyl-pyrrole-3-carboxylic acid (100 mg, 0.174 mmol) in anhydrous DCM (2.0 mL) was added dropwise oxalyl chloride (30 μL, 0.348 mmol) at 0 °C. The reaction solution was stirred at room temperature for 2 h. TLC analysis indicated that the starting material had been consumed. The solution was concentrated to remove the solvent to give crude product P36, which was used in the next step without purification.

[0426] Preparation 37. (S)-N-(4-(benzyloxy)phenyl)-5-(5-chloro-4-(difluoromethoxy)-2-(3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P37). To a solution of crude P36 in 1,2-dichloroethane (2.0 mL) were added pyridine (42.1 μL, 0.522 mmol) and 4-(benzyloxy)aniline (38.2 mg, 0.191 mmol) at room temperature. The reaction solution was stirred at 110 °C for 16 h. After cooling to room temperature, the solution was quenched with HO and extracted with EtOAc. The organic layer was filtered with MgSO. 4(s) The mixture was dried at 47° C., filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: EtOAc = 1:1) to give P37 (91.0 mg, 69% yield) as a gray solid. 1 H NMR (400 MHz, CDCl3), δ: 7.82-7.28 (m, 7H), 7.18-6.76 (m, 7H), 6.66-6.36 (m, 2H), 5.91-5.21 (m, 2H), 5.06 (s, 2H), 4.72-4.17 (m, 3H), 3.69-3.45 (m, 5H), 3.24-2.98 (m, 4H), 2.83-2.60 (m, 2H), 2.53-2.47 (m, 1H), 2.37 (m, 3H), 2.26-2.21 (m, 1H), 2.12-2.07 (m, 1H); LCMS (ESI) m / z C42 H 41 Calculated for ClF2N4O5 754.27; Found 755.3 [M + H] + .

[0427] Preparation 38. (S)-N-(4-(benzyloxy)phenyl)-5-(5-chloro-4-(difluoromethoxy)-2-(3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P38). To a solution of P37 (91.0 mg, 0.120 mmol) in tert-butanol (1.5 mL) was added potassium tert-butoxide (88.3 mg, 0.723 mmol) at room temperature. After stirring the reaction solution at 50 °C for 30 minutes, P35 (82.2 mg, 0.482 mmol) was added to the solution and further stirred at 60 °C for 1 hour. The reaction solution was cooled, quenched with HO, and extracted with EtOAc. The organic layer was then filtered with MgSO. 4(s) The mixture was dried at 47° C., filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: EtOAc = 1:1) to give P38 (40.0 mg, 37% yield) as a pale solid. 1 H NMR (400 MHz, CDCl3), δ: 7.71-7.29 (m, 7H), 7.25-6.40 (m, 12H), 5.52-5.47 (m, 1H), 5.15-4.92 (m, 3H), 4.79-4.61 (m, 1H), LCMS (ESI) m / z C 51 H 51 Calculated for ClF2N4O6 888.35; Found, 889.4 [M + H] + . 5-[4-chloro-5-(difluoromethyl)-2-[(3S)-3-(morpholinomethyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]phenyl]-1,2-dimethyl-pyrrole-3-carbonyl chloride [ka]

[0428] Preparation 39. 5-[4-Chloro-5-(difluoromethyl)-2-[(3S)-3-(morpholinomethyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]phenyl]-1,2-dimethyl-pyrrole-3-carbonyl chloride (P39). To a solution of 5-[4-chloro-5-(difluoromethyl)-2-[(3S)-3-(morpholinomethyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]phenyl]-1,2-dimethyl-pyrrole-3-carboxylic acid (150 mg, 0.27 mmol, 1.0 equiv.) in DCM (3.0 mL) was added oxalyl chloride (46 μL, 0.54 mmol, 2.0 equiv.) in an ice bath. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo to give crude P39, which was used in the next step without further isolation. (S)-N-(4-(benzyloxy)phenyl)-5-(4-chloro-5-(difluoromethyl)-2-(3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide [ka]

[0429] Preparation 40. (S)-N-(4-(benzyloxy)phenyl)-5-(4-chloro-5-(difluoromethyl)-2-(3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P40). To a solution of P39 (143 mg, 0.430 mmol) in dichloroethane (2.0 mL) was added a solution of pyridine (86 μL, 1.08 mmol) and 4-benzyloxy-N-[(3-methoxy-2-methyl-phenyl)methyl]aniline (crude, 0.358 mmol) in dichloroethane (4.0 mL) at room temperature. The mixture was stirred at 90 °C for 6 h. The reaction was quenched with NaHCO 3(aq) The mixture was quenched with and extracted with DCM. The organic layer was washed with MgSO 4(s) The mixture was dried at 77°C, filtered, and concentrated. The crude material was purified by silica gel column chromatography (0-100% EtOAc in n-hexane containing 3% triethylamine) to give P40 (65.9 mg, 21%) as a white solid. 1 H NMR (400 MHz, CDCl3), δ: 7.45-7.26 (m, 7H), 7.20-6.97 (m, 5H), 6.97-6.63 (m, 6H), 6.60-6.45 (m, 2H), 5.19-5.08 (m, 1H), 5.07-4.89 (m, 3H), 4.88-4.71 (m, 1H), 4.28-3.90 (m, 1H), 3.87-3.76 (m, 3H), 3.75-3.60 (m, 3H), 3.59-3.46 (m, 2H), 3.29-3.20 (m, 1H), 3.10 (s, 2H), 2.71-2.48 (m, LCMS (ESI) m / z C 51 H 51 Calculated for ClF2N4O5 872.35; Found, 873.4 [M + H] + . (S)-4-((1,2,3,4-tetrahydroisoquinolin-3-yl)methyl)morpholine (43) [ka]

[0430] Preparation 41. tert-Butyl (S)-3-(morpholine-4-carbonyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (P41). To a solution of tert-butyl (3S)-3-(morpholine-4-carbonyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (10 g, 36.06 mmol) in acetonitrile (100 mL) was added morpholine (3.98 mL, 46.16 mmol) and triethylamine (6.02 mL, 43.3 mmol) at room temperature, which was stirred for 20 minutes. O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) was added to the reaction mixture at room temperature. The reaction was stirred overnight at room temperature. The mixture was concentrated to give a residue. The mixture was diluted with EtOAc and then treated with aqueous sodium bicarbonate. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give product P41 (11.97 g, 94%) as a yellow solid, which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3), δ: 7.18-7.09 (m, 4H), 5.27 (br s, 1H), 4.94-4.82 (br m, 1H), 4.46-4.38 (br m, 1H), 3.69-3.58 (br m, 8H), 3.13-2.94 (m, 2H), 1.48 (br m, 9H).; LCMS (ESI) m / z C 19 H 26 Calculated for N2O4 346.19; Found 347.1 [M+H] + .

[0431] Preparation 42. (S)-Morpholino(1,2,3,4-tetrahydroisoquinolin-3-yl)methanone (P42). To a solution of P41 (9.07 g, 26.18 mmol) in 1,4-dioxane (25 mL) was added a solution of 4 M HCl in 1,4-dioxane (50 mL). The reaction was stirred at room temperature for 2 h. The solution was diluted with saturated NaCO 3(aq)The mixture was quenched with and extracted with DCM. The organic layer was dried over MgSO, filtered and concentrated to give P42 (5.1 g, 79%) as a white solid. 1 H NMR (400 MHz, DMSO-d6), δ: 7.10-7.07 (m, 3H), 7.01-6.99 (m, 1H), 3.88 (s, 2H), 3.87-3.83 (m, 1H), 3.71-3.37 (m, 9H), 2.85-2.78 (m, 1H), 2.69-2.64 (m, 1H); LCMS (ESI) m / z C 14 H 18 Calculated for N2O2 246.14; Found 247.3 [M + H] + .

[0432] Preparation 43. (S)-4-((1,2,3,4-tetrahydroisoquinolin-3-yl)methyl)morpholine (P43). To a solution of P42 (1.85 g, 7.51 mmol) in anhydrous THF (10 mL) was added LAH (15.02 mL, 15.02 mmol, 1 M in THF) at 0° C. The reaction was stirred at room temperature overnight and then diluted with water (0.60 mL) and 15% NaOH. (aq) (0.60 mL) at 0° C. The solution was filtered through a pad of Celite and washed with THF. The filtrate was collected and concentrated to give the product P43 (1.20 g, 69%) as an orange oil. 1 H NMR (400 MHz, CDCl3), δ: 7.15-7.08 (m, 3H), 7.06-7.04 (m, 1H), 4.09 (s, 2H), 3.76-3.73 (m, 4H), 3.10-3.03 (m, 1H), 2.73-2.55 (m, 4H), 2.50-2.40 (m, 4H).; LCMS (ESI) m / z C 14 H 20 Calculated for N2O 232.16; Found 233.2 [M + H] + . Ethyl 1,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-3-carboxylate (P45) [ka]

[0433] Preparation 44. Ethyl 1,2-dimethyl-1H-pyrrole-3-carboxylate (P44). To a solution of 2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (25.0 g, 163 mmol) in anhydrous DMF (200 mL) was slowly added sodium hydride (7.2 g, 18.0 mmol) at 0 °C and then stirred at room temperature for 30 minutes. The mixture was treated with methyl iodide (11 mL, 18.0 mmol) at 0 °C, and then stirred at room temperature for 16 hours. The mixture was treated with water in an ice bath and extracted with EtOAc. The combined organic layers were dried over Na SO , filtered, and concentrated under reduced pressure to give P44 (25.0 g, 91%) as an orange oil, which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3), δ: 6.50 (d, J = 3.0 Hz, 1H), 6.45 (d, J = 3.0 Hz, 1H), 4.25 (q, J = 7.2 Hz, 2H), 3.52 (s, 3H), 2.50 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H); LCMS (ESI) m / z C9H 13 Calculated for NO2 167.09; Found 168.1 [M + H] + .

[0434] Preparation 45. Ethyl 1,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-3-carboxylate (P45). To a solution of P44 (5.0 g, 30 mmol) and bis(pinacolato)diboron (8.4 g, 33 mmol) in THF (75 mL) was added 4,4'-di-tert-butyl-2,2'-bipyridyl (482 mg, 1.8 mmol) and (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (595 mg, 0.90 mmol) at room temperature. The reaction was stirred under nitrogen at 100 °C for 16 h, after which the mixture was concentrated under reduced pressure to give P45 (12.5 g, <99%) as a red solid, which was used in the next step without further purification. 1 LCMS (ESI) m / z C 15 H 24 Calculated for BNO4: 293.18; Found: 294.1 [M + H] + . (S)-(2-Bromo-4-chlorophenyl)(3-(morpholinomethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (P46) [ka]

[0435] Preparation 46. (S)-(2-Bromo-4-chlorophenyl)(3-(morpholinomethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (P46). To a solution of 2-bromo-4-chlorobenzoic acid (3.00 g, 12.7 mmol) and P43 (3.30 g, 14.0 mmol) in N,N-dimethylacetamide (42 mL) was added N,N-diisopropylethylamine (3.3 mL, 19.1 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (4.9 g, 15 mmol). After stirring the reaction at room temperature for 5 h, the mixture was treated with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0–80% EtOAc in n-hexane) to give P46 (4.9 g, 85%) as a yellow solid. 1 H NMR (400 MHz, CDCl3), δ: 7.68-7.60 (m, 1H), 7.43-7.29 (m, 2H), 7.24-7.11 (m, 3H), 6.92-6.88 (m, 1H), 5.46-5.28 (m, 1H), 4.49-4.34 (m, 1H), 4.25-4.20 (m, 1H), 3.72-3.69 (m, 3H), 3.64-3.54 (m, 2H), 3.35-3.12 (m, 1H), 2.94-2.74 (m, 1H), 2.68-2.40 (m, 2H), 2.35-2.22 (m, 1H), 2.21-2.09 (m, 2H); LCMS (ESI) m / z C 21 H 22 Calculated for BrClN2O2 448.06; Found, 449.2 [M + H] + . (S)-5-(5-chloro-2-(3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxylic acid (P48) [ka]

[0436] Preparation 47. Ethyl (S)-5-(5-chloro-2-(3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxylate (P47). A solution of P45 (559 mg, 1.3 mmol), P46 (500 mg, 1.1 mmol), and cesium carbonate (723 mg, 2.2 mmol) in DMF (5.5 mL) was degassed with argon for 30 min. The mixture was then treated with bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (39 mg, 0.06 mmol) and then degassed again with argon. The mixture was stirred at 130 °C under microwave irradiation for 2 h. The reaction was treated with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0–80% EtOAc in n-hexane) to give P47 (350 mg, 58%) as a yellow solid. 1 H NMR (400 MHz, CDCl3), δ: 7.44-7.38 (m, 2H), 7.13-7.05 (m, 3H), 6.98-6.96 (m, 1H), 6.83-6.76 (m, 1H), 6.20 (s, 1H), 5.28-5.22 (m, 1H), 4.31-4.14 (m, 4H), 3.71-3.52 (m, 5H), 3.38-3.31 (m, 1H), 3.23 (s, 3H), 3.00-2.75 (m, 1H), 2.55-2.38 (m, 4H), 2.24-2.16 (m, 4H), 2.03-1.98 (m, 2H), 1.26-1.19 (m, 3H); LCMS (ESI) m / z C 30 H 34 Calculated for ClN3O4 535.22; Found 536.4 [M + H] + .

[0437] Preparation 48. (S)-5-(5-chloro-2-(3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxylic acid (P48). To a solution of P47 (350 mg, 0.65 mmol) in ethanol (5.2 mL) and water (1.3 mL) was added sodium hydroxide (131 mg, 3.3 mmol), followed by stirring at 80° C. for 16 h. The mixture was diluted with 4 N HCl (aq) The pH was adjusted to 5 with HCl and extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-60% EtOAc in n-hexane) to give P48 (300 mg, 90%) as an orange solid. 1 H NMR (400 MHz, CDCl3), δ: 7.60-7.53 (m, 2H), 7.42 (s, 1H), 7.13-7.11 (m, 2H), 6.97-6.88 (m, 2H), 6.36 (s, 1H), 5.36 (br s, 1H), 4.30-4.16 (m, 2H), 3.89-3.79 (br m, 4H), 3.59-3.47 (m, 1H), 3.21-3.07 (m, 5H), 2.94-2.88 (m, 4H), 2.55-2.46 (m, 2H), 2.08 (s, 3H); LCMS (ESI) m / z C 28 H 30 Calculated for ClN3O4 507.19; Found 508.4 [M + H] + . N-(3-Methoxy-2-methylbenzyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (P51) [ka]

[0438] Preparation 49. 5-Nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (P48). To a solution of 5-nitro-1H-indazole (2.00 g, 12.3 mmol) in DCM (60 mL) was added 2,3-dihydropyran (2.34 mL, 24.5 mmol) and 4-methylbenzenesulfonic acid (471 mg, 2.45 mmol). After stirring the mixture at room temperature overnight, the mixture was concentrated to remove the solvent. The residue was treated with water and extracted with EtOAc. The organic layer was then washed with NaSO. 4(s) The mixture was dried at 77°C, filtered, and concentrated. The crude was purified by silica gel column chromatography (0-80% EtOAc in n-hexane) to give P49 (3.0 g, 99%). 1 H NMR (400 MHz, CDCl3), δ: 8.71 (d, J = 2.0 Hz, 1H), 8.27 (d, J = 9.2 Hz, 1H), 8.21 (s, 1H), 7.69 (d, J = 9.2 Hz, 1H), 5.77 (dd, J = 8.8, 2.4 Hz, 1H), 4.04-3.99 (m, 1H), 3.80-3.74 (m, 1H), 2.56-2.47 (m, 1H), 2.18-2.08 (m, 2H), 1.83-1.67 (m, 3H).

[0439] Preparation 50. 1-(Tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (P50). To a solution of P49 (3.00 g, 12.1 mmol) in EtOAc (120 mL) was added palladium on carbon (300 mg) at room temperature. The mixture was heated under H 2(g) The mixture was purged with HCl. The mixture was stirred at room temperature under an H atmosphere overnight. The mixture was filtered through a pad of Celite. The filtrate was then concentrated to give P50 (2.94 g, 100%), which was used in the next step without purification. 1H NMR (400 MHz, CDCl3), δ: 7.82 (s, 1H), 7.41 (d, J = 8.8 Hz, 1H), 6.93 (s, 1H), 6.89-6.87 (m, 1H), 5.64 (dd, J = 9.2, 2.8 Hz, 1H), 4.04-4.00 (m, 1H), 3.76-3.69 (m, 1H), 2.59-2.50 (m, 1H), 2.16-2.11 (m, 1H), 2.09-2.06 (m, 1H), 1.81-1.68 (m, 3H).

[0440] Preparation 51. N-(3-Methoxy-2-methylbenzyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (P51). To a solution of P50 (600 mg, 2.77 mmol) and 3-methoxy-2-methylbenzaldehyde (347 mg, 2.31 mmol) in DCM (15 mL), AcOH (1 drop) was added. The mixture was stirred at room temperature for 16 h and concentrated to remove the solvent. The residue was purified by silica gel column chromatography (10–80% EtOAc in n-hexane) to give P51 (610 mg, 75%). 1 H NMR (400 MHz, CDCl3), δ: 7.84 (s, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.14 (t, J = 8.0 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 6.85-6.79 (m, 3H), 5.64 (dd, J = 9.2, 2.8 Hz, 1H), 4.29 (s, 2H), 4.04-3.99 (m, 1H), 3.85 (s, 3H), 3.75-3.68 (m, 1H), 2.59-2.50 (m, 1H), 2.25 (s, 3H), 2.16-2.12 (m, 1H), 2.09 (s, 1H), 2.08-2.07 (m, 1H), 1.81-1.69 (m, 2H), 1.67-1.60 (m, 1H). 5-(5-chloro-2-((S)-3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-N-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1H-pyrrole-3-carboxamide (P53) [ka]

[0441] Preparation 52. (S)-5-(5-chloro-2-(3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1,2-dimethyl-1H-pyrrole-3-carbonyl chloride (P52). To a solution of P48 (200 mg, 0.390 mmol) in DCM (10 mL) was added oxalyl chloride (67 μL, 0.78 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated to remove the solvent to give P52 as a crude product, which was used in the next step without purification.

[0442] Preparation 53. 5-(5-chloro-2-((S)-3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-N-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1H-pyrrole-3-carboxamide (P53). To a solution of P51 (137 mg, 0.390 mmol) and P52 (0.390 mmol) in dichloroethane (6.5 mL) was added pyridine (94 μl, 1.17 mmol) at room temperature. The mixture was stirred at 90° C. overnight. The reaction was quenched with NaHCO 3(aq) The mixture was quenched with HCl and extracted with DCM. The organic layer was washed with NaSO. 4(s) The mixture was dried at 77°C, filtered, and concentrated. The crude was purified by silica gel column chromatography (0-10% MeOH in dichloromethane) to give P53 (212 mg, 65%). 1H NMR (400 MHz, CDCl3), δ: 7.89-7.84 (m, 1H), 7.42-7.28 (m, 2H),7.23-6.90 (m, 8H), 6.81-6.66 (m, 4H), 5.47 (br s, 1H), 5.15-4.88 (m, 4H), 3.82-3.79 (m, 3H), 3.72-3.61 (m, 3H), 3.49-3.47 (m, 2H), 3.30-3.23 (m, 2H), 3.05 (s, 2H), 2.78-2.72 (m, 1H), 2.64-2.57 (m, 1H), 2.54-2.48 (m, 2H), 2.37-2.28 (m, 2H), 2.24 (br m, 2H), 2.17 (br m, 1H), 2.07 (s, 2H), 2.04 (br s, 3H), 1.99-1.82 (m, 3H), 1.68 (br s, 3H); LCMS (ESI) m / z 841.5 [M+H] + . 2-(((1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)amino)methyl)benzonitrile (P54) [ka]

[0443] Preparation 54. 2-(((1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)amino)methyl)benzonitrile (P54). To a solution of P50 (274 mg, 1.26 mmol) and 2-(bromomethyl)benzonitrile (247 mg, 1.26 mmol) in acetonitrile (18 mL), potassium carbonate (261 mg, 1.87 mmol) was added. The mixture was stirred at 90 °C for 16 h. The mixture was concentrated to remove the solvent. The residue was purified by silica gel column chromatography (10–70% EtOAc in n-hexane) to give P54 (307 mg, 73%). 1H NMR (400 MHz, DMSO-d6), δ: 7.79 (s, 1H), 7.68-7.66 (m, 1H), 7.55-7.32 (m, 4H), 6.88-6.85 (m, 1H), 6.69 (d, J = 2.4 Hz, 1H), 5.61 (dd, J = 9.2, 2.8 Hz, 1H), 4.60 (s, 2H), 4.02-3.98 (m, 1H), 3.74-3.68 (m, 1H), 2.56-2.47 (m, 1H), 2.15-2.10 (m, 2H), 1.76-1.60 (m, 3H); LRMS (ESI) m / z 333.6 [M + H] + . 5-(5-chloro-2-((S)-3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(2-cyanobenzyl)-1,2-dimethyl-N-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1H-pyrrole-3-carboxamide (P55) [ka]

[0444] Preparation 55. 5-(5-chloro-2-((S)-3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(2-cyanobenzyl)-1,2-dimethyl-N-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1H-pyrrole-3-carboxamide (P55). To a solution of P54 (143 mg, 0.430 mmol) and P52 (crude, 0.390 mmol) in dichloroethane (6.5 mL) was added pyridine (94 μL, 1.17 mmol) at room temperature. The mixture was stirred at 90° C. overnight. The reaction was quenched with NaHCO 3(aq) The mixture was quenched with HCl and extracted with DCM. The organic layer was washed with NaSO. 4(s) The mixture was dried at 77°C, filtered, and concentrated. The crude was purified by silica gel column chromatography (0-10% MeOH in dichloromethane) to give P55 (40 mg, 12%).1 H NMR (400 MHz, CDCl3), δ: 7.88-7.81 (m, 1H), 7.66-7.60 (m, 1H),7.56-7.48 (m, 3H), 7.42-7.33 (m, 1H), 7.31-7.27 (m, 2H), 7.24-7.16 (m, 3H), 7.15-7.08 (m, 3H), 7.00-6.87 (m, 2H), 6.82-6.77 (m, 2H), 5.68-5.58 (m, 1H), 5.37-5.27 (m, 1H), 5.11-4.96 (m, 2H), 4.26-4.09 (m, 1H), 3.98-3.86 (m, 2H), 3.72-3.62 (m, 6H), 3.54-3.47 (m, 1H), 3.26-3.22 (m, 2H), 3.10 (s, 3H), 2.81-2.40 (m, 2H), 2.32-2.25 (m, LRMS (ESI) m / z 822.4 [M + H] + . N-(2-Methoxybenzyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (P56) [ka]

[0445] Preparation 56. N-(2-Methoxybenzyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (P56). To a solution of P50 (600 mg, 2.77 mmol) and 2-methoxybenzaldehyde (315 mg, 2.31 mmol) in DCM (15 mL), AcOH (1 drop) and sodium triacetoxyborohydride (1.17 g, 5.54 mmol) were added. The mixture was stirred at room temperature overnight and concentrated to remove the solvent. The residue was purified by silica gel column chromatography (10–80% EtOAc in n-hexane) to give P56 (850 mg, 91%). 1H NMR (400 MHz, CDCl3), δ: 7.80 (s, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.31-7.21 (m, 2H), 6.90-6.80 (m, 4H), 5.61 (dd, J = 9.2, 2.8 Hz, 1H), 4.31 (s, 2H), 4.01-3.97 (m, 1H), 3.86 (s, 3H), 3.73-3.67 (m, 1H), 2.53-2.49 (m, 1H), 2.16-2.00 (m, 2H), 1.76-1.60 (m, 3H); LCMS (ESI) m / z 338.2 [M + H] + . 5-(5-chloro-2-((S)-3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(2-methoxybenzyl)-1,2-dimethyl-N-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1H-pyrrole-3-carboxamide (P57) [ka]

[0446] Preparation 57. 5-(5-chloro-2-((S)-3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(2-methoxybenzyl)-1,2-dimethyl-N-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1H-pyrrole-3-carboxamide (P57). To a solution of N-(2-methoxybenzyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (P56, 238 mg, 0.71 mmol) and pyridine (140 mg, 1.77 mmol) in 1,2-dichloroethane (3.0 mL) was added a solution of P52 (311 mg, 0.59 mmol) in 1,2-dichloroethane (3.0 mL). The reaction was stirred for 16 hours at 80 °C. The solution was diluted with saturated NaHCO 3(aq) The mixture was quenched with a solution of 100 ml of NaSO and extracted with EtOAc. The combined organic layers were washed with NaSO. 4(s)The mixture was dried at 77°C, filtered, and concentrated to give a residue. The residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to give P57 (315 mg, 65% yield) as an orange solid. LCMS (ESI) m / z C 48 H 51 Calculated for ClN6O5 826.36; Found, 827.4 [M + H] + . 5-[5-chloro-4-cyano-2-[(3S)-3-(morpholinomethyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]phenyl]-N-[(3-methoxy-2-methyl-phenyl)methyl]-1,2-dimethyl-N-[4-(2-trimethylsilylethoxymethoxy)phenyl]pyrrole-3-carboxamide (P61) [ka]

[0447] Preparation 58.N 3 -(3-Methoxy-2-methylbenzyl)-1,2-dimethyl-N 3 -(4-[2-(1,1,1-trimethylsilyl)ethoxy]methoxyphenyl)-1H-pyrrole-3-carboxamide (P58). 1,2-Dimethyl-N 3 A mixture of -(4-[2-(1,1,1-trimethylsilyl)ethoxy]methoxyphenyl)-1H-pyrrole-3-carboxamide (0.85 g, 2.3 mmol), tert-BuOK (1 g, 8.9 mmol), and tert-BuOH (10 mL) was stirred at 60° C., and then 3-methoxy-2-methylbenzyl methanesulfonate (1.1 g, 4.4 mmol) was added. The reaction mixture was stirred at 60° C. for 3 hours and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel flash chromatography eluting with a mixture of EtOAc (0→100%) and DCM to give 0.95 g (82%) of the title compound. LCMS (ESI+) m / z 495 [M+H]+ .

[0448] Preparation 59. Methyl 4-chloro-5-cyano-2-4-[((3-methoxy-2-methylbenzyl)-4-[2-(1,1,1-trimethylsilyl)ethoxy]methoxyanilino)carbonyl]-1,5-dimethyl-1H-pyrrol-2-ylbenzoate (P59). A mixture of P58 (0.27 g, 0.5 mmol), methyl 2-bromo-4-chloro-5-cyanobenzoate (P63, 0.3 g, 1 mmol), KPO (0.58 g, 2.7 mmol), pivalic acid (17 mg, 0.3 equiv.), and PdCl(PPh) (77 mg, 0.2 equiv.) in N,N-dimethylacetamide (10 mL) was heated to 135 °C. The resulting mixture was stirred at 135 °C for 30 minutes, and then the reaction mixture was cooled to ambient temperature. After completion of the reaction, the mixture was diluted with water and EtOAc. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel flash chromatography eluting with a mixture of EtOAc (0 to 20%) and DCM to afford 70 mg (19%) of the title compound. LCMS (ESI+) m / z 689 [M+H] + .

[0449] Preparation 60. 4-Chloro-5-cyano-2-4-[((3-methoxy-2-methylbenzyl)-4-[2-(1,1,1-trimethylsilyl)ethoxy]methoxyanilino)carbonyl]-1,5-dimethyl-1H-pyrrol-2-ylbenzoic acid (P60). A solution of P59 (70 mg, 0.1 mmol) and NaOH (20 mg, 5.0 equiv.) in a mixture of EtOH (2 mL) and water (0.2 mL) was stirred at ambient temperature for 12 h. The volatiles were removed under reduced pressure, and water (2 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 3 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give 67 mg (99%) of the title compound, pure enough for use in the next step. LCMS (ESI+) m / z 675 [M+H] +.

[0450] Preparation 61. 5-(5-chloro-4-cyano-2-[(3R)-3-(morpholinomethyl)-3,4-dihydro-2(1H)-isoquinolinyl]carbonylphenyl)-N 3 -(3-Methoxy-2-methylbenzyl)-1,2-dimethyl-N 3 -(4-[2-(1,1,1-trimethylsilyl)ethoxy]methoxyphenyl)-1H-pyrrole-3-carboxamide (P61). A mixture of P60 (67 mg, 0.1 mmol), P43 (40 mg, 0.11 mol), DIPEA (0.04 mL, 0.15 mmol), TBTU (55 mg, 0.11 mmol), and DMF (2 mL) was stirred at 60 °C overnight. The reaction mixture was diluted with water (4 mL) and EtOAc (20 mL). The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 81 mg of crude compound, which was pure enough for use in the next step. LCMS (ESI+) m / z 889 [M+H] + Methyl-2-bromo-4-chloro-5-cyanobenzoate (P63) [ka]

[0451] Preparation 62. Methyl 2-amino-4-chloro-5-cyano-benzoate (P62). Methyl 2-amino-4-chloro-5-(1H)-isopropyl methyl ester in DMF (10 mL) 3To a stirred solution of (-iodoanilidinmethyl)benzoate (1 g, 3.2 mmol) was added Zn(CN) (0.23 g, 1.97 mmol) and Pd(PhP) (0.19 g, 0.16 mmol). The reaction mixture was then stirred at 120 °C under microwave irradiation for 2 h, then treated with water (20 mL) and extracted with EtO and EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The residue was subjected to silica gel flash chromatography eluting with a mixture of DCM to give 600 mg (89%) of compound P62.

[0452] Preparation 63. Methyl 2-bromo-4-chloro-5-cyano-benzoate (P63). To a stirred solution of P62 (150 mg, 0.7 mmol) in CHCN (3 mL) was added (CH)CNO (0.182 g, 1.8 equiv.) and CuBr (0.15 mL, 1.8 equiv.). The reaction mixture was then stirred at room temperature under microwave irradiation for 3 h, then treated with water (1 mL) and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The residue was subjected to silica gel flash chromatography eluting with a mixture of CCl:DCM to afford 0.27 g (99%) of the title compound. 2-[4-({[4-(benzyloxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]-4-chloro-5-methoxybenzoic acid (P65) [ka]

[0453] Preparation 64. Ethyl 2-[4-({[4-(benzyloxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]-4-chloro-5-methoxybenzoate (P64). A mixture of N-[4-(benzyloxy)phenyl]-1,2-dimethyl-1H-pyrrole-3-carboxamide (P15, 500 mg, 1.6 mmol), methyl 2-bromo-4-chloro-5-methoxybenzoate (870 mg, 3.1 mmol), KPO (1.6 g, 7.8 mmol), and pivalic acid (50 mg, 0.4 mmol) in N,N-dimethylacetamide (10 mL) was stirred at 135 °C for 15 minutes, and then PdCl(PPh) (0.22 g, 0.3 mmol) was added. The resulting mixture was stirred for 30 minutes at 135 °C. Upon completion of the reaction, the mixture was diluted with water (20 mL) and EtOAc (20 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica eluting with mixtures of EtOAc (0→20%) and DCM to afford 150 mg (19%) of the title compound.

[0454] Preparation 65. 2-[4-({[4-(benzyloxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]-4-chloro-5-methoxybenzoic acid (P65). A solution of P64 (150 mg, 0.29 mmol) and NaOH (58 mg, 1.4 mol) in a mixture of EtOH (10 mL) and water (2 mL) was stirred at ambient temperature for 12 h. The volatiles were removed under reduced pressure, and water (20 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 10 mL). The combined organic layers were dried over NaSO and evaporated to dryness under reduced pressure to give 130 mg (90%) of the title compound, which was sufficiently pure for use in the next step. N-[4-(benzyloxy)phenyl]-5-(5-chloro-4-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P66) [ka]

[0455] Preparation 66. N-[4-(benzyloxy)phenyl]-5-(5-chloro-4-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P66). A mixture of P65 (130 mg, 0.26 mmol), P43 (72 mg, 0.3 mmol), DIPEA (0.07 mL, 0.39 mmol), and TBTU (100 mg, 0.3 mmol) in DMF (5 mL) was stirred at 60° C. overnight. The reaction mixture was diluted with water (20 mL) and EtOAc (10 mL). The organic layer was separated, washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0 to 100%) and DCM to afford 80 mg (43%) of the title compound. N-[4-(benzyloxy)phenyl]-5-(5-chloro-4-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P67) [ka]

[0456] Preparation 67. N-[4-(Benzyloxy)phenyl]-5-(5-chloro-4-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P67). A mixture of P66 (80 mg, 0.1 mmol), tert-BuOK (50 mg, 0.4 mmol), and tert-BuOH (5 mL) was stirred at 50° C. for 30 min, then 3-methoxy-2-methylbenzyl methanesulfonate (46 mg, 0.2 mmol) was added. The reaction mixture was stirred at 60° C. for 1 h and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0 to 100%) and DCM to afford 80 mg (84%) of the title compound. [ka]

[0457] Preparation 68. Methyl 2-bromo-4-fluoro-5-methoxybenzoate (P68). To a solution of methyl 2-amino-4-fluoro-5-methoxybenzoate (0.6 g, 0.003 mol) and tert-butyl nitrite (0.55 g, 0.0054 mol) in acetonitrile (20 ml) was added CuBr (1.2 g, 0.0054 mol) at 0 °C, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was treated with water and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The residue was subjected to silica gel flash chromatography eluting with DCM to give 228 mg (29%) of the title compound. LCMS (ESI+) m / z 264 [M+H] + . 1 H NMR (400 MHz, CDCl3), δ: 7.70 (d, J=5.4Hz, 1H), 7.54 (d, J = 4.8 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H). 2-[4-({[4-(benzyloxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]-4-fluoro-5-methoxybenzoic acid (P70) [ka]

[0458] Preparation 69. Ethyl 2-[4-({[4-(benzyloxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]-4-chloro-5-methoxybenzoate (P69). A mixture of P15 (220 mg, 0.86 mmol), methyl 2-bromo-4-fluoro-5-methoxybenzoate (228 mg, 0.86 mmol), KPO (919 mg, 3.44 mmol), and pivalic acid (26 mg, 0.2 mmol) in N,N-dimethylacetamide (10 mL) was stirred at 135 °C for 15 min, and then PdCl(PPh) (150 mg, 0.17 mmol) was added. The resulting mixture was stirred for 30 min at 135 °C. Upon completion of the reaction, the mixture was diluted with water (20 mL) and EtOAc (20 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0 to 20%) and DCM to afford 180 mg (41%) of the title compound.

[0459] Preparation 70. 2-[4-({[4-(benzyloxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]-4-fluoro-5-methoxybenzoic acid (P70). A solution of P69 (365 mg, 0.729 mmol) and LiOH (174 mg, 7.29 mmol) in a mixture of THF (16 mL) and water (4 mL) was stirred at ambient temperature for 12 h. The volatiles were removed under reduced pressure, and water (20 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 10 mL). The combined organic layers were dried over NaSO and evaporated to dryness under reduced pressure to give 160 mg (55%) of the title compound, which was sufficiently pure for further use in the next step. N-[4-(benzyloxy)phenyl]-5-(5-fluoro-4-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P71) [ka]

[0460] Preparation 71. N-[4-(benzyloxy)phenyl]-5-(5-fluoro-4-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P71). A mixture of P70 (150 mg, 0.31 mmol), P43 (86 mg, 0.37 mmol), DIPEA (0.08 mL, 0.46 mmol), and TBTU (118 mg, 0.37 mmol) and DMF (8 mL) was stirred at 60° C. overnight. The reaction mixture was diluted with water (20 mL) and EtOAc (10 mL). The organic layer was separated, washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica eluting with a mixture of EtOAc (0 to 100%) and DCM to afford 50 mg (23%) of the title compound. N-[4-(benzyloxy)phenyl]-5-(5-fluoro-4-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P72) [ka]

[0461] Preparation 72. N-[4-(benzyloxy)phenyl]-5-(5-fluoro-4-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P72). A mixture of P71 (50 mg, 0.071 mmol), tert-BuOK (32 mg, 0.28 mmol), and tert-BuOH (5 mL) was stirred at 50° C. for 30 min, then 3-methoxy-2-methylbenzyl methanesulfonate (33 mg, 0.14 mmol) was added. The reaction mixture was stirred at 60° C. for 1 h and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0 to 100%) and DCM to afford 33 mg (55%) of the title compound. N-(4-chlorophenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P73) [ka]

[0462] Preparation 73. N-(4-Chlorophenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P73). To a stirred solution of P14 (1.0 g, 7.2 mmol) in pyridine (5 mL) was added SOCl (0.55 mL, 7.6 mmol) dropwise at 0 °C, and the reaction mixture was stirred at 0 °C for 3 h. Next, (4-chlorophenyl)amine (0.85 g, 7.2 mmol) in DIPEA (1.4 mL, 7.96 mmol) was added dropwise, maintaining the temperature at 0 °C. The reaction was allowed to warm to ambient temperature and then stirred at ambient temperature for 16 h. The volatiles were removed under reduced pressure. The residue was diluted with water and EtO. The organic layer was separated, washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel flash chromatography eluting with a mixture of EtOAc (0 to 20%) and DCM to afford 850 mg (50%) of the title compound. Methyl 2-bromo-5-cyano-4-fluorobenzoate (P77) [ka]

[0463] Preparation 74. Methyl 2-amino-4-fluorobenzoate (P74). SOCl2 (15.52 mL, 0.21 mol) was added to a solution of 2-amino-4-fluorobenzoic acid (30.0 g, 0.19 mol) in MeOH (0.3 L) at 0-5 °C for 15 min. After the addition was complete, the reaction was heated under reflux for an additional 16 h. MeOH was evaporated under reduced pressure. 2 M aqueous Na2CO3 (300 mL) was added to the residue, and the resulting mixture was extracted with EtOAc (400 mL). The combined organic layers were washed with brine (400 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give 18.1 g (56%) of compound P74.

[0464] Preparation 75. Methyl 2-amino-4-fluoro-5-iodobenzoate (P75). Potassium iodide (10.7 g, 64.5 mmol) in water (22.5 mL) was added dropwise over 2 h to a solution of compound P74 (10 g, 64.5 mmol), sodium periodate (13.7 g, 64.5 mmol), and sodium chloride (0.69 g, 129 mmol) in acetic acid (203.2 mL). The mixture was stirred overnight at room temperature and then poured into ice water (30 mL). The mixture was quenched with excess sodium thiosulfate solution, and the solution was extracted with DCM (6 × 50 mL). The pH of the solution was adjusted to 5 by adding 1 N NaOH. The solution was decolorized by the addition of NaHSO3, and the DCM layer was evaporated to give a brown solid. The solid was washed with water and dried in a vacuum oven to give 12.56 g (69%) of P75 as a brown solid.

[0465] Preparation 76. Methyl 2-amino-5-cyano-4-fluorobenzoate (P76). P75 (1.25 g, 4.14 mmol) was dissolved in N,N-dimethylformamide (10 mL), and zinc cyanide (0.268 g, 2.4 mmol) and tetrakis(triphenylphosphine)palladium (0.254 g, 0.2 mmol) were added. The mixture was reacted at room temperature for 0.5 hours and at 120 °C for 2 hours in a microwave oven. After the reaction was complete, the hot reaction mixture was filtered, the filtrate was poured into ice water, and the precipitate formed was filtered. The precipitate was heated with a small amount of n-hexane (3 mL), and the desired product was filtered to obtain P76 (0.6 g, 74.2%).

[0466] Preparation 77. Methyl 2-bromo-5-cyano-4-fluorobenzoate (P77). To a solution of methyl 2-amino-5-cyano-4-fluorobenzoate (0.4 g, 2.06 mmol) and tert-butyl nitrite (0.32 g, 3.12 mmol) in acetonitrile (7 ml) was added CuBr (0.69 g, 3.12 mmol) at 0 °C, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was treated with water and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The residue was subjected to silica gel flash chromatography eluting with DCM to give 500 mg (94%) of the title compound. LCMS (ESI+) m / z 259 [M+H] + . 1 H NMR (400 MHz, CDCl3), δ: 8.38 (d, J=3.6Hz, 1H), 8.15 (d, J = 4.6 Hz, 1H), 3.88 (s, 3H). 2-[4-{[(4-chlorophenyl)amino]carbonyl}-carbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]-5-cyano-4-methoxybenzoic acid (P80) [ka]

[0467] Preparation 78. Methyl 2-[4-{[(4chlorophenyl)amino]carbonyl}-1,5-dimethyl-1H-pyrrol-2-yl]-5-cyano-4-hydroxybenzoate (P78). A mixture of P73 (1.3 g, 5.2 mmol), methyl 2-bromo-5-cyano-4-fluorobenzoate (2.7 g, 10.4 mmol), KPO (5.55 g, 26 mmol), and pivalic acid (0.16 g, 1.5 mmol) in N,N-dimethylacetamide (125 mL) was stirred at 135 °C for 15 min, and then PdCl(PPh) (0.92 g, 1.07 mmol) was added. The resulting mixture was stirred for 30 min at 135 °C. Upon completion of the reaction, the mixture was diluted with water (70 mL) and EtOAc (120 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0 to 20%) and DCM to afford 800 mg (36%) of the title compound.

[0468] Preparation 79. Methyl 2-[4-{[(4chlorophenyl)amino]carbonyl}-carbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]-5-cyano-4-methoxybenzoate (P79). A suspension of P78 (0.8 g, 2.03 mmol) and KCO (0.421 g, 3.05 mmol) in DMF (10 ml) was treated with CHI (0.46 g, 3.1 mmol). The mixture was stirred at room temperature overnight, and the reaction mixture was poured into cold water. The resulting precipitate was filtered, washed with water, EtO, and air-dried to give 300 mg (34%) of the title compound.

[0469] Preparation 80. 2-[4-{[(4-chlorophenyl)amino]carbonyl}-carbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]-5-cyano-4-methoxybenzoic acid (P80). A solution of P79 (300 mg, 0.77 mmol) and LiOH (18 mg, 7.7 mmol) in a mixture of THF (8 mL) and water (2 mL) was stirred at ambient temperature for 12 h. The volatiles were removed under reduced pressure, and water (20 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 10 mL). The combined organic layers were dried over NaSO and evaporated to dryness under reduced pressure to give 280 mg (97%) of the title compound, which was sufficiently pure for use in the next step. N-(4-chlorophenyl)-5-(4-cyano-5-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P81) [ka]

[0470] Preparation 81. N-(4-chlorophenyl)-5-(4-cyano-5-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P81). A mixture of P80 (320 mg, 0.75 mmol), P43 (210 mg, 1.0 mmol), DIPEA (0.2 mL, 0.110 mmol), TBTU (292 mg, 1.0 mmol), and DMF (15 mL) was stirred at 60 °C overnight. The reaction mixture was diluted with water (20 mL) and EtOAc (10 mL). The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0 to 100%) and DCM to afford 300 mg (78%) of the title compound. 2-[4-({[4-(benzyloxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]-4-chloro-5-fluorobenzoic acid [ka]

[0471] Preparation 82. Methyl 2-[4-({[4-(benzyloxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]-4-chloro-5-fluorobenzoate (P82). A mixture of P15 (500 mg, 1.6 mmol), methyl 2-bromo-4-chloro-5-fluorobenzoate (835 mg, 3.1 mmol), KPO (1.6 g, 7.8 mmol), and pivalic acid (50 mg, 0.4 mmol) in N,N-dimethylacetamide (10 mL) was stirred at 135 °C for 15 min, and then PdCl(PPh) (0.22 g, 0.3 mmol) was added. The resulting mixture was stirred for 30 min at 135 °C. Upon completion of the reaction, the mixture was diluted with water (20 mL) and EtOAc (20 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0 to 20%) and DCM to afford 360 mg (46%) of the title compound.

[0472] Preparation 83. 2-[4-({[4-(benzyloxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]-4-chloro-5-fluorobenzoic acid (P83). A solution of P82 (360 mg, 0.7 mmol) and LiOH (82 mg, 3.5 mmol) in a mixture of THF (10 mL) and water (2 mL) was stirred at ambient temperature for 12 h. The volatiles were removed under reduced pressure, and water (20 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 10 mL). The combined organic layers were dried over NaSO and evaporated to dryness under reduced pressure to give 350 mg (99%) of the title compound, which was sufficiently pure for further use in the next step. N-[4-(benzyloxy)phenyl]-5-(5-chloro-4-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P84) [ka]

[0473] Preparation 84. N-[4-(Benzyloxy)phenyl]-5-(5-chloro-4-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P84). A mixture of P83 (350 mg, 0.7 mmol), P43 (198 mg, 0.85 mmol), DIPEA (0.18 mL, 1.1 mmol), TBTU (100 mg, 0.3 mmol), and DMF (5 mL) was stirred at 60 °C overnight. The reaction mixture was diluted with water (20 mL) and EtOAc (10 mL). The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0 to 100%) and DCM to afford 420 mg (84%) of the title compound. 5-(5-chloro-4-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-carboxamide (P87) [ka]

[0474] Preparation 85. 5-[5-chloro-4-fluoro-2-[(3S)-3-(morpholinomethyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]phenyl]-N-(4-hydroxyphenyl)-1,2-dimethyl-pyrrole-3-carboxamide (P85). A solution of P84 (420 mg, 0.6 mmol) in DCM (5 mL) was cooled to −78° C., and a solution of BBr (300 mg, 1.2 mmol) in THF (1 mL) was added over 5 min. The reaction mixture was stirred to −78° C. for 1 h and then diluted with an aqueous solution of saturated sodium bicarbonate (NaHCO). The organic layer was separated, washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was subjected to HPLC purification to give 250 mg (75%) of the title compound.

[0475] Preparation 86. 5-[5-chloro-4-fluoro-2-[(3S)-3-(morpholinomethyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]phenyl]-1,2-dimethyl-N-[4-(2-trimethylsilylethoxymethoxy)phenyl]pyrrole-3-carboxamide (P86). To a stirred solution of P85 (270 mg, 0.44 mmol) in DMF (5 mL) was added NaH (21 mg, 0.5 mmol, 60%), maintaining the temperature at 0 °C, and stirred for 30 min. Then, [2-(chloromethoxy)ethyl](trimethyl)silane (80 mg, 0.5 mmol) was added. The reaction mixture was stirred at ambient temperature overnight and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica eluting with a mixture of EtOAc (0 to 100%) and DCM to give 130 mg (40%) of the title compound.

[0476] Preparation 87. 5-(5-chloro-4-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-carboxamide (P87). A mixture of P86 (130 mg, 0.17 mmol), tert-BuOK (78 mg, 0.7 mmol), and tert-BuOH (5 mL) was stirred at 50° C. for 30 min, then 3-methoxy-2-methylbenzyl methanesulfonate (80 mg, 0.35 mmol) was added. The reaction mixture was stirred at 60° C. for 1 h and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0 to 100%) and DCM to afford 120 mg (78%) of the title compound. 2-[4-({[4-(benzyloxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]-5-cyano-4-methoxybenzoic acid (P90) [ka]

[0477] Preparation 88. Methyl 2-[4-({[4-(benzyloxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]-5-cyano-4-hydroxybenzoate (P88). A mixture of P15 (500 mg, 1.56 mmol), methyl 2-bromo-5-cyano-4-fluorobenzoate (806 mg, 3.12 mmol), KPO (1.66 mg, 7.8 mmol), and pivalic acid (47.6 mg, 0.5 mmol) in N,N-dimethylacetamide (25 mL) was stirred at 135 °C for 15 min, and then PdCl(PPh) (0.32 g, 0.3 mmol) was added. The resulting mixture was stirred for 30 min at 135 °C. Upon completion of the reaction, the mixture was diluted with water (70 mL) and EtOAc (120 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0 to 20%) and DCM to afford 520 mg (61%) of the title compound.

[0478] Preparation 89. Methyl 2-[4-({[4-(benzyloxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]-5-cyano-4-methoxybenzoate (P89). A suspension of P88 (0.5 g, 1.18 mmol) and KCO (0.245 g, 1.8 mmol) in DMF (6 ml) was treated with CHI (0.33 g, 1.8 mmol). The mixture was stirred at room temperature overnight, and the reaction mixture was poured into cold water. The formed precipitate was filtered, washed with water, EtO, and air-dried to give 240 mg (44%) of the title compound.

[0479] Preparation 90. 2-[4-({[4-(benzyloxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]-5-cyano-4-methoxybenzoic acid (P90). A solution of P89 (240 mg, 0.47 mmol) and LiOH (113 mg, 4.7 mmol) in a mixture of THF (8 mL) and water (2 mL) was stirred at ambient temperature for 12 h. The volatiles were removed under reduced pressure, and water (20 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 10 mL). The combined organic layers were dried over NaSO and evaporated to dryness under reduced pressure to give 158 mg (67%) of the title compound, which was sufficiently pure for further use in the next step. N-[4-(benzyloxy)phenyl]-5-(4-cyano-5-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P92) [ka]

[0480] Preparation 91. N-[4-(Benzyloxy)phenyl]-5-(4-cyano-5-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P91). A mixture of P90 (158 mg, 0.31 mmol), P43 (89 mg, 0.39 mmol), DIPEA (0.08 mL, 0.46 mmol), and TBTU (123 mg, 0.39 mmol) and DMF (8 mL) was stirred at 60° C. overnight. The reaction mixture was diluted with water (20 mL) and EtOAc (10 mL). The organic layer was separated, washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0 to 100%) and DCM to afford 200 mg (88%) of the title compound.

[0481] Preparation 92. N-[4-(Benzyloxy)phenyl]-5-(4-cyano-5-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P92). A mixture of P91 (200 mg, 0.28 mmol), tert-BuOK (127 mg, 1.12 mmol), and tert-BuOH (25 mL) was stirred at 50° C. for 30 min, then 3-methoxy-2-methylbenzyl methanesulfonate (130 mg, 0.56 mmol) was added. The reaction mixture was stirred at 60° C. for 1 h and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0 to 100%) and DCM to afford 160 mg (65%) of the title compound. 5-(5-nitro-2-[(3R)-3-(morpholinomethyl)-3,4-dihydro-2(1H)-isoquinolinyl]carbonylphenyl)-N 3 -(3-Methoxy-2-methylbenzyl)-1,2-dimethyl-N 3 -(1-Tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)-1H-pyrrole-3-carboxamide (P97) [ka]

[0482] Preparation 93. 1,2-Dimethyl-N 3 -(1-Tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)-1H-pyrrole-3-carboxamide (P93). To a solution of the acid (0.74 g, 5 mmol), amine P50 (1.1 g, 5 mmol), DMAP (0.8 g, 6.5 mmol), and EtN (3 mL, 5 eq.) in DCM (40 mL) was added EDCxHCl (1.2 g, 6 mmol). The reaction mixture was stirred overnight at ambient temperature and then diluted with water (40 mL). The organic layer was separated, washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0 to 100%) and CCl to give 1.35 g (75%) of P93. LCMS (ESI+) m / z 339 [M+H] + .

[0483] Preparation 94.N 3 -(3-Methoxy-2-methylbenzyl)-1,2-dimethyl-N 3 -(1-Tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)-1H-pyrrole-3-carboxamide (P94). A mixture of P93 (100 mg, 0.3 mmol), tert-BuOK (132 mg, 4 equiv.), and tert-BuOH (2 mL) was stirred at 50° C. for 5 minutes, and then 3-methoxy-2-methylbenzyl methanesulfonate (146 mg, 2 equiv.) was added. The reaction mixture was stirred at 80° C. for 2 hours and then partitioned between DCM and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0→100%) and DCM to give 50 mg of compound P94. LCMS (ESI+) m / z 473 [M+H] + .

[0484] Preparation 95. Methyl 4-nitro-2-(4-[(3-methoxy-2-methylbenzyl)(1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)amino]carbonyl-1,5-dimethyl-1H-pyrrol-2-yl)benzoate (P95). A mixture of compound P94 (400 mg, 0.8 mmol), bromide (430 mg, 1.66 mmol), KPO (896 mg, 5 equiv.), pivalic acid (26 mg, 0.3 equiv.), and PdCl(PPh) (118 mg, 0.2 equiv.) in N,N-dimethylacetamide (15 mL) was stirred at 130 °C for 2 h. Upon completion of the reaction, the reaction mixture was diluted with water (25 mL) and EtOAc (100 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0 to 20%) and DCM to afford 220 mg (45%) of the title compound. LCMS (ESI+) m / z 652 [M+H] + .

[0485] Preparation 96. 4-Nitro-2-(4-[(3-methoxy-2-methylbenzyl)(1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)amino]carbonyl-1,5-dimethyl-1H-pyrrol-2-yl)benzoic acid (P96). A solution of ester P95 (220 mg, 0.3 mmol) and NaOH (50 mg, 4 equiv.) in a mixture of MeOH / HO was stirred at ambient temperature for 12 h. The volatiles were removed under reduced pressure, and water (3 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 5 mL). The combined organic layers were dried over NaSO and evaporated to dryness under reduced pressure to give 180 mg (99%) of P96.

[0486] Preparation 97. 5-(5-nitro-2-[(3R)-3-(morpholinomethyl)-3,4-dihydro-2(1H)-isoquinolinyl]carbonylphenyl)-N 3 -(3-Methoxy-2-methylbenzyl)-1,2-dimethyl-N 3 -(1-Tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)-1H-pyrrole-3-carboxamide (P97). A mixture of P96 (180 mg, 0.28 mmol), P43 (72 mg, 0.3 mmol), DIPEA (0.0744 mL, 1.5 equiv.), and TBTU (0.10 g, 0.3 mmol) and DMF (4 mL) was stirred at 60° C. overnight. The reaction mixture was diluted with water (10 mL), and the precipitate was filtered and dried to give 180 mg of crude product P97. LCMS (ESI+) m / z 852 [M+H] + . 5-(5-nitro-2-[(3R)-3-(morpholinomethyl)-3,4-dihydro-2(1H)-isoquinolinyl]carbonylphenyl)-N 3 -(2-cyanobenzyl)-1,2-dimethyl-N 3 -(1-Tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)-1H-pyrrole-3-carboxamide (P101) [ka]

[0487] Preparation 98.N 3 -(2-cyanobenzyl)-1,2-dimethyl-N 3 -(1-Tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)-1H-pyrrole-3-carboxamide (P98). A mixture of P93 (800 mg, 2.3 mmol), tert-BuOK (1.06 g, 4 equiv.), and tert-BuOH (10 mL) was stirred at 50° C. for 5 min, then 2-(bromomethyl)benzonitrile (928 mg, 2 equiv.) was added. The reaction mixture was stirred at 80° C. for 2 h and then partitioned between DCM and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0→100%) and DCM to give 950 mg (89%) of P98. LCMS (ESI+) m / z 454 [M+H] + .

[0488] Preparation 99. Methyl 4-nitro-2-(4-[(2-cyanobenzyl)(1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)amino]carbonyl-1,5-dimethyl-1H-pyrrol-2-yl)benzoate (P99). A mixture of P98 (950 mg, 2 mmol), bromide (1.08 g, 4 mmol), KPO (2.2 g, 5 equiv.), pivalic acid (64 mg, 0.3 equiv.), PdCl (74 mg, 0.2 equiv.), and PPh (109 mg, 0.2 equiv.) in N,N-dimethylacetamide (40 mL) was stirred at 130 °C for 2 h. Upon completion of the reaction, the reaction mixture was diluted with water (40 mL) and EtOAc (150 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0 to 20%) and DCM to afford 800 mg (62%) of P99. LCMS (ESI+) m / z 633 [M+H] + .

[0489] Preparation 100. 4-Nitro-2-(4-[(2-cyanobenzyl)(1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)amino]carbonyl-1,5-dimethyl-1H-pyrrol-2-yl)benzoic acid (P100). A solution of ester P99 (800 mg, 1.3 mmol) and NaOH (300 mg, 6 equiv.) in a mixture of MeOH / HO was stirred at ambient temperature for 12 h. The volatiles were removed under reduced pressure, and water (3 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 10 mL). The combined organic layers were dried over NaSO and evaporated to dryness under reduced pressure to give 700 mg (90%) of P100.

[0490] Preparation 101. 5-(5-nitro-2-[(3R)-3-(morpholinomethyl)-3,4-dihydro-2(1H)-isoquinolinyl]carbonylphenyl)-N 3 -(2-cyanobenzyl)-1,2-dimethyl-N 3-(1-Tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)-1H-pyrrole-3-carboxamide (P101). A mixture of acid P100 (690 mg, 1.1 mmol), P43 (288 mg, 1.2 mmol), DIPEA (0.3 mL, 1.5 equiv.), and TBTU (0.4 g, 1.2 mmol) in DMF (7 mL) was stirred overnight at 60° C. The reaction mixture was diluted with water (10 mL), and the precipitate was filtered and dried to give 800 mg of P101. LCMS (ESI+) m / z 833 [M+H] + . 4-Cyano-2-(4-{[(2-methoxybenzyl)(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)amino]carbonyl}-1,5-dimethyl-1H-pyrrol-2-yl)benzoic acid (P105) [ka]

[0491] Preparation 102. Methyl 4-cyano-2-(1,5-dimethyl-4-{[(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)amino]carbonyl}-1H-pyrrol-2-yl)benzoate (P102). A mixture of 1,2-dimethyl-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-carboxamide (300 g, 0.83 mmol), methyl 2-bromo-5-cyanobenzoate (400 mg, 1.66 mol), KPO (880 g, 4.2 mmol), pivalic acid (254 g, 0.25 mmol), and PdCl(PPh) (1.2 g, 0.17 mmol) in N,N-dimethylacetamide (10 mL) was heated to 135 °C. The resulting mixture was stirred at 135 °C for 30 minutes, after which the reaction mixture was cooled to ambient temperature. After completion of the reaction, the mixture was diluted with water (30 mL) and EtO (30 mL). The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel flash chromatography eluting with a mixture of EtOAc (0→20%) and DCM to give 140 mg (33%) of the title compound. LCMS (ESI+) m / z 520 [M+H] + .

[0492] Preparation 103. 4-Cyano-2-(1,5-dimethyl-4-{[(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)amino]carbonyl}-1H-pyrrol-2-yl)benzoic acid (P103). A solution of P102 (140 mg, 0.27 mmol) and NaOH (54 mg, 1.4 mmol) in a mixture of EtOH (10 mL) and water (2 mL) was stirred at ambient temperature for 12 h. The volatiles were removed under reduced pressure, and water (20 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give 120 mg (88%) of the title compound, pure enough for use in the next step. LCMS (ESI+) m / z 506 [M+H] + .

[0493] Preparation 104. 5-(5-cyano-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-carboxamide (P104). A mixture of P103 (120 mg, 0.24 mmol), P43 (65 mg, 0.28 mmol), DIPEA (0.06 mL, 0.35 mmol), and TBTU (90 mg, 0.28 mmol) and DMF (10 mL) was stirred at 60° C. overnight. The reaction mixture was diluted with water (20 mL) and EtOAc (20 mL). The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel flash chromatography eluting with a mixture of EtOAc (0→100%) and DCM to afford 140 mg (82%) of the title compound. LCMS (ESI+) m / z 719 [M+H] + .

[0494] Preparation 105. 4-Cyano-2-(4-{[(2-methoxybenzyl)(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)amino]carbonyl}-1,5-dimethyl-1H-pyrrol-2-yl)benzoic acid (P105). A mixture of P104 (140 mg, 0.19 mmol), tert-BuOK (87 mg, 0.8 mmol), and tert-BuOH (20 mL) was stirred at 50° C. for 30 minutes, and then 1-(chloromethyl)-2-methoxybenzene (60 mg, 0.4 mmol) was added. The reaction mixture was stirred at 60° C. for 1 hour and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel flash chromatography eluting with a mixture of EtOAc (0→100%) and DCM to afford 110 mg (94%) of the title compound. LCMS (ESI+) m / z 863 [M+H] + . N-(3-Methoxy-2-methylbenzyl)-1,2-dimethyl-5-(5-(methylsulfonyl)-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-carboxamide (P109) [ka]

[0495] Preparation 106.N 3 -(3-Methoxy-2-methylbenzyl)-1,2-dimethyl-N 3 -(4-[2-(1,1,1-trimethylsilyl)ethoxy]methoxyphenyl)-1H-pyrrole-3-carboxamide (P106). A mixture of 1,2-dimethyl-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-carboxamide (0.85 g, 2.3 mmol), tert-BuOK (1 g, 8.9 mmol), and tert-BuOH (10 mL) was stirred at 60° C., and then 3-methoxy-2-methylbenzyl methanesulfonate (1.1 g, 4.4 mmol) was added. The reaction mixture was stirred at 60° C. for 3 h and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel flash chromatography eluting with a mixture of EtOAc (0→100%) and DCM to give 0.95 g (82%) of the title compound. LCMS (ESI+) m / z 495 [M+H] + .

[0496] Preparation 107. Methyl 2-(4-{[(3-methoxy-2-methylbenzyl)(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)amino]carbonyl}-1,5-dimethyl-1H-pyrrol-2-yl)-4-(methylsulfonyl)benzoate (P107). A mixture of P106 (0.3 g, 0.6 mmol), methyl 2-bromo-4-chloro-5-cyanobenzoate (P63, 0.3 g, 1.2 mmol), K3PO4 (0.58 g, 2.7 mmol), pivalic acid (17 mg, 0.3 equiv.), and PdCl2(PPh3)2 (77 mg, 2 equiv.) in N,N-dimethylacetamide (10 mL) was heated to 135 °C. The resulting mixture was stirred at 135 °C for 30 minutes, after which the reaction mixture was cooled to ambient temperature. After completion of the reaction, the mixture was diluted with water and EtOAc. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel flash chromatography eluting with a mixture of EtOAc (0 to 20%) and DCM to afford 200 mg (48%) of the title compound. LCMS (ESI+) m / z 706 [M+H] + .

[0497] Preparation 108. 2-(4-{[(3-Methoxy-2-methylbenzyl)(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)amino]carbonyl}-1,5-dimethyl-1H-pyrrol-2-yl)-4-(methylsulfonyl)benzoic acid (P108). A solution of P107 (200 mg, 0.28 mmol) and LiOH (32 mg, 1.4 mmol) in a mixture of THF (2 mL) and water (0.2 mL) was stirred at ambient temperature for 12 h. The volatiles were removed under reduced pressure, and water (2 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 3 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give 180 mg (92%) of the title compound, pure enough for use in the next step. LCMS (ESI+) m / z 692 [M+H] + .

[0498] Preparation 109. N-(3-Methoxy-2-methylbenzyl)-1,2-dimethyl-5-(5-(methylsulfonyl)-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-carboxamide (P109). A mixture of P108 (180 mg, 0.26 mmol), P43 (72 mg, 0.3 mol), DIPEA (0.07 mL, 0.4 mmol), TBTU (100 mg, 0.3 mmol), and DMF (2 mL) was stirred at 60 °C overnight. The reaction mixture was diluted with water (4 mL) and EtOAc (20 mL). The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 160 mg of crude compound, which was pure enough for use in the next step. LCMS (ESI+) m / z 908 [M+H] + . 1-(Tetrahydro-2H-pyran-2-yl)-1H-indazol-6-amine (P111) [ka]

[0499] Preparation 110. 6-Nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (P110). To a stirred solution of 6-nitro-1H-indazole (10.0 g, 0.06 mol) and dihydropyran (15.5 g, 0.18 mol) in DCM (250 mL) was added p-toluenesulfonic acid (1.06 g, 6 mmol). The mixture was stirred at room temperature for 8 hours, then diluted with DCM (100 mL), washed with saturated sodium bicarbonate solution, and purified by column chromatography (DCM:hexane = 1:2-1:1) to give the title compound (11.6 g, 76%) as a pale yellow precipitate.

[0500] Preparation 111. 1-(Tetrahydro-2H-pyran-2-yl)-1H-indazol-6-amine (P111). P110 (11.6 g, 0.47 mol) was dissolved in ethanol (300 mL). Pd / C (1.1 g, 10% w / w) was added, and the mixture was stirred under hydrogen at 20 bar for 3 hours. The catalyst was removed by filtration, and the solution was evaporated under reduced pressure to give 10 g (98%) of the title compound. 1 H NMR (400 MHz, CDCl3), δ: 7.74 (s, 1H), 7.36 (d, 1H, J = 4 Hz,) 6.61 (s, 1H), 6.53 (d, 1H, J = 4.4 Hz), 5.53 (d, 1H, J = 3.8 Hz), 5.34 (s, 1H), 3.87 (d, 1H, J = 6 Hz), 3.68-3.62 (m, 1H), 2.42 - 2.32 (m, 1H), 2.03 - 1.99 (m, 1H), 1.92 - 1.88 (m, 1H), 1.75 - 1.66 (m, 1H), 1.57 - 1.52 (m, 1H). 1,2-Dimethyl-N-[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl]-1H-pyrrole-3-carboxamide (P112) [ka]

[0501] Preparation 112. 1,2-Dimethyl-N-[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl]-1H-pyrrole-3-carboxamide (P112). To a stirred solution of P14 (7.1 g, 50.2 mmol), P111 (8.9 g, 40.1 mmol), DMAP (7.5 g, 60.1 mmol), and EtN (20 g, 28.5 mL, 0.2 mol) in DCM (50 mL) was added EDC*HCl (11.7 g, 60.1 mmol). The reaction mixture was stirred at ambient temperature overnight. After completion of the reaction (LCMS monitoring), the mixture was quenched with water (100 mL), and the organic layer was separated, washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel flash chromatography eluting with a mixture of EtOAc (0 to 20%) and DCM to afford 8.4 g (60%) of the title compound. N-(3-Methoxy-2-methylbenzyl)-1,2-dimethyl-5-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-5-nitrophenyl)-N-[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl]-1H-pyrrole-3-carboxamide (P116) [ka]

[0502] Preparation 113. N-(3-Methoxy-2-methylbenzyl)-1,2-dimethyl-N-[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl]-1H-pyrrole-3-carboxamide (P113). A mixture of P112 (1.5 g, 4.4 mmol), tert-BuOK (1.98 g, 17.6 mmol), and tert-BuOH (12 mL) was stirred at 50° C. for 30 minutes, and then 3-methoxy-2-methylbenzyl methanesulfonate (1.5 g, 8.8 mmol) was added. The reaction mixture was stirred at 60° C. for 1 hour and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0→100%) and DCM to give 1.64 g (78%) of P113. LCMS (ESI+) m / z 473 [M+H] + .

[0503] Preparation 114. Ethyl 2-[4-({(3-methoxy-2-methylbenzyl)[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl]amino}carbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]-4-nitrobenzoate (P114). A mixture of compound P113 (800 mg, 1.7 mmol), ethyl 2-bromo-4-nitrobenzoate (0.93 mg, 3.4 mmol), KPO (1.4 g, 6.8 mmol), pivalic acid (52 mg, 0.51 mmol), and PdCl(PPh) (151 mg, 0.34 mmol) in N,N-dimethylacetamide (15 mL) was stirred at 130 °C for 2 h. Upon completion of the reaction, the reaction mixture was diluted with water (25 mL) and EtOAc (100 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0 to 20%) and DCM to afford 300 mg (27%) of the title compound. LCMS (ESI+) m / z 652 [M+H] + .

[0504] Preparation 115. 2-[4-({(3-Methoxy-2-methylbenzyl)[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl]amino}carbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]-4-nitrobenzoic acid (P115). A solution of P114 (330 mg, 0.5 mmol) and NaOH (55 mg, 1.5 mmol) in a mixture of MeOH / HO was stirred at ambient temperature for 12 h. The volatiles were removed under reduced pressure, and water (20 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 10 mL). The combined organic layers were dried over NaSO and evaporated to dryness under reduced pressure to give 170 mg (53%) of the title compound, which was sufficiently pure for use in the next step.

[0505] Preparation 116. N-(3-Methoxy-2-methylbenzyl)-1,2-dimethyl-5-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-5-nitrophenyl)-N-[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl]-1H-pyrrole-3-carboxamide (P116). A mixture of P115 (170 mg, 0.26 mmol), P43 (68 mg, 0.28 mmol), DIPEA (0.07 mL, 0.39 mmol), and TBTU (94 mg, 0.28 mmol) and DMF (5 mL) was stirred at 60 °C overnight. The reaction mixture was diluted with water (10 mL), and the precipitate was filtered and dried to give 230 mg of crude product. LCMS (ESI+) m / z 853 [M+H] + . N-(2-Methoxybenzyl)-1,2-dimethyl-5-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-5-nitrophenyl)-N-[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl]-1H-pyrrole-3-carboxamide [ka]

[0506] Preparation 117. N-(2-Methoxybenzyl)-1,2-dimethyl-N-[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl]-1H-pyrrole-3-carboxamide (P117). A mixture of P112 (1.2 g, 3.5 mmol), tert-BuOK (1.6 g, 14.0 mmol), and tert-BuOH (12 mL) was stirred at 50° C. for 30 minutes, and then 2-methoxybenzyl chloride (1.1 g, 7.0 mmol) was added. The reaction mixture was stirred at 60° C. for 1 hour and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0→100%) and DCM to give 0.6 g (37%) of P117. LCMS (ESI+) m / z 459 [M+H] + .

[0507] Preparation 118. Ethyl 2-[4-({(2-methoxybenzyl)[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl]amino}carbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]-4-nitrobenzoate (P118). A mixture of compound P117 (600 mg, 1.3 mmol), ethyl 2-bromo-4-nitrobenzoate (0.71 mg, 2.6 mmol), KPO (1.1 g, 5.2 mmol), pivalic acid (40 mg, 0.39 mmol), and PdCl(PPh) (174 mg, 0.26 mmol) in N,N-dimethylacetamide (15 mL) was stirred at 130 °C for 2 h. Upon completion of the reaction, the reaction mixture was diluted with water (25 mL) and EtOAc (100 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0 to 20%) and DCM to afford 700 mg (83%) of the title compound. LCMS (ESI+) m / z 638 [M+H]+ .

[0508] Preparation 119. 2-[4-({(2-Methoxybenzyl)[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl]amino}carbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]-4-nitrobenzoic acid (P119). A solution of ethyl 2-[4-({(2-methoxybenzyl)[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl]amino}carbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]-4-nitrobenzoate (700 mg, 1.1 mmol) and NaOH (440 mg, 11.0 mmol) in a mixture of MeOH / HO was stirred at ambient temperature for 12 h. The volatiles were removed under reduced pressure, and water (20 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 50 mL). The combined organic layers were dried over NaSO and evaporated to dryness under reduced pressure to give 300 mg (44%) of the title compound of sufficient purity for further use in the next step.

[0509] Preparation 120. N-(2-Methoxybenzyl)-1,2-dimethyl-5-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-5-nitrophenyl)-N-[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl]-1H-pyrrole-3-carboxamide (P120). A mixture of P119 (300 mg, 0.48 mmol), P43 (123 mg, 0.96 mmol), DIPEA (0.125 mL, 1.43 mmol), and TBTU (174 mg, 0.72 mmol) and DMF (15 mL) was stirred at 60° C. overnight. The reaction mixture was diluted with water (100 mL), and the precipitate was filtered and dried to give 350 mg of crude product. LCMS (ESI+) m / z 838 [M+H] + . N-(2-cyanobenzyl)-1,2-dimethyl-5-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-5-nitrophenyl)-N-[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl]-1H-pyrrole-3-carboxamide (P124) [ka]

[0510] Preparation 121. N-(2-Cyanobenzyl)-1,2-dimethyl-N-[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl]-1H-pyrrole-3-carboxamide (P121). A mixture of P112 (1.5 g, 4.4 mmol), tert-BuOK (1.9 g, 17.6 mmol), and tert-BuOH (12 mL) was stirred at 50° C. for 30 minutes, and then 2-(bromomethyl)benzonitrile (1.7 g, 8.8 mmol) was added. The reaction mixture was stirred at 60° C. for 1 hour and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0→100%) and DCM to give 1.0 g (49%) of P121. LCMS (ESI+) m / z 454 [M+H] + .

[0511] Preparation 122. Ethyl 2-[4-({(2-cyanobenzyl)[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl]amino}carbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]-4-nitrobenzoate (P122). A mixture of compound P121 (1 g, 2.2 mmol), ethyl 2-bromo-4-nitrobenzoate (1.2 g, 4.4 mmol), KPO (1.8 g, 8.8 mmol), pivalic acid (67 mg, 0.66 mmol), and PdCl(PPh) (250 mg, 0.44 mmol) in N,N-dimethylacetamide (25 mL) was stirred at 130 °C for 2 h. Upon completion of the reaction, the reaction mixture was diluted with water (25 mL) and EtOAc (100 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0 to 20%) and DCM to afford 500 mg (36%) of the title compound. LCMS (ESI+) m / z 633 [M+H] + .

[0512] Preparation 123. 2-[4-({(2-cyanobenzyl)[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl]amino}carbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]-4-nitrobenzoic acid (P123). A solution of P122 (500 mg, 0.8 mmol) and NaOH (340 mg, 9.0 mmol) in a mixture of MeOH / HO was stirred at ambient temperature for 12 h. The volatiles were removed under reduced pressure, and water (20 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 50 mL). The combined organic layers were dried over NaSO and evaporated to dryness under reduced pressure to give 440 mg (94%) of the title compound, which was sufficiently pure for further use in the next step.

[0513] Preparation 124. N-(2-Cyanobenzyl)-1,2-dimethyl-5-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-5-nitrophenyl)-N-[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl]-1H-pyrrole-3-carboxamide (P124). A mixture of P123 (440 mg, 0.71 mmol), P43 (182 mg, 0.81 mmol), DIPEA (0.186 mL, 1.13 mmol), and TBTU (251 mg, 0.82 mmol) and DMF (15 mL) was stirred at 60° C. overnight. The reaction mixture was diluted with water (100 mL), and the precipitate was filtered and dried to give 350 mg of crude product. LCMS (ESI+) m / z 833 [M+H] + . 5-(5-chloro-4-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-cyanophenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P127) [ka]

[0514] Preparation 125. Methyl 4-chloro-2-(4-{[(4-cyanophenyl)amino]carbonyl}-1,5-dimethyl-1H-pyrrol-2-yl)-5-fluorobenzoate (P125). A mixture of P13 (250 mg, 1.0 mmol), methyl 2-bromo-4-chloro-5-fluorobenzoate (560 mg, 2.0 mmol), K3PO4 (1.1 g, 5.2 mmol), pivalic acid (32 mg, 0.3 mmol), and PdCl2(PPh3)2 (147 mg, 0.2 mmol) in N,N-dimethylacetamide (3 mL) was heated to 135 °C. The resulting mixture was stirred at 135 °C for 30 min, after which the reaction mixture was cooled to ambient temperature. After completion of the reaction, the mixture was diluted with water (10 mL) and Et2O (10 mL). The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel flash chromatography eluting with a mixture of EtOAc (0 to 20%) and DCM to afford 100 mg (23%) of the title compound. LCMS (ESI+) m / z 426 [M+H] + .

[0515] Preparation 126. 4-Chloro-2-(4-{[(4-cyanophenyl)amino]carbonyl}-1,5-dimethyl-1H-pyrrol-2-yl)-5-fluorobenzoic acid (P126). A solution of P125 (100 mg, 0.2 mmol) and LiOH (28 mg, 1.2 mmol) in a mixture of THF (10 mL) and water (2 mL) was stirred at ambient temperature for 12 h. The volatiles were removed under reduced pressure, and water (20 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give 80 mg (82%) of the title compound, pure enough for use in the next step. LCMS (ESI+) m / z 413 [M+H] + .

[0516] Preparation 127. 5-(5-chloro-4-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-cyanophenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P127). A mixture of P126 (80 mg, 0.05 mmol), P43 (54 mg, 0.23 mmol), DIPEA (0.050 mL, 0.3 mmol), and TBTU (75 mg, 0.23 mmol) and DMF (5 mL) was stirred at 60° C. overnight. The reaction mixture was diluted with water (200 mL) and EtOAc (200 mL). The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel flash chromatography eluting with a mixture of EtOAc (0→100%) and DCM to afford 90 mg (75%) of the title compound. LCMS (ESI+) m / z 627 [M+H] + . 2-(4-{[(4-chlorophenyl)amino]carbonyl}-1,5-dimethyl-1H-pyrrol-2-yl)-5-cyano-4-methoxybenzoic acid (P130) [ka]

[0517] Preparation 128. Methyl 2-(4-{[(4-chlorophenyl)amino]carbonyl}-1,5-dimethyl-1H-pyrrol-2-yl)-5-cyano-4-hydroxybenzoate (P128). A mixture of P73 (1.3 g, 5.2 mmol), P77 (2.7 g, 10.4 mmol), KPO (5.5 g, 26.0 mmol), and pivalic acid (0.16 g, 1.5 mmol) in N,N-dimethylacetamide (50 mL) was stirred at 135 °C for 15 min, and then PdCl(PPh) (0.9 g, 1.02 mmol) was added. The resulting mixture was stirred for 30 min at 135 °C. Upon completion of the reaction, the mixture was diluted with water (70 mL) and EtOAc (120 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0 to 20%) and DCM to afford 800 mg (36%) of the title compound.

[0518] Preparation 129. Methyl 2-(4-{[(4-chlorophenyl)amino]carbonyl}-1,5-dimethyl-1H-pyrrol-2-yl)-5-cyano-4-methoxybenzoate (P129). A suspension of methyl P128 (0.86 g, 2.03 mmol) and KCO (0.42 g, 3.0 mmol) in DMF (6 mL) was treated with CHI (0.46 g, 3.2 mmol). The mixture was stirred at room temperature overnight, and the reaction mixture was poured into cold water. The resulting precipitate was filtered, washed with water, EtO, and air-dried to give 300 mg (34%) of the title compound.

[0519] Preparation 130. 2-(4-{[(4-chlorophenyl)amino]carbonyl}-1,5-dimethyl-1H-pyrrol-2-yl)-5-cyano-4-methoxybenzoic acid (P130). A solution of P129 (100 mg, 0.223 mmol) and LiOH (55 mg, 2.23 mmol) in a mixture of THF (8 mL) and water (2 mL) was stirred at ambient temperature for 12 h. The volatiles were removed under reduced pressure, and water (20 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 10 mL). The combined organic layers were dried over NaSO and evaporated to dryness under reduced pressure to give 90 mg (93%) of the title compound, which was sufficiently pure for further use in the next step. N-(4-chlorophenyl)-5-(4-cyano-5-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P131) [ka]

[0520] Preparation 131. N-(4-chlorophenyl)-5-(4-cyano-5-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P131). A mixture of P130 (150 mg, 0.31 mmol), P43 (86 mg, 0.37 mmol), DIPEA (0.08 mL, 0.46 mmol), and TBTU (118 mg, 0.37 mmol) in DMF (8 mL) was stirred at 60 °C overnight. The reaction mixture was diluted with water (20 mL) and EtOAc (10 mL). The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0 to 100%) and DCM to afford 50 mg (23%) of the title compound. Methyl 2-bromo-4-cyanobenzoate (P132) [ka]

[0521] Preparation 132. Methyl 2-bromo-4-cyanobenzoate (P132). To a stirred solution of methyl 2-bromo-4-(iodomethyl)benzoate (1 g, 0.0028 mol) in DMF (10 mL) was added Zn(CN) (0.329 g, 0.0028 mol) and Pd(PhP) (0.325 g, 0.1 equiv.). The reaction mixture was then stirred at 100 °C overnight, then treated with water (20 mL) and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The residue was subjected to silica gel flash chromatography eluting with a mixture of DCM:CCl to afford 670 mg (99%) of the title compound. 1 H NMR (400 MHz, CDCl3), δ: 7.97 (s, 1H), 7.88 (dd, J = 2.3 Hz, J = 8.0 Hz, 1H), 7.68 (dd, J = 2.4 Hz, J = 8.1 Hz, 1H), 3.98 (s, 3H). 2-(4-[4-(benzyloxy)anilino]carbonyl-1,5-dimethyl-1H-pyrrol-2-yl)-4-cyanobenzoic acid (P134) [ka]

[0522] Preparation 133. Methyl 2-(4-[4-(benzyloxy)anilino]carbonyl-1,5-dimethyl-1H-pyrrol-2-yl)-4-cyanobenzoate (P133). A mixture of P15 (300 mg, 0.9 mmol), P132 (450 mg, 1.8 mmol), KPO (993 mg, 5 equiv.), pivalic acid (29 mg, 0.3 equiv.), and PdCl(PPh) (131 mg, 0.2 equiv.) in N,N-dimethylacetamide (15 mL) was stirred at 130 °C for 2 h. Upon completion of the reaction, the reaction mixture was diluted with water (25 mL) and EtOAc (100 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0 → 20%) and DCM to afford 266 mg (59%) of P133. LCMS (ESI+) m / z 480 [M+H] + .

[0523] Preparation 134. 2-(4-[4-(benzyloxy)anilino]carbonyl-1,5-dimethyl-1H-pyrrol-2-yl)-4-cyanobenzoic acid (P134). A solution of ester P133 (290 mg, 0.6 mmol) and LiOH (150 mg, 10 equiv.) in a mixture of THF / HO was stirred at ambient temperature for 12 h. The volatiles were removed under reduced pressure, and water (3 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 5 mL). The combined organic layers were dried over NaSO and evaporated to dryness under reduced pressure to give 280 mg (99%) of the title acid P134, pure enough for further use in the next step. LCMS (ESI+) m / z 466 [M+H] + . N 3 -[4-(Benzyloxy)phenyl]-5-(5-cyano-2-[3-(morpholinomethyl)-3,4-dihydro-2(1H)-isoquinolinyl]carbonylphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P135) [ka]

[0524] Preparation 135.N 3-[4-(Benzyloxy)phenyl]-5-(5-cyano-2-[3-(morpholinomethyl)-3,4-dihydro-2(1H)-isoquinolinyl]carbonylphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P135). A mixture of acid P134 (280 mg, 0.6 mmol), P43 (0.14 g, 0.66 mmol), DIPEA (0.14 mL, 1.5 equiv.), and TBTU (0.199 g, 0.66 mmol) and DMF (4 mL) was stirred at 60° C. overnight. The reaction mixture was diluted with water (6 mL) and EtOAc (50 ml). The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0→100%) and DCM to give 221 mg (54%) of the title compound. LCMS (ESI+) m / z 680 [M+H] + . 5-(5-cyano-2-[3-(morpholinomethyl)-3,4-dihydro-2(1H)-isoquinolinyl]carbonylphenyl)-N 3 -(4-Hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P136) [ka]

[0525] Preparation 136.N 3 -[4-(Benzyloxy)phenyl]-5-(5-cyano-2-[3-(morpholinomethyl)-3,4-dihydro-2(1H)-isoquinolinyl]carbonylphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P136). A solution of compound P135 (220 mg, 0.3 mmol) in DCM (5 mL) was cooled to -78 °C, and a solution of BBr3 (0.09 ml, 0.6 mmol) was added over 5 min. The reaction mixture was stirred at -78 °C for 1 h and then diluted with an aqueous solution of saturated sodium bicarbonate NaHCO3. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc to give 202 mg (98%) of the title compound. LCMS (ESI+) m / z 590 [M+H] + . 5-(5-cyano-2-[3-(morpholinomethyl)-3,4-dihydro-2(1H)-isoquinolinyl]carbonylphenyl)-1,2-dimethyl-N 3 -(4-[2-(1,1,1-trimethylsilyl)ethoxy]methoxyphenyl)-1H-pyrrole-3-carboxamide (P137) [ka]

[0526] Preparation 137. 5-(5-cyano-2-[3-(morpholinomethyl)-3,4-dihydro-2(1H)-isoquinolinyl]carbonylphenyl)-1,2-dimethyl-N 3 -(4-[2-(1,1,1-trimethylsilyl)ethoxy]methoxyphenyl)-1H-pyrrole-3-carboxamide (P137). To a stirred solution of P136 (200 mg, 0.3 mmol) in DMF (5 mL) was added NaH (0.5 mmol, 60%), maintaining the temperature at 0 °C, and stirred for 30 min. Then, [2-(chloromethoxy)ethyl](trimethyl)silane (0.1 mL, 0.45 mmol) was added. The reaction mixture was stirred overnight at ambient temperature and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0 → 100%) and DCM to give 123 mg (50%) of the title compound. LCMS (ESI+) m / z 720 [M+H] + . 5-(5-cyano-2-[3-(morpholinomethyl)-3,4-dihydro-2(1H)-isoquinolinyl]carbonylphenyl)-N 3 -(3-Methoxy-2-methylbenzyl)-1,2-dimethyl-N 3 -(4-[2-(1,1,1-trimethylsilyl)ethoxy]methoxyphenyl)-1H-pyrrole-3-carboxamide (P138) [ka]

[0527] Preparation 138. 5-(5-cyano-2-[3-(morpholinomethyl)-3,4-dihydro-2(1H)-isoquinolinyl]carbonylphenyl)-N 3 -(3-Methoxy-2-methylbenzyl)-1,2-dimethyl-N 3 -(4-[2-(1,1,1-trimethylsilyl)ethoxy]methoxyphenyl)-1H-pyrrole-3-carboxamide (P138). A mixture of P137 (120 mg, 0.16 mmol), tert-BuOK (80 mg, 4 equiv.), and tert-BuOH (3 mL) was stirred at 50° C. for 5 min, then 3-methoxy-2-methylbenzyl methanesulfonate (80 mg, 2 equiv.) was added. The reaction mixture was stirred at 80° C. for 0.5 h and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0→100%) and DCM to give 50 mg of P138. LCMS (ESI+) m / z 854 [M+H] + . 5-(5-(aminocarbonyl)-2-[3-(morpholinomethyl)-3,4-dihydro-2(1H)-isoquinolinyl]carbonylphenyl)-N 3 -(3-Methoxy-2-methylbenzyl)-1,2-dimethyl-N 3 -(4-[2-(1,1,1-trimethylsilyl)ethoxy]methoxyphenyl)-1H-pyrrole-3-carboxamide (P139) [ka]

[0528] Preparation 139. 5-(5-(aminocarbonyl)-2-[3-(morpholinomethyl)-3,4-dihydro-2(1H)-isoquinolinyl]carbonylphenyl)-N 3 -(3-Methoxy-2-methylbenzyl)-1,2-dimethyl-N 3 -(4-[2-(1,1,1-trimethylsilyl)ethoxy]methoxyphenyl)-1H-pyrrole-3-carboxamide (P139). A mixture of P138 (120 mg, 0.16 mmol), tert-BuOK (80 mg, 4 equiv.), and tert-BuOH (3 mL) was stirred at 50° C. for 30 minutes, and then 3-methoxy-2-methylbenzyl methanesulfonate (80 mg, 2 equiv.) was added. The reaction mixture was stirred at 60° C. for 3 hours and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0→100%) and DCM to give 70 mg of compound P139. LCMS (ESI+) m / z 872 [M+H] + . 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-cyanophenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P142) [ka]

[0529] Preparation 140. N-(4-Cyanophenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P140). To a stirred solution of P13 (1.0 g, 7.2 mmol) in pyridine (5 mL) was added neat SOCl (0.55 mL, 7.6 mmol) dropwise at 0 °C, and the reaction mixture was stirred at 0 °C for 3 h. Next, 4-aminobenzonitrile (0.85 g, 7.2 mmol) in DIPEA (1.4 mL, 7.96 mmol) was added dropwise, maintaining the temperature at 0 °C. The reaction was allowed to warm to ambient temperature and then stirred at ambient temperature for 16 h. The volatiles were removed under reduced pressure. The residue was diluted with water and EtO. The organic layer was separated, washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel flash chromatography eluting with a mixture of EtOAc (0 to 20%) and DCM to afford 850 mg (50%) of the title compound. 1H NMR (400 MHz, DMSO-d6), δ: 9.70 (br. s, 1H), 7.95 (d, 1H, J = 8.7 Hz,), 7.73 (d, 1H, J = 8.7 Hz), 6.73 - 6.64 (m, 1H), 3.54 (s, 3H), 2.47 (s, 3H). LCMS (ESI+) m / z 240 [M+H] + .

[0530] Preparation 141. 4-Chloro-2-(4-{[(4-cyanophenyl)amino]carbonyl}-1,5-dimethyl-1H-pyrrol-2-yl)benzoic acid (P141). A solution of P140 (200 mg, 0.47 mmol) and LiOH (54 mg, 2.4 mmol) in a mixture of EtOH (10 mL) and water (2 mL) was stirred at ambient temperature for 12 h. The volatiles were removed under reduced pressure, and water (20 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give 180 mg (96%) of the title compound, pure enough for use in the next step. LCMS (ESI+) m / z 394 [M+H] + .

[0531] Preparation 142. 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-cyanophenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P142). A mixture of P141 (180 mg, 0.45 mmol), P43 (127 mg, 0.55 mmol), DIPEA (0.12 mL, 0.69 mmol), and TBTU (176 mg, 0.55 mmol) and DMF (5 mL) was stirred at 60° C. overnight. The reaction mixture was diluted with water (200 mL) and EtOAc (200 mL). The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel flash chromatography eluting with a mixture of EtOAc (0→100%) and DCM to afford 170 mg (61%) of the title compound. LCMS (ESI+) m / z 609 [M+H] + . N-(2-cyanobenzyl)-1,2-dimethyl-5-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-5-nitrophenyl)-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-carboxamide (P146) [ka]

[0532] Preparation 143. Methyl 2-(1,5-dimethyl-4-{[(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)amino]carbonyl}-1H-pyrrol-2-yl)-4-nitrobenzoate (P143). A mixture of 1,2-dimethyl-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-carboxamide (500 g, 1.4 mmol), methyl 2-bromo-4-nitrobenzoate (720 mg, 2.8 mol), KPO (1.47 g, 6.9 mmol), pivalic acid (42 mg, 0.4 mmol), and PdCl(PPh) (194 mg, 0.28 mmol) in N,N-dimethylacetamide (50 mL) was heated to 135 °C. The resulting mixture was stirred at 135 °C for 30 minutes, after which the reaction mixture was cooled to ambient temperature. After completion of the reaction, the mixture was diluted with water (50 mL) and EtO (50 mL). The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel flash chromatography eluting with a mixture of EtOAc (0→20%) and DCM to give 40 mg (59%) of the title compound. LCMS (ESI+) m / z 540 [M+H] + .

[0533] Preparation 144. 2-(1,5-Dimethyl-4-{[(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)amino]carbonyl}-1H-pyrrol-2-yl)-4-nitrobenzoic acid (P144). A solution of P143 (440 mg, 0.8 mmol) and NaOH (162 mg, 4.0 mmol) in a mixture of EtOH (40 mL) and water (5 mL) was stirred at ambient temperature for 12 h. The volatiles were removed under reduced pressure, and water (50 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 40 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give 400 mg (94%) of the title compound, pure enough for use in the next step. LCMS (ESI+) m / z 525 [M+H] + .

[0534] Preparation 145. 1,2-Dimethyl-5-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-5-nitrophenyl)-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-carboxamide (P145). A mixture of P144 (400 mg, 0.76 mmol), P43 (210 mg, 0.9 mmol), DIPEA (0.2 mL, 1.15 mmol), and TBTU (290 mg, 0.9 mmol) and DMF (10 mL) was stirred at 60° C. overnight. The reaction mixture was diluted with water (20 mL) and EtOAc (20 mL). The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel flash chromatography eluting with a mixture of EtOAc (0→100%) and DCM to afford 450 mg (80%) of the title compound. LCMS (ESI+) m / z 740 [M+H] + .

[0535] Preparation 146. N-(2-Cyanobenzyl)-1,2-dimethyl-5-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-5-nitrophenyl)-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-carboxamide (P146). A mixture of P146 (150 mg, 0.2 mmol), tert-BuOK (87 mg, 0.8 mmol), and tert-BuOH (20 mL) was stirred at 50° C. for 30 minutes, and then 2-(bromomethyl)benzonitrile (80 mg, 0.4 mmol) was added. The reaction mixture was stirred at 60° C. for 1 hour and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel flash chromatography eluting with a mixture of EtOAc (0→100%) and DCM to give 120 mg (70%) of the title compound. LCMS (ESI+) m / z 856 [M+H]+ . N-(3-Methoxy-2-methylbenzyl)-1,2-dimethyl-5-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-5-nitrophenyl)-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-carboxamide (P147) [ka]

[0536] Preparation 147. N-(3-Methoxy-2-methylbenzyl)-1,2-dimethyl-5-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-5-nitrophenyl)-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-carboxamide (P146). A mixture of P145 (200 mg, 0.27 mmol), tert-BuOK (120 mg, 1.1 mmol), and tert-BuOH (20 mL) was stirred at 50° C. for 30 minutes, and then 3-methoxy-2-methylbenzyl methanesulfonate (124 mg, 0.54 mmol) was added. The reaction mixture was stirred at 60° C. for 1 hour and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel flash chromatography eluting with a mixture of EtOAc (0→100%) and DCM to give 210 mg (89%) of the title compound. LCMS (ESI+) m / z 875 [M+H] + . 5-(5-(Acetylamino)-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-carboxamide (P149) [ka]

[0537] Preparation 148. 5-(5-amino-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-carboxamide (P148). A stirred mixture of P145 (200 mg, 0.2 mmol), catalyst (5 mg of 5% Pd on activated carbon), and t-butanol (2 mL) was hydrogenated under an atmosphere of H220 for 56 h. The catalyst was filtered and the filtrate was evaporated to dryness to give 180 mg (93%) of the title compound.

[0538] Preparation 149. 5-(5-(Acetylamino)-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-carboxamide (P149). A stirred mixture of P148 (180 mg, 0.21 mmol), AcO (22 mg, 0.21 mmol), and DCM (2 mL) was stirred at ambient temperature for 3 h and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel flash chromatography eluting with a mixture of EtOAc (0→100%) and DCM to afford 150 mg (80%) of the title compound. LCMS (ESI+) m / z 887 [M+H] + . 2-[4-({[4-(benzyloxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]-4,5-difluorobenzoic acid (P151) [ka]

[0539] Preparation 150. Methyl 2-[4-({[4-(benzyloxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]-4,5-difluorobenzoate (P150). A mixture of N-[4-(benzyloxy)phenyl]-1,2-dimethyl-1H-pyrrole-3-carboxamide (500 mg, 1.6 mmol), methyl 2-bromo-4,5-difluorobenzoate (785 mg, 3.1 mmol), KPO (1.6 g, 7.8 mmol), and pivalic acid (50 mg, 0.4 mmol) in N,N-dimethylacetamide (10 mL) was stirred at 135 °C for 15 minutes, and then PdCl(PPh) (0.22 g, 0.3 mmol) was added. The resulting mixture was stirred for 30 minutes at 135 °C. Upon completion of the reaction, the mixture was diluted with water (20 mL) and EtOAc (20 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica eluting with mixtures of EtOAc (0→20%) and DCM to afford 400 mg (53%) of the title compound.

[0540] Preparation 151. 2-[4-({[4-(benzyloxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]-4,5-difluorobenzoic acid (P151). A solution of P150 (400 mg, 0.8 mmol) and NaOH (165 mg, 4.0 mmol) in a mixture of MeOH (10 mL) and water (2 mL) was stirred at ambient temperature for 12 h. The volatiles were removed under reduced pressure, and water (20 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 10 mL). The combined organic layers were dried over NaSO and evaporated to dryness under reduced pressure to give 380 mg (98%) of the title compound, which was sufficiently pure for further use in the next step. N-[4-(benzyloxy)phenyl]-5-(4,5-difluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P152) [ka]

[0541] Preparation 152. N-[4-(Benzyloxy)phenyl]-5-(4,5-difluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P152). A mixture of P151 (380 mg, 0.8 mmol), P43 (220 mg, 0.95 mmol), DIPEA (0.2 mL, 1.2 mmol), TBTU (300 mg, 0.95 mmol), and DMF (5 mL) was stirred at 60 °C overnight. The reaction mixture was diluted with water (20 mL) and EtOAc (10 mL). The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0 to 100%) and DCM to afford 300 mg (55%) of the title compound. N-[4-(benzyloxy)phenyl]-5-(4,5-difluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P153) [ka]

[0542] Preparation 153. N-[4-(Benzyloxy)phenyl]-5-(4,5-difluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P153). A mixture of P152 (100 mg, 0.14 mmol), tert-BuOK (65 mg, 0.56 mmol), and tert-BuOH (5 mL) was stirred at 50° C. for 30 min, then 3-methoxy-2-methylbenzyl methanesulfonate (67 mg, 0.28 mmol) was added. The reaction mixture was stirred at 60° C. for 1 h and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0 to 100%) and DCM to afford 70 mg (58%) of the title compound. N-[4-(benzyloxy)phenyl]-5-(4,5-difluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P154) [ka]

[0543] Preparation 154. N-[4-(Benzyloxy)phenyl]-5-(4,5-difluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P154). A mixture of P152 (100 mg, 0.14 mmol), tert-BuOK (65 mg, 0.56 mmol), and tert-BuOH (5 mL) was stirred at 50° C. for 30 min, then 2-(bromomethyl)benzonitrile (57 mg, 0.28 mmol) was added. The reaction mixture was stirred at 60° C. for 1 h and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0 to 100%) and DCM to afford 100 mg (86%) of the title compound. (4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)amine (P156) [ka]

[0544] Preparation 155. Trimethyl{2-[(4-nitrophenoxy)methoxy]ethyl}silane (P155). To a stirred solution of 4-nitrophenol (50.0 g, 0.36 mol) and EtN (78 mL, 0.54 mol) in DCM (500 mL) was added SemCl (100 mL, 0.40 mol, 70%) dropwise at 0 °C, and the reaction mixture was stirred at 0 °C for 30 min. The reaction was allowed to warm to ambient temperature and then stirred at ambient temperature for 4 h. Water was added, the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The residue was used in the next step without further purification or separation.

[0545] Preparation 156. 4-{[2-(trimethylsilyl)ethoxy]methoxy}aniline (P156). P155 (97 g, 0.36 mol) was dissolved in ethanol (1000 mL). Pd / C (5.0 g, 10% w / w) was added, and the mixture was stirred under hydrogen at 20 bar for 3 h. The catalyst was removed by filtration, and the solution was evaporated under reduced pressure. The residue was subjected to silica gel flash chromatography eluting with a mixture of EtOAc (0 to 10%) and DCM to give 60 g (70%) of the title compound. 1 H NMR (400 MHz, CDCl3), δ: 6.90-6.89 (m, 4H), 6.73 - 6.56 (m, 4H), 5.13 (s, 2H), 3.82 - 3.69 (m, 2H), 3.59 - 3.19 (m, 2H), 1.03 - 0.90 (m, 2H), 0.08 - -0.07 (m, 9H). 1,2-Dimethyl-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-carboxamide (P157) [ka]

[0546] Preparation 157. 1,2-Dimethyl-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-carboxamide (P157). To a stirred solution of P14 (45.0 g, 0.32 mol) in pyridine (500 mL) was added neat SOCl2 (28 mL, 0.39 mol) dropwise at 0 °C, and the reaction mixture was stirred at 0 °C for 3 h. Next, P156 (61.8 g, 0.26 mmol) in Et3N (117 mL, 0.8 mol) was added dropwise, maintaining the temperature at 0 °C. The reaction was allowed to warm to ambient temperature and then stirred at ambient temperature for 16 h. The volatiles were removed under reduced pressure. The residue was diluted with water and Et2O. The organic layer was separated, washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel flash chromatography eluting with a mixture of EtOAc (0 to 20%) and DCM to afford 48 g (42%) of the title compound. 1H NMR (400 MHz, DMSO-d6), δ: 9.21 (s, 1H), 7.91 (d, J = 9.0 Hz, 1H), 7.76-7.65 (m, 3H), 6.65 (dd, J = 13.8, 3.0 Hz, 1H), 6.96-9.62 (m, 2 LCMS (ESI+) m / z 361[M+H] + . 5-Chloro-2-(1,5-dimethyl-4-{[(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)amino]carbonyl}-1H-pyrrol-2-yl)-3-methylbenzoic acid (P159) [ka]

[0547] Preparation 158. Methyl 5-chloro-2-(1,5-dimethyl-4-{[(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)amino]carbonyl}-1H-pyrrol-2-yl)-3-methylbenzoate (P158). A mixture of P157 (0.5 g, 1.38 mmol), methyl 2-bromo-5-chloro-3-methylbenzoate (0.7 g, 2.76 mmol), K3PO4 (1.18 g, 5.6 mmol), and pivalic acid (0.04 g, 0.4 mmol) in N,N-dimethylacetamide (10 mL) was stirred at 135 °C for 15 min, and then PdCl2(PPh3)2 (0.25 g, 0.1 mmol) was added. The resulting mixture was stirred for 30 min at 135 °C. Upon completion of the reaction, the mixture was diluted with water (70 mL) and EtOAc (120 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0 to 20%) and DCM to afford 200 mg (26%) of the title compound.

[0548] Preparation 159. 5-Chloro-2-(1,5-dimethyl-4-{[(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)amino]carbonyl}-1H-pyrrol-2-yl)-3-methylbenzoic acid (P159). A solution of P158 (200 mg, 0.136 mmol) and LiOH (88 mg, 1.36 mmol) in a mixture of THF (8 mL) and water (2 mL) was stirred at ambient temperature for 12 h. The volatiles were removed under reduced pressure, and water (20 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 10 mL). The combined organic layers were dried over NaSO and evaporated to dryness under reduced pressure to give 190 mg (97%) of the title compound, which was sufficiently pure for further use in the next step. 5-(4-chloro-2-methyl-6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-carboxamide (P160) [ka]

[0549] Preparation 160. 5-(4-chloro-2-methyl-6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-carboxamide (P160). A mixture of P159 (190 mg, 0.378 mmol), P43 (105 mg, 0.42 mmol), DIPEA (0.098 mL, 0.56 mmol), TBTU (146 mg, 0.42 mmol), and DMF (15 mL) was stirred at 60 °C overnight. The reaction mixture was diluted with water (20 mL) and EtOAc (10 mL). The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0 to 100%) and DCM to afford 200 mg (72%) of the title compound. 5-(4-chloro-2-methyl-6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-carboxamide (P161) [ka]

[0550] Preparation 161. 5-(4-chloro-2-methyl-6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-carboxamide (P161). A mixture of P160 (80 mg, 0.112 mmol), tert-BuOK (51 mg, 0.448 mmol), and tert-BuOH (9 mL) was stirred at 50° C. for 30 min, then 3-methoxy-2-methylbenzyl methanesulfonate (53 mg, 0.224 mmol) was added. The reaction mixture was stirred at 60° C. for 1 h and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0 to 100%) and DCM to give 30 mg (21%). 5-(4-chloro-2-methyl-6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(2-methoxybenzyl)-1,2-dimethyl-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-carboxamide (P162) [ka]

[0551] Preparation 162. 5-(4-chloro-2-methyl-6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(2-methoxybenzyl)-1,2-dimethyl-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-carboxamide (P162). A mixture of P160 (80 mg, 0.112 mmol), tert-BuOK (48 mg, 0.448 mmol), and tert-BuOH (9 mL) was stirred at 50° C. for 30 min, then 2-methoxybenzyl methanesulfonate (34 mg, 0.224 mmol) was added. The reaction mixture was stirred at 60° C. for 1 h and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0 to 100%) and DCM to give 30 mg (21%). Methyl 2-bromo-4-fluorobenzoate (P163) [ka]

[0552] Preparation 163. Methyl 2-bromo-4-fluorobenzoate (P163). To a solution of P74 (2.2 g, 13.92 mmol) and tert-butyl nitrite (2.59 g, 25.06 mmol) in acetonitrile (50 ml) was added CuBr (5.69 g, 25.06 mmol) at 0 °C, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was treated with water and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The residue was subjected to silica gel flash chromatography eluting with DCM to give the title compound (1.4 g, 47%). LCMS (ESI+) m / z 234 [M+H] + . 1 H NMR (400 MHz, CDCl3), δ: 7.87(t, J=6.8Hz, 1H), 7.74 (d, J = 5.4 Hz, 1H), 7.39(t, J=8.8Hz, 1H), 3.85 (s, 3H). 2-[4-({[4-(benzyloxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]-4-fluorobenzoic acid (P165) [ka]

[0553] Preparation 164. Ethyl 2-[4-({[4-(benzyloxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]-4-fluorobenzoate (P164). A mixture of P15 (500 mg, 1.56 mmol), P163 (728 mg, 3.12 mmol), K3PO4 (1.32 g, 6.24 mmol), and pivalic acid (47 mg, 0.38 mmol) in N,N-dimethylacetamide (30 mL) was stirred at 135 °C for 15 min, and then PdCl2(PPh3)2 (250 mg, 0.31 mmol) was added. The resulting mixture was stirred for 30 min at 135 °C. Upon completion of the reaction, the mixture was diluted with water (50 mL) and EtOAc (50 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0 to 20%) and DCM to afford 215 mg (31%) of the title compound.

[0554] Preparation 165. 2-[4-({[4-(benzyloxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]-4-fluorobenzoic acid (P165). A solution of P164 (215 mg, 0.45 mmol) and LiOH (109 mg, 4.5 mmol) in a mixture of THF (16 mL) and water (4 mL) was stirred at ambient temperature for 12 h. The volatiles were removed under reduced pressure, and water (20 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 10 mL). The combined organic layers were dried over NaSO and evaporated to dryness under reduced pressure to give 116 mg (55%) of the title compound, which was sufficiently pure for further use in the next step. N-[4-(benzyloxy)phenyl]-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P166) [ka]

[0555] Preparation 166. N-[4-(Benzyloxy)phenyl]-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P166). A mixture of P165 (116 mg, 0.25 mmol), P43 (71 mg, 0.35 mmol), DIPEA (0.066 mL, 0.75 mmol), and TBTU (97 mg, 0.35 mmol) in DMF (15 mL) was stirred at 60° C. overnight. The reaction mixture was diluted with water (20 mL) and EtOAc (10 mL). The organic layer was separated, washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0 to 100%) and DCM to afford 100 mg (59%) of the title compound. N-[4-(benzyloxy)phenyl]-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(2-methoxybenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P167) [ka]

[0556] Preparation 167. N-[4-(benzyloxy)phenyl]-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(2-methoxybenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P167). A mixture of P166 (35 mg, 0.052 mmol), tert-BuOK (23 mg, 0.208 mmol), and tert-BuOH (9 mL) was stirred at 50° C. for 30 min, then 2-methoxybenzyl chloride (16 mg, 0.104 mmol) was added. The reaction mixture was stirred at 60° C. for 1 h and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica eluting with a mixture of EtOAc (0 to 100%) and DCM to give 33 mg (81%). N-[4-(benzyloxy)phenyl]-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P168) [ka]

[0557] Preparation 168. N-[4-(Benzyloxy)phenyl]-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (P168). A mixture of P166 (100 mg, 0.149 mmol), tert-BuOK (67 mg, 0.576 mmol), and tert-BuOH (15 mL) was stirred at 50° C. for 30 min, then 3-methoxy-2-methylbenzyl methanesulfonate (69 mg, 0.298 mmol) was added. The reaction mixture was stirred at 60° C. for 1 h and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0 to 100%) and DCM to afford 33 mg (27%) of the title compound. Examples of Compound (I)

[0558] Example 1: 3-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-chlorophenyl)-N-(2-cyanobenzyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide (1) [ka] A mixture of 3-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-chlorophenyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide (P6, 150 mg, 0.23 mmol), tert-BuOK (104 mg, 0.9 mmol), and tert-BuOH (5 mL) was stirred at 50° C. for 30 minutes, and then 2-(bromomethyl)benzonitrile (91 mg, 0.46 mmol) was added. The reaction mixture was stirred at 60° C. for 1 hour and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica eluting with mixtures of EtOAc (0→100%) and DCM to afford 154 mg (87%) of the title compound 1. 1H NMR (400 MHz, DMSO-d6), δ: 7.93 - 7.35 (m, 8H), 7.31 - 6.85 (m, 8H), 5.37 - 4.92 (m, 4H), 4.20 - 3.64 (m, 7H), 3.55 - 3.24 (m, 6H), 3.18 - 2.72 (m, 4H), 1.79 - 0.88 (m, 4H). ESI LCMS [MH] + : 758.

[0559] Example 2. 3-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-chlorophenyl)-N-(3-methoxy-2-methylbenzyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide (2) [ka] A mixture of 3-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-chlorophenyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide (P6, 150 mg, 0.23 mmol), tert-BuOK (104 mg, 0.9 mmol), and tert-BuOH (5 mL) was stirred at 50° C. for 30 minutes, and then 3-methoxy-2-methylbenzyl methanesulfonate (107 mg, 0.46 mmol) was added. The reaction mixture was stirred at 60° C. for 1 hour and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica eluting with mixtures of EtOAc (0→100%) and DCM to afford 60 mg (34%) of the title compound 2. 1H NMR (400 MHz, DMSO-d6), δ: 7.61 - 7.26 (m, 3H), 7.24 - 6.93 (m, 8H), 6.89 - 6.73 (m, 2H), 6.71 - 6.51 (m, 2H), 5.43 - 4.98 (m, 2H), 4.98 - 4.65 (m, 2H), 4.28 - 3.88 (m, 2H), 3.84 - 3.68 (m, 4H), 3.65 - 3.38 (m, 6H), 3.04 - 2.78 (m, 2H), 2.72 - 2.57 (m, 1H), 2.38 - 2.25 (m, 2H), 2.21 - 1.78 (m, 6H), 1.76 - 1.36 (m, 4H). ESI LCMS [MH] + : 777.

[0560] Example 3. 3-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(2-cyanobenzyl)-N-(4-hydroxyphenyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide (3) [ka] A solution of compound P11 (180 mg, 0.22 mmol) in DCM (5 mL) was cooled to −78° C., and a solution of BBr (108 mg, 0.43 mmol) in THF (1 mL) was added over 5 min. The reaction mixture was stirred to −78° C. for 1 h and then diluted with an aqueous solution of saturated sodium bicarbonate (NaHCO). The organic layer was separated, washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was subjected to HPLC purification to give 73 mg (46%) of the title compound 3. 1H NMR (400 MHz, DMSO-d6), δ: 9.60 - 9.26 (m, 1H), 7.83 - 7.25 (m, 7H), 7.21 - 6.79 (m, 5H), 6.74 - 6.32 (m, 4H), 5.39 - 4.71 (m, 4H), 4.34 - 3.82 (m, 2H), 3.72 - 3.38 (m, 6H), 3.14 - 2.77 (m, 2H), 2.75 - 2.56 (m, 1H), 2.41 - 2.25 (m, 2H), 2.20 - 1.82 (m, 2H), 1.80 - 1.33 (m, 6H). ESI LCMS [MH] + : 740.

[0561] Example 4. 3-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(3-methoxy-2-methylbenzyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide (4) and N-(4-hydroxyphenyl)-N-(3-methoxy-2-methylbenzyl)-3-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide (5) [ka] A stirred mixture of compound P12 (200 mg), catalyst (10 mg of 5% palladium on charcoal) and methanol (2 mL) was hydrogenated under a H atmosphere for 2 hours. The catalyst was filtered and the filtrate was evaporated to dryness. The residue was subjected to HPLC purification to give 40 mg (22%) of compound 4 and 14 mg (8%) of compound 5. Compound 4: 1H NMR (400 MHz, DMSO-d6), δ: 9.49 - 9.13 (m, 1H), 7.64 - 7.24 (m, 3H), 7.24 - 6.71 (m, 8H), 6.71 - 6.47 (m, 2H), 6.47 - 6.24 (m, 2H), 5.32 - 4.52 (m, 4H), 4.28 - 3.89 (m, 2H), 3.86 - 3.68 (m, 3H), 3.64 - 3.37 (m, 6H), 3.08 - 2.82 (m, 2H), 2.75 - 2.64 (m, 1H), 2.39 - 2.23 (m, 2H), 2.23 - 1.83 (m, 7H), 1.78 - 1.39 (m, 4H). ESI LCMS [MH] + : 759.Compound 5: 1 H NMR (400 MHz, DMSO-d6), δ: 9.45 - 9.12 (m, 1H), 7.55 - 7.32 (m, 3H), 7.32 - 6.71 (m, 9H), 6.70 - 6.45 (m, 3H), 6.44 - 6.22 (m, 2H), 5.27 - 4.49 (m, 4H), 4.31 - 3.94 (m, 2H), 3.86 - 3.68 (m, 3H), 3.68 - 3.37 (m, 6H), 3.07 - 2.86 (m, 2H), 2.79 - 2.56 (m, 1H), 2.37 - 2.23 (m, 2H), 2.15 - 1.36 (m, 10H). ESI LCMS [M−H] + : 725.

[0562] Example 5. 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(2-cyanobenzyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (6) [ka] A solution of P19 (100 mg, 0.12 mmol) in DCM (5 mL) was cooled to −78° C., and a solution of BBr (62 mg, 0.25 mmol) in THF (1 mL) was added over 5 min. The reaction mixture was stirred to −78° C. for 1 h and then diluted with an aqueous solution of saturated sodium bicarbonate (NaHCO). The organic layer was separated, washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was subjected to HPLC purification to give 60 mg (67%) of the title compound 6. 1 H NMR (400 MHz, DMSO-d6), δ: 9.59 - 9.26 (m, 1H), 7.93 - 7.65 (m, 2H), 7.62 - 7.06 (m, 8H), 7.04 - 6.68 (m, 3H), 6.63 - 6.32 (m, 3H), 5.54 - 4.71 (m, 4H), 4.34 - 3.88 (m, 2H), 3.69 - 3.39 (m, 5H), 3.18 - 3.02 (s, 2H), 2.98 - 2.65 (m, 2H), 2.43 - 2.25 (m, 3H), 2.25 - 1.66 (m, 5H). ESI LCMS [MH] + : 714.

[0563] Example 6. 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (7) and N-(4-hydroxyphenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-5-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1H-pyrrole-3-carboxamide (8) [ka] A stirred mixture of compound P20 (120 mg), catalyst (10 mg of 5% palladium on charcoal) and methanol (2 mL) was hydrogenated under an H atmosphere for 2 hours. The catalyst was filtered and the filtrate was evaporated to dryness. The residue was subjected to HPLC purification to give 28 mg (28%) of compound 7 and 18 mg (13%) of compound 8. Compound 7: 1 H NMR (400 MHz, DMSO-d6), δ: 9.48 - 9.09 (m, 1H), 7.65 - 7.38 (m, 2H), 7.38 - 6.91 (m, 7H), 6.91 - 6.73 (m, 2H), 6.69 - 6.43 (m, 2H), 6.41 - 6.26 (s, 2H), 5.46 - 4.54 (m, 4H), 4.31 - 3.85 (m, 2H), 3.86 - 3.69 (m, 3H), 3.65 - 3.39 (m, 5H), 3.19 - 3.02 (s, 2H), 3.00 - 2.63 (m, 1H), 2.43 - 2.23 (m, 3H), 2.22 - 1.71 (m, 9H). ESI LCMS [MH] + : 733.Compound 8: 1 H NMR (400 MHz, DMSO-d6), δ: 9.45 - 9.11 (m, 1H), 7.57 - 7.25 (m, 3H), 7.26 - 6.73 (m, 9H), 6.70 - 6.45 (m, 2H), 6.39 - 6.20 (s, 2H), 5.47 - 4.43 (m, 4H), 4.32 - 3.89 (m, 2H), 3.85 - 3.66 (m, 3H), 3.65 - 3.36 (m, 5H), 3.19 - 2.99 (s, 2H), 2.97 - 2.65 (m, 1H), 2.38 - 2.24 (m, 3H), 2.23 - 1.68 (m, 9H). ESI LCMS [M−H] + : 699.

[0564] Example 7. (S)—N-(4-chlorophenyl)-5-(4-(difluoromethoxy)-5-fluoro-2-(3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (26) [ka] To a solution of P23 (56 mg, 0.21 mmol) in dichloroethane (1.0 mL) was added a solution of pyridine (42 μL, 0.53 mmol) and P28 (crude, 0.179 mmol) in dichloroethane (2.0 mL) at room temperature. The mixture was stirred at 90° C. for 8 hours. The reaction was quenched with NaHCO 3 3(aq) The mixture was quenched with and extracted with DCM. The organic layer was washed with MgSO 4(s) The crude was dried at 77°C, filtered, and concentrated. The crude was 100% purified by reverse phase chromatography (0-100% ACN in HO) to give compound 26 (23 mg, 23%) as a white powder. 1 H NMR (400 MHz, CDCl3), δ: 7.19-6.44 (m, 15H), 5.62-5.00 (m, 3H), 4.95-4.67 (m, 1H), 4.26-3.98 (m, 1H), 3.84-3.78 (m, 3H), 3.68-3.50 (m, 4H), 3.32-3.11 (m, 3H), 2.76-2.03 (m, 14H); LCMS (ESI) m / z C 44 H 44 Calculated for ClF3N4O5 800.30; Found, 801.4 [M + H] + ; HPLC purity: 99.9%, t R = 27.232 minutes.

[0565] Example 8. (S)—N-(4-(benzyloxy)phenyl)-5-(4-(difluoromethoxy)-2-(3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (31) [ka] To a solution of P34 (24 mg, 0.028 mmol) in MeOH (4.0 mL) was added 10% Pd / C (28 mg) and the solution was immersed in H 2(g) The mixture was degassed with HCl. After stirring the mixture under hydrogen (1 atm) at room temperature for 30 min, the solution was diluted with a solution of 20% MeOH in DCM and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure and purified by reverse-phase chromatography (0 to 100% MeOH in H2O with 1% NH4HCO3) to give compound 31 (13.3 mg, 62%) as a white solid. 1 H NMR (400 MHz, DMSO-d6), δ: 9.39-9.22 (m, 1H), 7.54-7.25 (m, 2H), 7.25-7.04 (m, 6H), 7.03-6.85 (m, 3H), 6.80-6.48 (m, 1H), 6.28 (s, 2H), 5.39-4.96 (m, 2H), 4.94-4.52 (m, 2H), 4.30-4.14 (m, 1H), 4.03-3.89 (m, 1H), 3.82-3.68 (m, 3H), 3.62-3.47 (m, 4H), 3.30-3.27 (m, 1H), 3.07 (s, LCMS (ESI) m / z C 44 H 46 Calculated for F2N4O6 764.34; Found 765.4 [M + H] + ; HPLC purity: 98.9%, t R = 20.23 minutes.

[0566] Example 9. (S)-5-(5-chloro-4-(difluoromethoxy)-2-(3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(4-hydroxyphenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (36) [ka] To a solution of P38 (40.0 mg, 0.0449 mmol) in ethanol (4.0 mL) was added Pd / C (4.0 mg, 10% w / w) at room temperature. The reaction solution was heated under H 2(g) After stirring at room temperature under ambient conditions for 24 hours, the solution was filtered through a pad of Celite and washed with methanol. The filtrate was concentrated under reduced pressure, and the residue was purified by C18 flash column chromatography (0-100% methanol in HO) to give the compound (7.4 mg, 20% yield) as a white solid. 1 H NMR (400 MHz, CDCl3), δ: 7.22-6.34 (m, 14H), 5.50-5.33 (m, 1H), 5.12-4.76 (m, 4H), 4.26-3.93 (m, 2H), 3.82-3.78 (m, 3H), LCMS (ESI) m / z C 44 H 45 Calculated for ClF2N4O6 798.30; Found 799.4 [M + H] + ; HPLC purity: 97.8%, t R = 21.662 minutes.

[0567] Example 10. (S)-5-(4-chloro-5-(difluoromethyl)-2-(3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(4-chlorophenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (39) [ka] To a solution of P39 (0.27 mmol) in dichloroethane (3.0 mL) was added P23 (85 mg, 0.32 mmol, 1.2 equiv.) and pyridine (65 μL, 0.81 mmol, 3.0 equiv.). The reaction mixture was stirred at 90° C. for 16 h. The reaction mixture was treated with water and extracted with DCM. The combined organic layers were washed with MgSO 4 . 4(s) The residue was purified by flash column chromatography (1% NH4OH (aq) Purification with 0-2% MeOH in DCM gave 39 (43.7 mg, 21%) as a brown gum. 1 H NMR (400 MHz, CDCl3), δ: 7.41 (d, J = 8.8 Hz, 2H), 7.16-6.71 (m, 11H), 6.53 (d, J = 8.8 Hz, 2H), 5.15-4.76 (m, 4H), 4.23-4.19 (m, 1H), 3.99-3.95 (m, 1H), 3.83-3.79 (m, 5H), 3.70-3.55 (m, 4H), 3.28-3.26 (m, 2H), 3.11 (s, 3H), 2.85-2.30 (m, 5H), 2.22-1.95 (m, 6H); LRMS (ESI) m / z 801.4 [M + H] + ; HPLC purity: 97.7%, t R = 28.195 minutes.

[0568] Example 11. (S)-5-(5-chloro-4-(difluoromethoxy)-2-(3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(4-cyanophenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (40) [ka] To a solution of P36 (0.35 mmol) in pyridine (2.0 mL) was added 4-[(3-methoxy-2-methyl-phenyl)methylamino]benzonitrile (97 mg, 0.39 mmol, 1.1 equiv.). The reaction mixture was stirred at 120 °C for 2 days. The reaction mixture was treated with water and extracted with DCM. The combined organic layers were washed with MgSO 4(s) The residue was purified by flash column chromatography (1% NH4OH (aq) Purification by reverse-phase HPLC (10-90% acetonitrile in HO) gave 40 (3.2 mg, 1%) as a brown gum. 1 H NMR (400 MHz, CDCl3), δ: 7.25-6.67 (m, 15H), 5.13-4.79 (m, 4H), 4.22 (m, 1H), 3.99 (m, 1H), 3.84-3.81 (m, 5H), 3.67-3.55 (m, 7H), 3.17 (s, 3H), 2.84-2.00 (m, 14H); LRMS (ESI) m / z 808.3 [M + H] + ; HPLC purity: 99.3%, t R = 25.188 minutes.

[0569] Example 12. (S)-5-(5-chloro-4-(difluoromethoxy)-2-(3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(4-cyanophenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (43) [ka] To a solution of P40 (65 mg, 0.074 mmol) in EtOH (4.0 mL) was added 10% Pd / C (74 mg) and the solution was immersed in H 2(g) The mixture was degassed with HCl. After stirring the mixture under hydrogen (1 atm) at room temperature for 6 h, the solution was diluted with a solution of 20% MeOH in DCM and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure and purified by reverse-phase chromatography (0 to 100% ACN in HO) to give compound 43 (5.4 mg, 9%) as a white solid. 1 H NMR (400 MHz, DMSO-d6), δ: 7.63-7.28 (m, 2H), 7.25-6.88 (m, 6H), 6.85-6.63 (m, 4H), 6.55-6.32 (m, 3H), 5.56-4.77 (m, 3H), 4.29-3.88 (m, 1H), 3.84-3.78 (m, 3H), 3.75-3.61 (m, 3H), 3.58-3.47 (m, 2H), 3.27 (s, 1H), 3.08 (s, 2H), 2.83-2.45 (m, 3H), 2.43-2.29 (m, 2H), 2.27-2.14 (m, 3H), 2.11-1.87 (m, 5H); LCMS (ESI) m / z C 44 H 45 Calculated for ClF2N4O5 782.30; Found 783.4 [M + H] + ; HPLC purity: 98.6%, t R = 21.193 minutes.

[0570] Example 13. (S)—N-(4-cyanophenyl)-5-(4-(difluoromethoxy)-5-fluoro-2-(3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (44) [ka] To a solution of P28 (0.36 mmol) in pyridine (2.0 mL) was added 4-[(3-methoxy-2-methyl-phenyl)methylamino]benzonitrile (100 mg, 0.40 mmol, 1.1 equiv.). The reaction mixture was stirred at 120 °C for 2 days. The reaction mixture was treated with water and extracted with DCM. The combined organic layers were washed with MgSO 4(s) The residue was purified by flash column chromatography (1% NH4OH (aq) Purification by reverse-phase HPLC (0-90% acetonitrile in HO) gave 44 (5.5 mg, 4%) as a brown gum. 1 H NMR (400 MHz, CDCl3), δ: 7.28-6.62 (m, 15H), 5.15-4.80 (m, 4H), 4.24-4.22 (m, 1H), 4.01-3.97 (m 1H), 3.84-3.81 (m, 3H), 3.70-3.55 (m, 4H), 3.25-3.17 (m, 3H), 2.81-2.00 (m, 14H); LRMS (ESI) m / z 792.4 [M + H] + ; HPLC purity: 98.8%, t R = 23.896 minutes.

[0571] Example 14. (S)-5-(5-chloro-2-(3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(1H-indazol-5-yl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (70) [ka] To a solution of P53 (100 mg, 0.119 mmol) in DCM (1.0 mL) was added TFA (0.20 mL). The reaction was stirred at room temperature for 2 hours. The mixture was concentrated to remove the solvent. The crude was purified by preparative thin-layer chromatography (5% MeOH in DCM) to give compound 70 (29 mg, 37%). 1H NMR (400 MHz, CDCl3), δ: 7.89-7.84 (m, 1H), 7.42-7.28 (m, 2H), 7.22-6.90 (m, 8H), 6.81-6.67 (m, 4H), 5.47 (br s, 1H), 5.25-4.68 (m, 3H), 4.21-4.08 (m, 1H), 3.92-3.60 (m, 7H), 3.53-3.45 (m, 1H), 3.30-3.20 (m, 1H), 3.05 (br s, 2H), 2.78-2.72 (m, 1H), 2.66-2.50 (m, 2H), 2.40-2.32 (m, LCMS (ESI) m / z 757.4 [M + H] + .; HPLC purity: 95.1%, t R = 19.5 minutes.

[0572] Example 15. (S)-5-(5-chloro-2-(3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(2-cyanobenzyl)-N-(1H-indazol-5-yl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (68) [ka] To a solution of P55 (40 mg, 0.049 mmol) in DCM (1.0 mL) was added TFA (0.10 mL). The reaction was stirred at room temperature for 1 hour. The mixture was concentrated to remove the solvent. The crude was purified by preparative thin-layer chromatography (5% MeOH in DCM) to give compound 68 (1 mg, 44%). 1H NMR (400 MHz, CDCl3), δ: 7.92-7.87 (m, 1H), 7.71-7.63 (m, 1H), 7.51-7.49 (m, 2H), 7.41-7.01 (m, 9H), 6.95-6.92 (m, 1H), 6.82-6.77 (m, 2H), 5.45-5.27 (m, 2H), 5.13-4.95 (m, 2H), 4.21-4.10 (m, 1H), 3.94-3.87 (m, 1H), 3.65 (br m, 5H), 3.50-3.48 (m, 1H), 3.25 (br s, 2H), 3.09 (br s, 2H), 2.75-2.53 (m, 3H), 2.42-2.37 (m, 1H), 2.29 (s, 3H), 2.21-1.84 (m, 1H), 1.28-1.24 (m, 1H); LCMS (ESI) m / z 738.4 [M + H] + .; HPLC purity: 93.8%, t R = 17.896 minutes.

[0573] Example 16. (S)-5-(5-chloro-2-(3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(1H-indazol-5-yl)-N-(2-methoxybenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (69) [ka] To a solution of P57 (265 mg, 0.32 mmol) in DCM (4.0 mL) was added TFA (2.0 mL). The reaction was stirred at room temperature overnight and concentrated. The residue was purified by C18 reverse-phase column chromatography (0-100% MeOH in water) to give compound 69 (31 mg, 13% yield) as a white solid. 1H NMR (400 MHz, CDCl3), δ: 7.87-7.83 (m, 1H), 7.45-7.28 (m, 3H), 7.24-7.04 (m, 5H), 7.01-6.82 (m, 4H), 6.75-6.70 (m, 2H), 5.56-4.99 (m, 4H), 4.23-4.09 (m, 1H), 3.92-3.87 (m, 1H), 3.65-3.42 (m, 9H), 3.30-3.18 (m, 2H), 3.04-2.46 (m, 5H), 2.43-2.06 (m, 5H), 1.99-1.83 (m, 2H).; LCMS (ESI) m / z C 43 H 43 Calculated for ClN6O4 742.30; Found 743.3 [M + H] + .HPLC purity: 93.5%, t R = 18.577 minutes.

[0574] Example 17. 5-(5-chloro-4-cyano-2-[(3R)-3-(morpholinomethyl)-3,4-dihydro-2(1H)-isoquinolinyl]carbonylphenyl)-N 3 -(4-hydroxyphenyl)-N 3 -(3-Methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (9) [ka] A stirred mixture of P61, H2SO4 (0.1 mL), and methanol / THF (2 mL, 1:1) was stirred at ambient temperature for 2 h. 20% aqueous sodium carbonate (pH 7) was added, and the product was extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure on a rotary evaporator. The residue was subjected to silica gel flash chromatography eluting with a mixture of MeOH (0 to 2%) and DCM to afford 17 mg (25%) of the title compound. 1H NMR (400 MHz, DMSO-d6), δ: 9.32 - 9.24 (m, 1H), 8.01 - 7.81 (m, 1H), 7.74 - 7.58 (m, 1H), 7.24 - 6.24 (m, 10H), 5.63 - 5.25 (m, 1H), 5.12 - 4.54 (m, 4H), 4.28 - 3.83 (m, 2H), 3.83 - 3.65 (m, 3H), 3.65 - 3.36 (m, 6H), 3.13 (s, 2H), 3.00 - 2.62 (m, 1H), 2.44 - 2.25 (m, 5H), 2.25 - 1.61 (m, 7H). LCMS (ESI+) m / z 759 [M+H] + .

[0575] Example 18. 5-(5-chloro-4-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (11) [ka] A stirred mixture of P67, catalyst (5 mg of 5% palladium on charcoal), and methanol (2 mL) was hydrogenated under an H atmosphere for 2 h. The catalyst was filtered, and the filtrate was evaporated to dryness. The residue was subjected to HPLC purification to give 15 mg (21%). 1 H NMR (400 MHz, DMSO-d6), δ: 9.53 - 9.11 (m, 1H), 7.51 - 5.98 (m, 12H), 5.45 - 4.44 (m, 4H), 4.33 - 3.67 (m, 12H), 3.57 (s, 6H), 3.16 - 2.64 (m, 3H), 2.38 - 1.73 (m, 9H). LCMS (ESI+) m / z 764[M+H] + .

[0576] Example 19. 5-(5-Fluoro-4-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (21). [ka] A stirred mixture of P72, catalyst (5 mg of 5% palladium on charcoal), and methanol (2 mL) was hydrogenated under a H atmosphere for 2 h. The catalyst was filtered, and the filtrate was evaporated to dryness. The residue was subjected to HPLC purification to give 18 mg (64%) of compound 21. 1 H NMR (400 MHz, DMSO-d6), δ: 9.48 - 9.14 (m, 1H), 7.30 - 6.71 (m, 9H), 6.71 - 6.44 (m, 2H), 6.31 (s, 2H), 5.42 - 4.46 (m, 4H), 4.32 - 3.68 (m, 10H), 3.66 - 3.36 (m, 6H), 3.18 - 2.67 (m, 4H), 2.48 - 2.27 (m, 3H), 2.22 - 1.72 (m, 6H). MS (ESI+) m / z 747[M+H] + .

[0577] Example 20. N-(4-chlorophenyl)-5-(4-cyano-5-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(2-methoxybenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (56), 5-(4-(aminocarbonyl)-5-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-chlorophenyl)-N-(2-methoxybenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (63). [ka] A mixture of P81 (100 mg, 0.157 mmol), tert-BuOK (88 mg, 0.8 mmol), and tert-BuOH (25 mL) was stirred at 50° C. for 30 minutes, and then 2-methoxybenzyl methanesulfonate (60 mg, 0.314 mmol) was added. The reaction mixture was stirred at 60° C. for 1 hour and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to HPLC purification to give 16.0 mg (12%) of Compound 56 and 6 mg (4%) of Compound 63. Compound 56: 1 H NMR (400 MHz, DMSO-d6), δ: 7.86 - 7.59 (m, 1H), 7.34 - 6.67 (m, 15H), 5.12 - 4.65 (m, 4H), 4.28 - 3.85 (m, 5H), 3.76 - 3.36 (m, 8H), 3.19 (s, 2H), 2.95 - 2.63 (m, 1H), 2.42 - 2.25 (m, 2H), 2.20 - 1.75 (m, 6H). LCMS (ESI+) m / z 759 [M+H] + .Compound 63: LCMS (ESI+) m / z 777 [M+H] + .

[0578] Example 21. 5-(5-chloro-4-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (27). [ka] A stirred mixture of P87, H2SO4 (0.15 mL), and methanol / THF (2 mL, 1:1) was stirred at ambient temperature for 1 h. Volatiles were removed under reduced pressure, and the residue was stirred with 20% aqueous Na2CO3 for 5 min. The product was extracted with DCM (2 x 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated on a rotary evaporator under reduced pressure. The residue was subjected to HPLC purification to give 40 mg (40%) of the title compound. 1 H NMR (400 MHz, DMSO-d6), δ: 9.52 - 9.15 (m, 1H), 7.65 - 7.24 (m, 2H), 7.24 - 6.42 (m, 8H), 6.34 (s, 2H), 5.46 - 4.60 (m, 4H), 4.33 - 3.96 (m, 2H), 3.92 - 3.67 (m, 3H), 3.65 - 3.39 (m, 6H), 3.17 - 2.62 (m, 3H), 2.42 - 2.23 (m, 4H), 2.18 - 1.81 (m, 9H). LCMS (ESI+) m / z 752 [M+H] + .

[0579] Example 22. 5-(4-cyano-5-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (58). [ka] A stirred mixture of P92, catalyst (5 mg of 5% palladium on charcoal), and methanol (10 mL) was hydrogenated under a H atmosphere for 2 hours. The catalyst was filtered, and the filtrate was evaporated to dryness. The residue was subjected to HPLC purification to give 29 mg (25%) of compound 58. 1H NMR (400 MHz, DMSO-d6), δ: 9.52 - 9.15 (m, 1H), 7.87 - 7.46 (m, 1H), 7.29 - 6.72 (m, 9H), 6.72 - 6.43 (m, 2H), 6.43 - 6.27 (m, 2H), 5.25 (s, 1H), 5.07 - 4.57 (m, 4H), 4.37 - 3.99 (m, 2H), 3.92 (s, 3H), 3.83 - 3.69 (m, 3H), 3.62 - 3.40 (m, 6H), 3.18 (s, 2H), 3.01 - 2.57 (m, 2H), 2.45 - 2.22 (m, 3H), 2.20 - 1.82 (m, 6H). LCMS (ESI+) m / z 754[M+H] + .

[0580] Example 23. 5-(5-nitro-2-[(3R)-3-(morpholinomethyl)-3,4-dihydro-2(1H)-isoquinolinyl]carbonylphenyl)-N 3 -(1H-indazol-5-yl)-N 3 -(3-Methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (65). [ka] A stirred mixture of crude compound P97 (180 mg) and TFA (0.4 mL) in DCM (3 mL) was stirred at ambient temperature for 3 hours. Aqueous solution (20%, NaHCO3) was added (pH 7) and the product was extracted with DCM (2 x 6 ml). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by HPLC to give 40 mg of compound 65. LCMS (ESI+) m / z 768 [M+H] + . 1H NMR (400 MHz, DMSO-d6), δ: 13.18 - 12.76 (m, 1H), 8.38 - 8.08 (m, 1H), 8.00 - 7.80 (m, 3H), 7.66 - 6.45 (m, 11H), 5.55 - 4.68 (m, 4H), 4.40 - 3.85 (m, 2H), 3.84 - 3.66 (m, 3H), 3.64 - 3.37 (m, 6H), 3.08 (s, 2H), 2.81 - 2.56 (m, 1H), 2.43 - 2.16 (m, 3H), 2.09 - 1.71 (m, 8H).

[0581] Example 24. 5-(5-nitro-2-[(3R)-3-(morpholinomethyl)-3,4-dihydro-2(1H)-isoquinolinyl]carbonylphenyl)-N 3 -(1H-indazol-5-yl)-N 3 -(2-Cyanobenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (71). [ka] A stirred mixture of crude compound P101 (100 mg) and TFA (0.48 mL) in DCM (2 mL) was stirred at ambient temperature for 3 hours. An aqueous solution of NaHCO3 (20%) was added (to pH 7) and the product was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by HPLC to give 56 mg (64%) of compound 71. LCMS (ESI+) m / z 749 [M+H] + . 1H NMR (400 MHz, DMSO-d6), δ: 9.48 - 9.09 (m, 1H), 7.65 - 7.38 (m, 2H), 7.38 - 6.91 (m, 7H), 6.91 - 6.73 (m, 2H), 6.69 - 6.43 (m, 2H), 6.41 - 6.26 (s, 2H), 5.46 - 4.54 (m, 4H), 4.31 - 3.85 (m, 2H), 3.86 - 3.69 (m, 3H), 3.65 - 3.39 (m, 5H), 3.19 - 3.02 (s, 2H), 3.00 - 2.63 (m, 1H), 2.43 - 2.23 (m, 3H), 2.22 - 1.71 (m, 9H).

[0582] Example 25. 5-(5-cyano-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (55). [ka] A stirred mixture of P105, H2SO4 (1.2 mL), and methanol / THF (2 mL, 1:1) was stirred at ambient temperature for 2 hours. 20% aqueous sodium carbonate (pH 7) was added, and the product was extracted with DCM (2 x 200 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel flash chromatography eluting with a mixture of MeOH (0 to 2%) and DCM to afford 80 mg (86%) of the title compound. 1H NMR (400 MHz, DMSO-d6), δ: 9.51 - 9.10 (m, 1H), 8.10 - 7.33 (m, 3H), 7.33 - 6.65 (m, 10H), 6.64 - 6.29 (m, 3H), 5.60 - 4.50 (m, 4H), 4.36 - 3.85 (m, 2H), 3.80 - 3.40 (m, 8H), 3.10 (s, 2H), 3.00 - 2.61 (m, 1H), 2.45 - 2.21 (m, 3H), 2.23 - 1.74 (m, 6H). LCMS (ESI+) m / z 724 [M+H] + .

[0583] Example 26. N-(4-hydroxyphenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-5-(5-(methylsulfonyl)-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1H-pyrrole-3-carboxamide (49). [ka] A stirred mixture of P109, H2SO4 (1.5 mL), and methanol / THF (2 mL, 1:1) was stirred at ambient temperature for 2 h. 20% aqueous sodium carbonate (pH 7) was added, and the product was extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure on a rotary evaporator. The residue was subjected to silica gel flash chromatography eluting with a mixture of MeOH (0 to 2%) and DCM to afford 130 mg (95%) of the title compound. 1H NMR (400 MHz, DMSO-d6), δ: 9.48 - 9.14 (m, 1H), 8.11 - 7.85 (m, 1H), 7.82 - 7.43 (m, 2H), 7.29 - 6.24 (m, 12H), 5.58 - 4.58 (m, 4H), 4.33 - 3.90 (m, 2H), 3.87 - 3.67 (m, 3H), 3.67 - 3.48 (m, 8H), 3.12 (s, 2H), 3.02 - 2.66 (m, 1H), 2.43 - 2.27 (m, 4H), 2.26 - 1.74 (m, 8H). LCMS (ESI+) m / z 777 [M+H] + .

[0584] Example 27. N-1H-indazol-6-yl-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-5-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-5-nitrophenyl)-1H-pyrrole-3-carboxamide (67). [ka] A stirred mixture of crude compound P116 (230 mg, 0.27 mmol) and TFA (1 mL) in DCM (2 mL) was stirred at ambient temperature for 3 hours. A 20% aqueous solution of NaHCO was added (pH 7) and the product was extracted with DCM. The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0->20%) and DCM to give 23 mg (11%) of the title compound. LCMS (ESI+) m / z 768 [M+H] + . 1H NMR (400 MHz, DMSO-d6), δ: 13.01 - 12.60 (m, 1H), 8.37 - 8.07 (m, 1H), 8.01 - 7.78 (m, 2H), 7.72 - 6.35 (m, 12H), 5.53 - 4.70 (m, 4H), 4.30 - 3.82 (m, 2H), 3.84 - 3.68 (m, 3H), 3.67 - 3.36 (m, 6H), 3.07 (s, 2H), 2.95 - 2.62 (m, 1H), 2.43 - 2.16 (m, 3H), 2.08 - 1.64 (m, 8H).

[0585] Example 28. N-1H-indazol-6-yl-N-(2-methoxybenzyl)-1,2-dimethyl-5-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-5-nitrophenyl)-1H-pyrrole-3-carboxamide (72). [ka] A stirred mixture of crude compound P120 (350 mg, 0.4 mmol) and TFA (1 mL) in DCM (2 mL) was stirred at ambient temperature for 3 hours. A 20% aqueous solution of NaHCO was added (pH 7) and the product was extracted with DCM. The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0->20%) and DCM to give 6.6 mg (3%) of the title compound. LCMS (ESI+) m / z 754 [M+H] + .

[0586] Example 29. N-1H-indazol-6-yl-N-(2-cyanobenzyl)-1,2-dimethyl-5-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-5-nitrophenyl)-1H-pyrrole-3-carboxamide (66). [ka] A stirred mixture of crude compound P124 (350 mg, 0.4 mmol) and TFA (1 mL) in DCM (2 mL) was stirred at ambient temperature for 3 hours. 20% aqueous NaHCO3 was added (pH 7) and the product was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure on a rotary evaporator. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0→20%) and DCM to give 69 mg (23%) of the title compound. LCMS (ESI+) m / z 749 [M+H] + . 1 H NMR (400 MHz, DMSO-d6), δ: 13.11 - 12.82 (m, 1H), 8.37 - 8.08 (m, 1H), 8.07 - 7.84 (m, 2H), 7.83 - 7.33 (m, 6H), 7.28 - 6.42 (m, 7H), 5.67 - 4.74 (m, 4H), 4.33 - 3.80 (m, 2H), 3.74 - 3.46 (m, 6H), 3.08 (s, 2H), 2.98 - 2.58 (m, 1H), 2.39 - 2.22 (m, 2H), 2.21 - 1.66 (m, 6H).

[0587] Example 30. 5-(5-chloro-4-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-cyanophenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (73). [ka] A mixture of P127 (90 mg, 0.14 mmol), tert-BuOK (64 mg, 0.58 mmol), and tert-BuOH (5 mL) was stirred at 50° C. for 30 min, and then 3-methoxy-2-methylbenzyl methanesulfonate (66 mg, 0.29 mmol) was added. The reaction mixture was stirred at 60° C. for 1 h and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel flash chromatography eluting with a mixture of EtOAc (0 to 100%) and DCM to afford 20 mg (20%) of the title compound. 1 H NMR (400 MHz, DMSO-d6), δ: 7.82 - 7.33 (m, 5H), 7.27 - 6.52 (m, 9H), 5.91 - 5.48 (m, 1H), 5.33 - 4.74 (m, 4H), 4.35 - 3.92 (m, 2H), 3.86 - 3.67 (m, 3H), 3.67 - 3.40 (m, 4H), 3.16 - 2.81 (m, 2H), 2.69 (s, 3H), 2.42 - 2.14 (m, 3H), 2.09 - 1.76 (m, 7H). LCMS (ESI) m / z C 44 H 43 Calculated for ClFN5O4 760.32; Found 760.6 [M + H] + .

[0588] Example 31. N-(4-chlorophenyl)-5-(4-cyano-5-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (60). [ka] A mixture of P131 (95 mg, 0.149 mmol), tert-BuOK (67 mg, 0.57 mmol), and tert-BuOH (9 mL) was stirred at 50° C. for 30 min, then 3-methoxy-2-methylbenzyl methanesulfonate (69 mg, 0.29 mmol) was added. The reaction mixture was stirred at 60° C. for 1 h and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0 to 100%) and DCM to give 79 mg (68%). 1 H NMR (400 MHz, DMSO-d6), δ: 7.84 - 7.53 (m, 1H), 7.26 - 6.75 (m, 11H), 6.72 - 6.51 (m, 2H), 5.86 - 5.26 (m, 1H), 5.14 - 4.69 (m, 4H), 3.94 (s, 5H), 3.84 - 3.69 (m, 3H), 3.67 - 3.37 (m, 6H), 3.19 (s, 2H), 3.04 - 2.58 (m, 2H), 2.44 - 2.22 (m, 3H), 2.23 - 1.68 (m, 6H). LCMS (ESI+) m / z 773 [M+H] + .

[0589] Example 32. N-(4-chlorophenyl)-N-(2-cyanobenzyl)-5-(4-cyano-5-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (59). [ka] A mixture of P131 (190 mg, 0.298 mmol), tert-BuOK (134 mg, 1.14 mmol), and tert-BuOH (18 mL) was stirred at 50° C. for 30 min, then 2-(bromomethyl)benzonitrile (117 mg, 0.598 mmol) was added. The reaction mixture was stirred at 60° C. for 1 h and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (0 to 100%) and DCM to give 63 mg (28%). 1 H NMR (400 MHz, DMSO-d6), δ: 7.98 - 7.34 (m, 4H), 7.29 - 6.69 (m, 10H), 5.44 - 4.69 (m, 4H), 4.40 - 3.84 (m, 6H), 3.76 - 3.39 (m, 6H), 3.19 (s, 2H), 2.99 - 2.65 (m, 1H), 2.46 - 2.26 (m, 3H), 2.24 - 1.81 (m, 5H). LCMS (ESI+) m / z 754 [M+H] + .

[0590] Example 33. 5-(5-cyano-2-[3-(morpholinomethyl)-3,4-dihydro-2(1H)-isoquinolinyl]carbonylphenyl)-N 3 -(4-hydroxyphenyl)-N 3 -(3-Methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (57). [ka] A stirred mixture of P139 (50 mg) and H2SO4 (0.1 mL) in methanol / THF (2 mL, 1:1) was stirred at ambient temperature for 1 h. 20% aqueous NaHCO3 (pH 7) was added and the product was extracted with DCM (2 x 6 ml). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of MeOH (0 -> 2%) and DCM to give 20 (50%) mg of compound 57. LCMS (ESI+) m / z 724 [M+H] + . 1 H NMR (400 MHz, DMSO-d6), δ: 9.52 - 9.12 (m, 1H), 8.05 - 7.30 (m, 3H), 7.30 - 6.41 (m, 9H), 6.41 - 6.24 (m, 3H), 5.33 - 4.55 (m, 4H), 4.36 - 3.87 (m, 2H), 3.87 - 3.66 (m, 3H), 3.66 - 3.38 (m, 6H), 3.10 (s, 2H), 3.02 - 2.61 (m, 1H), 2.45 - 2.12 (m, 3H), 2.09 - 1.78 (m, 8H).

[0591] Example 34. 5-(5-(aminocarbonyl)-2-[3-(morpholinomethyl)-3,4-dihydro-2(1H)-isoquinolinyl]carbonylphenyl)-N 3 -(4-hydroxyphenyl)-N 3 -(3-Methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (64). [ka] A stirred mixture of compound P139 (70 mg) and H2SO4 (0.1 mL) in methanol / THF (2 mL, 1:1) was stirred at ambient temperature for 1 h. 20% aqueous NaHCO3 (pH 7) was added, and the product was extracted twice with DCM (2 x 6 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of MeOH (0 -> 2%) and DCM to give 40 mg (67%) of compound 64. LCMS (ESI+) m / z 742 [M+H] + . 1 H NMR (400 MHz, DMSO-d6), δ: 9.45 - 9.14 (m, 1H), 8.17 - 7.34 (m, 6H), 7.26 - 6.74 (m, 7H), 6.73 - 6.40 (m, 2H), 6.31 (s, 2H), 5.55 - 4.53 (m, 4H), 4.33 - 3.89 (m, 2H), 3.87 - 3.68 (m, 3H), 3.68 - 3.36 (m, 4H), 3.09 (s, 2H), 3.05 - 2.65 (m, 1H), 2.47 - 2.21 (m, 4H), 2.20 - 1.72 (m, 9H).

[0592] Example 35. 5-[5-chloro-2-[(3S)-3-(morpholinomethyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]phenyl]-N-(4-cyanophenyl)-N-[(3-methoxy-2-methyl-phenyl)methyl]-1,2-dimethyl-pyrrole-3-carboxamide (33). [ka] A mixture of P142 (170 mg, 0.28 mmol), tert-BuOK (125 mg, 1.1 mmol), and tert-BuOH (5 mL) was stirred at 50° C. for 30 min, then 3-methoxy-2-methylbenzyl methanesulfonate (128 mg, 0.56 mmol) was added. The reaction mixture was stirred at 60° C. for 1 h and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel flash chromatography eluting with a mixture of EtOAc (0 to 100%) and DCM to afford 17 mg (10%) of the title compound. 1 H NMR (400 MHz, DMSO-d6), δ: 7.83 - 6.47 (m, 15H), 5.87 - 5.52 (m, 1H), 5.41 - 4.68 (m, 5H), 4.31 - 3.91 (m, 2H), 3.87 - 3.69 (m, 3H), 3.69 - 3.40 (m, 6H), 3.19 - 2.62 (m, 3H), 2.41 - 2.21 (m, 2H), 2.21 - 1.71 (m, 7H). LCMS (ESI) m / z C 44 H 44 Calculated for ClN5O4 742.32; Found 742.3 [M + H] + . Example 36. N-(2-cyanobenzyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-5-nitrophenyl)-1H-pyrrole-3-carboxamide (62). [ka] A stirred mixture of P146, H2SO4 (1.4 mL), and methanol / THF (2 mL, 1:1) was stirred at ambient temperature for 2 h. 20% aqueous sodium carbonate (pH 7) was added, and the product was extracted with DCM (2 x 200 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure on a rotary evaporator. The residue was subjected to silica gel flash chromatography eluting with a mixture of MeOH (0 to 2%) and DCM to afford 64 mg (63%) of the title compound. 1 H NMR (400 MHz, DMSO-d6), δ: 9.61 - 9.28 (m, 1H), 8.48 - 7.91 (m, 2H), 7.86 - 7.29 (m, 6H), 7.29 - 6.81 (m, 5H), 6.62 - 6.28 (m, 3H), 5.37 - 4.77 (m, 4H), 4.31 - 3.88 (m, 2H), 3.74 - 3.34 (m, 7H), 3.13 (s, 2H), 2.96 - 2.63 (m, 1H), 2.43 - 2.17 (m, 3H), 2.17 - 1.72 (m, 4H). LCMS (ESI+) m / z 725 [M+H] + . Example 37. N-(4-Hydroxyphenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-5-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-5-nitrophenyl)-1H-pyrrole-3-carboxamide (61). A stirred mixture of P147, H2SO4 (1.4 mL), and methanol / THF (2 mL, 1:1) was stirred at ambient temperature for 2 hours. 20% aqueous sodium carbonate (pH 7) was added, and the product was extracted with DCM (2 x 200 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel flash chromatography eluting with a mixture of MeOH (0 to 2%) and DCM to afford 96 mg (54%) of the title compound. 1H NMR (400 MHz, DMSO), δ: 9.52 - 9.09 (m, 1H), 8.38 - 7.40 (m, Hz, 1H), 7.25 - 6.73 (m, 16H), 6.67 - 6.46 (m, 5H), 6.33 (s, 5H), 5.54 - 4.59 (m, 9H), 4.33-4.10 (m, 4H), 3.96 (s, 3H), 3.77 (s, 3H), 3.67-3.49 (m, 7H), 3.13 (s, 3H), 2.96 - 2.63 (m, 1H), 2.43 - 2.17 (m, 3H), 2.17 - 1.72 (m, 4H). LCMS (ESI+) m / z 744 [M+H] + . Example 38. 5-(5-(acetylamino)-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (48). [ka] A stirred mixture of P149, H2SO4 (1.7 mL), and methanol / THF (2 mL, 1:1) was stirred at ambient temperature for 2 hours. 20% aqueous sodium carbonate (pH 7) was added, and the product was extracted with DCM (2 x 200 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The dry residue was subjected to silica gel flash chromatography eluting with a mixture of MeOH (0 to 2%) and DCM to afford 15 mg (12%) of the title compound. 1H NMR (400 MHz, DMSO-d6), δ: 10.09 (s, 1H), 9.44 - 9.06 (m, 1H), 7.66 - 7.31 (m, 2H), 7.25 - 6.44 (m, 12H), 6.39 - 6.14 (m, 2H), 5.42 - 4.52 (m, 4H), 4.34 - 3.94 (m, 2H), 3.76 (d, J = 22.8 Hz, 3H), 3.70 - 3.38 (m, 6H), 3.08 (s, 2H), 2.96 - 2.64 (m, 1H), 2.40 - 2.23 (m, 2H), 2.22 - 1.71 (m, 11H). LCMS (ESI+) m / z 756 [M+H] + . Example 39. 5-(4,5-Difluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (51). [ka] A stirred mixture of P153, catalyst (5 mg of 5% palladium on charcoal), and methanol (2 mL) was hydrogenated under an H atmosphere for 2 hours. The catalyst was filtered, and the filtrate was evaporated to dryness. The residue was subjected to HPLC purification to give 25 mg (40%) of the title compound. 1H NMR (400 MHz,chloroform-d), δ: 9.48 - 9.16 (m, 1H), 7.61 - 7.24 (m, 2H), 7.24 - 6.72 (m, 7H), 6.71 - 6.44 (m, 3H), 6.41 - 6.21 (m, 2H), 5.45 - 4.60 (m, 4H), 4.32 - 3.95 (m, 2H), 3.91 - 3.70 (m, 3H), 3.68 - 3.42 (m, 8H), 3.08 (s, 2H), 2.96 - 2.65 (m, 1H), 2.45 - 2.22 (m, 3H), 2.22 - 1.75 (m, 6H). LCMS (ESI+) m / z 735 [M+H] + . Example 40. N-(2-cyanobenzyl)-5-(4,5-difluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (53). [ka] A stirred mixture of P154, catalyst (5 mg of 5% palladium on charcoal), and methanol (2 mL) was hydrogenated under an H atmosphere for 2 hours. The catalyst was filtered, and the filtrate was evaporated to dryness. The residue was subjected to HPLC purification to give 62 mg (70%) of the title compound. 1 H NMR (400 MHz,chloroform-d), δ: 9.58 - 9.27 (m, 1H), 7.97 - 7.26 (m, 7H), 7.22 - 6.66 (m, 6H), 6.62 - 6.31 (m, 3H), 5.50 - 4.69 (m, 4H), 4.35 - 3.94 (m, 2H), 3.73 - 3.42 (m, 6H), 3.09 (s, 2H), 2.84 - 2.57 (m, 1H), 2.41 - 2.26 (m, 2H), 2.20 - 1.75 (m, 5H). LCMS (ESI+) m / z 716 [M+H] + . Example 41. N-(4-chlorophenyl)-5-(4-cyano-5-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (50). [ka] A stirred mixture of P161, H2SO4 (0.03 mL), and methanol / THF (10 mL, 1:1) was stirred at ambient temperature for 2 hours. 20% aqueous sodium carbonate (pH 7) was added, and the product was extracted with DCM (2 x 10 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure on a rotary evaporator. The residue was subjected to silica gel flash chromatography eluting with a mixture of MeOH (0 -> 2%) and DCM to give 4 mg (16%) of the title compound. LCMS (ESI+) m / z 748 [M+H] + . Example 42. 5-(4-chloro-2-methyl-6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(2-methoxybenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (74). [ka] A stirred mixture of P162, H2SO4 (0.03 mL), and methanol / THF (10 mL, 1:1) was stirred at ambient temperature for 2 hours. 20% aqueous sodium carbonate (pH 7) was added, and the product was extracted with DCM (2 x 10 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel flash chromatography eluting with a mixture of MeOH (0 -> 2%) and DCM to give 12 mg (8%) of the title compound. LCMS (ESI+) m / z 734 [M+H] + . Example 43. 5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(2-methoxybenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (54). [ka] A stirred mixture of P167, catalyst (5 mg of 5% palladium on charcoal) and methanol (2 mL) was hydrogenated under an H atmosphere for 2 hours. The catalyst was filtered and the filtrate was evaporated to dryness. The residue was subjected to HPLC purification to give 3 mg (18%) of compound 54. LCMS (ESI+) m / z 703 [M+H] + . Example 44. 5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (52). [ka] A stirred ...

Claims

1. Compounds of formula (I): 【Chemistry 1】 、 or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, wherein: R １ represents halogen, —OH, —CN, and —CONH ２ Selected from: R １ａ is H; Or, R １ and R １ａ together with the atoms to which they are attached form a 3- to 10-membered heteroaryl ring further containing 1, 2, or 3 heteroatoms selected from N, O, and S; R ２ and R ３ are each independently C １ -C ６ alkyl; Or, R ２ and R ３ together with the atoms to which they are attached form a 3- to 10-membered heterocyclyl ring further containing 1, 2, or 3 heteroatoms selected from N, O, and S; Each R ４ is halogen, -OH, -CN, -NO ２ , -COOH, -CH ２ C.N., C.H. ２ N (R ８ ) ２ , C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Halogen alkyl, C １ -C ６ Halogen alkoxy, —O—(C ２ -C ６ alkenyl), —O—(C ２ -C ６ alkynyl), C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, —OH, —OP(O)(OH) ２ , —OC(O)(C １ -C ６ alkyl), —C(O)(C １ -C ６ alkyl), —OC(O)O(C １ -C ６ alkyl), -NH ２ , —NH(C １ -C ６ alkyl), -N(C １ -C ６ alkyl) ２ , -NHC(O)(C １ -C ６ alkyl), —C(O)NH ２ , -C(O)NH(C １ -C ６ alkyl), -S(O) ２ (C １ -C ６ alkyl), -S(O)NH(C １ -C ６ alkyl), and S(O)N(C １ -C ６ alkyl) ２ are independently selected from R ５ teeth, 【Chemistry 2】 , and 【Transformation 3】 Selected from: Each R ６ is a halogen, -OH, -CN, -COOH, -CH ２ CN, -CH ２ N (R ８ ) ２ , C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Halogen alkyl, C １ -C ６ Halogen alkoxy, —O—(C ２ -C ６ ) alkenyl, —O—(C ２ -C ６ ) alkynyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, —OH, —OP(O)(OH) ２ , —OC(O)(C １ -C ６ ) alkyl, —C(O)(C １ -C ６ ) alkyl, —OC(O)O(C １ -C ６ ) alkyl, —NH ２ , —NH(C １ -C ６ alkyl), -N(C １ -C ６ alkyl) ２ , -NHC(O)(C １ -C ６ ) alkyl, —C(O)NH(C １ -C ６ ) alkyl, —S(O) ２ (C １ -C ６ ) alkyl, —S(O)NH(C １ -C ６ ) alkyl, and S(O)N(C １ -C ６ alkyl) ２ are independently selected from Each R ７ is H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ independently selected from alkynyl, aryl; The C 1-6 alkyl or the aryl in each R 7 is halogen, —OH, —CN, —COOH, —CH ２ CN, -CH ２ N (R ８ ) ２ , C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Halogen alkyl, C １ -C ６ Halogen alkoxy, —O—(C ２ -C ６ ) alkenyl, —O—(C ２ -C ６ ) alkynyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, —OH, —OP(O)(OH) ２ , —OC(O)(C １ -C ６ ) alkyl, —C(O)(C １ -C ６ ) alkyl, —OC(O)O(C １ -C ６ ) alkyl, —NH ２ , —NH(C １ -C ６ alkyl), -N(C １ -C ６ alkyl) ２ , -NHC(O)(C １ -C ６ ) alkyl, —C(O)NH(C １ -C ６ ) alkyl, —S(O) ２ (C １ -C ６ ) alkyl, —S(O)NH(C １ -C ６ ) alkyl, and S(O)N(C １ -C ６ alkyl) ２ optionally substituted with one or more substituents independently selected from Or, two R ７ together with the nitrogen atom to which they are attached and any intervening atoms, represent halogen, —OH, —CN, —COOH, —CH ２ CN, -CH ２ N (R ８ ) ２ , C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Halogen alkyl, C １ -C ６ Halogen alkoxy, —O—(C ２ -C ６ ) alkenyl, —O—(C ２ -C ６ ) alkynyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, —OH, —OP(O)(OH) ２ , —OC(O)(C １ -C ６ ) alkyl, —C(O)(C １ -C ６ ) alkyl, —OC(O)O(C １ -C ６ ) alkyl, —NH ２ , —NH(C １ -C ６ alkyl), -N(C １ -C ６ alkyl) ２ , -NHC(O)(C １ -C ６ ) alkyl, —C(O)NH(C １ -C ６ ) alkyl, —S(O) ２ (C １ -C ６ ) alkyl, —S(O)NH(C １ -C ６ ) alkyl, and S(O)N(C １ -C ６ alkyl) ２ forming a heterocycle optionally substituted with one or more substituents independently selected from R ８ is H, C １－６ Alkyl, C ３－８ Cycloalkyl, aryl, C １－６ selected from halogen alkyl; R ９ is C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, -(CH ２ ) １－６ OR ８ , C ３－８ cycloalkyl, aryl, or heterocyclyl, and the C 1-6 alkyl, C 3-8 cycloalkyl, aryl, or heterocyclyl in R 9 is selected from halogen, —OH, —CN, —COOH, —CH ２ C.N., C. １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Halogen alkyl, C １ -C ６ Halogen alkoxy, —O—(C ２ -C ６ ) alkenyl, —O—(C ２ -C ６ ) alkynyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, —OH, —OP(O)(OH) ２ , —OC(O)(C １ -C ６ ) alkyl, —C(O)(C １ -C ６ ) alkyl, —OC(O)O(C １ -C ６ ) alkyl, —NH ２ , —NH(C １ -C ６ alkyl), -N(C １ -C ６ alkyl) ２ , -NHC(O)(C １ -C ６ ) alkyl, —C(O)NH(C １ -C ６ ) alkyl, —S(O) ２ (C １ -C ６ ) alkyl, —S(O)NH(C １ -C ６ ) alkyl, and S(O)N(C １ -C ６ alkyl) ２ optionally substituted with one or more substituents independently selected from x is an integer selected from 0, 1, 2, and 3; y is an integer selected from 0, 1, 2, and 3; m is an integer selected from 0, 1, and 2; each n is an integer independently selected from 1, 2, and 3; Aryl is a cyclic aromatic hydrocarbon group having 1 to 3 aromatic rings; The heterocycle is a saturated or partially unsaturated 3-10 membered monocyclic, 7-12 membered bicyclic, or 11-14 membered tricyclic ring system having one or more heteroatoms selected from O, N, S, P, Se, and B.

2. The compound has the structure of formula (I'): 【Chemistry 4】 、 10. The compound of claim 1, wherein R is 1 or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

3. The compound has the structure of formula (II): 【Transformation 5】 、 10. The compound of claim 1, wherein R is 1 or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

4. The compound has the structure of formula (II'): 【Transformation 6】 、 10. The compound of claim 1, wherein R is 1 or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

5. The compound has the structure of formula (II-A): 【Transformation 7】 、 or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof, the compound of claim 1.

6. The compound has the structure of formula (II'): 【Transformation 8】 、 10. The compound of claim 1, which is: or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

7. The compound has the formula (II-AA), the formula (II-AB), or the formula (II-AC): 【Chemistry 9】 、 10. The compound of claim 1, wherein R is 1 or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

8. The compounds are represented by formula (II-BA), formula (II-BB), and formula (II-BC): 【Chemistry 10】 10. The compound of claim 1, wherein R is 1 or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

9. A compound selected from: or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

10. 10. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier.

11. 11. The pharmaceutical composition of claim 10, further comprising an additional pharmaceutically active agent.

12. Use of a compound described in any one of claims 1 to 9 or a composition described in any one of claims 10 or 11 in the preparation of a medicament for inhibiting BCL-2 protein, wherein the compound or composition is administered to a subject in need of treatment.

13. Use of a compound according to any one of claims 1 to 9 or a composition according to any one of claims 10 or 11 in the preparation of a medicament for treating a disease or disorder associated with inhibition of BCL-2 protein, wherein the compound or composition is administered to a subject in need of treatment.

14. Use of a compound described in any one of claims 1 to 9 or a composition described in any one of claims 10 or 11 in the preparation of a medicament for treating cancer, wherein the compound or composition is administered to a subject in need of treatment for cancer.

15. 15. The use of claim 14, wherein the cancer is selected from bladder cancer, bone cancer, brain cancer, breast cancer, heart cancer, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, fibrosarcoma, stomach cancer, gastrointestinal cancer, head, spine and neck cancer, Kaposi's sarcoma, kidney cancer, leukemia, liver cancer, lymphoma, melanoma, multiple myeloma, pancreatic cancer, penile cancer, testicular germ cell cancer, thymic carcinoma, thymic carcinoma, lung cancer, ovarian cancer, and prostate cancer.

16. The use of claim 12, wherein the subject is a mammal.

17. The use of claim 16, wherein the subject is a human.

18. The use described in claim 12, wherein the BCL-2 protein is isoform 1.

19. The use described in claim 12, wherein the BCL-2 protein is isoform 2.

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