Inhibitors of cyclin-dependent kinase 7

Abstract

The present invention provides novel compounds of Formula (I) and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof. Also provided are methods and kits involving the compounds or compositions for treating or preventing proliferative diseases in a subject, wherein the proliferative diseases include cancer, benign neoplasm, angiogenesis, inflammatory disease, autoinflammatory disease, and autoimmune disease, and the cancer includes leukemia, melanoma, multiple myeloma. Treatment of a subject having a proliferative disease with the compounds or compositions of the present invention can inhibit abnormal activity of cyclin-dependent kinase 7, thus inducing apoptosis and / or inhibiting transcription in the subject.

Description

[0001] This application is a divisional application of the invention patent application filed on July 13, 2017, with application number 201780057760.8 and invention title "Inhibitor of Cyclin-dependent Kinase 7 (CDK7)".

[0002] Priority requirements This application claims priority to U.S. Provisional Application No. 62 / 361,852, filed July 13, 2016, which is incorporated herein by reference in its entirety. Background Technology

[0003] Members of the cyclin-dependent kinase (CDK) family play crucial regulatory roles in proliferation. CDK7, unique among mammalian CDKs, possesses integrated kinase activity, regulating cell cycle and transcription. In the cytosol, CDK7 exists as a heterotrimeric complex and is believed to act as CDK1 / 2 activated kinase (CAK), whereby phosphorylation of conserved residues in CDK1 / 2 is essential for fully catalytic CDK activity and cell cycle progression. In the nucleus, CDK7 forms the kinase core of the RNA polymerase (RNAP)II general transcription factor complex and is responsible for phosphorylating the C-terminal domain (CTD) of RNAPII, a necessary step in gene transcription initiation. These two functions of CDK7—CAK and CTD phosphorylation—together support key aspects of cell proliferation, cell cycle, and transcription.

[0004] Disruption of RNAP II CTD phosphorylation has been shown to preferentially affect short-lived proteins, including those of the anti-apoptotic BCL-2 family. Cancer cells have demonstrated the ability to circumvent pro-cell death signaling by upregulating BCL2 family members. Therefore, inhibition of human CDK7 kinase activity may lead to antiproliferative activity.

[0005] The high sequence and structural similarity of kinase domains among CDK family members has hindered the discovery of selective CDK7 inhibitors. Therefore, there is a need to discover and develop selective CDK7 inhibitors. Such CDK7 inhibitors hold promise as therapeutic agents for CLL and other cancers. Summary of the Invention

[0006] This invention provides inhibitors of one or more kinase families, such as serine / threonine kinases, or one or more CDK protein families. The invention further provides CDK7 inhibitors, particularly selective CDK7 inhibitors of formula (I), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof. The invention also provides methods of using the compounds of the invention and their pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, and compositions as therapeutic agents to prevent and / or treat diseases associated with overexpression and / or aberrant activity of one or more kinases, such as members of the serine / threonine kinase family (e.g., one or more CDK family members, such as CDK7 and / or CDK12 and / or CDK13). In some embodiments, the compounds of the invention can be used in subjects to prevent and / or treat proliferative diseases (e.g., cancers (e.g., leukemia, melanoma, multiple myeloma), benign growths, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases).

[0007] In one aspect, the present invention provides compounds of formula (I) and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, and isotopically labeled derivatives thereof, wherein rings A, L, and R 1 R 2 R 3 R 4 R 5 R 6 , m, n and their subvariables are defined as in this paper.

[0008] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and optionally a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof. This pharmaceutical composition may be used to treat and / or prevent proliferative or infectious diseases.

[0009] In another aspect, the present invention provides methods for treating and / or preventing proliferative diseases. Exemplary proliferative diseases include cancers (e.g., leukemia, melanoma, multiple myeloma), benign growths, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases. In other embodiments, the present invention provides methods for treating and / or preventing infectious diseases (e.g., viral infections).

[0010] In another aspect, the present invention provides a method for downregulating the expression of certain serine / threonine kinases (e.g., certain CDK family members, such as CDK7) in biological samples or subjects.

[0011] Another aspect of the present invention relates to a method for inhibiting the activity of certain serine / threonine kinases (e.g., certain CDK family members, such as CDK7) in biological samples or subjects.

[0012] The present invention also provides a method for inhibiting cell growth in biological samples or subjects.

[0013] In another aspect, the present invention provides a method for inducing apoptosis in biological samples or subjects.

[0014] In yet another aspect, the present invention provides compounds of formula (I) for treating proliferative disorders in subjects, as well as pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof.

[0015] In another aspect, the present invention provides compounds of formula (I) for treating or preventing infectious diseases in subjects, as well as pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof. In some embodiments, the infectious disease is a viral infection.

[0016] Another aspect of the invention relates to a kit comprising a container for a compound having formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, or a pharmaceutical composition thereof. In some embodiments, the kit described herein further includes instructions for administering a compound having formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, or a pharmaceutical composition thereof.

[0017] Details of one or more embodiments of the present invention are set forth herein. Other features, objects, and advantages of the invention will become apparent from the detailed description, the accompanying drawings, the embodiments, and the claims. Attached Figure Description

[0018] Figures 1A-1V A table of compounds of exemplary formula (I). Detailed Implementation

[0019] definition The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the periodic table (CAS version) on the inner cover of the 75th edition of the Handbook of Chemistry and Physics, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional groups and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987; the entire contents of each are incorporated herein by reference.

[0020] Unless otherwise stated, the structures described herein are also intended to include all isomers (e.g., enantiomers, diastereomers, and geometric isomers (or conformations)) of said structures; for example, including R and S configurations for each asymmetry center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers of the compounds of the present invention, as well as mixtures of enantiomers, diastereomers, and geometric isomers (or conformations), are within the scope of the present invention. Unless otherwise stated, all tautomers of the compounds of the present invention are within the scope of the present invention. Additionally, unless otherwise stated, the structures described herein are also intended to include compounds distinguished only by the presence of one or more isotopically enriched atoms. For example, compounds having the structures of the present invention (which include hydrogen replaced by deuterium or tritium, carbon replaced by...) 13 C or 14 C-enriched carbon replacements are within the scope of this invention. Such compounds can be used, for example, as analytical tools, probes in biological assays, or therapeutic agents according to the invention.

[0021] In some embodiments where specific enantiomers are preferred, substances substantially free of the corresponding enantiomers may be provided, and may also be referred to as “optically enriched.” As used herein, “optically enriched” means that the compound consists of a significantly larger proportion of one enantiomer. In some embodiments, the compound consists of at least about 90 wt% of the preferred enantiomer. In other embodiments, the compound consists of at least about 95 wt%, 98 wt%, or 99 wt% of the preferred enantiomer. The preferred enantiomers can be separated from the racemic mixture by any method known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC), and by the formation and crystallization of chiral salts or by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, EL Stereochemistry of Carbon Compounds (McGraw Hill, NY, 1962); Wilen, SHTables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

[0022] As used herein, the term "aliphatic" or "aliphatic group" refers to a hydrocarbon moiety that may be straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridged, and spirofused polycyclic rings), and may be fully saturated or contain one or more unsaturated units, but is not aromatic. Unless otherwise stated, an aliphatic group contains 1 to 6 carbon atoms. In some embodiments, the aliphatic group contains 1 to 4 carbon atoms, while in other embodiments, the aliphatic group contains 1 to 3 carbon atoms. Suitable aliphatic groups include, but are not limited to, straight-chain or branched alkyl, alkenyl, and alkynyl groups, and their hybrids, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl groups.

[0023] The term "alkyl," as used herein, refers to a monovalent, saturated, straight-chain or branched hydrocarbon, such as 112, 110, or a straight-chain or branched group with 16 carbon atoms, referred to herein as C1C, respectively. 12 Alkyl, C1C 10Alkyl and C1C6 alkyl. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, sec-pentyl, isopentyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, sec-hexyl, etc.

[0024] The terms "alkenyl" and "alkynyl" are recognized in the art and refer to unsaturated aliphatic groups that are similar in length and possible substitutions to the alkyl groups described above, but each contains at least one double or triple bond. Exemplary alkenyl groups include, but are not limited to, -CH=CH2 and CH2CH=CH2.

[0025] The term "alkylene" refers to a divalent group of an alkyl group.

[0026] The terms "alkenylyl" and "alkynylyl" refer to the divalent groups of alkenyl and alkynyl groups, respectively.

[0027] The term "carbon ring system" as used herein refers to a monocyclic, or fused, spirofused and / or bridged bicyclic or polycyclic hydrocarbon ring system in which each ring is fully saturated or contains one or more unsaturated units, but none of the rings are aromatic.

[0028] The term "carbocyclic group" refers to a group in a carbocyclic system. Representative carbocyclic groups include cycloalkyl (e.g., cyclopentyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) and cycloalkenyl (e.g., cyclopentenyl, cyclohexenyl, cyclopentadienyl, etc.).

[0029] The term "aromatic ring system" is recognized in the art and refers to a monocyclic, bicyclic, or polycyclic hydrocarbon ring system in which at least one ring is aromatic.

[0030] The term "aryl" refers to a group in an aromatic ring system. Representative aryl groups include fully aromatic ring systems, such as phenyl, naphthyl, and anthracene, and cyclic systems in which the aromatic carbide ring is fused to one or more non-aromatic carbide rings, such as indanyl, phthalimide, naphthimidyl, or tetrahydronaphthyl, etc.

[0031] The term "heterocyclic aromatic ring system" is recognized in the art and refers to a monocyclic, bicyclic, or polycyclic ring system in which at least one ring is aromatic and contains a heteroatom; and in which no other ring is a heterocyclic group (as defined below). In some cases, the aromatic ring containing a heteroatom contains one, two, three, or four independently chosen cyclic heteroatoms.

[0032] The term "heteroaryl" refers to a group in a heterocyclic ring system. Representative heteroaryl groups include ring systems in which (i) each ring contains a heteroatom and is aromatic, such as imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrrolel, furanyl, thiophenel, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indazinyl, purinel, naphthidyl, and pteridinyl; (ii) One ring is aromatic and contains a heteroatom, and each of the other rings is aromatic or carbocyclic, for example, indolyl, isoindolyl, benzothiophenyl, benzofuranyl, dibenzofuranyl, indazoleyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, terpineyl, phthalazinyl, quinazolinyl, quinoxalinyl, carbazolyl, acridineyl, phenazinyl, phenothiazinyl, phenoxazinyl, pyrido[2,3b]1,4oxazine 3(4H)-one, 5,6,7,8-tetrahydroquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl; and (iii) one ring is aromatic and fused, spirofused or bridged to a carbocyclic group, and the aromatic ring shares a bridgehead heteroatom with the carbocyclic group, for example, 5,6,7,8-tetrahydroindazinyl. In some embodiments, the heteroaryl group is a monocyclic or bicyclic ring, wherein each ring contains 5 or 6 ring atoms, wherein 1, 2, 3 or 4 of the ring atoms are heteroatoms independently selected from N, O and S.

[0033] The term "heterocyclic system" refers to a monocyclic, or fused, spirofused, and / or bridged bicyclic and polycyclic cyclic system, wherein at least one ring is saturated or partially unsaturated (but not aromatic) and contains heteroatoms. Heterocyclic systems may have any heteroatom or carbon atom attached to its side group that results in a stable structure, and any ring atom may optionally be substituted.

[0034] The term "heterocyclic group" refers to a group in a heterocyclic system. Representative heterocyclic groups include cyclic systems in which (i) each ring is non-aromatic and at least one ring contains a heteroatom, such as tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolyl, pyrrolidone, piperidinyl, pyrrololinyl, decahydroquinolinyl, oxazolyl, piperazine, dioxyl, dioxazolidinyl, diazacyclopentyl, diazacycloheptatrienyl, oxazolidinyl, thioazolidinyl, morpholinyl, and quininecycloyl; (ii) at least one ring is non-aromatic and contains a heteroatom, and at least one other ring is an aromatic carbocyclic ring, such as 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl; and (iii) at least one ring is non-aromatic and contains a heteroatom, and at least one other ring is aromatic and contains a heteroatom, such as 3,4-dihydro1Hpyrano[4,3c]pyridine and 1,2,3,4-tetrahydro2,6-naphthidine. In some embodiments, the heterocyclic group is a monocyclic or bicyclic ring, wherein each ring contains 37 ring atoms, wherein 1, 2, 3 or 4 of the ring atoms are heteroatoms independently selected from N, O and S.

[0035] The term "saturated heterocyclic group" refers to a heterocyclic system group in which each ring is saturated, such as tetrahydrofuran, tetrahydro-2Hpyran, pyrrolidine, piperidine, and piperazine.

[0036] "Partially unsaturated" means a group that includes at least one double or triple bond. A "partially unsaturated" ring system is also intended to include rings with multiple unsaturated sites, but not necessarily aromatic groups (e.g., aryl or heteroaryl) as defined herein. Similarly, "saturated" means a group that does not contain double or triple bonds, i.e., contains only single bonds.

[0037] As described herein, the compounds of the present invention may contain an “optionally substituted” portion. Generally, the term “substituted,” whether or not it follows the term “optionally,” means that one or more hydrogens of the specified portion are substituted by a suitable substituent. Unless otherwise stated, the “optionally substituted” group may have a suitable substituent at each substituted position of the group, and when more than one position in any given structure can be substituted by more than one substituent selected from a particular group, the substituents may be the same or different at each position. The combinations of substituents contemplated in this invention are preferably those that result in the formation of stable or chemically viable compounds. The term “stable” as used herein means a compound that remains substantially unchanged when subjected to conditions that allow for its production, detection, and, in some embodiments, recovery, purification, and use for one or more of the purposes disclosed herein.

[0038] The suitable monovalent substituent on the substituted carbon atom of the "optionally substituted" group (such as the carbon atom of alkyl, alkenyl, ynylene, alkylene, alkenylene, ynylene, or carbocyclic, aryl, heterocyclic, or heteroaryl groups) is independently selected from deuterium; halogen; -NO2; -CN; -N3; ​​-(CH2). 0-4 R°;-(CH2) 0-4 OR°;-O-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 SR°;-(CH2) 0-4 N(R°)2;-(CH2) 0-4 C(O)N(R°)2;-(CH2) 0-4 N(R°)C(O)R°;-(CH2) 0-4 N(R°)C(O)NR°2;-(CH2) 0-4 N(R°)C(O)OR°; -N(R°)N(R°)C(O) R°; -N(R°)N(R°)C(O)NR°2; -(CH2) 0-4 C(O)R°;-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 -C(O)-N(R o)-S(O)2-R o ;-(CH2) 0-4 OC(O)R;-(CH2) 0-4 C(O)NR°2;-(CH2) 0-4 OC(O)NR°2; -C(O)N(OR°)R°; -C(NOR°)R°; -C(NOR°)NR°2; -C(NCN)NR°2; -(CH2) 0-4 S(O)2R°;-S(O)2NR°2;-(CH2) 0-4 S(O)R°;-N(R°)S(O)2NR°2;-N(R°)S(O)R°;-C(NR°)NR°2;-P(O)(OR°)2;-P(O)(OR°)R°;-P(O)R°2;-OP(O)(OR°)2;-OP(O)(OR°)R°;-OP(O)R°2;-SiR°3;where each R° is arbitrarily substituted and independently hydrogen, deuterium, C as defined below. 1-6 An aliphatic group, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur; or, notwithstanding the above definition, two independently occurring R°, together with their intervening atom, can form a 3-7-membered heterocycle having 1-3 independent heteroatoms selected from nitrogen, oxygen, sulfur, or phosphorus.

[0039] Suitable monovalent substituents on R° (or the ring formed by two independent R°s with their inserted atoms) are independently selected from halogens, -CN, -NO2, -N3, and -R. ● -(CH2) 0-2 OH, -(CH2) 0-2 OR ● -(CH2) 0-2 C(O)R ● -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● -(CH2) 0-2 NH2、-(CH2) 0-2 NHR ● and -(CH2) 0-2 NR ● 2, where each R ● Selected independently from C 1-4 Aliphatic or 5-6-membered saturated, partially unsaturated, or aryl rings having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each R ● Optional replacement of one or more independently selected halogens.

[0040] Suitable divalent substituents on the saturated carbon atom of the "optionally substituted" group include the following: =O, =NN(R) * )2、=NNR * S(O)2R * =NR * =NOR * =NCN; where each independently occurring R * Selected from hydrogen, deuterium, and C 16 Aliphatic or having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, consisting of a 56-membered saturated, partially unsaturated, or aryl ring; and, despite the above definition, two independently occurring R... * Together with their inserted atoms, they can form 37-membered heterocycles with 1-2 independent heteroatoms selected from nitrogen or sulfur, wherein each R * Optional substitutions may include one or more substituents selected from the following: deuterium, halogens, -R ● -OH, -OR ● -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● -NR ● 2 and NO2.

[0041] Suitable substituents on the substituted nitrogen of the "optionally substituted" group include -R † -N(R) † )2;-C(O)R † -C(O)OR † -C(O)N(R) † )2、-S(O)2R † -S(O)2N(R) † )2-N(R † )S(O)2R † -C(NR) † )N(R † )2、-C(NOR † )N(R † )2, or -C(NCN)N)R † )2; where each R † Independently hydrogen, C 1-6 Aliphatic group, or a 57-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or, despite the above definition, two independently occurring R groups. † Together with their inserted atoms, they can form 37-membered saturated, partially unsaturated, aryl or heterocyclic groups having 1-3 independent heteroatoms selected from nitrogen, oxygen or sulfur, wherein each R †Optional and independent substitutions include one or more substituents independently selected from the following: deuterium, halogen, -R ● -OH, -OR ● -CN, -NH2, -NHR ● -NR ● 2 and -NO2.

[0042] "Halogen" or "halogen" refers to fluorine (fluorinated, -F), chlorine (chlorinated, -Cl), bromine (brominated, -Br), or iodine (iodinated, -I).

[0043] These and other exemplary substituents are described in more detail in the detailed description, drawings, embodiments, and claims. The invention is not intended to be limited in any way by the foregoing exemplary list of substituents.

[0044] Other definitions The following definitions are the more general terms used throughout this application: The term "pharmaceutically acceptable salt" means a salt that, to the extent of reasonable medical judgment, is suitable for use in contact with tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., in J. Pharmaceutical Sciences, 1977, 66, 1-19, describe pharmaceutically acceptable salts in detail, which are incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by amino groups with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed by using other methods known in the art (e.g., ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, disglucuronate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-heptahydrate, glyceryl phosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N salts. + (C 1-4 Alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium salts. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using balancing ions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0045] The term "solvent" refers to a compound that typically associates with a solvent phase via a solvent decomposition reaction. This physical association can include hydrogen bonding. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. Compounds of formula (I) can be prepared, for example, in crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric and non-stoichiometric solvates. In some cases, the solvate will be separable, for example, when one or more solvent molecules are incorporated into the lattice of a crystalline solid. "Solvent" encompasses both solution phases and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0046] The term "hydrate" refers to a compound that associates with water. Typically, the number of water molecules contained in a hydrate of a compound is in a certain ratio to the number of compound molecules in the hydrate. Therefore, a hydrate of a compound can be, for example, formed by the general chemical formula R. x H2O represents R, where R is a compound and x is a number greater than 0. The given compound can form more than one type of hydrate, including, for example, monohydrate (x is 1), lower hydrate (x is a number greater than 0 and less than 1, for example, hemihydrate (R)). 0.5 H2O)) and polyhydrates (x is a number greater than 1, for example, dihydrates (R 2 H2O) and hexahydrate (R 6 H2O)).

[0047] The term "tautomer" refers to compounds that have specific compound structures that are interchangeable in form and vary in terms of hydrogen atom and electron shifts. Thus, the two structures can be in equilibrium through the movement of π electrons and atoms (usually H). For example, enols and ketones are tautomers because they can be rapidly interconverted by treatment with an acid or base. Another example of tautomerism is the acid- and nitro-forms of phenylnitromethane, which are similarly formed by treatment with an acid or base.

[0048] Tautomerism can be associated with obtaining the optimal chemical reactivity and biological activity of compounds of interest.

[0049] It should also be understood that compounds with the same molecular formula but different in properties, in the bonding sequence of their atoms, or in the spatial arrangement of their atoms are called "isomers". Isomers whose atoms are different in spatial arrangement are called "stereoisomers".

[0050] Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are non-overlapping mirror images of each other are called "enantiomers." When a compound has an asymmetry center, for example, it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers are characterized by the absolute configuration of their asymmetry center and are described and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)- isomers, respectively) by the Cahn and Prelog R- and S-sorting rules, or by the method of rotating the plane of polarized light. Chiral compounds can exist as single enantiomers or mixtures thereof. A mixture containing enantiomers in equal proportions is called a "racemic mixture."

[0051] The “subject” to which the drug is administered is expected to include, but is not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or other non-human animals, such as mammals (e.g., primates (e.g., macaques, rhesus monkeys); commercially relevant mammals (e.g., cattle, pigs, horses, sheep, goats, cats, and / or dogs) and birds (e.g., commercially relevant birds such as chickens, ducks, geese, and / or turkeys). In some embodiments, the animal is a mammal. The animal may be male or female and at any developmental stage. The non-human animal may be a transgenic animal.

[0052] As used herein, the terms “give”, “administer”, or “apply” mean to implant, absorb, ingest, inject, inhale, or otherwise introduce the compound of the invention or a pharmaceutical composition thereof.

[0053] As described herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of a pathological state described herein, or inhibiting the progression of a pathological state (e.g., disease, disorder, or condition, or one or more of its signs or symptoms). In some embodiments, "treatment" requires that signs or symptoms of a disease or condition have been developed or observed. In other embodiments, treatment may be given even when there are no signs or symptoms of a disease or condition. For example, treatment may be given to a susceptible individual before the onset of symptoms (e.g., based on a history of symptoms and / or based on genetic or other susceptibility factors). Treatment may also continue after symptoms have subsided, for example, to delay or prevent recurrence.

[0054] The terms “symptom”, “disease” and “disorder” used in this application are used interchangeably.

[0055] The “effective amount” of a compound of formula (I) refers to an amount sufficient to elicit the expected biological response, i.e., to treat the condition. As those skilled in the art will appreciate, the effective amount of a compound of formula (I) can vary depending on factors such as the expected biological endpoint, the pharmacokinetics of the compound, the condition being treated, the administration method, and the age and health status of the subject. Effective amounts include therapeutically effective amounts and preventatively effective amounts. For example, in cancer treatment, an effective amount of the compound of the present invention can reduce tumor burden or stop tumor growth or spread.

[0056] The "therapeuticly effective amount" of a compound of formula (I) refers to an amount sufficient to provide therapeutic benefit in treating a condition, delaying or minimizing one or more symptoms associated with said condition. In some embodiments, a therapeutically effective amount is an amount sufficient to provide therapeutic benefit in treating a condition or to minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent used alone or in combination with other treatment regimens that is capable of providing therapeutic benefit in treating a condition. The term "therapeuticly effective amount" includes amounts that improve overall treatment, reduce or avoid symptoms or causes of disease, or enhance the therapeutic effect of another therapeutic agent.

[0057] The “preventive effective amount” of a compound of formula (I) refers to an amount sufficient to prevent the disease, prevent one or more symptoms associated with said disease, or prevent recurrence of said disease. The preventive effective amount of a compound means the amount used as a treatment alone or in combination with other drugs, and provides preventive benefit in disease prevention. The term “preventive effective amount” may also include an amount that improves overall prevention or enhances the preventive effect of another preventive agent.

[0058] "Proliferative disorders" are diseases caused by abnormal growth or expansion due to cell proliferation (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990). Proliferative disorders can be associated with: 1) pathological proliferation of normal quiescent cells; 2) pathological migration of cells from their normal locations (e.g., metastasis of tumor cells); 3) pathological expression of proteolytic enzymes (e.g., matrix metalloproteinases (e.g., collagenase, gelatinase, and elastase)); or 4) pathological angiogenesis in proliferative retinopathy and tumor metastasis. Exemplary proliferative disorders include cancer (i.e., "malignant tumors"), benign tumors, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases.

[0059] The terms “neoplasm” and “tumor” are used interchangeably herein and refer to an abnormal mass of tissue that grows beyond and out of sync with the growth of normal tissue. A neoplasm or tumor can be “benign” or “malignant”, depending on the following characteristics: degree of cell differentiation (including morphology and function), growth rate, local invasion, and metastasis. A “benign tumor” is typically well-differentiated, grows significantly slower than a malignant tumor, and remains confined to its site of origin. Furthermore, a benign tumor does not have the ability to infiltrate, invade, or metastasize to distant sites. Exemplary benign tumors include, but are not limited to, lipomas, chondromas, adenomas, alopecia areata, senile hemangiomas, seborrheic keratosis, lentigines, and sebaceous hyperplasia. In some cases, some “benign” tumors may later develop into malignant tumors, possibly due to additional genetic changes in a subset of tumor cells, and these tumors are referred to as “pre-malignant neoplasms.” An exemplary pre-malignant neoplasm is a teratoma. In contrast, "malignant tumors" are typically poorly differentiated (anaplasia) and exhibit remarkably rapid growth, accompanied by progressive infiltration, invasion, and destruction of surrounding tissues. Furthermore, malignant tumors often have the ability to metastasize to distant locations.

[0060] As described in this article, the term "cancer" refers to a malignant tumor (Stedman's Medical Dictionary, 25th edition; edited by Hensyl; Williams & Wilkins: Philadelphia, 1990). Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal carcinoma; anal cancer; and angiosarcoma. (e.g., lymphangiosarcoma, lymphangioendothelial sarcoma, hemangiosarcoma); appendix cancer; benign monoclonal globulinosis; biliary tract cancer (e.g., bile duct epithelial carcinoma); bladder cancer; breast cancer (e.g., breast adenocarcinoma, breast papillary carcinoma, breast cancer, breast medullary carcinoma); brain cancer (e.g., meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma, medulloblastoma); bronchial cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial cancer; ventricular cancer. Ductonoma; endothelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcomas); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma); Ewing sarcoma; ocular cancer (e.g., intraocular melanoma, retinoblastoma); familial eosinophilia; gallbladder cancer; gastric cancer (e.g., gastric adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), laryngeal cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic cancers (e.g., leukemia, such as acute lymphoblastic leukemia (ALL)). (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL));Lymphomas, such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL, such as diffuse large cell lymphoma (DLCL)). (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, lymph node marginal zone B-cell lymphoma, spleen marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenström macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-cell lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma; and T-cell NHL, such as precursor T-cell lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL). (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Cezari syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); mixed states of one or more of the above leukemias / lymphomas; and multiple myeloma (MM), heavy chain diseases (e.g., alpha chain disease, gamma chain disease, μ chain disease); hemangioblastoma; hypopharyngeal carcinoma; inflammatory myofibroblastic tumor Immune cell amyloidosis; renal cell carcinoma (e.g., nephroblastoma, also known as Wilms' tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular carcinoma (HCC), malignant hepatocellular carcinoma); lung cancer (e.g., bronchial protocarcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); myoma; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (For example, polycythemia vera (PV), essential thrombocythemia (ET), unexplained myeloid metaplasia (AMM), also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), eosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or 2, schwannomatosis); neuroendocrine tumors (e.g., gastrointestinal pancreatic neuroendocrine tumor (GEP-NET), carcinoid tumors); osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma;Pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous tumor (IPMN), islet cell carcinoma); penile cancer (e.g., Paget's disease of the penis and scrotum); pineal tumor; primitive neuroectodermal tumor (PNT); plasmacytoma; paraneoplastic syndromes. syndromes); intraepithelial neoplasms; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland cancer; small bowel cancer; sweat gland cancer; synovial tumor; testicular cancer (e.g., seminoma, embryonal testicular carcinoma); thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget's disease of the vulva).

[0061] The term "angiogenesis" refers to the formation and growth of new blood vessels. Normal angiogenesis occurs in healthy individuals to facilitate wound healing and restore blood flow to tissues after injury. The healthy body controls angiogenesis through various mechanisms, including angiogenesis-stimulating factors and angiogenesis-inhibiting factors. Many disease conditions, such as cancer, diabetic blindness, age-related macular degeneration, rheumatoid arthritis, and psoriasis, are characterized by abnormal (i.e., increased or excessive) angiogenesis. Abnormal angiogenesis refers to angiogenesis that is larger than normal in the body, particularly in adults, and is unrelated to normal angiogenesis (such as menstruation or wound healing). Abnormal angiogenesis can provide new blood vessels to supply diseased tissue and / or destroy normal tissue, and in the case of cancer, new blood vessels may allow tumor cells to escape into the circulation and remain in other organs (tumor metastasis).

[0062] As described herein, the term "inflammatory disease" refers to a disease caused, resulting from, or causing inflammation. The term "inflammatory disease" can also refer to a dysregulated inflammatory response that leads to an exaggerated reaction by macrophages, granulocytes, and / or T-lymphocytes, resulting in abnormal tissue damage and / or cell death. Inflammatory diseases can be acute or chronic and can be caused by infectious or non-infectious factors. Inflammatory diseases include, but are not limited to, atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendinitis, bursitis, psoriasis, cystic fibrosis, osteoarthritis, rheumatoid arthritis, inflammatory arthritis, Sjögren's syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, bullous pemphigoid, diabetes (e.g., type I), myasthenia gravis, Hashimoto's thyroiditis, Graves' disease, Goodpasser's disease, and mixed connective tissue disease. Tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, pernicious anemia, inflammatory dermatitis, common interstitial pneumonia (UIP), asbestosis, silicosis, bronchiectasis, beryllium poisoning, talc lung, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener's granulomatosis and related forms of vasculitis (temporal arteritis and polyarteritis nodosa), inflammatory dermatitis, hepatitis, delayed-type hypersensitivity reactions (e.g., poison ivy dermatitis), pneumonia, respiratory tract inflammation, adult respiratory distress syndrome ARDS, encephalitis, immediate-type hypersensitivity reaction, asthma, hay fever, allergy, acute allergic reaction, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, allogeneic transplant rejection, host-graft rejection, appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis. Ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, pharyngitis, pleurisy, phlebitis, pneumonia, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, orchitis, tonsillitis, urethritis, cystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, vasculitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis, and necrotizing enterocolitis.

[0063] As described in this article, "autoimmune disease" refers to a disease caused by an inappropriate immune response of the subject's body to substances and tissues normally present in said body. In other words, the immune system mistakes a part of the body for a pathogen and attacks its own cells. This can be limited to a specific organ (e.g., in autoimmune thyroiditis) or involve specific tissues in different locations (e.g., Goodpasseur disease, which may affect the basement membrane of the lungs and kidneys). Treatment for autoimmune diseases is usually with immunosuppression, such as drugs that reduce the immune response. Exemplary autoimmune diseases include, but are not limited to, glomerulonephritis, Goodpasser syndrome, necrotizing vasculitis, lymphadenitis, periarteritis nodosa, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis / polymyositis, antiphospholipid antibody syndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis (e.g., Wegener's granulomatosis, microscopic polyangiitis), uveitis, Sjögren's syndrome, Crohn's disease, Wright's syndrome, ankylosing spondylitis, Lyme arthritis, Guillain-Barré syndrome, Hashimoto's thyroiditis, and cardiomyopathy.

[0064] The term "autoinflammatory disease" refers to a class of diseases similar to, but distinct from, autoimmune diseases. Autoinflammatory diseases and autoimmune diseases share common characteristics because both groups are caused by the immune system attacking the subject's own tissues, resulting in increased inflammation. In autoinflammatory diseases, the subject's innate immune system initiates inflammation for unknown reasons. The innate immune system reacts even if it has never encountered autoantibodies or antigens in the subject. Autoinflammatory diseases are characterized by severe inflammatory episodes, causing symptoms such as fever, rash, or joint swelling. These diseases also carry the risk of amyloidosis, a potentially fatal accumulation of blood proteins in vital organs. Autoinflammatory diseases include, but are not limited to, familial Mediterranean fever (FMF), neonatal onset multisystem inflammatory disease (NOMID), tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), interleukin-1 receptor antagonist deficiency (DIRA), and Behçet's disease.

[0065] The term "biological sample" refers to any sample, including tissue samples (such as tissue sections and needle biopsies); cell samples (such as cytological smears (such as Pap smears or blood smears) or samples of cells obtained through microdissection); samples of whole organisms (such as samples of yeast or bacteria); or cell fractions, fragments, or organelles (such as those obtained by lysing cells and separating their components by centrifugation or other means). Other examples of biological samples include blood, serum, urine, semen, feces, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsy tissue (such as those obtained through surgical or needle biopsy), nipple aspiration fluid, breast milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any substance containing biomolecules derived from the first biological sample. Biological samples also include those of transgenic organisms, such as transgenic oocytes, sperm cells, blastocysts, embryos, fetuses, donor cells, or cell nuclei.

[0066] compound In one aspect of the invention, a compound of formula (I) is provided: Or, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the following bicyclic 6,5-ring systems: , and It contains no more than 4 cyclic nitrogen atoms; X is selected from N and C(R) 6 ), where R 6 Selected from hydrogen, -CN, -CH3, -CH2F, -CHF2, and -CF3; each Y is independently selected from N and C(R) 7 ), where R 7 Selected from hydrogen and R 5 Z is selected from N and C(R) 8 ), where R 8 Selected from hydrogen and fluorine; R 1 Selected from hydrogen, -C1-C6 alkyl, -O-(C1-C6-alkylene)-O-(C1-C4-alkyl), -(C0-C6-alkylene)-(C3-C8 cycloalkyl), -(C1-C6-alkylene)-heterocyclic, -(C1-C6-alkylene)-heteroaryl, -(C1-C6-alkylene)-N(R) 1’ 2、-(C1-C6 alkylene)-NR 1’ -S(O)2-(C1-C4 alkyl), -(C1-C6 alkylene)-NR 1’ -SO 2- N(R 1’ )2, -(C1-C6 alkylene)-S(O)2-(C1-C4 alkyl) and -(C1-C6 alkylene-S(O)2-N(R) 1’ )2, where R1 Any alkyl, alkylene, cycloalkyl, heterocyclic, or heteroaryl moiety may be optionally substituted: Each R 1’ Independently selected from hydrogen, and optionally substituted C1-C6 alkyl groups, or two R groups. 1’ The nitrogen atoms optionally bonded to them form a 4-6 membered, optionally substituted heterocyclic or heteroaryl ring, which contains at most two additional heteroatoms selected from N, O, and S, wherein: Each R 2 If present, independently selected from =O, halogen, -OH, -CN, -C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-heterocyclic, -(C0-C6 alkylene)-heteroaryl, -(C0-C6 alkylene)-aryl, -(C0-C6 alkylene)-C(O)heterocyclic, -(C0-C6 alkylene)-C(O)heterocyclic, etc. -C(O) heteroaryl, -O-(C1-C6-alkyl); -O-(C1-C6-alkylene)-O-(C1-C4-alkyl); -O-(C1-C4-alkylene)-(C3-C8 cycloalkyl), -O-(C1-C6-alkylene)-heterocyclic, -O-(C1-C6-alkylene)-heteroaryl and -O-(C1-C6-alkylene)-aryl, or R 1 And any R 2 The atoms bonded to them together form an optionally substituted heterocyclic or heteroaryl ring, which is fused, spirofused, or bridged to a piperidine ring, or two R... 2 One or more atoms bonded to them, together with any inserted ring atoms, form an optionally substituted aryl, cycloalkyl, heterocyclic, or heteroaryl ring, which is fused, spirofused, or bridged to a piperidine ring, wherein R 2 Any alkyl, alkylene, cycloalkyl, heterocyclic, or heteroaryl moiety, R 1 With R 2 Any ring formed together, or two R 2 Any rings formed together are arbitrarily substituted: R 3 Selected from hydrogen, halogen, -CN, optionally substituted C1-C6 alkyl, or optionally substituted C3-C8 cycloalkyl; R 4 Selected from halogens, CN, -C1-C6 alkyl, -C2-C6 alkenyl, C2-C6 ynyl, -OC1-C6 alkyl, -SC1-C6 alkyl, and C3-C8 cycloalkyl, wherein R 4 Any alkyl, alkenyl, or ynyl moiety may be optionally substituted; each R 5Independently selected from halogens, OH, -C1-C6 alkyl, -CN, -(C0-C6 alkylene)-C(O)OH, -(C0-C6 alkylene)-C(O)(C1-C4 alkyl), -(C0-C6 alkylene)-C(O)N(R) 1’ 2. -(C0-C6 alkylene)-S(O)2-(C1-C4 alkyl), -(C0-C6 alkylene)-S(O) 2- N(R 1’ 2, -(C0-C6 alkylene)-P(O)-O-(C1-C4 alkyl)2, -(C0-C6 alkylene)P(O)-(C1-C4 alkyl)(O-C1-C4 alkyl), -(C0-C6 alkylene)P(O)(C1-C4 alkyl)2, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-heterocyclic, -(C0-C6 alkylene)-heteroaryl -(C0-C6 alkylene)-C(O) heterocyclic, -(C0-C6 alkylene)-C(O) heteroaryl, -O-(C1-C6-alkyl), -O-(C1-C6-alkylene)-O-(C1-C4-alkyl), -O-(C0-C6-alkylene)-(C3-C8 cycloalkyl), -O-(C1-C6-alkylene)-heterocyclic and -O-(C1-C6-alkylene)-heteroaryl, wherein R 5 Any alkyl, alkylene, cycloalkyl, heterocyclic, and heteroaryl moiety may be optionally substituted; or Two neighboring R 5 Together with the ring atoms they bind, they form optionally substituted cycloalkyl or optionally substituted heterocyclic groups, wherein each cycloalkyl or heterocyclic group is fused to ring A; R 5’ Selected from hydrogen, -CN, -C1-C6 alkyl, -(C0-C6 alkylene)-S(O) 2- N(R 1’ )2、-(C0-C6 alkylene)-(C3-C8 cycloalkyl),-(C0-C6 alkylene)-C(O)N(R) 1’ 2. -(C0-C6 alkylene)-aryl, -(C0-C6 alkylene)-heterocyclic, -(C0-C6 alkylene)-heteroaryl, -(C0-C6 alkylene)-S(O)2-(C1-C4 alkyl), -(C1-C6 alkylene)-O-(C1-C3 alkylene)-C(O)N(R) 1’2、-(C1-C6 alkylene)-O-(C1-C4 alkylene)-P(O) (C1-C4 alkyl)2、-(C1-C6 alkylene)-O-(C1-C4 alkylene)-P(O) (C1-C4 alkyl)-O-(C1-C4 alkyl), -(C1-C6 alkylene)-O-(C1-C4 alkylene)-P(O)-(O-C1-C4 alkyl)2、-(C1-C6 alkylene)-O-(C1-C4 alkylene)-S(O)2-(C1-C4 alkyl), -(C1-C6 alkylene)-O-(C1-C4 alkylene)-S(O) 2- N(R 1’ )2, -(C1-C6 alkylene)-O-(C1-C4 alkyl), -(C1-C6 alkylene)-O-(C3-C8 cycloalkyl), -(C1-C6 alkylene)-O-heteroaryl, -(C1-C6 alkylene)-O-heterocyclic, -(C1-C6 alkylene)P(O)(C1-C4 alkyl)2, -(C1-C6 alkylene)P(O)(C1-C4 alkyl)-O-(C1-C4 alkyl), -(C1-C6 alkylene)-P(O)-(O-C1-C4 alkyl)2, -(C1-C6 alkylene)-C(O)(C1-C4 alkyl) and -(C1-C6 alkylene)-C(O)OH, wherein R 5’ Any alkyl, alkylene, cycloalkyl, heterocyclic, and heteroaryl moieties may be optionally substituted; and n is 0, 1, 2, 3, or 4.

[0067] In some implementation schemes, R 1 It is also selected from -C(O)-O(C1-C6 alkyl).

[0068] In some implementation schemes, R 1 It is also selected from (C0-C6 alkylene)-carbocyclic groups, wherein the carbocyclic group is optionally substituted.

[0069] In some implementation schemes, each R 2 If present, it is also selected from -NH-C(O)-C1-C4 alkyl and -C(O)-NH- (unsubstituted C1-C4 alkyl).

[0070] In some implementation schemes, each R 2 If present, it is also selected from -(C0-C6 alkylene)-carbocyclic or -O-(C1-C4 alkylene)-carbocyclic, wherein each alkylene or carbocyclic group is optionally substituted.

[0071] In some implementation schemes, R 3 It is also selected from optionally substituted carbocyclic groups.

[0072] In some implementation schemes, R 4It is also selected from optionally substituted carbocyclic groups.

[0073] In some implementation schemes, each R 5 It is also selected from -(C0-C6-alkylene)-carbocyclic, -O-(C0-C6-alkylene)-carbocyclic, phenyl, -(C2-C4-olefin)-phenyl, -S(O)-(C1-C4 alkyl), -S-(C1-C4 alkyl), -S(O)-OH and -S(O)2-OH, wherein any alkyl, alkylene, olefin, carbocyclic or phenyl is optionally substituted.

[0074] In some implementation schemes, R 5’ And any R 5 Together with the ring atoms they bind to, they form optionally substituted heterocyclic groups, wherein each heterocyclic group is fused to ring A.

[0075] In some implementations, the compound of formula (I) is not: Or medicinal salts of the above compounds.

[0076] In some implementations, the compound of formula (I) is not: , ,or , , or stereoisomers of the above compounds or pharmaceutical salts.

[0077] In some implementations, ring A is selected from: , , , , , , , , and .

[0078] In some embodiments, ring A is selected from indole-3-yl and indazole-3-yl. In some embodiments, ring A is indole-3-yl. In some embodiments, ring A is indazole-3-yl.

[0079] In some implementation schemes, R 1 Any alkyl or alkylene moiety may be optionally substituted with one or more independently selected monovalent substituents (e.g., the substituent does not include =O).

[0080] In some implementation schemes, R 1Any heterocyclic or heteroaryl moiety may optionally and independently be substituted with one or more substituents independently selected from the following: halogen, C1-C4 alkyl, C3-C6 cycloalkyl, -OH, =O, -CN, -C(O)N(R) 1’ 2. -S(O)2-(C1-C4-alkyl) and -S(O) 2- N(R 1’ )2; and R 1 Any alkyl, alkylene, or cycloalkyl moiety thereof or its substituents may optionally be replaced with one or more substituents independently selected from fluorine, OH, and CN.

[0081] In some implementation schemes, R 1 Selected from hydrogen, -C1-C6 alkyl, -O-(C1-C6-alkylene)-O-(C1-C4-alkyl), -(C1-C6-alkylene)-N(R) 1’ 2、-(C1-C6 alkylene)-NR 1’ -S(O)2-(C1-C4 alkyl), -(C1-C6 alkylene)-NR 1’ -SO 2- N(R 1’ )2、-(C1-C6 alkylene)-S(O)2-(C1-C4 alkyl),-(C1-C6 alkylene-S(O)2-N(R) 1’ )2 and (C0-C6 alkylene)-(C3-C8 cycloalkyl), wherein R 1 Any alkyl or alkylene moiety may be optionally substituted with one or more independently selected monovalent substituents, R 1 Any cycloalkyl moiety may be optionally substituted with one or more independently selected substituents; and wherein each R 1’ Independently selected from hydrogen and optionally substituted C1-C6 alkyl groups (i.e., two R groups). 1’ They cannot form a ring together.

[0082] In some implementation schemes, R 1 Selected from hydrogen, cyclopropyl, -CH3, -CH2CH3, -CH2CH2OCH3, -CH(CH3)2, or -CH2CH(CH3)2, or R therein. 1 With an R 2 Together with their respective bonded ring atoms, they form a ring, which in turn forms a ring with R. 1 and R 2 The combined rings together form In some implementations, R 1 Selected from hydrogen, -CH3, or -CH2CH2OCH3. In some embodiments, R 1 It is hydrogen.

[0083] In some implementations, any R1’ Each alkyl group may be optionally substituted with one or more substituents independently selected from fluorine, OH, and CN.

[0084] In some implementations, two R 1’ Any heterocyclic and heteroaryl rings formed may optionally be substituted with one or more substituents independently selected from: halogens; C1-C4 alkyl groups; C3-C6 cycloalkyl groups optionally substituted with one or more substituents independently selected from fluorine, OH, and CN; -OH; =O; -CN; -C(O)NH2; -C(O)NH(C1-C4 alkyl); -C(O)N(C1-C4 alkyl)2; -S(O)2-C1-C4-alkyl; -S(O)2-NH2; -S(O)2-NH(C1-C4 alkyl); and -S(O)2-N(C1-C4 alkyl)2, wherein the two R groups constitute the alkyl group. 1’ Any alkyl portion of any heterocyclic group and any substituent on the heteroaryl ring may optionally be replaced with one or more other substituents independently selected from fluorine, OH and CN.

[0085] In some implementation schemes, R 2 Any alkyl, alkylene, or aryl moiety may be optionally substituted with one or more independently selected monovalent substituents. In one aspect of these embodiments, R 2 Any alkyl, alkylene, aryl, cycloalkyl, heterocyclic, or heteroaryl moiety, R 1 With R 2 Any ring formed together, or two R 2 Any ring formed together may be optionally substituted with one or more independently chosen monovalent substituents.

[0086] In some implementation schemes, R 2 Any heterocyclic and heteroaryl moiety may be optionally substituted with one or more substituents independently selected from the following: halogen, -C1-C4 alkyl, -OH, =O, -CN, -C(O)N(R) 1’ )2、-C(O)OR 1’ -C(O)OH, -S(O)2-(C1-C4-alkyl), -S(O) 2- N(R 1’ )2; and R 2 Any alkyl, alkylene, and cycloalkyl moiety thereof or its substituents may optionally be replaced with one or more substituents independently selected from fluorine, OH, and CN.

[0087] In some implementations, when two R 2 Together they form a ring, or R 1 and R 2When they form a ring together, the resulting ring may optionally be substituted with one or more substituents independently selected from the following: halogen, C1-C4 alkyl, -OH, =O, CN, -C(O)NR. 1’ 2. -S(O)2-C1-C4-alkyl, -S(O) 2- N(R 1’ )2; and when two R 2 Together they form a ring or R 1 and R 2 When forming a ring together, any alkyl portion of the substituents on the ring may optionally be replaced with one or more substituents independently selected from fluorine, OH, and CN. In some embodiments, each R 2 If present, independently selected from =O, halogen, -OH, -C1-C6 alkyl, -NHC(O)-(C1-C4 alkyl), -C(O)NH-C1-C4 alkyl, -C(O)-(optionally substituted heterocyclic), optionally substituted aryl, and optionally substituted heteroaryl; or R 1 And any R 2 The atoms bonded to them together form an optionally substituted heterocyclic or heteroaryl ring, which is fused, spirofused, or bridged to a piperidine ring, or two R... 2 One or more atoms bonded to them, together with any inserted ring atoms, form an optionally substituted aryl, cycloalkyl, heterocyclic, or heteroaryl ring, which is fused, spirofused, or bridged to a piperidine ring, wherein R 2 Any alkyl or alkylene moiety, R 1 With R 2 Any ring formed together, or two R 2 Any ring formed together may be optionally substituted with one or more independently chosen monovalent substituents.

[0088] In some implementation schemes, each R 2 If present, it is independently selected from halogens, =O, -OH, optionally substituted C1-C4 alkyl groups, optionally substituted phenyl groups, and optionally substituted heteroaryl groups. In some embodiments, each R as a -C1-C4 alkyl or phenyl group... 2 Optional substitution may involve one or more independently selected monovalent substituents. In some embodiments, each R... 2 If present, it is independently selected from halogens or optionally substituted C1-C4 alkyl groups. In some embodiments, each R... 2 If present, it is independently selected from halogens or optionally substituted C1-C4 alkyl groups with one or more independently selected monovalent substituents. In some embodiments, each R... 2 If present, it is a halogen. In some implementations, each R... 2If present, it is an optionally substituted C1-C4 alkyl group. In some embodiments, each R... 2 If present, it is a C1-C4 alkyl group with one or more independently selected monovalent substituents.

[0089] In some implementations, n is 0, 1, 2, or 3. In some implementations, n is 0, 1, or 2. In some implementations, n is 0 or 1. In some implementations, n is 0. In some implementations, n is 1. In some implementations, n is 2. In some implementations, n is 3.

[0090] In some implementations, n is 0, 1, 2, or 3, and each R 2 If present, it is independently selected from fluorine, =O, -CH3, -CH2CH3, -OH and unsubstituted phenyl.

[0091] In some implementations, n is 0, 1, 2, or 3, and each R 2 If present, independently selected from -CH(CH3)2, -C(O)NHCH3, -NHC(O)CH2CH3, 3-methyl-1,2,4-oxadiazol-5-yl, 1,2,4-triazolo[4,3-a]pyridin-3-yl, 8-(methanesulfonyl)-1,2,4-triazolo[4,3-a]pyridin-3-yl, pyrrolidine-1-ylcarbonyl, and 3-hydroxypyrrolidine-1-ylcarbonyl; or two R atoms on different atoms. 2 The atoms bonded to them, along with any inserted ring atoms, form a ring, which is connected to two R atoms. 2 The combined piperidine ring together is ,or ; or two R atoms bound to the same ring atom 2 The atoms that bond with them form a ring, which is connected to two R atoms. 2 The combined piperidine rings together form: , or .

[0092] In some implementation schemes, R 3 Each of the alkyl or cycloalkyl moieties may optionally and independently be substituted with one or more fluorine molecules.

[0093] In some implementation schemes, R 3 It is hydrogen.

[0094] In some implementation schemes, R 4 Any alkyl, alkenyl, ynyl, or cycloalkyl moiety may optionally and independently be substituted with one or more substituents independently selected from the following: -OH and fluorine.

[0095] In some implementation schemes, R4 Selected from halogens, -CN, optionally substituted C1-C4 alkyl groups, optionally substituted C2-C4 alkynyl groups, optionally substituted -O-C1-C4 alkyl groups, and optionally substituted C3-C6 cycloalkyl groups. In some embodiments, R 4 Selected from halogens, -CN, optionally substituted C1-C4 alkyl groups, and optionally substituted C1-C4 haloalkyl groups. In some embodiments, R 4 Selected from halogens, C1-C4 alkyl groups, and C1-C4 haloalkyl groups. In some embodiments, R 4 It is a C1-C4 alkyl group. In some embodiments, R 4 It is a C1-C4 haloalkyl group. In some embodiments, R 4 It is a halogen.

[0096] In some implementation schemes, R 4 It is hydrogen or -C(O)- (optionally substituted C1-C4 alkyl).

[0097] In some implementation schemes, R 4 Selected from chlorine, fluorine, bromine, iodine, cyclopropyl, -CN, -CF3, -CH2CF3, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -OCH3, and -C≡CH. In some embodiments, R 4 Selected from chlorine, fluorine, -CF3, -CH2CF3, -CH3, -CH2CH3, and -C≡CH. In some embodiments, R 4 Selected from chlorine, -CF3, -CH3, and -CH2CH3. In some embodiments, R 4 Selected from chlorine and -CF3. In some embodiments, R 4 It is chlorine. In some implementations, R 4 It is -CF3.

[0098] In some implementation schemes, R 4 Selected from -CH2CH2F, -CH2CH2CH3, -CH(OH)CH3, -CH=CH2, -C(O)CH3, -OCHF2, -S-CH3, -S-CHF2 and -S-CF3.

[0099] In some implementation schemes, each R 5 Any heterocyclic or heteroaryl moiety or two adjacent R 5 The ring formed together may be optionally and independently substituted with one or two substituents independently selected from the following: halogen, -CN, C1-C6 alkyl, -OH, =O, CN, -C(O)NR. 1’ 2, or -SO 2- NR 1’ 2; and R5 Any alkyl, alkylene, and cycloalkyl moiety, R 5 Substituents on, or two R 5 The substituents on the ring formed together may optionally be replaced by one or more substituents independently selected from fluorine, OH, and CN.

[0100] In some implementations, an R 5 The substituted heteroaryl group or the substituted heterocyclic group is optionally substituted. In one aspect of these embodiments, the heteroaryl or heterocyclic group is selected from pyrazol-4-yl, imidazol-1-yl, morpholino-4-yl, pyridin-4-yl, pyridazin-4-yl, 1H-pyrrolo-3-yl, pyridazin-4-yl, 1,2,4-triazol-3-yl, and 1,2,4-oxadiazol-3-yl; and the optional substitution has one or two substituents selected from: halogen, -CN, C1-C6 alkyl, -OH, CN, -C(O)N(R) 1’ )2, or -SO 2- N(R 1’ )2.

[0101] In some implementation schemes, each R 7 Independently selected from hydrogen, halogen, -C1-C6 alkyl, -CN, -C(O)OH, -C(O)(C1-C4 alkyl), -C(O)N(R) 1’ )2, -S(O)2-(C1-C4 alkyl), -P(O)(C1-C4 alkyl)-O-C1-C4 alkyl, -P(O)(O-(C1-C4 alkyl))2, heterocyclic and heteroaryl, wherein any alkyl, heterocyclic or heteroaryl group is optionally substituted.

[0102] In some implementation schemes, each R 7 Independently selected from -C(O)- heterocyclic groups, -S(O)2N(R) 1’ 2. -(C1-C4 alkylene)-S(O)2-(C1-C4 alkyl), carbocyclic, -O-(C0-C6-alkylene)-carbocyclic, phenyl, -(C2-C4 alkenyl)-phenyl, -S(O)-(C1-C4 alkyl), -S-(C1-C4 alkyl), -S(O)-OH and -S(O)2-OH, wherein any alkyl, alkylene, alkenyl, carbocyclic, phenyl or heterocyclic group is optionally substituted.

[0103] In some implementation schemes, each R 7Independently selected from hydrogen, fluorine, chlorine, bromine, -CN, -CH3, -CH2CH2C(CH3)2OH, -C(O)-CH3, -C(O)OH, -C(O)-NH-CH3, -P(=O)(OCH2CH3)2, -P(=O)(OCH2CH3)CH3, -S(O)2CH3, 1H-pyrazole-4-yl, 1-methylpyrazole-4-yl, 1,3-dimethylpyrazole-4-yl, 5-methyl-1H-pyrazole-4-yl, 1-methyl-2-oxoimidazolidine-3-yl, 4-methyl Imidazol-1-yl, morpholin-4-yl, pyridin-4-yl, 4-hydroxycyclohexyl, 4-hydroxy-4-methylcyclohexyl, 5-methyl-1,2,4-triazol-3-yl, 5-methyl-1,2,4-oxadiazol-3-yl, 1,3-dimethylpyridazin-4-yl, 1,5-dimethylpyridazin-4-yl, 3-methyl-1H-pyridazin-4-yl, 1-(2-methyl-2-hydroxypropyl)pyridazin-4-yl, imidazol-1-yl, 1-methyl-5-cyanopyrrole-3-yl, 5-cyano-1H-pyrrole-3-yl, and pyridazin-4-yl.

[0104] In some implementation schemes, each R 7Independently selected from -P(O)-(CH3)2, -P(O)-(CH2CH3)2, -S(O)2N(CH3)2, -S(O)2CH(CH3)2, -S(O)2CH2F, -S(O)2CHF2, -SCHF2, -S(O)CHF2, -S(O)OH, -S(O)2OH, -S(O)2NHCH3, -(CH2)4CH3, -CH2S(O)2CH3, -S(O)2-CH2CH3, 1H-pyrazole-3-yl, 1-difluoromethyl- Pyrazol-3-yl, 1-difluoromethyl-pyrazol-4-yl, 1-methylpyrazol-3-yl, 3-methyl-1H-pyrazol-4-yl, 3-methyl-3-hydroxypyrrolidine-1-ylcarbonyl, 3-hydroxypyrrolidine-1-ylcarbonyl, 4-hydroxycyclohexyl, 4-hydroxycyclohexyl-1-enyl, 1,1-dioxothiomorpholino-4-yl, 4-cyano-1H-imidazol-1-yl, 2,3-dimethyl-1,2,4-triazol-5-yl, 1,5-dimethyl-pyrazol-4-yl, pyridin-3-yl, 1-(2-methyl-2-hydroxypropyl) -1-yl)pyrazole-4-yl, pyrrolidine-1-yl, pyrrolidine-1-ylcarbonyl, 1H-pyrazole-2-yl, 3-hydroxy-3-trifluoromethylpyrrolidine-1-ylcarbonyl, 3-methoxypyrrolidine-1-ylcarbonyl, 3-cyanopyrrolidine-1-ylcarbonyl, 4-hydroxy-4-methylpiperidin-1-ylcarbonyl, 3-oxopyrrolidine-1-ylcarbonyl, 3-(pyrrolidine-1-ylcarbonyl)phenyl, 3-phenoxyphenyl, thiazolyl-2-yl, pyrazin-2-yl, 2,4-dioxo-1H,3H-pyrimidin-5-yl, 3-methyl-3 -Hydroxypyrrolidine-1-ylsulfonyl, 5-fluoropyridin-3-yl, 2-hydroxypyridin-3-yl, 3,3-difluoro-4-hydroxy, 3,5-dimethyloxazol-4-yl, 3-fluorophenyl, 4-methylpyridin-3-yl, 2-hydroxymethylpyridin-3-yl, 6-hydroxymethylpyridin-2-yl, 5-hydroxymethylpyridin-3-yl, 1-methyl-6-oxopyridin-3-yl, 4-aminosulfonylphenyl, 3-aminosulfonylphenyl, 3-hydroxy-3-ethylpyrrolidine-1-ylcarbonyl, 3-cyano-4-hydroxyphenyl, benzo[ d ]Thiazol-6-yl, 2H-indazole-6-yl, 1H-benzimidazole-5-yl, 2-oxo-3-cyano-4-methylpyridin-5-yl, 2-aminobenzo[ dThiazol-2-yl, 3-aminocarbonylphenyl, 6-trifluoromethyl-1H-pyrrolo[3,2-c]pyridin-3-yl, 2-aminoquinazoline-8-yl, styrylyl, 1-methyl-1H-indazole-6-yl, 2,3-dihydrobenzo[b][1,4]dioxanediene-7-yl, 2-ethoxyphenyl, 3-(2-hydroxyethyl)phenyl, 3-(methylcarbonylaminomethyl)phenyl, 1-methyl-6-trifluoromethyl-1H-pyrrolo[3,2-c]pyridin-3-yl, quinoline-4-yl, isoquinoline-5-yl, isoquinoline-7-yl and 2-oxo-3,4-dihydroquinoline-7-yl.

[0105] In some implementation schemes, R 5’ Each heterocyclic and heteroaryl moiety may be optionally substituted with one or more substituents independently selected from the following: halogen, C1-C4 alkyl, -OH, =O, CN, -C(O)NR. 1’ 2, or -SO 2- NR 1’ 2, and R 5’ The various alkyl, alkylene, and cycloalkyl portions or R 5’ The substituents may be optionally substituted with one or more substituents independently selected from fluorine, OH, and CN.

[0106] In some implementation schemes, R 5’ Selected from hydrogen, C1-C4 alkyl, -(C0-C3 alkylene)-aryl, and -(C1-C3 alkylene)-O-(C1-C4 alkyl). In one aspect of these embodiments, R 5’ Selected from hydrogen, methyl, isopropyl, -CH2-O-CH3, -(CH2)2-O-CH3 and phenyl.

[0107] In some implementation schemes, R 6 Selected from hydrogen and methyl. In one aspect of these embodiments, R 6 For hydrogen. In another aspect of these implementations, R 6 It is a methyl group.

[0108] In some embodiments, the compound of formula (I) is the same as the compound of formula (Ia): (Ia) or a pharmaceutically acceptable salt thereof, wherein rings A, R 1 R 2 R 3 R 4 And n are each defined as in equation (I).

[0109] In some embodiments, the compound of formula (I) is a compound of formula (Ib): (Ib) or a pharmaceutically acceptable salt thereof, wherein rings A, R 1 R2 R 3 R 4 And n are each defined as in equation (I).

[0110] In some embodiments, the compound of formula (I) is the same as the compound of formula (Ic): (Ic), or a pharmaceutically acceptable salt thereof, wherein X, R 2 R 4 R 5’ R 7 R 8 Y and n are each defined as in equation (I); 1 Selected from N and C(R) 7a );Y 2 Selected from N and C(R) 7b ); and X, Y 1 Or Y 2 No more than one of them is N, where R 7a R 7b and R 7c Each is independently selected from R as defined by equation (I). 7 .

[0111] In some embodiments, the compound of formula (Ic) is a compound of formula (I-c1): (I-c1), or a pharmaceutically acceptable salt thereof, wherein R 6 As defined in equation (I).

[0112] In some embodiments, the compound of formula (Ic) is a compound of formula (I-c2): (I-c2), or a pharmaceutically acceptable salt thereof.

[0113] In some embodiments, the compound of formula (I) is the same as the compound of formula (II): (II), or a pharmaceutically acceptable salt thereof, wherein: Y 3 Selected from N and C(R) 7e ); R 2a and R 2b Each is independently selected from hydrogen and C1-C3 alkyl groups; or R 2a and R 2b Together they form a cycloalkyl or heterocyclic ring fused with piperidine cyclospiro, wherein the cycloalkyl or heterocyclic ring is optionally substituted with one or more independently selected C1-C4 alkyl or C1-C4 haloalkyl rings; R 7dSelected from hydrogen, -C(O)-(C1-C4 alkyl), -CN, and heteroaryl groups optionally substituted with one or more independently selected C1-C4 alkyl or C1-C4 haloalkyl groups; R 7e If present, the aryl group is selected from hydrogen, halogen, -S(O)2-(C1-C4 alkyl), -P(O)(C1-C4 alkyl)2, -C(O)NH-(C1-C4 alkyl), -C(O)N(C1-C4 alkyl)2, -S(O)2NH-(C1-C4 alkyl), -S(O)2N-(C1-C4 alkyl)2, and optionally substituted with one or more independently selected C1-C4 alkyl or C1-C4 haloalkyl groups; and R 14 Selected from C1-C3 alkyl and C1-C3 haloalkyl.

[0114] In some embodiments, the compound of formula (II) is the same as the compound of formula (IIa): (IIa), or a pharmaceutically acceptable salt thereof, wherein Y 3 R 2a R 2b R 7d R 7e and R 14 As defined in Equation II.

[0115] In some embodiments, the compound of formula (II) is a compound of formula (IIb): (IIb), or a pharmaceutically acceptable salt thereof, wherein Y 3 R 2a R 2b R 7d R 7e and R 14 As defined in Equation II.

[0116] In some embodiments, the compound of formula (I) is a compound of formula (III): (III), or a pharmaceutically acceptable salt thereof, wherein Y 3 R 2a R 2b R 7d R 7e and R 14 As defined in Equation II.

[0117] In some embodiments, the compound of formula (III) is a compound of formula (IIIa): (IIIa), or a pharmaceutically acceptable salt thereof, wherein Y 3 R2a R 2b R 7d R 7e and R 14 As defined in Equation II.

[0118] In some embodiments, the compound of formula (III) is a compound of formula (IIIb): (IIIb), or a pharmaceutically acceptable salt thereof, wherein Y 3 R 2a R 2b R 7d R 7e and R 14 As defined in Equation II.

[0119] In some embodiments, in compounds of any one of formula II, IIa, IIb, III, IIIa, or IIIb: R 2a Selected from hydrogen and -CH3; R 2b Selected from hydrogen, -CH3, -CH2CH3 and -CH(CH3)2; or R 2a and R 2b Together they form oxetane-3-yl; R 7d Selected from hydrogen, -C(O)CH3, -CN, pyridin-3-yl, pyridin-4-yl, 1-methyl-5-cyanopyrrole-3-yl, 1-methylpyrazole-4-yl, 1-methylpyrazole-3-yl, 1H-pyrazole-4-yl, 1H-pyrazole-3-yl, 1H-imidazol-2-yl, 1,3-dimethylpyrazole-4-yl, 1,5-dimethylpyrazole-4-yl, 1,5-dimethyl-1,2,4-triazol-3-yl, imidazol-1-yl, 1-difluoromethylpyrazole-3-yl, 1-difluoromethylpyrazole-4-yl, and thiazole-2-yl; R 7e If present, it is selected from hydrogen, fluorine, chlorine, bromine, -CN, -P(O)(CH3)2, -S(O)2CH(CH3)2, -S(O)2CH2CH3, -S(O)2N(CH3)2, -C(O)NHCH3, pyridin-4-yl, pyridazin-4-yl, 5-methyl-1H-pyrazole-4-yl, 1-methylpyrazole-4-yl, 4-methyl-1H-imidazol-1-yl, and 1,3-dimethylpyrazole-4-yl; and R 14 Selected from -CH3, -CF3, -CH2CH3, -CH2CF3, -CH2CH2F and -CH(CH3)2.

[0120] In some embodiments, in the compound of formula (II) R2a Selected from hydrogen and -CH3; R 2b Selected from hydrogen and -CH3; R 7d Selected from hydrogen, -CN, pyrazin-2-yl, thiazolyl-2-yl, and 3,5-dimethylisoxazol-4-yl; R 7e If present, it is selected from hydrogen, fluorine, -C(O)NHCH3, -P(O)(CH3)2, -S(O)2CH3, -S(O)2N(CH3)2, 1,3-dimethylpyrazol-4-yl and pyridazin-4-yl; and R 14 Selected from -CH2CH3 and -CF3.

[0121] In some embodiments, the compound of formula (I) is selected from any of the compounds in the table in Figure 1 and their pharmaceutically acceptable salts, tautomers, stereoisomers and isotopically labeled derivatives.

[0122] Pharmaceutical composition, kit and administration This invention provides pharmaceutical compositions comprising a compound of formula (I), such as a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, as described herein, and optionally a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical compositions of this invention comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof is provided in the pharmaceutical composition in an effective amount. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylacticly effective amount.

[0123] The pharmaceutical compositions described herein can be prepared by any method known in the field of pharmacology. Typically, such preparation methods include the following steps: combining a compound of formula (I) (i.e., the “active ingredient”) with a carrier and / or one or more other adjuvants, and then, if necessary and / or desired, shaping and / or packaging the product into the desired single or multiple dose units.

[0124] Pharmaceutical compositions may be prepared, packaged, and / or sold in bulk in single unit doses and / or multiple single unit doses. As described herein, a “unit dose” is a discrete amount of a pharmaceutical composition containing a predetermined amount of active ingredient. The amount of said active ingredient is typically equal to the dose of the active ingredient to be administered to a subject and / or a simple fraction of that dose, such as half or one-third of the dose.

[0125] The relative amounts of the active ingredient, pharmaceutically acceptable excipients, and / or any additional ingredients in the pharmaceutical composition of the present invention will vary depending on the characteristics, body size, and / or condition of the subject being treated and further depending on the route of administration of the composition. As an example, the composition may contain 0.1% to 100% (w / w) of the active ingredient.

[0126] The term "pharmaceuticalally acceptable excipient" refers to a non-toxic carrier, excipient, diluent, or medium that does not impair the pharmacological activity of the compound formulated with it. Pharmaceutically acceptable excipients that can be used to manufacture the pharmaceutical compositions of the present invention are any of those known in the field of pharmaceutical formulation and include inert diluents, dispersants and / or granulators, surfactants and / or emulsifiers, disintegrants, binders, preservatives, buffers, lubricants, and / or oils. Pharmaceutically acceptable excipients that can be used to manufacture the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin; serum proteins, such as human serum albumin; buffering substances, such as phosphates; glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acid metaglycerides, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin.

[0127] The compositions of the present invention can be administered orally, parenterally (including subcutaneously, intramuscularly, intravenously, and intradermally), by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via implanted reservoirs. In some embodiments, the provided compounds or compositions are available for intravenous and / oral administration.

[0128] As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intraocular, intravitreal, intra-articular, intrasynovial, intrasternal, intrasheath, intrahepatic, intraperitoneal, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, subcutaneously, intraperitoneally, or intravenously. The sterile injectable form of the compositions of the present invention can be an aqueous or oily suspension. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. The sterile injectable formulation can also be a sterile injectable solution or suspension in a non-toxic, parenteral-acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable media and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile, non-volatile oils are routinely used as solvents or suspension media.

[0129] The pharmaceutically acceptable compositions of the present invention can be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions. In the case of tablets for oral administration, common carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral administration, the active ingredient is combined with an emulsifier and a suspending agent. Certain sweeteners, flavoring agents, or coloring agents may also be added if desired. In some embodiments, the provided oral formulations are formulated for immediate or sustained / delayed release. In some embodiments, the compositions are suitable for buccal or sublingual administration, including tablets, sugar tablets, and lozenges. The provided compounds may also be in the form of microencapsulation.

[0130] Alternatively, the pharmaceutically acceptable compositions of the present invention can be used for administration in the form of suppositories for rectal administration. The pharmaceutically acceptable compositions of the present invention can also be used topically, particularly when the therapeutic target includes sites or organs easily accessible by topical application, including diseases of the eyes, skin, or lower intestine. Suitable topical formulations are readily prepared for each of these sites or organs.

[0131] Local application to the lower intestine can be achieved using rectal suppositories (see above) or suitable enemas. Topical transdermal patches can also be used.

[0132] For ophthalmic use, the pharmaceutically acceptable compositions provided may be formulated as micronized suspensions or ointments, such as petrolatum.

[0133] The pharmaceutically acceptable compositions of the present invention can also be administered via nasal aerosol or inhalation.

[0134] To prolong the action of a drug, it is often desirable to slow down the absorption of drugs administered subcutaneously or intramuscularly. This can be achieved by using liquid suspensions of crystalline or amorphous materials with poor water solubility. The absorption rate of the drug then depends on its dissolution rate, which in turn may depend on the crystal size and crystal form. Alternatively, delayed absorption of parenteral drug forms can be achieved by dissolving or suspending the drug in an oil medium.

[0135] Although the description of the pharmaceutical compositions provided herein is primarily directed toward those intended for human administration, those skilled in the art will understand that these compositions are generally intended for administration to a wide variety of animals. It is well understood that modifications can be made to pharmaceutical compositions intended for human administration to make them suitable for administration to a wide variety of animals, and veterinary pharmacologists of ordinary skill can design or perform such modifications using standard experimental techniques.

[0136] The compounds described herein are typically formulated in dosage units, such as single-unit formulations, to facilitate administration and ensure uniform dosage. However, it will be understood that the total daily dosage of the compositions of this invention will be determined by the attending physician within a reasonable medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend on a variety of factors including: the severity of the disease and condition being treated; the activity of the specific active ingredient used; the specific composition used; the subject's age, weight, general health condition, sex, and diet; the time of administration, route of administration, and the excretion rate of the specific active ingredient used; the duration of treatment; drugs used in combination with or concurrently with the specific active ingredient used; and similar factors known in the medical field.

[0137] The exact amount of compound required to achieve an effective dose will vary from subject to subject, depending on factors such as the subject's species, age, general condition, severity of side effects or illness, characteristics of one or more specific compounds, method of administration, etc. The desired dose may be delivered three times daily, twice daily, once daily, every other day, every three days, once weekly, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, the desired dose may be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more).

[0138] In some embodiments, the effective amount of the compound administered to a 70 kg adult once or more daily may include about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg per unit dosage form.

[0139] In some embodiments, the compound of formula (I) may be administered at dose levels sufficient to deliver about 0.001 mg to about 100 mg, about 0.01 mg to about 50 mg per kilogram of body weight per day, preferably about 0.1 mg to about 40 mg per kilogram of body weight per day, preferably about 0.5 mg to about 30 mg, about 0.01 mg to about 10 mg, about 0.1 mg to about 10 mg per kilogram of body weight per day, and more preferably about 1 mg to about 25 mg per kilogram of body weight per day, once or more daily, to obtain the desired therapeutic effect.

[0140] It should be understood that the dosage ranges described herein provide guidance for administering the provided pharmaceutical composition to adults. The amount to be administered to, for example, children or adolescents, can be determined by a licensed physician or someone skilled in the art and may be less than or equal to the amount administered to adults.

[0141] It will also be understood that the compounds or compositions described herein can be administered in combination with one or more other pharmaceutical agents. These other agents may enhance their bioavailability, reduce and / or alter their metabolism, inhibit their excretion, and / or alter their distribution in the body. It will also be understood that the treatment used may achieve the desired effect on the same condition, and / or it may achieve different effects.

[0142] The compounds or compositions described herein may be administered simultaneously, before, or after one or more additional agents, which can be used as, for example, combination therapy. The agents include therapeutic agents. The agents also include prophylactic agents. Each additional agent may be administered at a dose and / or schedule determined for that agent. The additional agents may also be administered in a single dose or separately in different doses, together with each other and / or with the compounds or compositions described herein. Specific combinations used in the dosing regimen will take into account the compatibility of the compounds of the invention with the additional agents and / or the desired therapeutic and / or prophylactic effects to be achieved. Generally, the additional agents intended for combination use are to be used at levels not exceeding those used individually. In some embodiments, the combined level will be lower than the level used individually.

[0143] Other exemplary agents include, but are not limited to, antiproliferative agents, anticancer agents, antidiabetic agents, anti-inflammatory agents, immunosuppressants, and pain relievers. Agents include small organic molecules such as pharmaceutical compounds (e.g., compounds approved by the US Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.

[0144] This invention also covers kits (e.g., pharmaceutical packaging). The kits of this invention can be used for the prevention and / or treatment of proliferative diseases (e.g., cancers (e.g., leukemia, melanoma, multiple myeloma), benign growths, angiogenesis, inflammatory diseases, autoinflammatory diseases, or autoimmune diseases). The provided kits may include the pharmaceutical compositions or compounds of this invention and containers (e.g., vials, ampoules, bottles, syringes, and / or dispenser packaging, or other suitable containers). In some embodiments, the provided kits may optionally also include a second container containing pharmaceutical excipients for diluting or suspending the pharmaceutical compositions or compounds of this invention. In some embodiments, the pharmaceutical compositions or compounds of this invention provided in the first and second containers are combined to form a unit dosage form.

[0145] Therefore, in one aspect, a kit is provided comprising a first container containing a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, or a pharmaceutical composition thereof. In some embodiments, the kit of the present invention comprises a first container containing a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the kit is used for the prevention and / or treatment of proliferative diseases in a subject. In some embodiments, the kit further comprises instructions for administering the compound, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, or a pharmaceutical composition thereof, to a subject for the prevention and / or treatment of proliferative diseases.

[0146] Treatment methods and uses The present invention also provides methods for treating or preventing proliferative diseases (e.g., cancer, benign growths, angiogenesis, inflammatory diseases, autoinflammatory diseases, or autoimmune diseases) or infectious diseases (e.g., viral diseases) in a subject. These methods include the step of administering to a subject in need an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, or a pharmaceutical composition thereof. In some embodiments, the methods described herein include administering to a subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0147] In some embodiments, the treated subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In some embodiments, the subject is a companion animal, such as a dog or cat. In some embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In some embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal, such as a rodent, dog, or non-human primate. In some embodiments, the subject is a non-human transgenic animal, such as a transgenic mouse or transgenic pig.

[0148] The proliferative diseases to be treated or prevented by compounds of formula (I) are generally associated with aberrant CDK7 activity. Aberrant CDK7 activity can be elevated and / or inappropriate (e.g., abnormal). In some embodiments, CDK7 is not overexpressed, and CDK7 activity is elevated and / or inappropriate. In some other embodiments, CDK7 is overexpressed, and CDK7 activity is elevated and / or inappropriate. Compounds of formula (I), as well as their pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof, can inhibit CDK7 activity and can be used to treat and / or prevent proliferative diseases.

[0149] In other embodiments, the proliferative disease to be treated or prevented by the compound of formula (I) is generally associated with aberrant activity of CDK12 and / or CDK13. Aberrant activity of CDK12 and / or CDK13 may be elevated and / or inappropriate (e.g., abnormal). In some embodiments, CDK12 and / or CDK13 are not overexpressed, and the activity of CDK12 and / or CDK13 is elevated and / or inappropriate. In some other embodiments, CDK12 and / or CDK13 are overexpressed, and the activity of CDK12 and / or CDK13 is elevated and / or inappropriate. The compound of formula (I), as well as its pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof, can inhibit the activity of CDK12 and / or CDK13 and can be used to treat and / or prevent proliferative diseases.

[0150] In the implementation plan, the disease treated or prevented by using the compound of formula (I) is associated with abnormal kinase activity. Exemplary kinases include BRAF, CDK1 / cyclin A2, CDK1 / cyclin B, CDK14 (PFTK1) / cyclin Y, CDK16 (PCTK1) / cyclin Y, CDK17 / cyclin Y, CDK18 / cyclin Y, CDK2 / cyclin A, CDK2 / cyclin E1, CDK3 / cyclin E1, CDK5 / p35, CDK7 / cyclin H / MNAT1, CDK9 / cyclin T1, CDKL5, CLK1, CLK2, CLK3, CLK4, DYRK2, DYRK3, ERN1, GAK, GSG2 (Haspin), GSK3A (GSK3 α), GSK3B (GSK3 β), HIPK4, MAP2K1 (MEK1), MAP2K2 (MEK2), MAP2K6 (MKK6), and MAP3K8. (COT), MAPK1 (ERK2), MAPK10 (JNK3), MAPK12(p38 γ), MAPK13 (p38 δ), MAPK15 (ERK7), MAPK3 (ERK1), MAPK8 (JNK1), MAPK9 (JNK2), PRKCA (PKC α), PRKCB2 (PKC β II), PRKD1 (PKCμ), PRKD2 (PKD2), RAF1 (cRAF) Y340DY341D, TAOK1, TLK1 and TLK2.

[0151] Proliferative disorders may also be associated with the inhibition of apoptosis in cells of biological samples or subjects. All types of biological samples described herein or known in the art are contemplated to fall within the scope of this invention. Inhibition of CDK7 activity is expected to produce cytotoxicity via the induction of apoptosis. Compounds of formula (I), as well as their pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof, can induce apoptosis and are therefore suitable for the treatment and / or prevention of proliferative disorders.

[0152] In some embodiments, the proliferative disease to be treated or prevented by the compound of formula (I) is cancer. All types of cancer disclosed herein or known in the art are contemplated to fall within the scope of this invention. In some embodiments, the proliferative disease is cancer associated with BCL-2-dependent anti-apoptotic proteins (e.g., MCL-1 and / or XIAP). In some embodiments, the proliferative disease is cancer associated with overexpression of MYC (a gene encoding a transcription factor). In some embodiments, the proliferative disease is a hematologic malignancy. In some embodiments, the proliferative disease is a blood cancer. In some embodiments, the proliferative disease is leukemia. In some embodiments, the proliferative disease is chronic lymphocytic leukemia (CLL). In some embodiments, the proliferative disease is acute lymphoblastic leukemia (ALL). In some embodiments, the proliferative disease is T-cell acute lymphoblastic leukemia (T-ALL). In some embodiments, the proliferative disease is chronic myeloid leukemia (CML). In some embodiments, the proliferative disease is acute myeloid leukemia (AML). In some embodiments, the proliferative disease is lymphoma. In some embodiments, the proliferative disease is melanoma. In some embodiments, the proliferative disease is multiple myeloma. In some embodiments, the proliferative disease is bone cancer. In some embodiments, the proliferative disease is osteosarcoma. In some embodiments, the proliferative disease is Ewing sarcoma. In some embodiments, the proliferative disease is triple-negative breast cancer (TNBC). In some embodiments, the proliferative disease is brain cancer. In some embodiments, the proliferative disease is neuroblastoma. In some embodiments, the proliferative disease is lung cancer. In some embodiments, the proliferative disease is small cell lung cancer (SCLC). In some embodiments, the proliferative disease is large cell lung cancer. In some embodiments, the proliferative disease is a benign growth. All types of benign growths disclosed herein or known in the art are contemplated to fall within the scope of this invention.

[0153] In some embodiments, the proliferative disease is associated with angiogenesis. All types of angiogenesis disclosed herein or known in the art are contemplated to fall within the scope of this invention.

[0154] In some embodiments, the proliferative disease is an inflammatory disease. All types of inflammatory diseases disclosed herein or known in the art are contemplated to fall within the scope of this invention. In some embodiments, the inflammatory disease is rheumatoid arthritis. In some embodiments, the proliferative disease is an autoinflammatory disease. All types of autoinflammatory diseases disclosed herein or known in the art are contemplated to fall within the scope of this invention. In some embodiments, the proliferative disease is an autoimmune disease. All types of autoimmune diseases disclosed herein or known in the art are contemplated to fall within the scope of this invention.

[0155] The cells described herein may be abnormal cells. The cells may be present in vitro or in vivo. In some embodiments, the cells are proliferating cells. In some embodiments, the cells are blood cells. In some embodiments, the cells are lymphocytes. In some embodiments, the cells are cancer cells. In some embodiments, the cells are leukemia cells. In some embodiments, the cells are CLL cells. In some embodiments, the cells are melanoma cells. In some embodiments, the cells are multiple myeloma cells. In some embodiments, the cells are benign neoplastic cells. In some embodiments, the cells are endothelial cells. In some embodiments, the cells are immune cells.

[0156] In another aspect, the present invention provides a method for downregulating the expression of CDK7 in biological samples or subjects.

[0157] In some embodiments, the method described herein includes the additional step of administering one or more additional agents in combination with a compound of formula (I), a pharmaceutically acceptable salt thereof, or a composition comprising such compound or a pharmaceutically acceptable salt thereof. These additional agents include, but are not limited to, antiproliferative agents, anticancer agents, antidiabetic agents, anti-inflammatory agents, immunosuppressants, and pain relievers. One or more additional agents may synergistically enhance the inhibition of CDK7 or CDK12 and / or CDK13 induced by the compounds or compositions of the present invention in biological samples or subjects. Therefore, combinations of the compounds or compositions of the present invention and one or more additional agents can be used to treat proliferative diseases resistant to treatment using one or more additional agents without the use of the compounds or compositions of the present invention.

[0158] In another aspect, the present invention provides compounds of formula (I) for treating proliferative disorders in subjects, and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof. In some embodiments, the present invention provides compounds described herein for treating proliferative disorders in subjects, and pharmaceutically acceptable salts and compositions thereof. In some embodiments, the present invention provides compounds described herein for inhibiting cell growth, and pharmaceutically acceptable salts and compositions thereof. In some embodiments, the present invention provides compounds described herein for inducing apoptosis in cells, and pharmaceutically acceptable salts and compositions thereof. In some embodiments, the present invention provides compounds described herein for inhibiting transcription, and pharmaceutically acceptable salts and compositions thereof.

[0159] Example To provide a fuller understanding of the invention described herein, the following embodiments are illustrated. Synthetic and biological embodiments described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and these embodiments should not be construed as limiting their scope in any way.

[0160] The compounds described herein can be prepared from readily available starting materials using modifications of the specific synthetic schemes (known to those skilled in the art) set forth below. It will be understood that, unless otherwise stated, other process conditions may be used, provided that typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but these conditions can be determined by those skilled in the art through conventional optimization procedures.

[0161] Furthermore, as will be apparent to those skilled in the art, conventional protecting groups may be required to prevent certain functional groups from undergoing undesirable reactions. The selection of suitable protecting groups for specific functional groups, and the appropriate conditions for protection and deprotection, are well known in the art. For example, many protecting groups and their introduction and removal are described in Greene et al., *Protecting Groups in Organic Synthesis*, 2nd ed., Wiley, New York, 1991, and the references cited therein.

[0162] abbreviation

[0163] Example 1 Synthesis of (S)-5-chloro-4-(5,6-difluoro-1H-indol-3-yl)-N-(piperidin-3-yl)pyrimidine-2-amine.

[0164] Step 1: 3-(2,5-dichloropyrimidin-4-yl)-5,6-difluoro-1H-indole

[0165] Aluminum chloride (940 mg, 7.05 mmol) was added to a solution of 2,4,5-trichloropyrimidine (700 µL, 6.11 mmol) in dichloroethane (40 mL). The resulting suspension was stirred at 80 °C for 30 min. The reaction mixture was then cooled to room temperature and 5,6-difluoroindole (1.00 g, 6.54 mmol) was added, and the resulting solution was stirred at 80 °C for 18 h. The reaction mixture was cooled to room temperature and crushed ice (15 mL) was added. The resulting slurry was stirred vigorously for 30 min and then further diluted with EtOAc (200 mL) and water (60 mL). The mixture was warmed to dissolve the suspended solids, the layers were separated, and the aqueous layer was extracted with warm EtOAc (150 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was ground in Et2O to give the title compound (1.49 g, 4.97 mmol, 81% yield) as a beige solid.

[0166] Step 2: (S)-3-((5-chloro-4-(5,6-difluoro-1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-carboxylic acid tert-butyl ester

[0167] A solution of 3-(2,5-dichloropyrimidin-4-yl)-5,6-difluoro-1H-indole (136 mg, 0.45 mmol), (S)-3-aminopiperidin-1-carboxylic acid tert-butyl ester (130 mg, 0.65 mmol), and diisopropylethylamine (0.24 mL, 1.38 mmol) in NMP (3.0 mL) was heated in a microwave (MW) reactor at 135°C for 4 h. The mixture was diluted with EtOAc (150 mL), washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated to dryness. The crude residue was purified by SiO2 chromatography (EtOAc in DCM, 0 to 100% gradient) to give the title compound (100 mg, 0.216 mmol, 48% yield) as a pale yellow solid.

[0168] Step 3: (S)-5-chloro-4-(5,6-difluoro-1H-indol-3-yl)-N-(piperidin-3-yl)pyrimidin-2-amine

[0169] A solution of (S)-3-((5-chloro-4-(5,6-difluoro-1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-carboxylic acid tert-butyl ester (100 mg, 0.216 mmol) in DCM (2.0 mL) was treated with trifluoroacetic acid (150 µL, 1.96 mmol) and stirred overnight at room temperature. The mixture was concentrated under reduced pressure and co-evaporated three times with DCM (20 mL). The resulting residue was neutralized with DIPEA (100 µL) and purified by reversed-phase chromatography (C18, H2O / ACN + 0.1% HCO2H, 0 to 90% gradient) to give the title compound (60 mg, 0.165 mmol, 77% yield), which was a grayish-white solid after lyophilization.

[0170] Example 2 Synthesis of (S)-N-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)quinine-3-amine (compound 131).

[0171]

[0172] A solution of (S)-N-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)quininecyclo-3-amine (50 mg, 0.101 mmol) and 5M NaOH (1 mL, 5.00 mmol) in dioxane (1.0 mL) was heated at 70°C for 6 h. The cooled mixture was then concentrated under reduced pressure. The crude residue was purified by reversed-phase chromatography (C18, H2O / ACN + 0.1% HCO2H, 0 to 100% gradient) to give the title compound (24 mg, 0.067 mmol, 67% yield), which was a white solid after lyophilization.

[0173] Example 3 Synthesis of 3-(5-bromo-2-chloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole. Step 1: 3-(2,5-dichloropyrimidin-4-yl)-5,6-difluoro-1H-indole

[0174] Aluminum chloride (328 mg, 2.46 mmol) was added to a solution of 5-bromo-2,4-dichloropyrimidine (500 mg, 2.194 mmol) in dichloroethane (30 mL). The resulting suspension was stirred at 80 °C for 30 min. The reaction mixture was then cooled to room temperature and indole (231 mg, 1.975 mmol) was added. The resulting solution was stirred at 80 °C for 18 h. The reaction mixture was cooled to room temperature and crushed ice (15 mL) was added. The resulting slurry was stirred vigorously for 30 min and then further diluted with MeTHF (200 mL) and water (60 mL). The mixture was warmed to dissolve the suspended solids, the layers were separated, and the aqueous layer was extracted once more with MeTHF (150 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (666 mg, 2.16 mmol, 98% yield) as an orange solid.

[0175] Step 2: 3-(5-bromo-2-chloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole

[0176] NaOtBu (249 mg, 2.59 mmol) was added at 0°C to a stirred solution of 3-(2,5-dichloropyrimidin-4-yl)-5,6-difluoro-1H-indole (666 mg, 2.16 mmol) in THF (10 mL). The resulting solution was stirred at 0°C for 30 min, and then benzenesulfonyl chloride (330 µL, 2.59 mmol) was added dropwise. The resulting solution was stirred at 0°C for 30 min, and then added dropwise to 50 mL of water and stirred for 30 min. A brown solid precipitated from the reaction mixture and was collected by filtration. The resulting solid was washed with hexane (30 mL), a minimal amount of ether (5 mL), and dried under vacuum to give the title compound (666 mg, 1.48 mmol, 69% yield) as a brown solid.

[0177] Example 4 Synthesis of (S)-3-((5-cyclopropyl-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester. Step 1: (S)-3-((5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-carboxylic acid tert-butyl ester

[0178] A solution of 3-(2,5-dichloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole (700 mg, 1.73 mmol), (S)-3-aminopiperidin-1-carboxylic acid tert-butyl ester (382 mg, 1.91 mmol), and diisopropylethylamine (0.60 mL, 3.46 mmol) in NMP (9.0 mL) was heated in a microwave (MW) reactor at 135°C for 45 min. The mixture was diluted with EtOAc (200 mL), washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to a yellow oil. The residue was purified by SiO2 chromatography (EtOAc in DCM, 0 to 100% gradient) to give the title compound (694 mg, 1.22 mmol, 64% yield) as a light pink solid.

[0179] Step 2: (S)-3-((5-cyclopropyl-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0180] A degassed solution of (S)-3-((5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-carboxylic acid tert-butyl ester (142 mg, 0.25 mmol), Cs₂CO₃ (244 mg, 0.75 mmol), and potassium cyclopropyltrifluoroborate (111 mg, 0.75 mmol) in 2 / 1 toluene / H₂O (6 mL) was treated with a premixed solution of Pd(OAc)₂ (2.8 mg, 0.013 mmol) and butyldi-1-adamantylphosphine (9.0 mg, 0.025 mmol) in degassed toluene (2 mL). The resulting solution was heated at 140 °C for 2 h. The cooled mixture was then diluted with EtOAc (50 mL) and saturated NaHCO₃ (50 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by SiO2 chromatography (EtOAc 0 to 50% gradient in DCM) to give the title compound (105 mg, 0.183 mmol, 73% yield) as a yellow foam.

[0181] Example 5 Synthesis of (S)-5-chloro-N-(1-methylpiperidin-3-yl)-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidine-2-amine.

[0182] Step 1: (S)-5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)-N-(piperidin-3-yl)pyrimidin-2-amine

[0183] A solution of (S)-3-((5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-carboxylic acid tert-butyl ester (272 mg, 0.479 mmol) in DCM (4.8 mL) was treated with trifluoroacetic acid (1.83 mL, 24.0 mmol) and stirred overnight at room temperature. The mixture was concentrated under reduced pressure and co-evaporated three times with DCM (20 mL). The resulting residue was dissolved in MeTHF (20 mL), washed with NaHCO3 (2 x 20 mL), the phases were separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (224 mg, 0.479 mmol, 100%) as a yellow foam, which was used without further purification.

[0184] Step 2: (S)-5-chloro-N-(1-methylpiperidin-3-yl)-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-amine

[0185] Acetic acid (7 μL, 0.12 mmol) was added to a solution of (S)-5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)-N-(piperidin-3-yl)pyrimidin-2-amine (112 mg, 0.24 mmol) in DCE (3.0 mL), followed by the addition of paraformaldehyde (9 mg, 0.31 mmol). The reaction mixture was stirred at room temperature for 10 min, followed by the single addition of NaBH(OAc)3 (91 mg, 0.43 mmol), and the resulting mixture was stirred at room temperature for 24 h. The mixture was diluted with DCM (20 mL), washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (111 mg, 0.23 mmol, 96% yield) as a pale yellow foam.

[0186] Example 6 Synthesis of (S)-3-((5-ethyl-4-(7-fluoro-1H-indol-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester. Step 1: (S)-3-((4-(7-fluoro-1H-indol-3-yl)-5-vinylpyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0187] Catacxium (8.0 mg, 0.022 mmol) and Pd(OAc)₂ (2.5 mg, 0.011 mmol) were added to a mixture of (S)-3-((5-chloro-4-(7-fluoro-1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-carboxylic acid tert-butyl ester (99 mg, 0.22 mmol), potassium vinyltrifluoroborate (91 mg, 0.67 mmol), and Cs₂CO₃ (217 mg, 0.67 mmol) in degassed toluene (4 mL) and H₂O (3 mL) under nitrogen atmosphere. The resulting solution was heated at 120 °C for 4 h. The cooled mixture was diluted with EtOAc (50 mL) and water (50 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na₂SO₄, filtered, and evaporated to dryness. The residue was purified by SiO2 chromatography (THF gradient from 0 to 60% in DCM) to give the title compound (59 mg, 0.13 mmol, 61% yield) as a yellow foam.

[0188] Step 2: (S)-3-((5-ethyl-4-(7-fluoro-1H-indol-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0189] Pd / C (10% w / w on activated carbon) was added to a solution of (S)-3-((4-(7-fluoro-1H-indol-3-yl)-5-vinylpyrimidin-2-yl)amino)piperidin-1-carboxylic acid tert-butyl ester (59 mg, 0.133 mmol) in EtOH (13 mL). The reaction mixture was stirred at room temperature for 16 h under positive hydrogen pressure (1 atm). The resulting solution was degassed with N2, filtered through diatomaceous earth, and concentrated under reduced pressure to give the title compound (59 mg, 0.13 mmol, 100% yield) as a pale yellow oil.

[0190] Example 7 Synthesis of (S)-5-chloro-N-(1-isopropylpiperidin-3-yl)-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidine-2-amine.

[0191]

[0192] Titanium isopropoxide (0.32 mL, 1.07 mmol) was added to a solution of (S)-5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)-N-(piperidin-3-yl)pyrimidin-2-amine (100 mg, 0.21 mmol) and anhydrous acetone (24 µL, 0.32 mmol) in DCE (3.0 mL). The reaction mixture was stirred overnight at room temperature. Then, NaBH4 (24 mg, 0.64 mmol) was added, and the mixture was stirred for 6 h. The reaction mixture was then diluted with DCM (150 mL), a saturated aqueous solution of NaHCO3 (30 mL), and filtered through diatomaceous earth. The phases were then separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (109 mg, 0.21 mmol, 100% yield) as a pale yellow oil.

[0193] Example 8 Synthesis of (S)-5-chloro-N-(1-(2-methoxyethyl)piperidin-3-yl)-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidine-2-amine.

[0194]

[0195] 2-Bromoethyl methyl ether (25 μL, 0.27 mmol) was added to a solution of (S)-5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)-N-(piperidin-3-yl)pyrimidin-2-amine (100 mg, 0.21 mmol) and potassium carbonate (37 mg, 0.27 mmol) in DMF (2.1 mL) at 0°C. The reaction mixture was stirred overnight at room temperature. It was then quenched with saturated aqueous NaHCO3 solution (20 mL) and extracted with EtOAc (3 x 30 mL). The organic layers were combined, washed with water (2 x 20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (92 mg, 0.18 mmol, 82% yield) as a yellow oil.

[0196] Example 9 Synthesis of (S)-3-((5-cyano-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester.

[0197] A premixed solution of Zn (2.5 mg, 0.04 mmol), Pd2dba3 (35 mg, 0.04 mmol), X-Phos (36 mg, 0.08 mmol), and Zn(CN)2 (27 mg, 0.23 mmol) in degassed DMA (3.6 mL), heated at 95 °C for 10 min, was added to a solution of degassed (S)-3-((5-iodo-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-carboxylic acid tert-butyl ester (250 mg, 0.379 mmol) in DMA (4 mL). The reaction mixture was heated at 95 °C for 10 min. ° The solution was stirred at C for 18 h. The cooled solution was diluted with EtOAc (20 mL) and washed with H2O (3 x 5 mL) and brine (5 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by SiO2 chromatography (EtOAc in DCM, 0 to 50% gradient) to give the title compound (212 mg, 0.38 mmol, 100% yield) as a pale yellow solid.

[0198] Example 10 Synthesis of (S)-3-((4-(1-(phenylsulfonyl)-1H-indol-3-yl)-5-(2,2,2-trifluoroethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester. Step 1: (S)-3-((4-(1-(phenylsulfonyl)-1H-indol-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0199] A stirred solution of (S)-3-((5-bromo-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-carboxylic acid tert-butyl ester (900 mg, 1.47 mmol), di(pinacolyl)diboron (933 mg, 3.67 mmol), and potassium acetate (721 mg, 7.35 mmol) in dioxane (11 mL) was degassed with nitrogen for 10 min. Then, a 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloromethane complex (120 mg, 0.147 mmol) was added, and the reaction was heated at 80 °C for 4 h. The cooled mixture was then diluted with EtOAc (100 mL) and water (50 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic layers were dried with Na2SO4, filtered, and evaporated to dryness to give the title compound (969 mg, 1.47 mmol, 100% yield) as a brown solid.

[0200] Step 2: (S)-3-((4-(1-(phenylsulfonyl)-1H-indol-3-yl)-5-(2,2,2-trifluoroethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0201] Pd2(dba)3 under nitrogen atmosphere . A solution of CHCl3 (76 mg, 0.074 mmol), XantPhos (145 mg, 0.250 mmol), and Cs2CO3 (1.92 g, 5.88 mmol) in dioxane (7 mL) was added to a stirred solution of (S)-3-((4-(1-(phenylsulfonyl)-1H-indol-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (969 mg, 1.47 mmol) and ICH2CF3 (350 µL, 2.938 mmol) in degassed dioxane (8 mL) and water (0.98 mL, 54.4 mmol). The reaction was heated at 80 °C for 18 h. The cooled mixture was then diluted with EtOAc (100 mL) and water (50 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by SiO2 chromatography (EtOAc 0 to 100% gradient in DCM) to give the title compound (304 mg, 0.49 mmol, 34% yield) as a light brown foam.

[0202] Example 11 Synthesis of (S)-3-((4-(7-(pyridin-4-yl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester. Step 1: tert-butyl 7-bromo-1H-indole-1-carboxylate

[0203] A solution of 7-bromoindole (10.0 g, 51.0 mmol), di-tert-butyl dicarbonate (12.2 g, 56.1 mmol), and DMAP (623 mg, 5.1 mmol) in acetonitrile (100 mL) was stirred at room temperature for 72 h. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (500 mL), and washed with water (300 mL) and brine (2 x 300 mL). The phases were separated and dried over Na₂SO₄, and concentrated under reduced pressure to give the title compound (15.1 g, 51.0 mmol, 100% yield) as a pale yellow oil.

[0204] Step 2: 7-Bromo-3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-indole-1-carboxylic acid tert-butyl ester

[0205] Under an inert atmosphere, HBpin (4.9 mL, 33.8 mmol) and Et3N (2.4 mL, 16.9 mmol) were added to a solution of tert-butyl 7-bromo-1H-indole-1-carboxylate (5.0 g, 16.9 mmol) in previously degassed THF (17 mL). The reaction vessel was sealed and heated at 80 °C for 10 min. [Ir(OMe)COD]2 (2.8 mg, 0.25 mol%) and 3,4,7,8-tetramethyl-1,10-phenanthroline (4.0 mg, 1.0 mol%) were added, the reaction vessel was sealed, and heated at 80 °C overnight. The reaction mixture was allowed to return to room temperature, diluted with EtOAc (300 mL), and washed with brine (100 mL). The organic layer was dried with Na2SO4 and concentrated under reduced pressure to give the title compound (5.6 g, 16.9 mmol, 100% yield), which was a brown semi-solid.

[0206] Step 3: (S)-3-((4-(7-bromo-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0207] Pd(PPh3)4 (376 mg, 0.195 mmol) and Cs2CO3 (3.82 g, 11.7 mmol) were added to (S)-3-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-carboxylic acid tert-butyl ester (PCT International Application, 2014124230, August 14, 2014) (1.56 g, 4.10 mmol) and 7-bromo-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-indole-1-carboxylic acid tert-butyl ester (1.65 g, 3.91 mmol) in a previously degassed dioxane / H2O (65 mL, 2:1) stirred solution. The resulting mixture was heated at 95 °C under N2 for 2 h. The reaction mixture was cooled to room temperature, and water (100 mL) and EtOAc (100 mL) were added. The phases were separated, and the aqueous phase was extracted with EtOAc (2 x 150 mL). The combined organic layers were dried over Na₂SO₄, filtered, and evaporated to dryness to give an orange oil. The residue was purified by reversed-phase chromatography (C18, H₂O / ACN + 0.1% HCO₂H, 0 to 80% gradient) to give the title compound (343 mg, 0.635 mmol, 16% yield) as a pale yellow foam.

[0208] Step 4: (S)-3-((4-(7-(pyridin-4-yl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0209] Pd(PPh3)4 (16 mg, 0.014 mmol) and Cs2CO3 (91 mg, 0.28 mmol) were added to a stirred solution of (S)-3-((4-(7-bromo-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (80 mg, 0.14 mmol) and pyridin-4-ylboronic acid (20 mg, 0.15 mmol) in a previously degassed dioxane / H2O (1.5 mL, 2:1). The resulting mixture was then heated at 100 °C under N2 for 18 h. The reaction mixture was cooled to room temperature, and water (500 mL) and EtOAc (500 mL) were added. The phases were separated, and the aqueous phase was extracted twice more with EtOAc (50 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated to dryness to give an orange oil. The residue was purified by SiO2 chromatography (MeOH gradient in DCM from 0 to 20%) to give the title compound (40 mg, 0.070 mmol, 50% yield) as a yellow solid.

[0210] Example 12 Synthesis of (S)-3-((4-(7-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester.

[0211] Pd(PPh3)4 (5.0 mg, 0.003 mmol) and Cs2CO3 (51 mg, 0.16 mmol) were added to a stirred solution of (S)-3-((4-(7-bromo-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-carboxylic acid tert-butyl ester (28 mg, 0.052 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-pyrazole (28 mg, 0.052 mmol) in a previously degassed DME / EtOH (1.8 mL; 2:1). The resulting mixture was then heated in a microwave (MW) reactor at 100 °C for 30 min. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and evaporated to dryness. The residue was purified by SiO2 chromatography (EtOAc 0 to 85% gradient in DCM) to give the title compound (24.0 mg, 0.044 mmol, 85% yield) as a yellow oil.

[0212] Example 13 Synthesis of (S)-3-((4-(7-(diethoxyphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester.

[0213] In a microwave-safe container under an inert atmosphere, tert-butyl (S)-3-((4-(7-bromo-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-carboxylate (81 mg, 0.15 mmol), Cs₂CO₃ (58 mg, 0.18 mmol), and tetrakis(triphenylphosphine)palladium (16 mg, 0.014 mmol) were added to THF (1.2 mL) and diethyl phosphonate (36 μL, 0.28 mmol). The reaction vessel was sealed and heated to 120 °C under microwave irradiation. oC was maintained for 10 minutes. The reaction mixture was cooled to room temperature, the solid was filtered off and washed with DCM (10 mL). The combined filtrate and washes were concentrated and evaporated to dryness. The residue was purified by SiO2 chromatography (MeOH in DCM, 0 to 20% gradient) to give the title compound (54 mg, 0.090 mmol, 60% yield) as a pale yellow solid.

[0214] Example 14 Synthesis of (S)-3-((4-(7-(4-methyl-1H-imidazol-1-yl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester.

[0215] A solution of Pd2(dba)3 (7.2 mg, 0.008 mmol) and Me4(t-Bu)2XPhos (7.6 mg, 0.016 mmol) in degassed toluene (0.8 mL) and dioxane (0.2 mL) was stirred at 120°C for 5 minutes. Tert-butyl (S)-3-((4-(7-bromo-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate (126 mg, 0.20 mmol), 4-methyl-1H-imidazolium (25 mg, 0.30 mmol), and K3PO4 (84 mg, 0.39 mmol) were added to this solution. The reaction vessel was sealed and heated at 120°C overnight. The reaction mixture was filtered and concentrated to dryness. The reaction mixture was purified by SiO2 chromatography (MeOH in DCM, 0 to 20% gradient) to give the title compound (35 mg, 0.065 mmol, 33% yield) as a beige solid.

[0216] Example 15 Synthesis of (S)-3-((4-(7-(3-methyl-2-oxoimidazolidine-1-yl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester.

[0217] To a mixture of (S)-3-((4-(7-bromo-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-carboxylic acid tert-butyl ester (150 mg, 0.28 mmol), 1-methylimidazolidine-2-one (56 mg, 0.56 mmol) in degassed toluene (1.3 mL), K₂CO₃ (77 mg, 0.56 mmol), CuI (5.3 mg, 0.03 mmol), and N,N'-dimethylethane-1,2-diamine (6 μL, 0.06 mmol) were added. The reaction vessel was sealed and heated overnight at 110 °C. The reaction mixture was cooled to room temperature, diluted with EtOAc (20 mL), and washed with water (30 mL) and brine (30 mL). The phases were separated, and the organic layer was dried over Na₂SO₄ and concentrated to dryness. The reaction mixture was purified by SiO2 chromatography (EtOAc in DCM, 0 to 100% gradient) to give the title compound (52 mg, 0.093 mmol, 33% yield) as a yellow solid.

[0218] Example 16 Synthesis of (S)-3-((4-(7-(ethoxy(methyl)phosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester.

[0219] In a microwave-safe bottle, tert-butyl (51 mg, 0.09 mmol) of (S)-3-((4-(7-bromo-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-carboxylic acid was added to a degassed solution of (S)-3-((4-(7-bromo-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-carboxylic acid (7.7 mg, 0.009 mmol) in DMF (0.4 mL). Diethyl methylphosphonite (18 μL, 0.12 mmol) was added. The bottle was sealed and immediately heated to 130°C under microwave irradiation. ° C was maintained for 5 minutes. The reaction mixture was cooled to room temperature and diluted with EtOAc (10 mL), washed with saturated NaHCO3 aqueous solution (15 mL) and brine (15 mL). The phases were separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The reaction mixture was purified by SiO2 chromatography (MeOH in DCM, 0 to 20% gradient) to give the title compound (53 mg, 0.093 mmol, 98% yield) as a brown oil.

[0220] Example 17 Synthesis of (S)-3-((4-(7-(pyridazin-4-yl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester. Step 1: (S)-3-((4-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0221] To a degassed solution of (S)-3-((4-(7-bromo-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-carboxylic acid tert-butyl ester (100 mg, 0.19 mmol), di(pinacolyl)diboron (117 mg, 0.46 mmol), and potassium acetate (91 mg, 0.93 mmol) in degassed dioxane (1.5 mL), a 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloromethane complex (15 mg, 0.019 mmol) was added. The reaction vessel was sealed and heated overnight at 100 °C. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), and washed with water (20 mL) and brine (20 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (109 mg, 0.19 mmol) as a brown foam.

[0222] Step 2: (S)-3-((4-(7-(pyridazin-4-yl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0223] To a solution of (S)-3-((4-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-carboxylic acid tert-butyl ester (109 mg, 0.19 mmol) in DMF (3.0 mL), 4-bromopyridazine hydrochloride (43 mg, 0.22 mmol), Na2CO3 (53 mg, 0.50 mmol), and water (250 µl) were added. Nitrogen was bubbled through the mixture for 15 min, and [1,1'-bis(diphenyl-phosphino)ferrocene]palladium(II) chloride DCM complex (15 mg, 0.019 mmol) was added, and the reaction mixture was heated at 80 °C for 2 h. 4-Bromopyridazine hydrochloride (50 mg, 0.26 mmol), Na₂CO₃ (50 mg, 0.47 mmol), and [1,1'-bis(diphenyl-phosphino)ferrocene]palladium(II) chloride DCM complex (8 mg, 0.009 mmol) were added to the reaction mixture, and the mixture was stirred at the same temperature for 3 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (20 mL), and washed with saturated NaHCO₃ (20 mL) and brine (20 mL). The phases were separated and dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The reaction mixture was purified by SiO₂ chromatography (EtOAc in DCM, 0 to 100% gradient) to give the title compound (62 mg, 0.12 mmol, 57% yield) as a gray-beige solid.

[0224] Example 18 Synthesis of (S)-3-(2-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-5,6-difluoro-1H-indole-1-carboxylic acid tert-butyl ester. Step 1: tert-butyl 5,6-difluoro-3-(2-(methanesulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-1-carboxylic acid

[0225] Di-tert-butyl dicarbonate (45 mg, 0.20 mmol) and DMAP (3.3 mg, 0.027 mmol) were added to a stirred solution of 5,6-difluoro-3-(2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole (47 mg, 0.14 mmol) in THF (1 mL). The reaction mixture was stirred for 1 h and diluted with EtOAc (50 mL), washed with saturated NaHCO3 aqueous solution, and the phases were separated. The organic layer was dried over Na2SO4, filtered, and evaporated to dryness to give an orange oil. The oil was dissolved in anhydrous THF / DCM (2 mL, 1:1), and mCPBA (92 mg, 0.41 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was evaporated to dryness and purified by SiO2 chromatography (EtOAc in hexane, 0 to 100% gradient) to give the title compound (30 mg, 0.063 mmol, 46% yield) as a pale yellow solid.

[0226] Step 2: (S)-3-(2-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-5,6-difluoro-1H-indole-1-carboxylic acid tert-butyl ester

[0227] (S)-3-aminopiperidin-1-carboxylic acid tert-butyl ester (14 mg, 0.069 mmol) and diisopropylethylamine (12 µL, 0.069 mmol) were added to a stirred solution of 5,6-difluoro-3-(2-(methanesulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-1-carboxylic acid tert-butyl ester (30 mg, 0.063 mmol) in THF (1 mL). The reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with EtOAc (50 mL) and washed with a saturated solution of NaHCO3 (50 mL) and brine (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (38 mg, 0.063 mmol, 100% yield) as a yellow solid.

[0228] Example 19 Synthesis of (S)-3-((4-(7-((1r,4S)-4-hydroxycyclohexyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester. Step 1: (S)-3-((4-(7-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0229] PtO2 (100 mg, 75 m 2 (g) was added to a stirred solution of (S)-3-((4-(7-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (260 mg, 0.434 mmol) in EtOAc (15 mL). The resulting solution was stirred at hydrogen (1 atm) for 72 h. The mixture was filtered through diatomaceous earth and washed with EtOAc (50 mL) and MeOH (20 mL). The combined filtrates were evaporated to dryness to give the title compound (162 mg, 0.269 mmol, 62% yield) as a brown foam.

[0230] Step 2: (S)-3-((4-(7-(4-oxocyclohexyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0231] Water (0.5 mL) and p-toluenesulfonic acid monohydrate (26 mg, 0.135 mmol) were added to a solution of (S)-3-((4-(7-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-carboxylic acid tert-butyl ester (162 mg, 0.27 mmol) in acetone (5 mL). The reaction mixture was stirred at 60 °C for 3 h. The reaction mixture was cooled to room temperature; saturated aqueous solution of NaHCO3 (50 mL) and EtOAc (100 mL) were added. The phases were separated and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by SiO2 chromatography (EtOAc 0 to 100% gradient in DCM) to give the title compound (62 mg, 0.11 mmol, 41% yield) as a white foam.

[0232] Step 3: (S)-3-((4-(7-((1r,4S)-4-hydroxycyclohexyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0233] Sodium borohydride (5.0 mg, 0.14 mmol) was added to a solution of (S)-3-((4-(7-(4-oxocyclohexyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-carboxylic acid tert-butyl ester (50 mg, 0.09 mmol) in anhydrous THF (2 mL). The reaction mixture was stirred at room temperature for 1 h. It was then quenched with methanol (1 mL) and water (1 mL) and concentrated to remove volatile organic compounds. A saturated aqueous solution of NaHCO3 (50 mL) and EtOAc (100 mL) were added. The phases were separated and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated to dryness to give the title compound (50.0 mg, 0.09 mmol, 100% yield) as a grayish-white solid.

[0234] Example 20 Synthesis of (S)-3-((5-methoxy-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester. Step 1: 3-(2-chloro-5-methoxypyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole

[0235] PdCl2(PPh3)2 (97 mg, 0.083 mmol) was added to a stirred solution of (1-(phenylsulfonyl)-1H-indol-3-yl)boronic acid (500 mg, 1.66 mmol) and 2,4-dichloro-5-methoxypyrimidine (267 mg, 1.49 mmol) in a previously degassed dioxane / H2O (6.6 mL, 10:1). The resulting reaction mixture was heated at 110 °C for 5 h. It was then cooled to room temperature and evaporated to dryness to give a yellow-brown oil. The reaction mixture was purified by SiO2 chromatography (EtOAc in DCM, 0 to 30% gradient) to give the title compound (440 mg, 1.10 mmol, 66% yield) as a pale yellow solid.

[0236] Step 2: (S)-3-((5-methoxy-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0237] Cs₂CO₃ (367 mg, 1.13 mmol), Pd(OAc)₂ (14.0 mg, 0.038 mmol), and racemic-Binap (46.7 mg, 0.075 mmol) were added to a stirred solution of 3-(2-chloro-5-methoxypyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole (150 mg, 0.375 mmol) and (S)-3-aminopiperidine-1-carboxylic acid tert-butyl ester (113 mg, 0.56 mmol) in previously degassed toluene (4.2 mL). The resulting solution was heated to 100 °C. ° C overnight. The resulting mixture was cooled to room temperature and concentrated to dryness to give a brown oil. The reaction mixture was purified by SiO2 chromatography (EtOAc in DCM, 0 to 50% gradient) to give the title compound (10 mg, 0.018 mmol, 5% yield) as a pale yellow solid.

[0238] Example 21 Synthesis of (S)-N-(6,6-dimethylpiperidin-3-yl)-4-(1-(phenylsulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine.

[0239] Step 1: (S)-(1-benzyl-6-oxoperidin-3-yl)tert-butyl carbamate

[0240] NaH (221 mg, 5.52 mmol) was added at 0°C to a stirred solution of (S)-5-aminopiperidin-2-one (Tetrahedron Letters, 1995, 36, 8205-8) (789 mg, 3.68 mmol) in DMF (18 mL). The resulting suspension was stirred for 30 min, at which point benzyl bromide (701 µL, 5.89 mmol) was added dropwise and stirred for another 30 min. The reaction was then diluted with water (50 mL) and EtOAc (100 mL), and the resulting solution was acidified to pH 7 with 1 M HCl. The phases were separated, and the aqueous layer was extracted twice more with EtOAc (100 mL). The combined organic layers were dried over Na₂SO₄, filtered, and evaporated to dryness. The residue was purified by SiO2 chromatography (EtOAc0 to 100% gradient in hexane) to give the title compound (690 mg, 2.27 mmol, 62% yield) as a white foam.

[0241] Step 2: (S)-(1-Benzyl-6,6-dimethylpiperidin-3-yl)tert-butyl carbamate

[0242] (S)-(1-benzyl-6-oxoperidin-3-yl)carbamate tert-butyl ester (43 mg, 0.14 mmol) was dissolved in THF (1.4 mL) and cooled to -10 °C. ZrCl4 (39 mg, 0.17 mmol) was added, and the reaction was stirred for 30 min. Then MeMgBr (0.30 mL, 3 M, 0.91 mmol) was added to the reaction mixture, and the solution was slowly warmed and stirred for 16 h. The solution was quenched with 30% NaOH (30 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered, evaporated to dryness, and the title compound (37 mg, 0.12 mmol, 83% yield) was given as an orange oil.

[0243] Step 3: (S)-1-Benzyl-6,6-dimethylpiperidin-3-amine

[0244] TFA (2.10 mL, 27.3 mmol) was added to a stirred solution of (S)-(1-benzyl-6,6-dimethylpiperidin-3-yl)carbamate (87 mg, 0.27 mmol) at room temperature. The resulting solution was stirred for 2 h, concentrated under reduced pressure, and azeotropically reacted with DCM (3 x 25 mL) to give the title compound (60 mg, 0.27 mmol, 100% yield) as an orange oil.

[0245] Step 4: 3-(2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole

[0246] Pd(PPh3)4 (1.01 g, 0.87 mmol) and Cs2CO3 (5.70 g, 17.5 mmol) were added to a stirred solution of 4-chloro-2-(methylthio)-5-(trifluoromethyl)pyrimidine (US Patent Application Publication, 20130017194, January 17, 2013) (2.00 g, 8.75 mmol) and (1-(phenylsulfonyl)-1H-indol-3-yl)boronic acid (2.77 g, 9.19 mmol) in a previously degassed dioxane / H2O (180 mL, 2:1). The resulting mixture was then heated at 100 °C under N2 for 1.5 h. The reaction mixture was cooled to room temperature, and a saturated solution of NaHCO3 (100 mL) and EtOAc (200 mL) were added. The phases were separated, and the aqueous phase was extracted with EtOAc (2 x 200 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by SiO2 chromatography (EtOAc0 to 100% gradient in hexane) to give the title compound (2.13 g, 4.73 mmol, 54% yield) as a light green foam.

[0247] Step 5: 3-(2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole

[0248] 3-(2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole (2.13 g, 4.73 mmol) was dissolved in anhydrous THF / DCM (50 mL, 1:1), and mCPBA (2.45 g, 14.2 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was evaporated to dryness and purified by SiO2 chromatography (EtOAc in hexane, 0 to 70% gradient) to give the title compound (2.15 g, 4.47 mmol, 95% yield) as a pale yellow foam.

[0249] Step 6: (S)-N-(1-benzyl-6,6-dimethylpiperidin-3-yl)-4-(1-(phenylsulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine

[0250] (S)-1-benzyl-6,6-dimethylpiperidin-3-amine (61 mg, 0.28 mmol) and diisopropylethylamine (146 µL, 0.84 mmol) were added to a stirred solution of 3-(2-(methanesulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole (135 mg, 0.28 mmol) in THF (4.6 mL). The reaction mixture was evaporated to dryness and purified by SiO2 chromatography (EtOAc in DCM, 0 to 50% gradient) to give the title compound (46 mg, 0.074 mmol, 27% yield) as a pale yellow oil.

[0251] Step 7: (S)-N-(6,6-dimethylpiperidin-3-yl)-4-(1-(phenylsulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine

[0252] A mixture of Pd / C (10% w / w on activated carbon) / Pd(OH)₂ / C was added to a degassed solution of (S)-N-(1-benzyl-6,6-dimethylpiperidin-3-yl)-4-(1-(phenylsulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (46 mg, 0.074 mmol) in EtOH (7 mL). The reaction mixture was then stirred at room temperature for 16 h under positive hydrogen pressure (1 atm). The reaction mixture was degassed with N₂, filtered through diatomaceous earth, and concentrated under reduced pressure to give the title compound (27 mg, 0.052 mmol, 70% yield) as a pale yellow solid.

[0253] Example 22 Synthesis of (S)-3-((4-(7-((1r,4S)-4-hydroxy-4-methylcyclohexyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (A) and (S)-3-((4-(7-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (B).

[0254]

[0255] MeMgBr (68 µL, 3M, 0.20 mmol) was added to a solution of (S)-3-((4-(7-(4-oxocyclohexyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-carboxylic acid tert-butyl ester (57 mg, 0.10 mmol) in THF (0.5 mL) at -78 °C. The reaction mixture was stirred at -78 °C for 1 h and allowed to slowly return to room temperature over 3 h. The reaction mixture was quenched with 10 mL of saturated aqueous NH4Cl solution and extracted with DCM (3 x 30 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated to dryness to give the title compound (59 mg, 0.10 mmol, 100% yield) as a yellow oil. The crude oil was used as is for the next step.

[0256] Example 23 Synthesis of (S)-3-((4-(7-(3-hydroxy-3-methylbutyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester. Step 1: (S)-3-((4-(7-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0257] Add NaOtBu (71 mg, 0.44 mmol) to a solution of (S)-3-((4-(7-bromo-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-carboxylic acid tert-butyl ester (200 mg, 0.37 mmol) in DMF (2.0 mL). Stir the solution at room temperature for 1 h, then cool to 0. ° C was added to (2-(chloromethoxy)ethyl)trimethylsilane (74 mg, 0.44 mmol), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (25 mL), extracted with EtOAc (3 x 50 mL), dried over Na₂SO₄, and concentrated to dryness. The reaction mixture was purified by SiO₂ chromatography (EtOAc in hexane, 0 to 50% gradient) to give the title compound (237 mg, 0.35 mmol, 95% yield) as a grayish-white oil.

[0258] Step 2: (S)-3-((4-(7-(3-methoxy-3-oxopropyl-1-en-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0259] Pd(OAc)₂ (7.9 mg, 0.035 mmol) and P(o-MeC₆H₄)₃ (32 mg, 0.11 mmol) were added to a solution of (S)-3-((4-(7-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-carboxylic acid tert-butyl ester (237 mg, 0.35 mmol) and methyl acrylate (95 µL, 1.06 mmol) in Et₃N (1.01 mL). The reaction mixture was sealed and heated to 100 °C with stirring for 4 h. The reaction mixture was diluted with EtOAc (50 mL) and extracted with H₂O (3 x 60 mL). The organic layer was washed with brine (60 mL), dried over Na₂SO₄, and concentrated to dryness. The reaction mixture was purified by SiO2 chromatography (EtOAc in hexane, 0 to 100% gradient) to give the title compound (148 mg, 0.219 mmol, 62% yield) as a yellow oil.

[0260] Step 3: (S)-3-((4-(7-(3-methoxy-3-oxopropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0261] Pd / C (10% w / w on activated carbon) (3 mg, 0.023 mmol) was added to a degassed solution of (S)-3-((4-(7-(3-methoxy-3-oxopropyl-1-en-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-carboxylic acid tert-butyl ester (83 mg, 0.15 mmol) in EtOH (10 mL) and THF (10 mL), and the reaction mixture was stirred overnight at room temperature under H2 (1 atm). The reaction mixture was degassed with N2, filtered through diatomaceous earth, and concentrated under reduced pressure to give the title compound (148 mg, 0.219 mmol, 100% yield) as a yellow oil.

[0262] Step 4: (S)-3-((4-(7-(3-hydroxy-3-methylbutyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0263] MeMgBr (0.44 mL, 3 M, 1.31 mmol) was added to a solution of (S)-3-((4-(7-(3-methoxy-3-oxopropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-carboxylic acid tert-butyl ester (148 mg, 0.218 mmol) in THF (0.5 mL) at 0°C. The reaction mixture was warmed to room temperature and stirred overnight. The reaction was quenched with 10 mL of saturated aqueous NH4Cl solution and extracted with EtOAc (30 mL). The phases were separated and the organic layer was washed with brine (20 mL), dried over Na2SO4, and concentrated to dryness. The reaction mixture was purified by SiO2 chromatography (EtOAc in hexane, 0 to 100% gradient) to give the title compound (60 mg, 0.089 mmol, 41% yield) as a grayish-white solid.

[0264] Step 5: (S)-3-((4-(7-(3-hydroxy-3-methylbutyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0265] At 0°C, tert-butyl (30 mg, 0.044 mmol) of (S)-3-((4-(7-(3-hydroxy-3-methylbutyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-carboxylic acid was added to a solution of tert-butyl fluoride in THF (0.18 mL, 0.18 mmol). The reaction mixture was stirred at room temperature for 1 h, and then heated to 70°C. o C and stirred overnight. The reaction mixture was quenched with 10 mL of saturated aqueous NH4Cl solution and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over Na2SO4 and concentrated to dryness. The reaction mixture was purified by SiO2 chromatography (EtOAc in hexane, 0 to 100% gradient) to give the title compound (20 mg, 0.037 mmol, 83% yield) as a pale yellow oil.

[0266] Example 24 Synthesis of (S)-3-((5-ethynyl-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (A) and (S)-3-((5-ethynyl-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (B).

[0267] Step 1: (S)-3-((4-(1-(phenylsulfonyl)-1H-indol-3-yl)-5-((trimethylsilyl)ethynyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0268] A degassed solution of (S)-3-((5-iodo-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-carboxylic acid tert-butyl ester (150 mg, 0.23 mmol), ethynyltrimethylsilane (64 μL, 0.45 mmol), Cul (3.4 mg, 0.018 mmol), PdCl₂(PPh₃)₂ (13 mg, 0.018 mmol), and Et₃N (0.316 mL, 2.27 mmol) in DMF (2.7 mL) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and dissolved in EtOAc (50 mL), washed with NH₄OH (50 mL) and brine (50 mL). The phases were separated, and the organic layer was dried over Na₂SO₄, filtered, and concentrated to dryness. The reaction mixture was purified by SiO2 chromatography (EtOAcs in hexane:DCM (1:1), 0 to 100% gradient) to give the title compound (143 mg, 0.23 mmol, 100% yield), which is a beige foam.

[0269] Step 2: (S)-5-ethynyl-4-(1H-indol-3-yl)-N-(piperidin-3-yl)pyrimidin-2-amine (A) and (S)-5-ethynyl-4-(1-methyl-1H-indol-3-yl)-N-(piperidin-3-yl)pyrimidin-2-amine (B)

[0270] K₂CO₃ (31 mg, 0.23 mmol) was added to a solution of (S)-3-((4-(1-(phenylsulfonyl)-1H-indol-3-yl)-5-((trimethylsilyl)ethynyl)pyrimidin-2-yl)amino)piperidin-1-carboxylic acid tert-butyl ester (143 mg, 0.23 mmol) in degassed MeOH (2.3 mL). The reaction mixture was stirred at room temperature for 2 h. It was then concentrated to dryness, dissolved in dioxane (2.3 mL), and 5M NaOH (1.4 mL, 6.8 mmol) was added. The reaction mixture was heated at 75°C overnight. The reaction mixture was concentrated under reduced pressure and extracted with MeTHF (3 x 50 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated to dryness. The reaction mixture was purified by SiO₂ chromatography (MeOH in DCM, 0-20% gradient) to give a brown oil. The oily substance was dissolved in DCM (2.0 mL), and TFA (0.87 mL, 11.4 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, dissolved in MeTHF (10 mL), and washed twice with saturated NaHCO3 (20 mL). The phases were separated, and the organic layer was dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by reversed-phase chromatography (C18, H2O / ACN [10 mM ammonium formate in H2O solution], 0 to 100% gradient) to give title compound A (18 mg, 0.057 mmol, 25% yield) (which was a pale yellow solid after lyophilization) and title compound B (10 mg, 0.030 mmol, 13% yield) (which was a pale yellow solid after lyophilization).

[0271] Example 25 Synthesis of (S)-5-ethyl-4-(7-fluoro-1H-indazol-3-yl)-N-(piperidin-3-yl)pyrimidin-2-amine (compound 143).

[0272] Step 1: 2-[[3-(2-chloro-5-ethylpyrimidin-4-yl)-7-fluoro-indazole-1-yl]methoxy]ethyl-trimethylsilane

[0273] Pd(dppf)Cl2 (261.09 mg, 357.00 μmol) and K2CO3 (986.33 mg, 7.14 mmol) were added in a single batch to a mixture of 2-[[7-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)indazol-1-yl]methoxy]ethyl-trimethyl-silane (2 g, 3.57 mmol) and 2,4-dichloro-5-ethyl-pyrimidine (947.53 mg, 5.36 mmol) in DME (25 mL) and H2O (5 mL) at 20 °C under N2. The mixture was stirred at 80 °C for 2 h. The mixture was poured into water (100 mL) and extracted with EA (50 mL x 2). The combined organic phases were washed with brine (100 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EA = 100 / 1, 40 / 1) to give 2-[[3-(2-chloro-5-ethylpyrimidin-4-yl)-7-fluoro-indazole-1-yl]methoxy]ethyl-trimethyl-silane (600 mg, crude product), which was a colorless oil. LCMS: M+H + : 407.1 @ 1.087 min (5-95% ACN in H2O, 1.5 min).

[0274] Step 2: (3S)-3-[[5-ethyl-4-[7-fluoro-1-(2-trimethylsilylethoxymethyl)indazol-3-yl]pyrimidin-2-yl]amino]piperidine-1-carboxylic acid tert-butyl ester

[0275] DIPEA (794.83 mg, 6.15 mmol) was added in a single step to a mixture of 2-[[3-(2-chloro-5-ethylpyrimidin-4-yl)-7-fluoro-indazole-1-yl]methoxy]ethyl-trimethyl-silane (500 mg, 1.23 mmol) and (3S)-3-aminopiperidin-1-carboxylic acid tert-butyl ester (369.52 mg, 1.84 mmol) in NMP (5 mL). The mixture was stirred at 140 °C for 24 h, then poured into water (20 mL) and extracted with EA (10 mL x 2). The combined organic phases were washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EA = 50 / 1, 20 / 1) to give (3S)-3-[[5-ethyl-4-[7-fluoro-1-(2-trimethylsilylethoxymethyl)indazol-3-yl]pyrimidin-2-yl]amino]piperidin-1-carboxylic acid tert-butyl ester (350 mg, 49.85%), which was a yellow oil. TLC: R f = 0.11 (PE:EA=3:1) Step 3: 5-Ethyl-4-(7-fluoro-1H-indazol-3-yl)-N-[(3S)-3-piperidinyl]pyrimidin-2-amine

[0276] HCl / MeOH (50 mL) was added in a single addition to a mixture of (3S)-3-[[5-ethyl-4-[7-fluoro-1-(2-trimethylsilylethoxymethyl)indazole-3-yl]pyrimidin-2-yl]amino]piperidin-1-carboxylic acid tert-butyl ester (200 mg, 350.40 μmol) in MeOH (3 mL). The mixture was stirred at 20 °C for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA) to give 5-ethyl-4-(7-fluoro-1H-indazole-3-yl)-N-[(3S)-3-piperidinyl]pyrimidin-2-amine (22 mg, 16.25%, FA) as a white solid. LCMS: M+H + 341.3 @ 2.038 minutes (10-80% ACN / water, 4.5 min). 1HNMR: (MeOD, 400 MHz) δ 8.53 (s, 1 H), 8.32 (s, 1 H), 8.21 (d, J = 7.78 Hz, 1 H), 7.25-7.13 (m, 2 H), 4.34-4.25 (m, 1 H), 3.57 (dd, J = 12.42, 3.39 Hz, 1 H), 3.13-2.98 (m, 4 H), 2.27-2.18 (m, 1 H), 2.16-2.06 (m, 1 H), 1.96-1.73 (m, 2 H), 1.20 (t, J = 7.40 Hz, 3 H).

[0277] Example 26: Synthesis of the intermediate for the synthesis of 3-(2-chloro-5-(2-fluoroethyl)pyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole (Compound 206) Step 1: 2-(2-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-5-yl)acetaldehyde

[0278] PdCl₂(PPh₃)₂ (78.2 mg, 0.111 mmol) was added to a solution of 3-(5-bromo-2-chloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole (500 mg, 1.114 mmol) and (Z)-tributyl(2-ethoxyvinyl)stanane (409 μL, 1.226 mmol) in anhydrous DMF (2.3 mL). The flask was evacuated and backfilled twice with nitrogen, then sealed and heated at 80 °C for 3 hours. The reaction mixture was quenched with 2M KF (10 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated to give a crude intermediate (1.0 g) as a brown semi-solid. The resulting compound was diluted with THF (9 mL) and 2N HCl aq. (1 mL) was added. The resulting brown solution was stirred overnight at 70 °C, and then the organic solvent was removed under reduced pressure. The residue was diluted with water and the pH was neutralized with 5N NaOH. The product was extracted with MeTHF. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by SiO2 chromatography (EtOAc / hexane (1:1) in DCM, 0 to 100% gradient) to give the title compound (300 mg, 0.728 mmol, 65% yield, in 2 steps) as a pale yellow semi-solid.

[0279] Step 2: 2-(2-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-5-yl)ethanol

[0280] Sodium borohydride (41 mg, 1.093 mmol) was added to a methanol (15 mL) solution of 2-(2-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-5-yl)acetaldehyde (300 mg, 0.728 mmol) at 0°C. The reaction mixture was stirred at 0°C for 1 h, then left overnight at room temperature. Water (2 mL) was added to concentrate the mixture. The crude material was redissolved in MeTHF (15 mL), washed with brine (15 mL), and the organic layer was separated, dried over Na2SO4, filtered, and concentrated. The residue was purified by SiO2 chromatography (EtOAc in DCM, 0 to 100% gradient) to give the title compound (125 mg, 0.302 mmol, 42% yield) as a pale yellow solid.

[0281] Step 3: 3-(2-chloro-5-(2-fluoroethyl)pyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole

[0282] Deoxo-Fluor® (170 μL, 0.906 mmol) was added to a suspension of 2-(2-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-5-yl)ethanol (125 mg, 0.302 mmol) in 2 mL of chloroform / DCE (1:1) at 25°C under an inert atmosphere. The reaction mixture became homogeneous immediately. The reaction was then quenched with a saturated aqueous solution of NaHCO3 (5 mL), and the crude product was extracted with chloroform (3 x 5 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated to give the crude title compound (148 mg) as a yellow gel, which was used without further purification.

[0283] Example 27 Synthesis of (S)-3-((4-(7-((1s,4S)-4-hydroxycyclohexyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester intermediate (compound 207) for synthesis.

[0284]

[0285] At -20°C, tert-butyl trisec-butyl borohydride (1M in THF, 167 μL, 0.167 mmol) was added to a solution of (S)-3-((4-(7-(4-oxocyclohexyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-carboxylic acid (62 mg, 0.111 mmol) in anhydrous THF (1 mL). The reaction mixture was stirred at room temperature for 15 minutes. It was then quenched with water (1 mL) and concentrated to remove volatile organic compounds. A saturated aqueous solution of NaHCO3 (5 mL) and MeTHF (10 mL) were added. The phases were separated and the aqueous layer was extracted with MeTHF (2 x 10 mL). The combined organic layers were dried with Na2SO4, filtered, and evaporated to dryness to give the title compound (62.0 mg, 0.11 mmol, quantitative yield) as a pale yellow solid, which was used without further purification for final deprotection.

[0286] Example 28 Synthesis of (S)-N-(4,4-dimethylpiperidin-3-yl)-4-(1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (compound 210) and (R)-N-(4,4-dimethylpiperidin-3-yl)-4-(1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (compound 209) Step 1: 1-Benzyl-4,4-dimethylpiperidine-2,6-dione

[0287] K₂CO₃ (16.3 g, 70.84 mmol) was added to a suspension of 4,4-dimethylpiperidin-2,6-dione (5.0 g, 35.42 mmol) in acetone (177 mL) at 25°C, and BnBr (4.63 mL, 38.96 mmol) was added dropwise while stirring. The suspension was then placed in an oil bath set to 50°C and stirred for 6 h. The reaction was cooled to 25°C and stirred for another 48 h. The fine white suspension was vacuum filtered through a fine-pore glass frit, and the colorless filtrate was concentrated under reduced pressure. The residue was purified by rapid chromatography on SiO₂ (EtOAc in hexane, 10 to 40% gradient) to give the title compound as a white solid (7.19 g, 31.09 mmol, 88%).

[0288] Step 2: (Z)-1-Benzyl-3-(hydroxyimino)-4,4-dimethylpiperidine-2,6-dione

[0289] A solution of 1-benzyl-4,4-dimethylpiperidin-2,6-dione (3.00 g, 12.97 mmol) in THF (60 mL) was added to a flame-dried flask at 25°C under nitrogen. The solution was cooled to -78°C (internal temperature), and then a solution of LiHMDS in 1M hexane (13 mL, 12.97 mmol) was added dropwise to form a milky white suspension. The mixture was stirred at -78°C for 20 minutes, followed by the slow addition of isoamyl nitrite (2.08 mL, 15.66 mmol) over 15 minutes, forming a mango-yellow suspension. The reaction mixture was stirred for another 30 minutes, then heated to 25°C for 1 h, quenched with a saturated NH4Cl solution, and stirred for 16 h. Water was added and the mixture was extracted with MeTHF (3 x 60 mL). The combined organic phases were washed with water (2 x 40 mL) and brine (2 x 40 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. 10% EtOAc in hexane (10 mL) was added to the resulting oil, and a white solid slowly precipitated from the solution. The mixture was cooled in an ice bath, filtered, and washed with hexane to give the title compound as a white solid (526.1 mg, 2.02 mmol, 16%).

[0290] Step 3: 1-Benzyl-4,4-dimethylpiperidin-3-amine

[0291] A suspension of LiAlH4 (383 mg, 10.10 mmol) in anhydrous THF (5 mL) was added to a solution of (Z)-1-benzyl-3-(hydroxyimino)-4,4-dimethylpiperidin-2,6-dione (526 mg, 2.02 mmol) in anhydrous THF (15 mL) at 0°C under nitrogen atmosphere. The suspension was gradually heated to 25°C and stirred at that temperature for 1 h, then placed in an oil bath at 60°C for 48 h. The mixture was cooled to 0°C in an ice bath, and Na2SO4 (wetted with water) was added until no more gas was released. Finally, EtOAc (30 mL) was added at 25°C and stirred for 1 h. The solid material was filtered off through a Buchner funnel, washed with EtOAc and MeOH, and the filtrate was dried with Na2SO4. The solid was filtered off and the filtrate was concentrated to give the crude title compound (1 g), which was a yellow oil and was used without further purification.

[0292] Step 4: (S)-N-(1-benzyl-4,4-dimethylpiperidin-3-yl)-4-(1-(phenylsulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (A), (R)-N-(1-benzyl-4,4-dimethylpiperidin-3-yl)-4-(1-(phenylsulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (B)

[0293] The crude 1-benzyl-4,4-dimethylpiperidin-3-amine (2.02 mmol), 3-(2-(methanesulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole (650 mg, 1.35 mmol), and N,N-diisopropylethylamine (0.96 mL, 6.06 mmol) (dried in Na₂SO₄) from the previous steps were dissolved in anhydrous THF (34 mL, dried in Na₂SO₄). The mixture was stirred at 25 °C for 3 h and then concentrated under reduced pressure. The residue was purified by rapid chromatography on SiO₂ (EtOAc 0 to 100% gradient in DCM) to give the title compound as a red foam (260 mg, 0.42 mmol, 21% yield, in 2 steps). The material was separated into the corresponding (S)- and (R)-enantiomers using a ChiralPak IA column, injected with 5,000 μL of hexane containing 0.5% EtOH and 0.1% DCM for elution. Peak 1 (A, provisionally designated as the (S)-enantiomer): 109.1 mg (>96% purity, 99.7% ee), a pale yellow solid, and Peak 2 (B, provisionally designated as the (R)-enantiomer): 98.0 mg (>93% purity, 90.0% ee), a pale yellow solid.

[0294] Step 5: Methyl (S)-4,4-dimethyl-3-((4-(1-(phenylsulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid

[0295] Methyl chloroformate (0.90 mL, 8.53 mmol) and N,N-diisopropylamine (1.15 mL, 8.15 mmol) were added to a solution of (S)-N-(1-benzyl-4,4-dimethylpiperidin-3-yl)-4-(1-(phenylsulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (A, stereochemically designated) (103.2 mg, 0.167 mmol) in toluene (1.4 mL), and the resulting mixture was heated to 100 °C under nitrogen and held for 16 h. The solution was concentrated under reduced pressure, and then MeOH (5 mL) was added, and the resulting mixture was heated at 65 °C for 2 h, stirred at 25 °C for 16 h, and finally concentrated under reduced pressure. The residue was then purified by reversed-phase chromatography on a C18 plate (MeCN in aqueous ammonium formate, 10 mM, pH 3.8, 0 to 100% gradient). The title compound was obtained as a yellow solid (50 mg, 0.085 mmol, 51% yield).

[0296] Step 6: (S)-N-(4,4-dimethylpiperidin-3-yl)-4-(1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine

[0297] Methyl (S)-4,4-dimethyl-3-((4-(1-(phenylsulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-carboxylate (50 mg, 0.085 mmol) in 1,4-dioxane (0.3 mL) was added to a solution of 1,4-dioxane (2.65 mL), and the reaction mixture was stirred at 75°C for 16 h. The reaction was cooled to 25°C and the crude product was extracted with MeTHF (3 x 10 mL). The combined organic extracts were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by reversed-phase chromatography on C18 (MeCN in aqueous ammonium formate, 10 mM, pH 3.8, 0 to 100% gradient). The title compound was given as a white, fluffy solid (6.79 mg, 0.017 mmol, 10% yield).

[0298] Example 29 Synthesis of N-((3S,6R)-6-ethylpiperidin-3-yl)-4-(1-(phenylsulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (A) and N-((3S,6S)-6-ethylpiperidin-3-yl)-4-(1-(phenylsulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (B) intermediates for the synthesis of compounds 211 and 217 Step 1: ((3S,6R)-1-benzyl-6-ethylpiperidin-3-yl)tert-butyl carbamate (A) and ((3S,6S)-1-benzyl-6-ethylpiperidin-3-yl)tert-butyl carbamate (B)

[0299] Tf₂O (71 μL, 0.418 mmol) was added dropwise to a solution of (S)-(1-benzyl-6-oxoperidin-3-yl)carbamate tert-butyl ester (106 mg, 0.348 mmol) and 2,6-di-tert-butyl-4-methylpyridine (DTBMP) (85.8 mg, 0.418 mmol) in DCM (3.5 mL) at -78 °C. The reaction mixture was then incubated at -78 °C. o Stir at C for 45 minutes. Add 120 μL of EtMgBr solution (3.0 M in ether, 0.418 mmol) dropwise to the reaction mixture and slowly warm the mixture to room temperature while stirring at room temperature for 1 h. Then add LiAlH4 (39.6 mg, 1.045 mmol) in a single addition. After stirring for 1 h, dilute the reaction mixture with ether and quench it by carefully adding 0.11 mL H2O, 0.06 mL 30% NaOH, and 0.33 mL H2O. Stir the resulting mixture for 20 minutes, add MgSO4, and stir overnight. Filter the reaction mixture through diatomaceous earth and wash with DCM and ether. The filtrate was concentrated under reduced pressure and purified by SiO2 chromatography (EtOAc:hexane (1:1) in DCM, 0 to 100% gradient) to give the title compound (A), a clear oil (35.9 mg, 0.113 mmol, 32% yield) and (B), a white semi-solid (27.3 mg, 0.086 mmol, 25% yield).

[0300] Step 2: (3S,6R)-1-benzyl-6-ethylpiperidine-3-amine

[0301] TFA (1.67 mL, 21.762 mmol) was added to a solution of ((3S,6R)-1-benzyl-6-ethylpiperidin-3-yl)carbamate (69 mg, 0.218 mmol) in DCM (4.4 mL) at 0 °C, and the reaction mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was concentrated under reduced pressure and azeotropically with DCM three times to give the title compound as a yellow oil (47 mg, 0.218 mmol, 100%), which was used without further purification.

[0302] Step 3: N-((3S,6R)-1-benzyl-6-ethylpiperidin-3-yl)-4-(1-(phenylsulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine

[0303] (3S,6R)-1-benzyl-6-ethylpiperidin-3-amine (47 mg, 0.218 mmol) and diisopropylethylamine (0.19 mL, 1.088 mmol) were added to a stirred solution of 3-(2-(methanesulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole (121 mg, 0.250 mmol) in THF (3.6 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on SiO2 (EtOAc in DCM, 0 to 50% gradient) to give the title compound as a pale yellow oil (106 mg, 0.171 mmol, 79% yield).

[0304] Step 4: N-((3S,6R)-6-ethylpiperidin-3-yl)-4-(1-(phenylsulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine

[0305] A mixture of Pd / C (10% w / w on activated carbon) / Pd(OH)₂ / C (20% dispersion) was added to a degassed solution of N-((3S,6R)-1-benzyl-6-ethylpiperidin-3-yl)-4-(1-(phenylsulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (106 mg, 0.171 mmol) in EtOH (13 mL), and the reaction mixture was stirred overnight at room temperature under H₂ (1 atm). The reaction mixture was degassed with N₂, filtered through a diatomaceous earth pad, and then concentrated under reduced pressure to give the title compound as a grayish-white solid (34 mg, 0.063 mmol, 37% yield), which was used without further purification.

[0306] Example 30 Synthesis of (S)-4-azaspiro[2.5]octyl-6-amine intermediate (compound 212) for synthesis Step 1: (S)-Benzyl(1-Benzyl-6-oxoperidin-3-yl)tert-butyl carbamate

[0307] NaH (221 mg, 5.52 mmol) was added at 0°C to a stirred solution of (S)-5-aminopiperidin-2-one (Tetrahedron Letters, 1995, 36, 8205-8) (789 mg, 3.68 mmol) in DMF (18 mL). The resulting suspension was stirred for 30 minutes, during which time benzyl bromide (701 μL, 5.89 mmol) was added dropwise and stirred for another 30 minutes. The reaction was then diluted with water (50 mL) and EtOAc (100 mL), and the resulting solution was acidified to pH 7 with 1 M HCl. The phases were separated, and the aqueous layer was extracted twice more with EtOAc (100 mL). The combined organic layers were dried over Na₂SO₄, filtered, and evaporated to dryness. The residue was purified by SiO2 chromatography (EtOAc in hexane, 0 to 100% gradient) to give the title compound (384 mg, 0.973 mmol, 26% yield) as a yellow oil.

[0308] Step 2: (S)-Benzyl(4-benzyl-4-azaspiro[2.5]oct-6-yl)carbamate tert-butyl ester

[0309] Titanium isopropoxide (325 uL, 1.097 mmol) was added to a solution of ethyl magnesium bromide (831 uL, 2.5 mmol; 3.0 M / Et2O) in THF (10 mL) at -78 °C, and the solution was stirred for 10 min. Then, a solution of (S)-benzyl (1-benzyl-6-oxopiperidin-3-yl) tert-butyl carbamate (328 mg, 0.831 mmol) in THF (1 mL) was added dropwise at the same temperature. The mixture was warmed to room temperature for 2 h, followed by heating to 70 °C overnight. The reaction mixture was cooled to room temperature, quenched with 10% NaOH aqueous solution (0.5 mL), diluted with MeTHF (20 mL), washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by SiO2 chromatography (EtOAc in hexane, 0 to 100% gradient) to give the title compound as a colorless oil (170 mg, 0.418 mmol, 50% yield).

[0310] Step 3: (S)-4-azaspiro[2.5]octyl-6-amine

[0311] Pd / C (10% w / w on activated carbon) was added to a degassed solution of (S)-benzyl(4-benzyl-4-azaspiro[2.5]oct-6-yl)carbamate tert-butyl ester (144 mg, 0.352 mmol) in 5% HCl (3.5 mL) in MeOH. The reaction mixture was then stirred at room temperature for 16 h under positive hydrogen pressure (1 atm). The reaction was monitored by LCMS. The reaction mixture was degassed with N2, filtered through a diatomaceous earth pad, and concentrated under reduced pressure to give the title compound as a pale yellow solid (44 mg, 0.352 mmol, quantitative yield).

[0312] Example 31: Synthesis of the intermediate 2-benzyl-N-(4-(1-(phenylsulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinoline-4-amine used in the synthesis of compounds 215 and 216 Step 1: N-(isoquinoline-4-yl)benzamide

[0313] A solution of benzoic anhydride (1.57 g, 6.94 mmol) in pyridine (7 mL) was added to a solution of isoquinoline-4-amine (1.00 g, 6.94 mmol) in pyridine (7 mL) at 25°C under nitrogen atmosphere. The resulting solution was heated at 100 °C for 4 h, then cooled to 25°C and quenched with a saturated solution of NaHCO3 (5 mL). The crude product was extracted with CHCl3 (5 x 10 mL). The combined organic phases were washed with water (2 x 15 mL) and brine (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound as a purple-red solid (1.66 g, 6.70 mmol, 97% yield), which was used without further purification.

[0314] Step 2: N-(1,2,3,4-tetrahydroisoquinoline-4-yl)benzamide

[0315] PtO2 (240 mg, 1.074 mmol) was added to a degassed solution of N-(isoquinoline-4-yl)benzamide (1.66 g, 6.70 mmol) in AcOH (134 mL) at 25°C, and the reaction mixture was stirred under hydrogen (1 atm) for 24 h. The mixture was filtered through a diatomaceous earth mat and concentrated to a residue of 30 mL, then diluted with CHCl3 (50 mL) and alkalized to pH 9 with moistened NaHCO3. Water (100 mL) was added and the product was extracted with CHCl3 (3 x 100 mL). The combined organic phases were then washed with water (2 x 50 mL) and brine (2 x 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a dark yellow foam of the title compound (1.36 g, 5.38 mmol, 80% yield), which was used without further purification.

[0316] Step 3: N-(2-benzyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzamide

[0317] AcOH (0.05 mL, 0.86 mmol) was added to a solution of N-(1,2,3,4-tetrahydroisoquinoline-4-yl)benzamide (434.3 mg, 1.72 mmol) in 1,2-dichloroethane (11.5 mL), followed by benzaldehyde (237 mg, 2.24 mmol). The emulsion mixture was stirred at 25°C under nitrogen for 10 min, followed by a single addition of NaBH(OAc)3 (657 mg, 3.10 mmol), and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with DCM (50 mL) and water was slowly added at 0°C, followed by basification with saturated NaHCO3 to pH 8. The crude product was extracted with DCM (2 x 30 mL). The combined organic phases were then washed with water (2 x 30 mL) and brine (2 x 30 mL), dried with Na2SO4, filtered, and concentrated to give the title compound as a white powder (565 mg, 1.65 mmol, 96% yield), which was used without further purification.

[0318] Step 4: 2-Benzyl-1,2,3,4-Tetrahydroisoquinoline-4-amine

[0319] A solution of N-(2-benzyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzamide (430 mg, 1.256 mmol) in 6 M HCl (30 mL) was heated at 100 °C for 40 h under nitrogen atmosphere. The resulting solution was then concentrated under reduced pressure. The residue was dissolved in DCM (10 mL) and MeOH (2 mL) and dried over Na2SO4, filtered, and concentrated to give the title compound as a viscous brown-orange solid (299 mg, 1.26 mmol, quantitative yield), which was used without further purification.

[0320] Step 5: 2-Benzyl-N-(4-(1-(phenylsulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinoline-4-amine

[0321] A solution of 2-benzyl-1,2,3,4-tetrahydroisoquinoline-4-amine (299 mg, 1.26 mmol) in anhydrous THF (12.5 mL) and N,N-diisopropylethylamine (2.75 mL, 6.27 mmol, dried over Na₂SO₄) was added at 25°C under nitrogen atmosphere to a solution of 3-(2-(methanesulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole (404 mg, 0.84 mmol). The reaction mixture was stirred at room temperature for 16 h, concentrated under reduced pressure, and the crude material was then purified by column chromatography on SiO₂ (EtOAc in DCM, 0 to 100% gradient). The title compound was obtained as a gray-green solid (484 mg, 0.757 mmol, 60% yield). 440 mg of this material was separated into the corresponding (S)- and (R)-enantiomers using a ChiralPak IA column, with 5,000 μL injections of 10% MeOH and 10% DCM in hexane for elution. Peak 1 (A, provisionally designated as the (S)-enantiomer): 161.8 mg (>99% purity, 99.3% ee), a pale yellow solid, and Peak 2 (B, provisionally designated as the (R)-enantiomer): 148.3 mg (>99% purity, 99.2% ee), a pale yellow solid.

[0322] Example 32 Synthesis of (2R,5S)-5-amino-2-(pyrrolidine-1-carbonyl)piperidine-1-carboxylic acid tert-butyl ester intermediate for the synthesis of compound 228. Step 1: (2R,5R)-1-(tert-butoxycarbonyl)-5-((tert-butyldimethylsilyl)oxy)piperidine-2-carboxylic acid

[0323] NaOH (0.54 mL, 2 M) was added to a solution of (2R,5R)-5-((tert-butyldimethylsilyl)oxy)piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (270 mg, 0.72 mmol) in MeOH (0.50 mL) at 0 °C. The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was concentrated under reduced pressure to remove MeOH and 1 M HCl was carefully added until the pH of the reaction mixture was 2. The reaction mixture was extracted with MeTHF (3 x 10 mL). The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure to give the title compound as a white solid (219 mg, 0.61 mmol, 84% yield), which was used without further purification.

[0324] Step 2: (2R,5R)-5-((tert-butyldimethylsilyl)oxy)-2-(pyrrolidine-1-carbonyl)piperidine-1-carboxylic acid tert-butyl ester

[0325] HOBt (54 mg, 0.40 mmol) and EDC (95 mg, 0.50 mmol) were added to a solution of (2R,5R)-1-(tert-butoxycarbonyl)-5-((tert-butyldimethylsilyl)oxy)piperidine-2-carboxylic acid (119 mg, 0.33 mmol) in DMF (1.0 mL). After stirring at room temperature for 1 h, pyrrolidine (31 mg, 0.43 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was then diluted with MeTHF (10 mL) and washed with a saturated solution of NaHCO3 (50 mL). The phases were separated and the organic matter was washed twice more with H2O (50 mL) and brine (50 mL). The organic phase was then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by SiO2 chromatography (EtOAc in hexane, 0 to 100% gradient) to give the title compound as a grayish-white solid (112 mg, 0.27 mmol, 82% yield).

[0326] Step 3: (2R,5R)-5-hydroxy-2-(pyrrolidine-1-carbonyl)piperidine-1-carboxylic acid tert-butyl ester

[0327] TBAF (1.99 mL, 1 M solution in THF) was added to a solution of (2R,5R)-5-((tert-butyldimethylsilyl)oxy)-2-(pyrrolidine-1-carbonyl)piperidine-1-carboxylate (205 mg, 0.50 mmol) in THF (16.6 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was quenched with saturated NH4Cl solution (50 mL, initially added slowly) and extracted with EtOAc (3 x 100 mL). The phases were separated, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by reversed-phase chromatography (C18, MeCN in 10 mM ammonium formate aqueous solution, pH 3.8, 0 to 100% gradient) to give the title compound as a white solid (112 mg, 0.375 mmol, 76% yield).

[0328] Step 4: (2R,5R)-5-((methanesulfonyl)oxy)-2-(pyrrolidine-1-carbonyl)piperidine-1-carboxylic acid tert-butyl ester

[0329] Methanesulfonyl chloride (16 μL, 0.253 mmol) was added dropwise to a solution of (2R,5R)-5-hydroxy-2-(pyrrolidine-1-carbonyl)piperidine-1-carboxylic acid tert-butyl ester (72 mg, 0.241 mmol) and 4-dimethylaminopyridine (2.9 mg, 0.024 mmol) in pyridine (1.6 mL) at 0 °C. The reaction mixture was stirred at room temperature for 16 h and then concentrated under reduced pressure to remove most of the solvent. Brine (50 mL) was added and the reaction mixture was extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by SiO₂ chromatography (EtOAc in hexane, 0 to 100% gradient) to give the title compound as a clear oil (55 mg, 0.146 mmol, 61% yield).

[0330] Step 5: (2R,5S)-5-azido-2-(pyrrolidine-1-carbonyl)piperidine-1-carboxylic acid tert-butyl ester

[0331] NaN3 (28.5 mg, 0.438 mmol) was added to a solution of (2R,5R)-5-((methanesulfonyl)oxy)-2-(pyrrolidine-1-carbonyl)piperidine-1-carboxylic acid tert-butyl ester (55 mg, 0.146 mmol) in DMF (1.5 mL) at room temperature. The reaction mixture was heated to 60 °C. oStirred at C for 2 days, monitored by LCMS. The reaction mixture was diluted with water (20 mL), and the crude product was extracted with EtOAc (2 x 50 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by SiO2 chromatography (EtOAc in hexane, 0 to 100% gradient) to give the title compound as a light-colored oil (13 mg, 0.040 mmol, 28% yield).

[0332] Step 6: (2R,5S)-5-amino-2-(pyrrolidine-1-carbonyl)piperidine-1-carboxylic acid tert-butyl ester

[0333] The reaction mixture was added to a degassed solution of (2R,5S)-5-azido-2-(pyrrolidine-1-carbonyl)piperidine-1-carboxylic acid tert-butyl ester (13 mg, 0.040 mmol) in EtOH (1.3 mL), Pd / C (10% w / w on activated carbon; 1 mg, 0.004 mmol), and the reaction mixture was stirred overnight at room temperature under H2 (1 atm). The reaction mixture was degassed with N2, filtered through a diatomaceous earth pad, and then concentrated under reduced pressure to give the title compound (12 mg, 0.040 mmol, quantitative yield) as a grayish-white solid, which was used without further purification.

[0334] Example 33 Synthesis of (3S)-3-((5-(1-hydroxyethyl)-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester intermediate for the synthesis of compound 234 and its enantiomers 238 and 239.

[0335] Sodium borohydride (32.0 mg, 0.855 mmol) was added to a solution of (S)-3-((5-acetyl-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-carboxylic acid tert-butyl ester (328 mg, 0.570 mmol) in MeOH (6 mL). The reaction mixture was stirred at room temperature for 1 h, and then another portion of sodium borohydride (32.0 mg, 0.855 mmol) was added. The reaction mixture was stirred at room temperature for another 1 h and monitored by LCMS. The reaction mixture was then concentrated, and the residue was redissolved in MeTHF (20 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to dryness. The crude product was purified by SiO2 chromatography (EtOAc in DCM, 0 to 100% gradient) to give the racemic title compound (230 mg, 0.398 mmol, 70% yield) as a pale yellow solid. 166 mg of the racemic compound was separated by preparative chiral HPLC (Chiralpak IA, 5 μm, 20 x 250 mm, 6:6:88 = MeOH / DCM / hexane + 0.1% DEA, 16–22 mg / inj) to obtain peak 1 (79 mg), a white solid, 99.9% DE, and peak 2 (75 mg), a white solid, 98.0% DE. Example 34 Synthesis of N-((3S)-1-benzyl-6-pentylpiperidin-3-yl)-4-(1-(phenylsulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine and (S)-1-benzyl-N-(4-(1-(phenylsulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-1-azaspiro[5.5]undecane-3-amine intermediates for the synthesis of compounds 240 and 241 Step 1: ((3S)-1-benzyl-6-pentylpiperidin-3-yl)tert-butyl carbamate (A) and (S)-(1-benzyl-1-azaspiro[5.5]undecane-3-yl)tert-butyl carbamate (B)

[0336] Di-tert-butylmethylpyridine (243 mg, 1.183 mmol) was added to a solution of (S)-(1-benzyl-6-oxoperidin-3-yl)carbamate tert-butyl ester (300 mg, 0.986 mmol) in DCM (10 mL) and the mixture was cooled to -78 °C. f₂O (0.20 mL, 1.183 mmol) was added dropwise to the mixture, and the resulting orange solution was stirred at -78 °C for 1 h. Pentamethylenedi-(magnesium bromide) (2.07 mL, 1.035 mmol) was then added dropwise. The resulting solution was stirred at -78 °C for 7 h and then slowly heated to 25 °C over 16 h. The reaction mixture was then cooled again to -78 °C and additional Tf₂O (0.20 mL, 1.183 mmol) was added to form a bright orange suspension, which was stirred at this temperature for 2 h, followed by the addition of additional pentamethylene di-(magnesium bromide) (2.07 mL, 1.04 mmol). The reaction mixture was slowly warmed to 25 °C for 16 h, then quenched with water (2 mL) and concentrated under reduced pressure. Water (10 mL) and EtOAc (10 mL) were added, and the aqueous layer was extracted with EtOAc (2 x 15 mL). The collected organic matter was washed with water (2 x 15 mL), (1:1) water / saline (2 x 10 mL), and saline (10 mL), then dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was redissolved in DCM (3 mL, dried over Na₂SO₄), and di-tert-butylmethylpyridine (243 mg, 1.183 mmol) was added and the mixture was cooled to -78 °C. Tf₂O (0.20 mL, 1.183 mmol) was added dropwise, and the mixture was stirred at -78°C for 1 h. Then, pentamethylenedi-(magnesium bromide) (4.14 mL, 2.07 mmol) was added dropwise, and the mixture was stirred for 3 h. The mixture was then heated to 25°C and stirred for 16 h. The reaction mixture was then cooled to 0°C, and LiAlH₄ (135 mg, 3.55 mmol) was added. The mixture was stirred for 1 h and then heated to room temperature. Wetted Na₂SO₄ (150 mg) was added, and the reaction mixture was stirred for 1 h. The mixture was then filtered under vacuum. After concentration under reduced pressure, the green-brown oily residue was dissolved in MeTHF (10 mL), washed with water (5 mL), and extracted from the aqueous layer with MeTHF (2 x 15 mL). The collected organic matter was washed with water (2 x 10 mL) and brine (10 mL), dried with Na2SO4, filtered, and concentrated to give a mixture of 780 mg of title compounds (A) and (B).

[0337] Step 2: (3S)-1-benzyl-6-pentylpiperidin-3-amine (C) and (S)-1-benzyl-1-azaspiro[5.5]undecane-3-amine (D)

[0338] TFA (3.35 mL, 49.23 mmol) was added to the mixture of (A) and (B) (473 mg, 0.985 mmol) in DCM (10 mL) from the previous experiment, and the resulting solution was stirred at 25 °C for 48 h. The reaction mixture was then concentrated under reduced pressure and azeotropically reacted with DCM several times to provide a mixture of title compounds (C) and (D) as an orange oil (85 mg, 0.325 mmol, 33%), which was used without further purification.

[0339] Step 3: N-((3S)-1-benzyl-6-pentylpiperidin-3-yl)-4-(1-(phenylsulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (E) and (S)-1-benzyl-N-(4-(1-(phenylsulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-1-azaspiro[5.5]undecane-3-amine (F)

[0340] A mixture of amines (C) and (D) (85 mg, 0.325 mmol) in anhydrous THF (4 mL) was supplemented with 3-(2-(methanesulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole (314 mg, 0.650 mmol) and anhydrous N,N-diisopropylethylamine (1.42 mL, 3.25 mmol). The resulting reaction mixture was stirred at 25 °C for 16 h and then concentrated under reduced pressure. The residue was redissolved in MeTHF (5 mL) and water (10 mL), and the aqueous layer was extracted with MeTHF (2 x 5 mL). The combined organic matter was washed with water (3 x 10 mL) and brine (2 x 10 mL), dried over Na2SO4, filtered, and concentrated. The crude material was purified by reversed-phase column chromatography (C18, MeCN in ammonium formate aqueous solution, pH 3.8, 10 mM, 0 to 100% gradient) to give the title compound (E) (impure, enriched (E), 76.0 mg, 0.115 mmol, 35% yield), which is a yellow solid, and pure (F) (24.1 mg, 0.037 mmol, 11% yield), which is an orange paste.

[0341] Example 35 Synthesis of (2R,5S)-5-amino-2-((S)-3-hydroxypyrrolidine-1-carbonyl)piperidine-1-carboxylic acid tert-butyl ester intermediate for the synthesis of compounds 244 and 250. Step 1: (2R,5R)-5-((methanesulfonyl)oxy)piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester

[0342] Methanesulfonyl chloride (89 μL, 1.396 mmol) was added dropwise to a solution of (2R,5R)-5-hydroxypiperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (329 mg, 1.269 mmol) (WO 2006125974) and 4-dimethylaminopyridine (140 mg, 1.14 mmol) in pyridine (12.7 mL) at 0 °C. The reaction mixture was stirred at room temperature for 12 h and then concentrated under reduced pressure. Brine (50 mL) was added and the reaction mixture was extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by SiO2 chromatography (EtOAc:hexane (1:1) in DCM, 0 to 60% gradient) to give the title compound as a clear oil (182 mg, 0.539 mmol, 43% yield).

[0343] Step 2: (2R,5S)-5-azidopiperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester

[0344] NaN3 (105 mg, 1.62 mmol) was added to a solution of (2R,5R)-5-((methanesulfonyl)oxy)piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (182 mg, 0.539 mmol) in DMF (5.4 mL) at room temperature. The reaction mixture was heated to 60 °C. o The mixture was stirred at C for 16 h, monitored by LCMS. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 50 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by SiO2 chromatography (EtOAcs in hexane:DCM (1:1), 0 to 40% gradient) to give the title compound as a light-colored oil (95 mg, 0.330 mmol, 62% yield).

[0345] Step 3: (2R,5S)-5-azido-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid

[0346] NaOH (0.10 mL, 5 M) was added to a solution of (2R,5S)-5-azidopiperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (95 mg, 0.330 mmol) in MeOH (2.2 mL) at 0 °C. The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was concentrated under reduced pressure to remove MeOH and 1 M HCl was carefully added until the pH of the reaction mixture was 2. The reaction mixture was extracted with MeTHF (3 x 10 mL). The combined organic phases were dried over Na₂SO₄. ， The compound was concentrated under reduced pressure to give the title compound (90 mg, 0.330 mmol, quantitative yield) as a white solid, which was used without further purification.

[0347] Step 4: (2R,5S)-5-azido-2-((S)-3-hydroxypyrrolidine-1-carbonyl)piperidine-1-carboxylic acid tert-butyl ester

[0348] To a solution of (2R,5S)-5-azido-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (90 mg, 0.330 mmol) and (S)-pyrrolidine-3-ol (31 μL, 0.383 mmol) in DMF (6.7 mL), HBTU (189 mg, 0.499 mmol) and DIPEA (290 μL, 1.66 mmol) were added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was then diluted with MeTHF (10 mL) and washed with a saturated solution of NaHCO3 (50 mL). The phases were separated, and the organic phase was washed with H2O (2 x 50 mL) and brine (50 mL). The organic phase was then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by SiO2 chromatography (THF in DCM, 0 to 50% gradient) to give the title compound as a clear oil (92 mg, 0.271 mmol, 81% yield).

[0349] Step 5: (2R,5S)-5-amino-2-((S)-3-hydroxypyrrolidine-1-carbonyl)piperidine-1-carboxylic acid tert-butyl ester

[0350] Pd / C (10% w / w on activated carbon; 4.3 mg, 0.041 mmol) was added to a degassed solution of (2R,5S)-5-azido-2-((S)-3-hydroxypyrrolidine-1-carbonyl)piperidine-1-carboxylic acid tert-butyl ester (92 mg, 0.271 mmol) in EtOH (5.4 mL), and the reaction mixture was stirred overnight at room temperature under hydrogen (1 atm). The reaction mixture was degassed with N2, filtered through a diatomaceous earth pad, and then concentrated under reduced pressure to give the title compound (66 mg, 0.211 mmol, 78% yield) as a clear oil, which was used without further purification.

[0351] Example 36 Synthesis of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-6-carboxynitrile intermediate for the synthesis of compound 246. Step 1: 3-Iodo-1H-indole-6-carboxynitrile

[0352] KOH (1.58 g, 28.1 mmol) and iodine (3.61 g, 14.2 mmol) were added to a suspension of 6-cyanoyindole (2.00 g, 14.1 mmol) in DMF (40 mL) at 0°C, and the reaction mixture was stirred for 30 min. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL). The organic layer was washed with a saturated solution of Na₂S₂O₃ (100 mL), water (100 mL), and brine (100 mL), dried over Na₂SO₄, and concentrated under reduced pressure to give the title compound (3.73 g, 13.9 mmol, 99% yield) as a light brown to orange solid.

[0353] Step 2: 3-Iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-6-carboxynitrile

[0354] NaH (60% suspension in mineral oil) (668 mg, 16.7 mmol) was added to a suspension of 3-iodo-1H-indole-6-carboxynitrile (3.73 g, 13.9 mmol) in DMF (70 mL) at 0°C. The reaction was stirred at this temperature for 1 h, and then SEM-Cl (2.96 mL, 16.7 mmol) was added. The reaction mixture was then stirred for another 1 h. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (3 x 150 mL). The organic compounds were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid chromatography on SiO2 (EtOAc in hexane, 0 to 30% gradient) to give the title compound (4.05 g, 10.17 mmol, 73% yield) as a pale yellow oil.

[0355] Step 3: 3-Iodo-1H-indole-6-carboxynitrile

[0356] At -10°C, isopropyl magnesium chloride-lithium chloride complex (TurboGrignard) (1.06 mL, 1.3 M, 1.38 mmol) was added dropwise to a solution of 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-6-carboxynitrile (500 mg, 1.26 mmol) in THF (8.4 mL). The solution was stirred for 10 min, and then 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (0.44 mL, 2.13 mmol) was added dropwise. The reaction mixture was stirred for 1 h. The reaction mixture was then quenched with saturated ammonium chloride solution (100 mL) and extracted with EtOAc (3 x 150 mL). The organic compounds were then combined, dried with Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (500 mg, 1.26 mmol, quantitative yield), which was a light green oil and was used without further purification.

[0357] Example 37 Synthesis of the 5-(1-methoxyethyl)-4-(1-(phenylsulfonyl)-1H-indol-3-yl)-N-((S)-piperidin-3-yl)pyrimidine-2-amine intermediate for the synthesis of compound 247.

[0358] In a 0.5–2.5 mL MW tube, 1 mL of methanol (1 mL) solution of (3S)-3-((5-(1-hydroxyethyl)-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-carboxylic acid tert-butyl ester (32 mg, 0.055 mmol) was added, followed by the addition of CAN (12 mg, 0.022 mmol). The reaction mixture was then heated to 100 mL. o C was stirred twice under MW irradiation for 15 minutes. The reaction mixture was then concentrated, redissolved in MeTHF (5 mL), and washed with saturated NaHCO3 solution (5 mL). The organic phase was dried over Na2SO4, filtered, and concentrated to give the title compound (25 mg, 0.051 mmol, 93% yield), which was used without further purification.

[0359] Example 38 Synthesis of (3R,5S)-3-(methylcarbamoyl)-5-((4-(1-(phenylsulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (A), (3S,5R)-3-(methylcarbamoyl)-5-((4-(1-(phenylsulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino Intermediates of (3R,5R)-3-(methylcarbamoyl)-5-((4-(1-(phenylsulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (C) and (3S,5S)-3-(methylcarbamoyl)-5-((4-(1-(phenylsulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (D). Step 1: 5-(((benzyloxy)carbonyl)amino)piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester

[0360] Triethylamine (2.26 mL, 16.08 mmol) and diphenyl azide phosphate (DPPA) (1.19 mL, 5.51 mmol) were added to a solution of 1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)piperidine-3-carboxylic acid (1.32 g, 4.59 mmol) (synthesized as in US5817678A) in toluene (18.4 mL). The resulting solution was stirred at 110 °C for 1 h. The mixture was then cooled to 80 °C, and benzyl alcohol (2.38 mL, 22.97 mmol) and triethylamine (2.26 mL, 16.08 mmol) were added, and the resulting mixture was stirred at 80 °C for 18 h. The reaction mixture was then cooled to room temperature, diluted with water (30 mL), and extracted with EtOAc (3 x 50 mL). The organic phase was combined and washed with brine (2 x 50 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by SiO2 chromatography (EtOAc in DCM, 0 to 100% gradient) to give the title compound (556 mg, 1.42 mmol, 31% yield), which was a pale yellow oil.

[0361] Step 2: 5-(((benzyloxy)carbonyl)amino)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid

[0362] A solution of 1-tert-butyl 3-methyl 5-((benzyloxy)carbonyl)amino)piperidine-1,3-dicarboxylic acid in distilled water (14.2 mL) was added to a solution of 5-(((benzyloxy)carbonyl)amino)piperidine-1,3-dicarboxylic acid (1-tert-butyl ester) in THF (14.2 mL), and the resulting suspension was stirred at 23 °C for 1 h. The mixture was then concentrated under reduced pressure, diluted with water (20 mL), carefully acidified to pH 4 with 2N HCl, and extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with water (3 x 10 mL) and brine (10 mL) at pH 4, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (536 mg, 1.42 mmol, quantitative yield), which was a white foam and used without further purification.

[0363] Step 3: 3-(((benzyloxy)carbonyl)amino)-5-(methylcarbamoyl)piperidine-1-carboxylic acid tert-butyl ester

[0364] In a sealable tube, DIPEA (1.27 mL, 7.31 mmol), HBTU (832 mg, 2.19 mmol), and MeNH2 (2M in THF, 14.6 mL, 29.2 mmol) were added to a solution of 5-(((benzyloxy)carbonyl)amino)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (536 mg, 1.42 mmol) in DMF (7.3 mL). The tube was sealed, and the reaction mixture was incubated at 23°C. o The mixture was stirred at C for 1 h. It was then concentrated, diluted with water (20 mL), and carefully acidified to pH 5 with 1N HCl. The aqueous phase was extracted with EtOAc (3 x 20 mL), and the combined organic matter was washed with brine (5 x 10 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by rapid chromatography on SiO₂ (EtOAc in DCM, 0 to 100% gradient) to give the title compound (514 mg, 1.31 mmol, 92% yield) as a white foam.

[0365] Step 4: tert-butyl 3-amino-5-(methylcarbamoyl)piperidine-1-carboxylate

[0366] Pd / C (10% w / w; 70 mg, 0.066 mmol) was added to a solution of tert-butyl 3-(((benzyloxy)carbonyl)amino)-5-(methylcarbamoyl)piperidine-1-carboxylate (514 mg, 1.31 mmol) in EtOH (13 mL). The reaction mixture was stirred for 15 h under a hydrogen atmosphere (1 atm). The suspension was filtered through a diatomaceous earth pad, washed with EtOH and MeTHF, and then concentrated under reduced pressure to give the title compound (338 mg, 1.31 mmol, quantitative yield) as a yellow oil, which was used without further purification.

[0367] Step 5: (3R,5S)-3-(methylcarbamoyl)-5-((4-(1-(phenylsulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (A), (3S,5R)-3-(methylcarbamoyl)-5-((4-(1-(phenylsulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (B) ), (3R,5R)-3-(methylcarbamoyl)-5-((4-(1-(phenylsulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (C), (3S,5S)-3-(methylcarbamoyl)-5-((4-(1-(phenylsulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (D).

[0368]

[0369] Racemic tert-butyl 3-amino-5-(methylcarbamoyl)piperidin-1-carboxylate (338 mg, 1.31 mmol) was added to a solution of anhydrous THF (13 mL) with DIPEA (2.88 mL, 6.57 mmol) and 3-(2-(methanesulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole (632 mg, 1.31 mmol) and stirred at 23°C for 48 h. The reaction mixture was then concentrated under reduced pressure, water (20 mL) was added, and the crude product was extracted with MeTHF (3 x 20 mL). The combined organics were washed with water (2 x 20 mL) and brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid chromatography on SiO₂ (EtOAc in DCM, 0 to 100% gradient). The obtained racemic compound (566 mg, 0.859 mmol, 65% yield) was separated by preparative chiral HPLC (ChiralPak IA column, eluted with 10% MeOH and 10% DCM in hexane containing 0.1% MeNH2, 5,000 μL inj.) to give four stereoisomers, AD, as white foam. Peak 1 (C, 70 mg, 0.107 mmol, 8% yield, 98.3% de), peak 2 (A, 147 mg, 0.224 mmol, 17% yield, 98.1% de), peak 3 (B, 151 mg, 0.229 mmol, 17% yield, 98.2% de), peak 4 (D, 64 mg, 0.096 mmol, 7% yield, 99.4% de); stereochemistry provisionally designated.

[0370] Example 39 Synthesis of cis-3-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-5-((4-(1-(benzenesulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester intermediate for the synthesis of compound 266. Step 1: 1-tert-butyl 3-methyl cis-5-aminopiperidine-1,3-dicarboxylic acid

[0371] Palladium on carbon (10% w / w; 233 mg, 0.219 mmol) was added to a solution of cis-5-(((benzyloxy)carbonyl)amino)piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (860 mg, 2.191 mmol) in MeOH (22 mL) at 23°C under an inert atmosphere. The reaction mixture was stirred for 1 h under a hydrogen atmosphere (1 atm). The suspension was then filtered through a diatomaceous earth pad and concentrated under reduced pressure to give the title compound (566 mg, 2.191 mmol, quantitative yield) as a beige solid, which was used without further purification.

[0372] Step 2: cis-5-((4-(1-(phenylsulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester

[0373] 3-methyl 1-tert-butyl cis-5-aminopiperidine-1,3-dicarboxylic acid (566 mg, 2.191 mmol) and DIPEA (1.15 mL, 6.57 mmol) were added to a stirred solution of 3-(2-(methanesulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole (1.05 g, 2.191 mmol) in anhydrous THF (37 mL). The reaction mixture was stirred overnight at room temperature. The mixture was then diluted with EtOAc (30 mL), washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by SiO2 chromatography (EtOAc in DCM, 0 to 100% gradient) to give the title compound (430 mg, 0.652 mmol, 30% yield) as a pale yellow oil.

[0374] Step 3: cis-1-(tert-butoxycarbonyl)-5-((4-(1-(phenylsulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-3-carboxylic acid

[0375] A solution of cis-5-((4-(1-(phenylsulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (414 mg, 0.627 mmol) in THF (5 mL) was added to a solution of LiOH·H2O (26.3 mg, 0.627 mmol) in H2O (5 mL). The reaction mixture was stirred at room temperature for 56 h. Another portion of LiOH·H2O (79 mg, 1.881 mmol) was added, and the mixture was stirred again for 18 h. The reaction mixture was quenched by adding 1 M HCl until pH 3, and then concentrated from THF under reduced pressure. The aqueous phase was extracted with EtOAc (2 x 30 mL), and the organic phase was then washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (394 mg, 0.610 mmol, 97% yield) as a white solid, which was used without further purification.

[0376] Step 4: cis-3-((4-(1-(phenylsulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-(2-(pyridin-2-yl)hydrazine-1-carbonyl)piperidine-1-carboxylic acid tert-butyl ester

[0377] HOBt (99 mg, 0.740 mmol), EDC (176 mg, 0.920 mmol), and DIPEA (214 uL, 1.230 mmol) were added to a solution of cis-1-(tert-butoxycarbonyl)-5-((4-(1-(phenylsulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-3-carboxylic acid (394 mg, 0.610 mmol) in DMF (6 mL). After stirring at room temperature for 1 h, 2-hydrazinopyridine (134 mg, 1.230 mmol) was added. The reaction was stirred overnight at room temperature. The reaction mixture was then diluted with EtOAc (50 mL), washed with a saturated solution of NaHCO3 (50 mL), water (2 x 50 mL), and brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by SiO2 chromatography (THF in DCM, 0 to 100% gradient) to give the title compound (375 mg, 0.509 mmol, 83% yield) as a beige semi-solid.

[0378] Step 5: cis-3-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-5-((4-(1-(benzenesulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0379] Tert-butyl cis-3-((4-(1-(phenylsulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-(2-(pyridin-2-yl)hydrazide-1-carbonyl)piperidin-1-carboxylate (375 mg, 0.509 mmol) was added in portions to a solution of acetonitrile (11 mL) with triethylamine (0.20 mL, 1.43 mmol) and PPh3Cl2 (339 mg, 1.02 mmol). The reaction mixture was stirred at 80°C for 1 hour under heating. The mixture was cooled to room temperature, diluted with EtOAc (30 mL), and washed with a saturated aqueous solution of NaHCO3 (50 mL). The aqueous phase was extracted with EtOAc (30 mL), and the combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase chromatography (C18, MeCN in 10 mM ammonium formate aqueous solution, pH 3.8, 0 to 100% gradient) to give the title racemic cis-compound (300 mg, 0.417 mmol, 82% yield) as a yellow solid.

[0380] Example 40 5-Chloro-4-[7-(1,1-dioxo-1,4-thiazin-4-yl)-1H-indol-3-yl]-N-[(3S)-3-piperidinyl]pyrimidine-2-amine (Compound 196).

[0381] Step 1: 4-(1H-indol-7-yl)thiomorpholine

[0382] NaOt-Bu (1.96 g, 20.40 mmol, 2.00 eq) and [2-(2-aminoethyl)phenyl]chloro-palladium; di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine (700.56 mg, 1.02 mmol, 0.10 eq) were added in a single batch to a mixture of 7-bromo-1H-indole (2.00 g, 10.20 mmol, 965.82 uL, 1.00 eq) in THF (50.00 mL) at 15 °C under N2. The mixture was stirred at 85 °C for 12 h. The mixture (combined with another batch) was poured into water (100 mL) and extracted with EtOAc (30 mL x 2). The combined organic phases were washed with brine (50 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EtOAc = 20 / 1, 5 / 1) to give the title compound (2.20 g, 10.08 mmol, 98.79% yield) as a yellow-green solid.

[0383] Step 2: 4-[3-(2,5-dichloropyrimidin-4-yl)-1H-indol-7-yl]thiomorpholine

[0384] A mixture of AlCl3 (122.15 mg, 916.09 μmol, 50.06 μL, 1.00 eq) and 2,4,5-trichloropyrimidine (202 mg, 10.99 mmol, 1.20 eq) in a DCE (50.00 mL) was stirred at 80 °C for 30 min, followed by stirring of 4-(1H-indol-7-yl)thiomorpholine (200.00 mg, 916.09 μmol, 1.00 eq) at 80 °C for 12 h. The mixture (combined with another batch) was poured into water (200 mL) and extracted with EtOAc (100 mL x 2). The combined organic phases were washed with brine (100 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EtOAc = 10 / 1, 1 / 1) to give the title compound (2.00 g, 5.48 mmol, 59.83% yield) as a yellow solid.

[0385] Step 3: 4-[1-(benzenesulfonyl)-3-(2,5-dichloropyrimidin-4-yl)indol-7-yl]thiomorpholine

[0386] NaH (82.20 mg, 2.06 mmol, 60% purity, 1.50 eq) was added to a solution of 4-[3-(2,5-dichloropyrimidin-4-yl)-1H-indol-7-yl]thiomorpholine (500.00 mg, 1.37 mmol, 1.00 eq) in DMF (10.00 mL). The mixture was stirred at 0 °C for 0.5 h, and then benzenesulfonyl chloride (362.95 mg, 2.06 mmol, 263.01 μL, 1.50 eq) was added, and the mixture was stirred at 20 °C for 1 h. The residue was poured into water (100 mL). The aqueous phase was extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to give the title compound (500.00 mg, crude substance) as a yellow solid.

[0387] Step 4: 4-[1-(benzenesulfonyl)-3-(2,5-dichloropyrimidin-4-yl)indol-7-yl]-1,4-thiazine 1,1-dioxide

[0388] m-CPBA (243.88 mg, 989.22 μmol, 70% purity, 2.50 eq) was added in a single batch to a mixture of 4-[1-(benzenesulfonyl)-3-(2,5-dichloropyrimidin-4-yl)indol-7-yl]thiomorpholine (200.00 mg, 395.69 μmol, 1.00 eq) in DCM (3.00 mL). The mixture was stirred at 15 °C for 2 h. The mixture (combined with another batch) was poured into water (10 mL) and extracted with DCM (5 mL x 2). The combined organic phases were washed with aqueous NaHCO3 solution (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EtOAc = 5 / 1, 0 / 1) to give the title compound (250.00 mg, crude) as a yellow solid.

[0389] Step 5: (3S)-3-[[4-[1-(benzenesulfonyl)-7-(1,1-dioxo-1,4-thiazin-4-yl)indol-3-yl]-5-chloro-pyrimidin-2-yl]amino]piperidine-1-carboxylic acid tert-butyl ester

[0390] DIPEA (300.59 mg, 2.33 mmol, 406.20 uL, 5.00 eq) was added in a single dose to a mixture of 4-[1-(benzenesulfonyl)-3-(2,5-dichloropyrimidin-4-yl)indol-7-yl]-1,4-thiazine 1,1-dioxide (250.00 mg, 465.17 μL, 1.00 eq) and (3S)-3-aminopiperidin-1-carboxylic acid tert-butyl ester (139.75 mg, 697.76 μL, 1.50 eq) in NMP (5.00 mL). The mixture was stirred at 120 °C for 12 h. The mixture was then poured into water (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic phases were washed with brine (20 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (DCM / MeOH = 100 / 1, 20 / 1) to give the title compound (300.00 mg, crude) as a yellow solid.

[0391] Step 6: (3S)-3-[[5-chloro-4-[7-(1,1-dioxo-1,4-thiazin-4-yl)-1H-indol-3-yl]pyrimidin-2-yl]amino]piperidine-1-carboxylic acid tert-butyl ester

[0392] NaOH (34.22 mg, 855.62 μmol, 2.00 eq) was added in a single dose to a mixture of (3S)-3-[[4-[1-(benzenesulfonyl)-7-(1,1-dioxo-1,4-thiazin-4-yl)indol-3-yl]-5-chloro-pyrimidin-2-yl]amino]piperidin-1-carboxylic acid tert-butyl ester (300.00 mg, 427.81 μmol, 1.00 eq) in dioxane (5.00 mL) and H2O (1.00 mL). The mixture was stirred at 80 °C for 12 h. The residue was poured into water (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic phases were washed with brine (10 mL x 2), dried with anhydrous Na2SO4, filtered and concentrated under vacuum to give the title compound (200.00 mg, crude substance) as a yellow solid.

[0393] Step 7: 5-Chloro-4-[7-(1,1-dioxo-1,4-thiazin-4-yl)-1H-indol-3-yl]-N-[(3S)-3-piperidinyl]pyrimidin-2-amine

[0394] TFA (1.00 mL) was added in portions to a mixture of (3S)-3-[[5-chloro-4-[7-(1,1-dioxo-1,4-thiazinyl-4-yl)-1H-indol-3-yl]pyrimidin-2-yl]amino]piperidin-1-carboxylic acid tert-butyl ester (150.00 mg, 267.34 μmol, 1.00 eq) in DCM (5.00 mL). The mixture was stirred at 15 °C for 1 h. The mixture (combined with another batch) was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA) to the title compound (50.00 mg, 98.62 μmol, 36.89% yield, FA) as a white solid.

[0395] Example 41 5-Fluoro-3-[2-[[(3S)-3-piperidinyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]-1H-indol-6-carboxynitrile (Compound 197).

[0396] Step 1: (E)-2-(4-bromo-5-fluoro-2-nitro-phenyl)-N,N-dimethyl-ethyleneamine

[0397] DMFDMA (3.36 g, 28.20 mmol, 3.73 mL, 1.10 eq) was added in a single addition to a mixture of 1-bromo-2-fluoro-4-methyl-5-nitrobenzene (6.00 g, 25.64 mmol, 1.00 eq) in DMF (60.00 mL) at 15°C under N2. The mixture was stirred at 135°C for 3 hours. The mixture was poured into water (200 mL) and extracted with EtOAc (100 mL x 2). The combined organic phases were washed with brine (100 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EtOAc = 50 / 1, 10 / 1) to give the title compound (6.00 g, crude substance) as a brown solid.

[0398] Step 2: 6-Bromo-5-Fluoro-1H-Indole

[0399] Fe (1.93 g, 34.60 mmol, 5.00 eq) was added in a single step to a mixture of (E)-2-(4-bromo-5-fluoro-2-nitro-phenyl)-N,N-dimethyl-ethyleneamine (2.00 g, 6.92 mmol, 1.00 eq) in EtOH (30.00 mL) and AcOH (30.00 mL) under N2 at 15°C. The mixture was stirred at 100°C for 12 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography (PE / EtOAc = 20 / 1, 5 / 1) to give the title compound (700.00 mg, 3.27 mmol, 47.26% yield) as a yellow solid.

[0400] Step 3: 5-Fluoro-1H-indole-6-carboxynitrile

[0401] Na₂CO₃ (347.65 mg, 3.28 mmol, 2.00 eq) and Pd(dppf)Cl₂.CH₂Cl₂ (133.93 mg, 164.00 μmol, 0.10 eq) were added in a single dose to a mixture of 6-bromo-5-fluoro-1H-indole (350.00 mg, 1.64 mmol, 1.00 eq) and potassium ferrocyanide (tetrapotassium; hexacyanoiron) (906.12 mg, 2.46 mmol, 1.50 eq) in DMA (10.00 mL) at 15°C under N₂. The mixture was stirred at 125°C under MW for 3 h. The mixture was poured into water (30 mL) and extracted with EA (20 mL x 2). The combined organic phases were washed with brine (30 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (PE / EtOAc = 20 / 1, 5 / 1) to give the title compound (600.00 mg, crude) as a white solid.

[0402] Step 4: 5-Fluoro-1-(2-Trimethylsilylethoxymethyl)indole-6-carboxynitrile

[0403] NaH (175.20 mg, 4.38 mmol, 60% purity, 2.00 eq) was added fractionally to a mixture of 5-fluoro-1H-indol-6-carboxynitrile (350.00 mg, 2.19 mmol, 1.00 eq) in DMF (10.00 mL) at 0°C under N2. The mixture was stirred at 15°C for 30 min, then SEM-Cl (438.14 mg, 2.63 mmol, 466.11 μL, 1.20 eq) was added and stirred at 15°C for 2 h. The mixture was poured into water (50 mL) and extracted with EtOAc (20 mL x 2). The combined organic phases were washed with brine (30 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (PE / EtOAc = 20 / 1, 5 / 1) to give the title compound (600.00 mg, crude) as a white solid.

[0404] Step 5: 3-Bromo-5-fluoro-1-(2-trimethylsilylethoxymethyl)indole-6-carboxynitrile

[0405] NBS (337.07 mg, 1.89 mmol, 1.10 eq) was added in a single dose to a mixture of 5-fluoro-1-(2-trimethylsilylethoxymethyl)indol-6-carboxynitrile (500.00 mg, 1.72 mmol, 1.00 eq) in THF (3.00 mL) at 0°C under N2. The mixture was stirred at 20 °C for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 20 / 1, 5 / 1) to give the title compound (450.00 mg, used directly) as a white solid.

[0406] Step 6: 5-Fluoro-3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1-(2-trimethylsilylethoxymethyl)indol-6-carboxynitrile KOAc (186.02 mg, 1.90 mmol, 2.00 eq) and Pd(dppf)Cl2 (69.35 mg, 94.77 μmol, 0.10 eq) were added in a single dose to a mixture of 3-bromo-5-fluoro-1-(2-trimethylsilylethoxymethyl)indol-6-carboxynitrile (350.00 mg, 947.74 μmol, 1.50 eq) and BPD (361.00 mg, 1.42 mmol, 1.50 eq) in dioxane (10.00 mL) at 15°C under N2. The mixture was stirred at 100°C for 12 h. The mixture was poured into water (30 mL) and extracted with EtOAc (15 mL x 2). The combined organic phases were washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EtOAc = 20 / 1, 5 / 1) to give the title compound (250.00 mg, crude substance), which was a yellow oil.

[0407] Step 7: (3S)-3-[[4-[6-cyano-5-fluoro-1-(2-trimethylsilylethoxymethyl)indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidine-1-carboxylic acid tert-butyl ester

[0408] K3PO4 (250.00 mg, 600.43 μmol, 1.00 eq) and di-tert-butyl(cyclopentanyl)phosphine; palladium dichloride; iron (39.13 mg, 60.04 μmol, 1.00 eq) were added in a single step to a mixture of 5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexane-2-yl)-1-(2-trimethylsilylethoxymethyl)indolyl-6-carboxynitrile (250.00 mg, 600.43 μmol, 1.00 eq) and (3S)-3-[[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidine-1-carboxylic acid tert-butyl ester (342.96 mg, 900.65 μmol, 1.50 eq) in dioxane (10.00 mL) and H2O (2.00 mL) at 15°C under N2. The mixture was stirred at 110 °C for 6 h. The mixture was poured into water (20 mL) and extracted with EtOAc (10 mL x 2). The combined organic phases were washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EtOAc = 30 / 1, 5 / 1) to give the title compound (200.00 mg, 315.09 μmol, 52.48% yield) as a yellow oil.

[0409] Step 8: 5-Fluoro-3-[2-[[(3S)-3-piperidinyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]-1H-indole-6-carboxynitrile

[0410] HCl (500.00 μL) was added in portions to a mixture of (3S)-3-[[4-[6-cyano-5-fluoro-1-(2-trimethylsilylethoxymethyl)indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidin-1-carboxylic acid tert-butyl ester (150.00 mg, 236.32 μmol, 1.00 eq) in dioxane (5.00 mL). The mixture was stirred at 80 °C for 1 h. The mixture was concentrated under reduced pressure. The residue (combined with another batch) was purified by preparative HPLC (FA) to the title compound (20.00 mg, 44.41 μmol, 18.79% yield, FA) as a white solid.

[0411] Example 42 4-(6-methylsulfonyl-1H-indol-3-yl)-N-[(3S)-3-piperidinyl]-5-(trifluoromethyl)pyrimidin-2-amine (compound 199).

[0412] Step 1: 6-Methylsulfonyl-1H-indole

[0413] A mixture of 6-bromo-1H-indole (2.00 g, 10.20 mmol, 1.00 eq), sodium BLAH (1.35 g, 13.26 mmol, 1.30 eq), CuI (388.59 mg, 2.04 mmol, 0.20 eq), and L-proline (469.82 mg, 4.08 mmol, 0.40 eq) in DMSO (20.00 mL) was degassed and purged three times with N2. The mixture was then stirred at 80 °C under N2 atmosphere for 12 h. The reaction mixture was quenched at 20 °C by adding 200 mL of saturated NH4Cl aqueous solution, and then extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (300 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, PE / EtOAc = 10:1 to 1:1) to give the title compound (700 mg) as a grayish-white solid.

[0414] Step 2: 3-[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]-6-methylsulfonyl-1H-indole

[0415] AlCl3 (765.90 mg, 5.74 mmol, 313.90 μL, 1.60 eq) was added to a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.17 g, 5.39 mmol, 1.50 eq) in DCE (20.00 mL). After addition, the mixture was stirred at 90 °C for 30 min, and then 6-methylsulfonyl-1H-indole (700.00 mg, 3.59 mmol, 1.00 eq) was added at 90 °C. The resulting mixture was stirred at 90 °C for 15.5 h. The reaction was stopped. The reaction mixture was diluted with 30 mL of water and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue (500 mg). The residue was purified by preparative HPLC (TFA conditions) to give the desired compound. The pH of the eluent solution was adjusted to 8 with a saturated aqueous solution of NaHCO3, and the solution was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (300.00 mg, 758.48 μmol, 21.13% yield, 95% purity) as a yellow solid.

[0416] Step 3: (3S)-3-[[4-(6-methylsulfonyl-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidine-1-carboxylic acid tert-butyl ester

[0417] A mixture of 3-[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]-6-methylsulfonyl-1H-indole (320.00 mg, 851.63 μol, 1.00 eq), (3S)-3-aminopiperidin-1-carboxylic acid tert-butyl ester (255.85 mg, 1.28 mmol, 1.50 eq), and DIEA (330.19 mg, 2.55 mmol, 446.21 μL, 3.00 eq) in NMP (5.00 mL) was stirred at 140 °C for 1 h. The reaction mixture was then stopped. The reaction mixture was diluted with 50 mL of water and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, PE / EtOAc = 10:1 to 2:1) to give the title compound (200.00 mg, 326.19 μmol, 38.30% yield, 88% purity) as a yellow oil.

[0418] Step 4: 4-(6-Methylsulfonyl-1H-indol-3-yl)-N-[(3S)-3-piperidinyl]-5-(trifluoromethyl)pyrimidin-2-amine

[0419] A mixture of (3S)-3-[[4-(6-methylsulfonyl-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidin-1-carboxylic acid tert-butyl ester (200.00 mg, 370.67 μmol, 1.00 eq) and HCl / EtOAc (4 M, 2.00 mL) was stirred at 20 °C for 1 h. The reaction was stopped. The reaction mixture was concentrated under reduced pressure to give the desired compound as a yellow solid. The residue was pH adjusted to 8 with a saturated aqueous solution of NaHCO3 and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue (120 mg). The residue was purified by preparative HPLC (FA conditions) to give the title compound (52.70 mg, 107.47 μmol, 28.99% yield, 99% purity, FA) as a white solid.

[0420] Example 43 N-methyl-3-[2-[[(3S)-3-piperidinyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]-1H-indole-6-sulfonamide (compound 200).

[0421] Step 1: 1H-indole-6-sulfonyl chloride

[0422] NaH (408.00 mg, 10.20 mmol, 60% purity, 1.00 eq) was added fractionally to a solution of 6-bromo-1H-indole (2.00 g, 10.20 mmol, 1.00 eq) in THF (20 mL) at 0°C. After addition, the mixture was stirred at this temperature for 30 minutes and then cooled to -78°C. oC, then t-BuLi (1.3 M, 15.69 mL, 2.00 eq) was added dropwise. The resulting mixture was stirred at -78 °C for 30 min, then SO2 (3.1 M in THF, 6.58 mL, 19% purity, 2.00 eq) was added dropwise, and the mixture was stirred at 20 °C for 16 h. (30 mL Et2O and 0.76 mL glacial acetic acid were added to the resulting solid. The mixture was stirred at 0 °C for 30 min and filtered). The solid was then suspended in 30 mL Et2O, cooled to 0 °C, and 1.36 g NCS was carefully added. The resulting suspension was stirred rapidly for 30 min. The reaction was stopped. The reaction mixture was filtered and the filtrate was concentrated to give the title compound (1.22 g), which is a dark brown solid. It was used directly for the next step.

[0423] Step 2: N-methyl-1H-indole-6-sulfonamide

[0424] A mixture of 1H-indole-6-sulfonyl chloride (1.22 g, 5.66 mmol, 1.00 eq) and methylamine (2 M in THF, 14.15 mL, 5.00 eq) in THF (5.00 mL) was stirred at 20 °C for 12 h. The reaction mixture was diluted with 30 mL of water and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, PE / EtOAc = 5:1 to 2:1) to give the title compound (520 mg) as a dark brown oil.

[0425] Step 3: 3-[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]-N-methyl-1H-indole-6-sulfonamide

[0426] AlCl3 (559.36 mg, 4.20 mmol, 229.25 μL, 2.10 eq) was added to a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (866.89 mg, 4.00 mmol, 2.00 eq) in DCE (6.00 mL). The mixture was heated to 90 °C. oThe mixture was stirred at C for 30 minutes, then N-methyl-1H-indole-6-sulfonamide (420.00 mg, 2.00 mmol, 1.00 eq) was added. The resulting mixture was stirred at 90 °C for 15.5 h. The reaction was stopped. The reaction mixture was filtered. The filtrate was diluted with water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, PE / EtOAc = 10:1 to 1:1) to give the desired product as a red solid (330 mg), which was then purified by preparative HPLC (TFA conditions). The pH of the solution after preparative HPLC was adjusted to 8 with saturated NaHCO3 aqueous solution and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (140 mg) as a yellow solid. (Note: This was combined with two other batches purified at a scale of 50 mg under the same conditions).

[0427] Step 4: (3S)-3-[[4-[6-(methylaminosulfonyl)-1H-indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidine-1-carboxylic acid tert-butyl ester

[0428] A mixture of 3-[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]-N-methyl-1H-indole-6-sulfonamide (120.00 mg, 307.09 μol, 1.00 eq), (3S)-3-aminopiperidin-1-carboxylic acid tert-butyl ester (92.26 mg, 460.63 μol, 1.50 eq), and DIEA (119.06 mg, 921.27 μol, 160.89 μL, 3.00 eq) in NMP (2.00 mL) was stirred at 140 °C for 1 h. The reaction mixture was stopped. The reaction mixture was diluted with 20 mL of water and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (540.00 mg, crude substance) as a dark brown oil. Use it directly in the next step.

[0429] Step 6: N-Methyl-3-[2-[[(3S)-3-piperidinyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]-1H-indole-6-sulfonamide

[0430] A mixture of (3S)-3-[[4-[6-(methylaminosulfonyl)-1H-indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidin-1-carboxylic acid tert-butyl ester (540.00 mg, 973.69 μmol, 1.00 eq) and HCl / EtOAc (4 M, 5.00 mL) was stirred at 20 °C for 1 h. The reaction was then stopped. The reaction mixture was concentrated under reduced pressure to give the desired compound as a yellow solid. The pH of the residue was adjusted to 8 with a saturated aqueous solution of NaHCO3 and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried with Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (FA conditions) to give the title compound (20.30 mg, 40.56 μmol, 4.17% yield, 100% purity, FA) as a yellow solid.

[0431] Example 44 5-Chloro-4-(1H-indol-3-yl)-N-[(3S,5R)-5-methyl-3-piperidinyl]pyrimidine-2-amine (Compound 201).

[0432] Step 1: (2S)-5-oxopyrrolidine-2-carboxylic acid methyl ester

[0433] SOCl2 (36.86 g, 309.82 mmol, 22.48 mL, 2.00 eq) was added to a solution of (2S)-5-oxopyrrolidine-2-carboxylic acid (20.00 g, 154.91 mmol, 1.00 eq) in MeOH (100.00 mL). The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated. The residue was diluted with EtOAc (250 mL) and TEA (20 mL), and a solid was formed and filtered. The filtrate was concentrated to give the title compound (27.90 g, crude substance) as a yellow oil. The crude product was used in the next step without further purification.

[0434] Step 2: (2S)-5-oxopyrrolidine-1,2-dicarboxylic acid O1-tert-butyl ester O2-methyl ester

[0435] To a solution of (2S)-5-oxopyrrolidine-2-carboxylate (27.90 g, 194.91 mmol, 1.00 eq) and DMAP (2.86 g, 23.39 mmol, 0.12 eq) in EtOAc (150.00 mL), tert-butoxycarbonyl tert-butyl carbonate (55.30 g, 253.39 mmol, 58.21 mL, 1.30 eq) was added dropwise. The mixture was stirred at 20 °C for 16 h. The reaction mixture was washed with HCl (1 M, 50 mL), saturated NaHCO3 (150 mL), and brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by recrystallization from MTBE (250 mL) to give the title compound (21.75 g, 88.52 mmol, 45.41% yield, 99% purity) as a yellow solid.

[0436] Step 3: (2S)-4-methyl-5-oxo-pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl ester O2-methyl ester

[0437] LiHMDS (1 M, 98.35 mL, 1.10 eq) was added dropwise to a solution of (2S)-5-oxopyrrolidine-1,2-dicarboxylic acid O1-tert-butyl ester O2-methyl ester (21.75 g, 89.41 mmol, 1.00 eq) in THF (400.00 mL) at -78°C under N2 atmosphere. After addition, the mixture was stirred at this temperature for 0.5 h, and then iodomethane (31.73 g, 223.53 mmol, 13.92 mL, 2.50 eq) was added dropwise at -78°C under N2 atmosphere. The resulting mixture was stirred at 20°C for 15.5 h. A solution of ice-cold HOAc (10 mL) in THF (50 mL) was used to quench the reaction. The solvent was removed by a rotary evaporator and the mixture was treated with water (500 mL) and EtOAc (150 mL) and stirred for 10 min. The aqueous layer was removed and the mixture was extracted with EtOAc (200 mL x 3). The organic phase was dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc = 10:1 to 5:1) to give the title compound (17.57 g, used directly) as a yellow oil.

[0438] Step 4: N-[(1S)-4-hydroxy-1-(hydroxymethyl)-3-methyl-butyl]carbamate tert-butyl ester

[0439] NaBH4 (7.75 g, 204.87 mmol, 3.00 eq) was added dropwise to a solution of (2S)-4-methyl-5-oxo-pyrrolidine-1,2-dicarboxylic acid O1-tert-butyl ester O2-methyl ester (17.57 g, 68.29 mmol, 1.00 eq) in THF (200.00 mL) at 0°C under a nitrogen atmosphere. Following the addition, EtOH (34.70 g, 753.24 mmol, 43.93 mL, 11.03 eq) was added dropwise at 0°C. The resulting mixture was stirred at 20°C for 16 h. The pH of the reaction mixture was adjusted to 5 with AcOH, followed by the addition of H2O (200 mL) and extraction with EtOAc (100 mL x 3). The combined organic layers were washed with saturated NaHCO3, dried with Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (11.00 g, crude substance), which was a yellow oil.

[0440] Step 5: [(2R,4S)-4-(tert-butoxycarbonylamino)-2-methyl-5-methylsulfonyloxy-pentyl]methanesulfonate and [(2S,4S)-4-(tert-butoxycarbonylamino)-2-methyl-5-methylsulfonyloxy-pentyl]methanesulfonate

[0441] MsCl (16.20 g, 141.45 mmol, 10.95 mL, 3.00 eq) was added dropwise to a solution of N-[(1S)-4-hydroxy-1-(hydroxymethyl)-3-methyl-butyl]carbamate (11.00 g, 47.15 mmol, 1.00 eq) and TEA (19.08 g, 188.60 mmol, 26.14 mL, 4.00 eq) in EA (110.00 mL) at 0 °C. The resulting mixture was stirred at 20 °C for 1 h. The reaction mixture was poured into 200 mL of water and then extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue providing [(2R,4S)-4-(tert-butoxycarbonylamino)-2-methyl-5-methylsulfonyloxy-pentyl]methanesulfonate and [(2S,4S)-4-(tert-butoxycarbonylamino)-2-methyl-5-methylsulfonyloxy-pentyl]methanesulfonate (17.70 g, crude matter), as yellow solids. (Note: The isomer (2S,4S) was detected in this step. It was less and should be derived from step 3.) Step 6: N-[(3S,5R)-1-benzyl-5-methyl-3-piperidinyl]tert-butyl carbamate

[0442] A mixture of [(2S,4S)-4-(tert-butoxycarbonylamino)-2-methyl-5-methylsulfonyloxy-pentyl]methanesulfonate; [(2R,4S)-4-(tert-butoxycarbonylamino)-2-methyl-5-methylsulfonyloxy-pentyl]methanesulfonate (13.70 g, 35.18 mmol, 1.00 eq), and phenylmethylamine (12.06 g, 112.56 mmol, 12.31 mL, 3.20 eq) in DME (30.00 mL) was stirred at 70 °C for 16 h. The reaction mixture was diluted with 300 mL of water and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (500 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, PE / EtOAc = 40:1 to 20:1) to give the title compound (850.00 mg, 1.95 mmol, 5.54% yield, 70% purity) as a white solid.

[0443] Step 7: (3S,5R)-1-benzyl-5-methyl-piperidin-3-amine

[0444] A mixture of N-[(3S,5R)-1-benzyl-5-methyl-3-piperidinyl]tert-butyl carbamate (1.15 g, 3.78 mmol, 1.00 eq) and HCl / EtOAc (4 M, 10.00 mL) was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was the title compound (860.00 mg, crude, HCl) as a white solid. This compound was used directly in the next step.

[0445] Step 8: 4-[1-(benzenesulfonyl)indol-3-yl]-N-[(3S,5R)-1-benzyl-5-methyl-3-piperidinyl]-5-chloro-pyrimidin-2-amine

[0446] A mixture of (3S,5R)-1-benzyl-5-methylpiperidin-3-amine (595.00 mg, 2.47 mmol, 1.20 eq, HCl), 1-(benzenesulfonyl)-3-(2,5-dichloropyrimidin-4-yl)indole (832.54 mg, 2.06 mmol, 1.00 eq), Cs₂CO₃ (1.34 g, 4.12 mmol, 2.00 eq), Pd(OAc)₂ (46.23 mg, 205.83 μmol, 0.10 eq) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (128.23 mg, 205.83 μmol, 0.10 eq) in toluene (6.00 mL) and THF (3.00 mL) was degassed and purged three times with N₂. The mixture was then heated in 100 mL of water. The mixture was stirred at °C under a N2 atmosphere for 12 h. The reaction mixture was diluted with 60 mL of water and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, PE / EtOAc = 10:1 to 5:1) to give the title compound (310 mg) as a yellow solid.

[0447] Step 9: N-[(3S,5R)-1-benzyl-5-methyl-3-piperidinyl]-5-chloro-4-(1H-indol-3-yl)pyrimidin-2-amine

[0448] A mixture of 4-[1-(benzenesulfonyl)indol-3-yl]-N-[(3S,5R)-1-benzyl-5-methyl-3-piperidinyl]-5-chloro-pyrimidin-2-amine (310.00 mg, 541.84 μmol, 1.00 eq) and NaOH (5 M, 1.08 mL, 10.00 eq) in dioxane (5.00 mL) was stirred at 90 °C for 12 h. The reaction mixture was diluted with 10 mL of water and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (15 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue as the title compound (260.00 mg, crude substance) as a yellow solid.

[0449] Step 10: 5-Chloro-4-(1H-indol-3-yl)-N-[(3S,5R)-5-methyl-3-piperidinyl]pyrimidin-2-amine

[0450] Pd / C (10%, wet, 10 mg) was added to a solution of N-[(3S,5R)-1-benzyl-5-methyl-3-piperidinyl]-5-chloro-4-(1H-indol-3-yl)pyrimidin-2-amine (160.00 mg, 370.40 μmol, 1.00 eq) and AcOH (66.73 mg, 1.11 mmol, 63.55 μL, 3.00 eq) in MeOH (2.00 mL) under N2. The suspension was degassed under vacuum and washed three times with H2. The mixture was stirred at 20°C for 16 h under H2 (50 psi). The reaction mixture was filtered and the filtrate was concentrated to give the desired compound (100 mg). The residue was purified by preparative HPLC (FA conditions) to give the title compound (10.30 mg, 25.76 μmol, 6.95% yield, 97% purity, FA) as a yellow solid.

[0451] Example 45 4-[6-(1H-imidazol-2-yl)-1H-indol-3-yl]-N-[(3S)-3-piperidinyl]-5-(trifluoromethyl)pyrimidin-2-amine (compound 202).

[0452] Step 1: (3S)-3-[[4-[1-(benzenesulfonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidine-1-carboxylic acid tert-butyl ester

[0453] (3S)-3-[[4-[1-(benzenesulfonyl)-6-bromo-indole-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidin-1-carboxylic acid tert-butyl ester (1.23 g, 1.81 mmol, 1.00 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1,3,2-dioxaborhexacyclopentanane (689.45 mg, 2.72 mmol, 1.50 eq), Pd(dppf)Cl2.CH2Cl2 (147.81 mg, 181.00 umol, 0.10 eq), and AcOK (355.27 mg, 3.62 mmol, 2.00 eq) were dissolved in DME (10.00 mmol). The mixture in mL was degassed and purged three times with N2, then stirred at 65°C under N2 atmosphere for 12 h. The reaction mixture was diluted with 100 mL of water and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, PE / EtOAc = 10 / 1 to 3:1) to give the title compound (700 mg) as a yellow solid (Note: purified in combination with another batch. Scale: 100 mg).

[0454] Step 2: 2-[(2-bromoimidazole-1-yl)methoxy]ethyl-trimethyl-silane

[0455] NaH (106.00 mg, 2.65 mmol, 60% purity, 1.30 eq) was added dropwise to a solution of 2-bromo-1H-imidazole (300.00 mg, 2.04 mmol, 1.00 eq) in THF (5.00 mL) at 0°C. After addition, the mixture was stirred at this temperature for 0.5 h, and then 2-(chloromethoxy)ethyl-trimethylsilane (442.14 mg, 2.65 mmol, 470.36 μL, 1.30 eq) was added dropwise at 0°C. The resulting mixture was stirred at 20°C for 15.5 h. It was quenched by adding 50 mL of water, extracted with EtOAc (20 mL x 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, PE / EtOAc = 20 / 1 to 5:1) to give the title compound (500.00 mg, 1.80 mmol, 88.41% yield) as a colorless oil.

[0456] Step 3: (3S)-3-[[5-(trifluoromethyl)-4-[6-[1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]-1H-indol-3-yl]pyrimidin-2-yl]amino]piperidine-1-carboxylic acid tert-butyl ester

[0457] (3S)-3-[[4-[1-(benzenesulfonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidin-1-carboxylic acid tert-butyl ester (300.00 mg, 412.31 μmol, 1.00 eq), 2-[(2-bromoimidazole-1-yl)methoxy]ethyl-trimethylsilane (137.17 mg, 494.77 μmol, 1.20 eq), Pd(PPh3)4 (47.65 mg, 41.23 μmol, 0.10 eq), Na2CO3 (5 M, 164.92 μL, 2.00 eq) were dissolved in DMF (3.00 The mixture was degassed and purged three times with N2, then stirred at 130°C for 3 h under N2 atmosphere. The reaction mixture was poured into 50 mL of water, extracted with EtOAc (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, PE / EtOAc = 10 / 1 to 1:2) to give the title compound (150 mg) as a yellow oil. (Note: purified in combination with another batch. Scale: 100 mg).

[0458] Step 4: 4-[6-(1H-imidazol-2-yl)-1H-indol-3-yl]-N-[(3S)-3-piperidinyl]-5-(trifluoromethyl)pyrimidin-2-amine

[0459] A mixture of (3S)-3-[[5-(trifluoromethyl)-4-[6-[1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]-1H-indol-3-yl]pyrimidin-2-yl]amino]piperidin-1-carboxylic acid tert-butyl ester (200.00 mg, 304.04 μmol, 1.00 eq) in HCl / EtOAc (4 M, 2.28 mL, 30.00 eq) was stirred for 1 h at 20°C. The reaction mixture was concentrated and the pH was adjusted to 8 with saturated NaHCO3, then extracted with EtOAc (50 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (FA conditions) to give the title compound (5.30 mg, 10.52 μmol, 3.46% yield, 94% purity, FA) as a white solid.

[0460] Example 46 5-Chloro-4-[7-(1,1-dioxo-1,4-thiazin-4-yl)-1H-indol-3-yl]-N-[(3S)-3-piperidinyl]pyrimidine-2-amine (compound 203).

[0461] Step 1: (2R,4R)-4-hydroxypyrrolidine-2-carboxylic acid

[0462] A mixture of AcOH (628.70 g, 10.47 mol) and Ac₂O (203.45 g, 1.99 mol) was heated to 50°C, followed by the addition of (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid (47.00 g, 358.42 mmol) in a single batch. The mixture was heated to 120°C and stirred for 5.5 h. After cooling to room temperature, the solvent was removed. The residue was dissolved in HCl (650 mL), and the mixture was then heated to 120°C and stirred for 3 h. Activated carbon (2.5 g) was then added, and the hot mixture was immediately filtered through a diatomaceous earth layer, with the filter cake washed with hot water. The colorless solution was neutralized with triethylamine and evaporated to dryness. The crude product was refluxed in ethanol (2500 mL), and water was carefully added to the mixture until boiling and the solids disappeared (but the solution remained slightly turbid). The solution was then left to stand overnight at -20°C to obtain white crystals, which were filtered off and washed with cold ethanol to obtain the title compound (22.00 g, 44.5%), which was a white solid.

[0463] Step 2: (2R,4R)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester

[0464] SOCl2 (23.95 g, 201.32 mmol) was added to a solution of (2R,4R)-4-hydroxypyrrolidine-2-carboxylic acid (22.00 g, 167.77 mmol) in MeOH (500 mL) at 0 °C. The mixture was stirred at 60 °C under N2 for 16 h. The mixture was concentrated to give the title compound (16.00 g, crude substance).

[0465] Step 3: (2R,4R)-1-benzyl-4-hydroxy-pyrrolidine-2-carboxylic acid methyl ester

[0466] A mixture of (2R,4R)-4-hydroxypyrrolidine-2-carboxylate (16.00 g, 88.10 mmol), BnBr (18.08 g, 105.72 mmol), and TEA (26.74 g, 264.29 mmol) in DCM (200 mL) was degassed and purged three times with N2, then stirred at 60 °C under N2 atmosphere for 16 h. The residue was poured into water (500 mL). The aqueous phase was extracted with EtOAc (300 mL x 3). The combined organic phases were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (SiO2, PE / EtOAc = 20 / 1, 10 / 1) to give the title compound (18.00 g, 78.2%).

[0467] Step 4: Methyl (2R,4R)-1-benzyl-4-[tert-butyl(dimethyl)silyl]oxy-pyrrolidine-2-carboxylate.

[0468] TBDMSCl (17.30 g, 114.75 mmol) was added to a solution of (2R,4R)-1-benzyl-4-hydroxypyrrolidine-2-carboxylate (18.00 g, 76.50 mmol) and imidazole (15.63 g, 229.50 mmol) in DCM (300 mL) at 0 °C. The mixture was stirred at 60 °C for 16 h. The residue was poured into water (1000 mL). The aqueous phase was extracted with EtOAc (500 mL x 3). The combined organic phases were washed with brine (1000 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (SiO2, PE / EtOAc = 10 / 1, 5 / 1) to give the title compound (25.00 g, 79.46%).

[0469] Step 5: [(2R,4R)-1-benzyl-4-[tert-butyl(dimethyl)silyl]oxy-pyrrolidine-2-yl]methanol

[0470] LiBH4 (3.12 g, 143.04 mmol) was added to a solution of methyl (2R,4R)-1-benzyl-4-[tert-butyl(dimethyl)silyl]oxy-pyrrolidine-2-carboxylate (25.00 g, 71.52 mmol) in THF (300 mL) at 0°C under N2. The mixture was stirred at 30 °C for 16 h. The residue was poured into water (1000 mL). The aqueous phase was extracted with EtOAc (500 mL x 3). The combined organic phases were washed with brine (1000 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, PE / EtOAc = 5 / 1 to 3:1) to give the title compound (22.00 g, 86.1%).

[0471] Step 6: [(3R,5S)-5-azido-1-benzyl-3-piperidinyl]oxy-tert-butyl-dimethyl-silane

[0472] (Difluoro-thiocarbonyl)-diethyl-ammonium; tetrafluoroborate (3.92 g, 17.11 mmol) and tetrabutylammonium azide (4.42 g, 15.55 mmol) were added dropwise at 10 min / hr to a solution of [(2R,4R)-1-benzyl-4-[tert-butyl(dimethyl)silyl]oxy-pyrrolidine-2-yl]methanol (5.00 g, 15.55 mmol) in CH2Cl2 (20 mL). After addition, the mixture was stirred at this temperature for 4.5 h and then concentrated. The residue was purified by column chromatography (SiO2, PE / EtOAc = 20 / 1) to give the title compound (6 g, crude).

[0473] Step 7: (3S,5R)-1-benzyl-5-[tert-butyl(dimethyl)silyl]oxy-piperidine-3-amine

[0474] Ra-Ni (1 g) was added to a solution of [(3R,5S)-5-azido-1-benzyl-3-piperidinyl]oxy-tert-butyl-dimethyl-silane (6.00 g, 17.31 mmol) in MeOH (20 mL) under N2. The suspension was degassed under vacuum and washed several times with H2. The mixture was stirred at 20°C for 2 h under H2 (40 psi). The mixture was filtered and concentrated. The mixture was purified by preparative HPLC (TFA) to give the title compound (1.50 g, 33.9%).

[0475] Step 8: N-[(3S,5R)-1-benzyl-5-[tert-butyl(dimethyl)silyl]oxy-3-piperidinyl]-4-(1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine

[0476] DIPEA (403 mg, 3.12 mmol) and 3-[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]-1H-indole (511 mg, 1.72 mmol) were added to a solution of (3S,5R)-1-benzyl-5-[tert-butyl(dimethyl)silyl]oxy-piperidin-3-amine (500 mg, 1.56 mmol) in NMP (5 mL). The mixture was stirred at 140 °C for 5 h. The residue was poured into water (100 mL). The aqueous phase was extracted with EtOAC (50 mL x 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, PE / EtOAc = 10 / 1 to 5 / 1) to give the title compound (600 mg, 60.69%).

[0477] Step 9: N-[(3S,5R)-5-[tert-butyl(dimethyl)silyl]oxy-3-piperidinyl]-4-(1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine

[0478] Pd-C (10%, 0.05 g) was added to a mixture of N-[(3S,5R)-1-benzyl-5-[tert-butyl(dimethyl)silyl]oxy-3-piperidinyl]-4-(1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (450 mg, 773.53 μmol) and NH3·H2O (81 mg, 2.32 mmol) in MeOH (5 mL) under N2. The suspension was degassed under vacuum and washed several times with H2. The mixture was stirred at 20°C for 4 h under H2 (15 psi). The mixture was concentrated to give the title compound (200 mg, crude substance).

[0479] Step 10: (3R,5S)-5-[[4-(1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidin-3-ol

[0480] TBAF (0.5 mL, 1 M) was added to a solution of N-[(3S,5R)-5-[tert-butyl(dimethyl)silyl]oxy-3-piperidinyl]-4-(1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (200 mg, 406.82 μmol) in THF (5 mL). The mixture was stirred at 20 °C for 2 h. The mixture was concentrated. The residue was purified by preparative HPLC (FA) to give the title compound (87 mg, 56.10%).

[0481] Example 47 [(3S)-3-hydroxypyrrolidine-1-yl]-[3-[2-[[(3S)-3-piperidinyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]-1H-indol-6-yl] methyl ketone (compound 204).

[0482] Step 1: Methyl 3-[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]-1H-indole-6-carboxylate

[0483] AlCl3 (15.98 g, 119.87 mmol, 6.55 mL, 2.10 eq) was added to a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (24.77 g, 114.16 mmol, 2.00 eq) in DCE (200.00 mL). The mixture was stirred at 90 °C for 30 min, and then methyl 1H-indole-6-carboxylate (10.00 g, 57.08 mmol, 1.00 eq) was added at 90 °C. The resulting mixture was stirred at 90 °C for 15.5 h. The reaction mixture was filtered. The filtrate was diluted with water (200 mL) and extracted with DCM (80 mL x 3). The combined organic layers were washed with brine (200 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was washed with MeOH (50 mL) and filtered to give the title compound (4.00 g, 10.57 mmol, 18.52% yield, 94% purity) as a yellow solid.

[0484] Step 2: Methyl 3-[2-[[(3S)-1-tert-butoxycarbonyl-3-piperidinyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]-1H-indole-6-carboxylic acid

[0485] A mixture of methyl 3-[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]-1H-indole-6-carboxylate (2.50 g, 7.03 mmol, 1.00 eq), tert-butyl (3S)-3-aminopiperidin-1-carboxylate (1.83 g, 9.14 mmol, 1.30 eq), and DIEA (4.54 g, 35.15 mmol, 6.14 mL, 5.00 eq) in NMP (10.00 mL) was stirred at 140 °C for 1 h. The reaction mixture was poured into 200 mL of water and then extracted with EtOAc (70 mL x 3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, PE / EtOAc = 5:1 to 1:1) to give the title compound (2.20 g, 3.39 mmol, 48.19% yield, 80% purity) as a yellow solid.

[0486] Step 3: 3-[2-[[(3S)-1-tert-butoxycarbonyl-3-piperidinyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]-1H-indole-6-carboxylic acid

[0487] A mixture of methyl 3-[2-[[(3S)-1-tert-butoxycarbonyl-3-piperidinyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]-1H-indole-6-carboxylate (2.20 g, 4.23 mmol, 1.00 eq), LiOH (5 M, 1.69 mL, 2.00 eq), and MeOH (20.00 mL) was stirred for 3 h at 25 °C. The reaction mixture was concentrated, diluted with 100 mL of water, and extracted with EtOAc (50 mL x 3). The organic layer was removed, and the pH of the aqueous phase was adjusted to 1 with HCl (1 M) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (1.80 g, 3.20 mmol, 75.57% yield, 90% purity) as a yellow solid.

[0488] Step 4: (3S)-3-[[4-[6-[(3S)-3-hydroxypyrrolidine-1-carbonyl]-1H-indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidine-1-carboxylic acid tert-butyl ester

[0489] A mixture of 3-[2-[[(3S)-1-tert-butoxycarbonyl-3-piperidinyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]-1H-indole-6-carboxylic acid (100.00 mg, 197.83 μol, 1.00 eq), (3S)-pyrrolidine-3-ol (24.45 mg, 197.83 μol, 22.64 μL, 1.00 eq, HCl), HATU (75.22 mg, 197.83 μol, 1.00 eq), and DIEA (25.57 mg, 197.83 μol, 34.55 μL, 1.00 eq) in DMF (3.00 mL) was stirred at 20 °C for 16 h. The reaction mixture was concentrated. The residue was purified by preparative HPLC (TFA conditions) and concentrated. The residue was treated with water (50 mL) and adjusted to pH 8 with NaHCO3 and extracted with EtOAc (30 mL x 3), dried with Na2SO4, and concentrated to give the title compound (80.00 mg, 125.31 μmol, 63.34% yield, 90% purity) as a white solid.

[0490] Step 5: [(3S)-3-hydroxypyrrolidone-1-yl]-[3-[2-[[(3S)-3-piperidinyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]-1H-indol-6-yl] methyl ketone

[0491] A mixture of (3S)-3-[[4-[6-[(3S)-3-hydroxypyrrolidine-1-carbonyl]-1H-indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidin-1-carboxylic acid tert-butyl ester (90.00 mg, 156.63 μmol, 1.00 eq) in HCl / EtOAc (4 M, 1.17 mL, 30.00 eq) was stirred at 20 °C for 1 h. The reaction mixture was concentrated. The residue was purified by preparative HPLC (FA conditions) to the title compound (14.10 mg, 26.55 μmol, 16.95% yield, 98% purity, FA) as a white solid.

[0492] Example 48 [(3R)-3-hydroxypyrrolidine-1-yl]-[3-[2-[[(3S)-3-piperidinyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]-1H-indol-6-yl] methyl ketone (compound 205).

[0493] Step 1: (3S)-3-[[4-[6-[(3R)-3-hydroxypyrrolidine-1-carbonyl]-1H-indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidine-1-carboxylic acid tert-butyl ester

[0494] A mixture of 3-[2-[[(3S)-1-tert-butoxycarbonyl-3-piperidinyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]-1H-indole-6-carboxylic acid (100.00 mg, 197.83 μol, 1.00 eq), (3R)-pyrrolidine-3-ol (24.45 mg, 197.83 μol, 22.64 μL, 1.00 eq, HCl), HATU (75.22 mg, 197.83 μol, 1.00 eq), and DIEA (25.57 mg, 197.83 μol, 34.55 μL, 1.00 eq) in DMF (3.00 mL) was stirred at 20 °C for 16 h. The reaction mixture was poured into 50 mL of water and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with 100 mL of brine, dried with Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (200.00 mg, crude substance), which was a yellow oil.

[0495] Step 2: [(3R)-3-hydroxypyrrolidone-1-yl]-[3-[2-[[(3S)-3-piperidinyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]-1H-indol-6-yl] methyl ketone

[0496] A mixture of (3S)-3-[[4-[6-[(3R)-3-hydroxypyrrolidine-1-carbonyl]-1H-indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidin-1-carboxylic acid tert-butyl ester (200.00 mg, 348.07 μmol, 1.00 eq) in HCl / EtOAc (4 M, 4.35 mL, 50.00 eq) was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated. The residue was purified by preparative HPLC (FA conditions) to give the title compound (10.50 mg, 19.77 μmol, 5.68% yield, 98% purity, FA) as a yellow solid.

[0497] Example 49 N-[(3S)-3-piperidinyl]-4-(6-pyrrolidine-1-yl-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (compound 213).

[0498] Step 1: (3S)-3-[[4-(6-pyrrolidone-1-yl-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidine-1-carboxylic acid tert-butyl ester

[0499] (3S)-3-[[4-[1-(benzenesulfonyl)-6-bromo-indole-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidin-1-carboxylic acid tert-butyl ester (200.00 mg, 293.89 μol, 1.00 eq), pyrrolidine (313.52 mg, 4.41 mmol, 368.85 μL, 15.00 eq), t-BuONa (56.49 mg, 587.78 μol, 2.00 eq), [2-(2-aminoethyl)phenyl]chloro-palladium; di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine (20.18 mg, 29.39 μol, 0.10 eq) were dissolved in THF (5.00 The mixture was degassed and purged three times with N2, then stirred at 80°C under N2 atmosphere for 16 h. The reaction mixture was poured into 50 mL of water and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, PE / EtOAc = 10:1 to 2:1) to give the title compound (160 mg) as a yellow solid. (Note: purified in combination with another batch. SM scale: 100 mg).

[0500] Step 2: N-[(3S)-3-piperidinyl]-4-(6-pyrrolidine-1-yl-1H-indole-3-yl)-5-(trifluoromethyl) Pyrimidine-2-amine

[0501] A mixture of (3S)-3-[[4-(6-pyrrolidin-1-yl-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidin-1-carboxylic acid tert-butyl ester (160.00 mg, 301.55 μmol, 1.00 eq) in HCl / EtOAc (4 M, 2.26 mL, 30.00 eq) was stirred at 20°C for 0.5 h. The mixture was concentrated, and the residue was purified by preparative HPLC (FA conditions) to give the title compound (51.50 mg, 106.89 μmol, 35.45% yield, 98.9% purity, FA) as a yellow solid.

[0502] Example 50 2-Methyl-1-[4-[3-[2-[[(3S)-3-piperidinyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]-1H-indol-6-yl]pyrazol-1-yl]prop-2-ol (compound 214).

[0503] Step 1: 2-Methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazol-1-yl]prop-2-ol

[0504] Cs₂CO₃ (2.01 g, 6.18 mmol) was added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-pyrazole (800 mg, 4.12 mmol) in 2,2-dimethyloxacyclopropane (3.86 g, 53.60 mmol) at 20°C. The mixture was heated at 120°C for 30 min under N₂ with microwave irradiation. The reaction mixture was filtered and washed with DCM. The filtrate was concentrated under reduced pressure to give the title compound (970 mg, 79.62%) as a white solid.

[0505] Step 2: (3S)-3-[[4-[1-(benzenesulfonyl)-6-[1-(2-hydroxy-2-methyl-propyl)pyrazol-4-yl]indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidine-1-carboxylic acid tert-butyl ester

[0506] 2-Methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazol-1-yl]prop-2-ol (117 mg, 440.82 μmol) and (3S)-3-[[4-[1-(benzenesulfonyl)-6-bromo-indole-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidin-1-carboxylic acid tert-butyl ester (200 mg, 293.88 μmol) were dissolved in dioxane (6 mL), and then Pd(dppf)Cl2 (21 mg, 29.39 μmol) and K3PO4 (124 mg, 587.76 μmol) were added to the mixture at 20°C. The suspension was degassed under vacuum and washed three times with N2. The mixture was stirred at 100°C for 5 h under N2. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc = 10 / 1-5 / 1) to give the title compound (200 mg, 73.59%) as a yellow solid.

[0507] Step 3: (3S)-3-[[4-[6-[1-(2-hydroxy-2-methyl-propyl)pyrazol-4-yl]-1H-indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidine-1-carboxylic acid tert-butyl ester

[0508] A solution of NaOH (40 mg, 1.01 mmol) in H₂O (1 mL) was added to a solution of (3S)-3-[[4-[1-(benzenesulfonyl)-6-[1-(2-hydroxy-2-methyl-propyl)pyrazol-4-yl]indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidin-1-carboxylic acid tert-butyl ester (150 mg, 202.75 μmol) in dioxane (5 mL) at 20 °C. The mixture was heated to 100 °C and stirred for 1 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (120 mg, crude substance) as a yellow oil.

[0509] Step 4: 2-Methyl-1-[4-[3-[2-[[(3S)-3-piperidinyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]-1H-indol-6-yl]pyrazol-1-yl]prop-2-ol

[0510] HCl / MeOH (4 M, 20 mL) was added to a solution of (3S)-3-[[4-[6-[1-(2-hydroxy-2-methyl-propyl)pyrazol-4-yl]-1H-indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidin-1-carboxylic acid tert-butyl ester (100 mg, 166.76 μmol) in MeOH (2 mL). The mixture was stirred at 20 °C for 0.5 h. The mixture was then concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (FA) to give the title compound (51.20 mg, 55.15%) as a pale yellow solid.

[0511] Example 51 4-[6-(methylsulfonylmethyl)-1H-indol-3-yl]-N-[(3S)-3-piperidinyl]-5-(trifluoromethyl)pyrimidin-2-amine (compound 219).

[0512] Step 1: Methyl 3-[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]-1-(2-trimethylsilylethoxymethyl)indole-6-carboxylate

[0513] NaH (168.68 mg, 4.22 mmol, 60% purity, 1.50 eq) was added to a solution of methyl 3-[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]-1H-indole-6-carboxylate (1.00 g, 2.81 mmol, 1.00 eq) in THF (10.00 mL) at 0°C. After addition, the mixture was stirred at this temperature for 30 min, and then 2-(chloromethoxy)ethyl-trimethylsilane (703.06 mg, 4.22 mmol, 747.94 μL, 1.50 eq) was added dropwise at 0°C. The resulting mixture was stirred at 20 °C for 1 h. The reaction mixture was quenched with 20 mL of water and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, PE / EtOAc = 20:1 to 10:1) to give the title compound (860.00 mg, 1.63 mmol, 57.94% yield, 92% purity) as a white solid.

[0514] Step 2: Methyl 3-[2-[[(3S)-1-tert-butoxycarbonyl-3-piperidinyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]-1-(2-trimethylsilylethoxymethyl)indole-6-carboxylic acid

[0515] A mixture of methyl 3-[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]-1-(2-trimethylsilylethoxymethyl)indole-6-carboxylate (860.00 mg, 1.77 mmol, 1.00 eq), tert-butyl (3S)-3-aminopiperidin-1-carboxylate (531.65 mg, 2.66 mmol, 1.50 eq), and DIEA (686.15 mg, 5.31 mmol, 927.23 μL, 3.00 eq) in NMP (8.00 mL) was stirred at 140 °C for 1 h. The reaction mixture was diluted with 50 mL of water and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, PE / EtOAc = 10:1 to 3:1) to give the title compound (1.07 g, 1.43 mmol, 80.94% yield) as a yellow oil.

[0516] Step 3: (3S)-3-[[4-[6-(hydroxymethyl)-1-(2-trimethylsilylethoxymethyl)indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidine-1-carboxylic acid tert-butyl ester

[0517] DIBAL-H (1 M, 3.96 mL, 2.40 eq) was added dropwise to a solution of methyl 3-[2-[[(3S)-1-tert-butoxycarbonyl-3-piperidinyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]-1-(2-trimethylsilylethoxymethyl)indole-6-carboxylate (1.07 g, 1.65 mmol, 1.00 eq) in toluene (10.00 mL) at -50°C. The mixture was stirred at -50°C for 30 min. The reaction mixture was quenched at 0°C by the addition of MeOH (2 mL) and H₂O (2 mL) and filtered. The filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, PE / EtOAc = 5:1 to 1:1) to give the title compound (600.00 mg, 878.15 μmol, 53.22% yield, 91% purity), which was a yellow oil.

[0518] Step 4: (3S)-3-[[4-[6-(chloromethyl)-1-(2-trimethylsilylethoxymethyl)indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidine-1-carboxylic acid tert-butyl ester and (3S)-3-[[4-[6-(methanesulfonyloxymethyl)-1-(2-trimethylsilylethoxymethyl)indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidine-1-carboxylic acid tert-butyl ester

[0519] Add TEA (146.47 mg, 1.45 mmol, 200.64 uL, 1.50 eq) and methanesulfonyl chloride (331.62 mg, 2.90 mmol, 224.07 uL, 3.00 eq) to a solution of (3S)-3-[[4-[6-(hydroxymethyl)-1-(2-trimethylsilylethoxymethyl)indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidin-1-carboxylic acid tert-butyl ester (600.00 mg, 965.00 μL, 1.00 eq) in DCM (6.00 mL) to a solution of (3S)-3-[[4-[6-(hydroxymethyl)-1-(2-trimethylsilylethoxymethyl)indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidin-1-carboxylic acid tert-butyl ester (600.00 mg, 965.00 μL, 1.00 eq) in DCM (6.00 mL). Heat the mixture in 20 mL of DCM. oStirred at C for 16 h. The reaction mixture was diluted with 20 mL of water and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 740 mg of the title compound as a crude mixture. This was used directly in the next step without further purification.

[0520] Step 5: (3S)-3-[[4-[6-(methylsulfonylmethyl)-1-(2-trimethylsilylethoxymethyl)indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidine-1-carboxylic acid tert-butyl ester

[0521] Add sodium methanesulfonyl (108.44 mg, 1.06 mmol, 2.00 eq) and KI (105.79 mg, 637.29 mmol, 1.20 eq) to a solution of (3S)-3-[[4-[6-(chloromethyl)-1-(2-trimethylsilylethoxymethyl)indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidin-1-carboxylic acid tert-butyl ester (340.00 mg, 531.08 μmol, 1.00 eq) in DMF (5.00 mL). The mixture was stirred at 60 °C for 16 h. The reaction mixture was diluted with 50 mL of water and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO₂, PE / EtOAc = 10:1 to 1:1) to give the title compound (210.00 mg, 251.81 μmol, 47.41% yield, 82% purity) as a yellow solid.

[0522] Step 6: 4-[6-(methylsulfonylmethyl)-1H-indol-3-yl]-N-[(3S)-3-piperidinyl]-5-(trifluoromethyl)pyrimidin-2-amine

[0523] H₂SO₄ (301.18 mg, 3.07 mmol, 163.69 μL, 10.00 eq) was added to a solution of (3S)-3-[[4-[6-(methanesulfonylmethyl)-1-(2-trimethylsilylethoxymethyl)indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidin-1-carboxylic acid tert-butyl ester (210.00 mg, 307.08 μL, 1.00 eq) in dioxane (5.00 mL). The mixture was stirred at 60 °C for 16 h. The reaction mixture was poured into water (20 mL) at 0 °C, and the pH of the mixture was adjusted to 8 by aqueous NaOH solution. The mixture was extracted with dichloromethane (10 mL x 3), the combined organic layers were washed with brine (30 mL x 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue (200 mg). The residue was purified by preparative HPLC (FA conditions) to the title compound (8.80 mg, 16.91 μmol, 5.51% yield, 96% purity, FA) as a white solid (Note: purified in combination with another batch. SM scale: 50 mg).

[0524] Example 52 [(3S)-3-hydroxy-3-methyl-pyrrolidine-1-yl]-[3-[2-[[(3S)-3-piperidinyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]-1Hindol-6-yl] ketone (compound 220) and [(3R)-3-hydroxy-3-methyl-pyrrolidine-1-yl]-[3-[2-[[(3S)-3-piperidinyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]-1Hindol-6-yl] ketone (compound 221).

[0525] Step 1: (3S)-3-[[4-[6-(3-hydroxy-3-methyl-pyrrolidine-1-carbonyl)-1H-indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidine-1-carboxylic acid tert-butyl ester

[0526] A mixture of 3-[2-[[(3S)-1-tert-butoxycarbonyl-3-piperidinyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]-1H-indole-6-carboxylic acid (300.00 mg, 593.48 μol, 1.00 eq), 3-methylpyrrolidone-3-ol (60.03 mg, 593.48 μol, 1.00 eq), HATU (225.66 mg, 593.48 μol, 1.00 eq), and DIEA (230.10 mg, 1.78 mmol, 310.95 μL, 3.00 eq) in DMF (5.00 mL) was degassed and purged three times with N2. The mixture was then stirred at 25 °C under N2 atmosphere for 16 h. The reaction mixture was poured into 50 mL of water and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with 100 mL of brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (500.00 mg, crude substance) as a yellow oil. This was used directly in the next step.

[0527] Step 2: (3-hydroxy-3-methyl-pyrrolidone-1-yl)-[3-[2-[[(3S)-3-piperidinyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]-1H-indol-6-yl] methyl ketone

[0528] A mixture of (3S)-3-[[4-[6-(3-hydroxy-3-methyl-pyrrolidine-1-carbonyl)-1H-indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidin-1-carboxylic acid tert-butyl ester (500.00 mg, 849.44 μmol, 1.00 eq) in HCl / EtOAc (4 M, 6.37 mL, 30.00 eq) was stirred at 20 °C for 0.5 h. The mixture was concentrated, and the residue was purified by preparative HPLC (TFA conditions) to give the title compound (80.00 mg, 163.77 μmol, 19.28% yield) as a yellow solid.

[0529] Step 3: [(3S)-3-hydroxy-3-methyl-pyrrolidine-1-yl]-[3-[2-[[(3S)-3-piperidinyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]-1Hindol-6-yl] methyl ketone & [(3R)-3-hydroxy-3-methyl-pyrrolidine-1-yl]-[3-[2-[[(3S)-3-piperidinyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]-1Hindol-6-yl] methyl ketone

[0530] (3-hydroxy-3-methyl-pyrrolidone-1-yl)-[3-[2-[[(3S)-3-piperidinyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]-1H-indol-6-yl] methyl ketone (80 mg) was separated by SFC. P1 (20 mg) was further purified by preparative HPLC (TFA conditions) and concentrated. The residue was treated with saturated NaHCO3 and extracted with DCM (2 x 10 mL), dried over Na2SO4 and concentrated. The mixture was then purified and concentrated by preparative HPLC (FA conditions) to give [(3S)-3-hydroxy-3-methyl-pyrrolidine-1-yl]-[3-[2-[[(3S)-3-piperidinyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]-1Hindol-6-yl] ketone (3.00 mg, 6.02 μmol, 3.68% yield, 98% purity), which was a white solid (P1, provisionally designated) and [(3R)-3-hydroxy-3-methyl-pyrrolidine-1-yl]-[3-[2-[[(3S)-3-piperidinyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]-1Hindol-6-yl] ketone (18.00 mg, 35.37 μmol, 21.60% yield, 96% purity) (P2, provisionally designated).

[0531] Example 53 N-[4-(1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]-3-azabicyclo[2.2.1]hept-7-amine (compound 222).

[0532] Step 1: 5-[(1S)-1-phenylethyl]-5-azabicyclo[2.2.1]hept-2-ene

[0533] AcOH (2.48 g, 41.26 mmol) in H2O (29 mL) was added to a solution of (1S)-1-phenylethylamine (5.00 g, 41.26 mmol) in H2O (56 mL) at 0 °C, followed by the addition of cyclopentadienyl-1,3-diene (5.45 g, 82.52 mmol) and formaldehyde (5.02 g, 61.89 mmol) at sample temperature. The mixture was stirred at 0 °C for 22 h. The mixture was poured into water (300 mL). The aqueous phase was extracted with EA (150 mL x 3). The combined organic phases were washed with brine (150 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound (5.20 g, 37.94%) as a yellow oil.

[0534] Step 2: (12S)-14-BLAH-12-bromo-14-[(1S)-1-phenylethyl]-14-azatricycloheptane

[0535] A solution of Br2 (882.47 mg, 5.52 mmol) was added to a solution of 5-[(1S)-1-phenylethyl]-5-azabicyclo[2.2.1]hept-2-ene (1.00 g, 5.02 mmol) in DCM (20 mL) at 0 °C. The mixture was stirred at 0 °C for 4 h. The mixture was concentrated. The residue was washed with DCM / PE = 1 / 50 to give the title compound (1.60 g, crude matter) as a pale yellow solid.

[0536] Step 3: [3-[(1S)-1-phenylethyl]-3-azabicyclo[2.2.1]hept-7-yl]isodihydroindole-1,3-dione

[0537] Sodium bis(2-methoxyethoxy)alumanuide (1.28 g, 4.46 mmol) was added to a solution of (12S)-14-BLAH-12-bromo-14-[(1S)-1-phenylethyl]-14-azatricycloheptane (800.00 mg, 2.23 mmol) in THF (20.00 mL) at -10°C. The mixture was stirred at -10°C for 2 hours under N2. The mixture was poured into water (100 mL). The aqueous phase was extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The product was purified by preparative TLC (PE / EtOAc = 3 / 1) to give the title compound (300 mg, 20.40%).

[0538] Step 4: 2-[3-[(1S)-1-phenylethyl]-3-azabicyclo[2.2.1]hept-7-yl]isodihydroindole-1,3-dione

[0539] A mixture of (7S)-7-bromo-3-[(1S)-1-phenylethyl]-3-azabicyclo[2.2.1]heptane (250 mg, 892.22 μmol) and (1,3-dioxoisodihydroindol-2-yl)potassium (181.78 mg, 981.44 μmol) in DMF (5.00 mL) was degassed and purged three times with N2, then stirred at 100 °C for 2.5 h under N2 atmosphere. The mixture was poured into water (100 mL). The mixture was extracted with EtOAc (50 mL x 3), and the combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give the title compound (350.00 mg, crude).

[0540] Step 5: 3-[(1S)-1-phenylethyl]-3-azabicyclo[2.2.1]hept-7-amine

[0541] N₂H₄·H₂O (412.74 mg, 8.08 mmol) was added to a solution of 2-[3-[(1S)-1-phenylethyl]-3-azabicyclo[2.2.1]hept-7-yl]isodihydroindole-1,3-dione (1.40 g, 4.04 mmol) in MeOH (15.00 mL). The mixture was stirred at 70 °C for 2 h. The mixture was filtered and concentrated to give the title compound (600.00 mg, 65.22%). Step 6: N-[4-(1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]-3-[(1S)-1-phenylethyl]-3-azabicyclo[2.2.1]hept-7-amine

[0542] DIEA (358.47 mg, 2.77 mmol) was added to a solution of 3-[(1S)-1-phenylethyl]-3-azabicyclo[2.2.1]hept-7-amine (200.00 mg, 924.56 μmol) in NMP (5.00 mL). The mixture was stirred at 130 °C for 4 h. The mixture was poured into water (100 mL). The mixture was extracted with EtOAc (50 mL x 3), and the combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give the title compound (300.00 mg, crude substance).

[0543] Step 7: N-[4-(1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]-3-azabicyclo[2.2.1]hept-7-amine

[0544] Pd-C (10%, 50 mg) was added to a solution of N-[4-(1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]-3-[(1S)-1-phenylethyl]-3-azabicyclo[2.2.1]hept-7-amine (150.00 mg, 314.12 μmol) in MeOH (5.00 mL) under N2. The suspension was degassed under vacuum and washed several times with H2. The mixture was stirred at 40°C for 4 h under H2 (50 psi). The mixture was concentrated. The residue was purified by preparative HPLC (FA) to give the title compound (50.00 mg, 18.43%).

[0545] Example 54 N-[(3S)-3-piperidinyl]-4-[6-(3-pyridinyl)-1H-indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (compound 223).

[0546] Step 1: (3S)-3-[[4-[1-(benzenesulfonyl)-6-(3-pyridyl)indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidin-1-carboxylic acid tert-butyl ester

[0547] (3S)-3-[[4-[1-(benzenesulfonyl)-6-bromo-indole-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidin-1-carboxylic acid tert-butyl ester (100 mg, 146.94 μmol) and 3-pyridylboronic acid (18 mg, 146.94 μmol) were dissolved in dioxane (5 mL) and H2O (1 mL). Pd(dppf)Cl2.CH2Cl2 (12 mg, 14.69 μmol) and K3PO4 (93 mg, 440.83 μmol) were added to the mixture. The mixture was heated to 100 °C and stirred under N2 for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, PE / EtOAc = 10 / 1-5 / 1) to give the title compound (80 mg, 72.19%) as a yellow solid.

[0548] Step 2: (3S)-3-[[4-[6-(3-pyridyl)-1H-indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidin-1-carboxylic acid tert-butyl ester

[0549] NaOH (23 mg, 589.34 μmol) and H₂O (500 μL) were added to a solution of (3S)-3-[[4-[1-(benzenesulfonyl)-6-(3-pyridyl)indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidin-1-carboxylic acid tert-butyl ester (80 mg, 117.87 μmol) in dioxane (2 mL). The mixture was heated to 100 °C and stirred under N₂ for 1 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (60 mg, crude substance) as a yellow oil.

[0550] Step 3: N-[(3S)-3-piperidinyl]-4-[6-(3-pyridinyl)-1H-indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine

[0551] A solution of (3S)-3-[[4-[6-(3-pyridyl)-1H-indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidin-1-carboxylic acid tert-butyl ester (60 mg, 111.41 μmol) in HCl / EtOAc (4 M, 10 mL) was stirred at 20°C for 1 h. The mixture was then concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (FA) to give the title compound (11.10 mg, 20.06%) as a white solid.

[0552] Example 55 N-[(3S)-3-piperidinyl]-4-[6-(4-pyridinyl)-1H-indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine (compound 224).

[0553] Step 1: 6-Bromo-3-[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]-1H-indole

[0554] AlCl3 (7.48 g, 56.11 mmol, 3.07 mL, 1.10 eq) was added to a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (16.60 g, 76.52 mmol, 1.50 eq) in DCE (50 mL). After addition, the mixture was stirred at 80 °C for 0.5 h, followed by the addition of a solution of 6-bromo-1H-indole (10.00 g, 51.01 mmol, 1.00 eq) in DCE (50 mL). The resulting mixture was stirred at 80 °C for 15.5 h. The reaction mixture was quenched by the addition of saturated NaHCO3, then extracted with EtOAc (150 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc = 10:1 to 1:1) to give a crude product. The crude product was washed with MeOH (100 mL) and filtered to collect the filter cake, giving the title compound (6.00 g, 15.62 mmol, 30.61% yield, 98% purity) as a yellow solid.

[0555] Step 2: 1-(benzenesulfonyl)-6-bromo-3-[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]indole

[0556] NaH (956.02 mg, 23.90 mmol, 60% purity, 1.50 eq) was added dropwise to a solution of 6-bromo-3-[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]-1H-indole (6.00 g, 15.93 mmol, 1.00 eq) in THF (54.00 mL) and DMF (6.00 mL) at 0°C. After the addition, the mixture was stirred at this temperature for 30 min, and then benzenesulfonyl chloride (4.22 g, 23.90 mmol, 3.06 mL, 1.50 eq) was added dropwise at 0°C. The resulting mixture was stirred at 20°C for 1 h. The reaction mixture was quenched at 0°C by adding 200 mL of water and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (200 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, PE / EtOAc = 10:1 to 5:1) to give the title product (5.3 g), which is a yellow solid.

[0557] Step 3: (3S)-3-[[4-[1-(benzenesulfonyl)-6-(4-pyridyl)indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidin-1-carboxylic acid tert-butyl ester

[0558] (3S)-3-[[4-[1-(benzenesulfonyl)-6-bromo-indole-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidin-1-carboxylic acid tert-butyl ester (200 mg, 293.89 μmol) and 4-pyridylboronic acid (72 mg, 587.78 μmol) were dissolved in dioxane (5 mL) and H2O (1 mL). Pd(dppf)Cl2.CH2Cl2 (24 mg, 29.39 μmol) and K3PO4 (187 mg, 881.67 μmol) were added to the mixture. The mixture was heated to 100 °C and stirred under N2 for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, PE / EtOAc = 10 / 1-5 / 1) to give the title compound (200 mg, 90.24%) as a yellow solid.

[0559] Step 4: (3S)-3-[[4-[6-(4-pyridyl)-1H-indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidin-1-carboxylic acid tert-butyl ester

[0560] NaOH (44.20 mg, 1.11 mmol) and H₂O (500 μL) were added to a solution of (3S)-3-[[4-[1-(benzenesulfonyl)-6-(4-pyridyl)indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidin-1-carboxylic acid tert-butyl ester (150 mg, 221.00 μmol) in dioxane (2 mL). The mixture was heated to 100 °C and stirred under N₂ for 1 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (20 mL * 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (120 mg, crude substance) as a white solid.

[0561] Step 5: N-[(3S)-3-piperidinyl]-4-[6-(4-pyridinyl)-1H-indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine

[0562] Tert-butyl (3S)-3-[[4-[6-(4-pyridyl)-1H-indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidin-1-carboxylic acid (120 mg, 222.82 μmol) was stirred for 0.5 h at 20°C in HCl / EtOAc (4 M, 10 mL). The mixture was then concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (FA) to give the title compound (67.70 mg, 60.76%) as a yellow solid.

[0563] Example 56 1-Methyl-4-[3-[2-[[(3S)-3-piperidinyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]-1H-indol-6-yl]pyrrole-2-carboxynitrile (compound 225).

[0564] Step 1: 1-Methylpyrrole-2-carboxynitrile

[0565] NaH (156.40 mg, 3.91 mmol, 60% purity, 1.20 eq) was added dropwise to a solution of 1H-pyrrolo-2-carboxynitrile (300.00 mg, 3.26 mmol, 1.00 eq) in THF (5.00 mL) at 0°C. After addition, the mixture was stirred at this temperature for 0.5 h, and then iodomethane (601.54 mg, 4.24 mmol, 263.83 μL, 1.30 eq) was added dropwise at 0°C. The resulting mixture was stirred at 20°C for 15.5 h. The reaction mixture was quenched by adding 50 mL of water and then extracted with EtOAc (20 mL * 3). The combined organic layers were washed with 100 mL of brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, PE / EtOAc = 50 / 1 to 20:1) to give the title compound (200.00 mg, 1.88 mmol, 57.81% yield), which was a yellow oil.

[0566] Step 2: 4-Bromo-1-methyl-pyrrole-2-carboxynitrile

[0567] NBS (335.40 mg, 1.88 mmol, 1.00 eq) was added to a solution of 1-methylpyrrolo-2-carboxynitrile (200.00 mg, 1.88 mmol, 1.00 eq) in DMF (5.00 mL). The mixture was stirred at 20 °C for 16 h. The reaction mixture was poured into 50 mL of water and then extracted with EtOAc (20 mL * 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, PEr / EtOAc = 50:1 to 20:1) to give the title compound (190.00 mg, 1.03 mmol, 54.62% yield) as a brown solid.

[0568] Step 3: (3S)-3-[[4-[6-(5-cyano-1-methyl-pyrrolo-3-yl)-1H-indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidine-1-carboxylic acid tert-butyl ester

[0569] The mixture of 4-[1-(benzenesulfonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)indol-3-yl]-N-[(3S)-3-piperidinyl]-5-(trifluoromethyl)pyrimidin-2-amine (300.00 mg, 478.10 μmol, 1.00 eq), 4-bromo-1-methyl-pyrrole-2-carboxynitrile (132.69 mg, 717.15 μmol, 1.50 eq), Pd(PPh3)4 (55.25 mg, 47.81 μmol, 0.10 eq), and Na2CO3 (5 M, 191.24 μL, 2.00 eq) in DMF (3.00 mL) was degassed and purged three times with N2. The mixture was then stirred at 130°C under N2 atmosphere for 16 h. The reaction mixture was poured into 100 mL of water and then extracted with EtOAc (50 mL * 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (500.00 mg, crude matter) as a brown oil (treated in combination with another batch, SM scale: 100 mg). This was used directly in the next step.

[0570] Step 4: (3S)-3-[[4-[6-(5-cyano-1-methyl-pyrrolo-3-yl)-1H-indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidine-1-carboxylic acid tert-butyl ester

[0571] To a solution of (3S)-3-[[4-[1-(benzenesulfonyl)-6-(5-cyano-1-methyl-pyrrolo-3-yl)indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidin-1-carboxylic acid tert-butyl ester (500.00 mg, 708.47 μL, 1.00 eq) in dioxane (10.00 mL), NaOH (5 M, 708.47 μL, 5.00 eq) was added. The mixture was stirred at 100°C for 16 h. The reaction mixture was poured into 50 mL of water and then extracted with EtOAc (25 mL * 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, PE / EtOAc = 5:1 to 1:1) to give the title compound (160 mg) as a yellow solid.

[0572] Step 5: 1-Methyl-4-[3-[2-[[(3S)-3-piperidinyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]-1H-indol-6-yl]pyrrole-2-carboxynitrile

[0573] A mixture of (3S)-3-[[4-[6-(5-cyano-1-methyl-pyrrolo-3-yl)-1H-indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidin-1-carboxylic acid tert-butyl ester (160.00 mg, 282.89 μmol, 1.00 eq) in HCl / EtOAc (4 M, 2.12 mL, 30.00 eq) was stirred at 20 °C for 0.5 h. The mixture was then concentrated. The residue was purified by preparative HPLC (FA conditions) to give the title compound (24.90 mg, 48.68 μmol, 17.21% yield, 100% purity, FA) as a yellow oil.

[0574] Example 57 4-[6-(1,3-dimethylpyrazol-4-yl)-1H-indol-3-yl]-N-[(3S)-3-piperidinyl]-5-(trifluoromethyl)pyrimidin-2-amine (compound 226).

[0575] Step 1: (3S)-3-[[4-[1-(benzenesulfonyl)-6-(1,3-dimethylpyrazol-4-yl)indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidine-1-carboxylic acid tert-butyl ester

[0576] Pd(PPh3)4 (23.82 mg, 20.62 μol) and Cs2CO3 (134.34 mg, 412.32 μol) were added to a solution of (3S)-3-[[4-[1-(benzenesulfonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidine-1-carboxylic acid tert-butyl ester (150.00 mg, 206.16 μol) and 4-bromo-1,3-dimethylpyrazole (54.13 mg, 309.24 μol) in dioxane (5.00 mL) and H2O (1.00 mL). The mixture was stirred at 100 °C under N2 for 4 h. The mixture was then poured into water (100 mL). The aqueous phase was extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 2 / 1) to give the title compound (150 mg, crude).

[0577] Step 2: The product of Step 1 is then converted into the title compound according to steps 4 and 5 of Example 56.

[0578] Example 58 4-[6-(1,5-dimethylpyrazol-4-yl)-1H-indol-3-yl]-N-[(3S)-3-piperidinyl]-5-(trifluoromethyl)pyrimidin-2-amine (compound 227).

[0579] Step 1: (3S)-3-[[4-[1-(benzenesulfonyl)-6-(1,5-dimethylpyrazol-4-yl)indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidine-1-carboxylic acid tert-butyl ester

[0580] Pd(PPh3)4 (19.06 mg, 16.49 μmol) and Cs2CO3 (107.47 mg, 329.85 μmol) were added to a solution of (3S)-3-[[4-[1-(benzenesulfonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidine-1-carboxylic acid tert-butyl ester (120.00 mg, 164.93 μmol) and 4-bromo-1,5-dimethylpyrazole (31.75 mg, 181.42 μmol) in dioxane (5 mL) and H2O (500 μL). The mixture was stirred at 100 °C under N2 for 4 h. The mixture was then poured into water (100 mL). The aqueous phase was extracted with EA (50 mL x 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 2:1) to give the title compound (150 mg, crude).

[0581] Step 2: The product of Step 1 is then converted into the title compound according to Steps 4 and 5 of Example 56.

[0582] Example 59 Synthesis of 4-[6-(3-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl]-N-[(3S)-3-piperidinyl]-5-(trifluoromethyl)pyrimidin-2-amine (compound 229).

[0583] Step 1: 2-[(4-bromo-3-methyl-pyrazol-1-yl)methoxy]ethyl-trimethyl-silane

[0584] NaH (13.66 mg, 341.61 μmol, 1.10 eq) was added to a solution of 4-bromo-3-methyl-1H-pyrazole (50.00 mg, 310.56 μmol, 1.00 eq) in THF (5.00 mL). The mixture was stirred at 0°C for 0.5 h. 2-(chloromethoxy)ethyl-trimethylsilane (54.37 mg, 326.09 μmol, 57.84 μL, 1.05 eq) was added, and the mixture was stirred at 25°C for 4 h. The residue was poured into water (100 mL). The aqueous phase was extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to give the title compound (50.00 mg, 44.22%).

[0585] Step 2: Starting with (3S)-3-[[4-[1-(benzenesulfonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidine-1-carboxylic acid tert-butyl ester and the product of step 1, the title compound was prepared according to steps 3, 4 and 5 of Example 56.

[0586] Example 60 N-[(3S)-3-piperidinyl]-4-(6-pyridazin-4-yl-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (compound 230).

[0587] Step 1: (3S)-3-[[4-(6-pyridazin-4-yl-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidine-1-carboxylic acid tert-butyl ester

[0588] The mixture of 4-[1-(benzenesulfonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)indol-3-yl]-N-[(3S)-3-piperidinyl]-5-(trifluoromethyl)pyrimidin-2-amine (400.00 mg, 637.47 μol, 1.00 eq), 4-bromopyridazine (124.59 mg, 637.47 μol, 1.00 eq, HCl), Pd(PPh3)4 (73.66 mg, 63.75 μol, 0.10 eq), and Na2CO3 (5 M, 254.99 μL, 2.00 eq) in dioxane (10.00 mL) was degassed and purged three times with N2. The mixture was then stirred at 100°C under N2 atmosphere for 16 h. The reaction mixture was poured into 50 mL of water, then extracted with EtOAc (25 mL * 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, PE / EtOAc = 5 / 1 to 1:3) to give the title compound (100 mg) as a yellow solid, which was used directly in the next step.

[0589] Step 2: The product of Step 1 is then converted into the title compound according to steps 4 and 5 of Example 56.

[0590] Example 61 5-Ethyl-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-[(3S)-3-piperidinyl]pyrimidine-4-amine (Compound 231).

[0591] Step 1: 5-Fluoro-3-(2-Trimethylsilylethynyl)pyridine-2-amine

[0592] TEA (5.93 g, 58.63 mmol, 8.12 mL, 1.40 eq) was added dropwise to a solution of 3-bromo-5-fluoro-pyridin-2-amine (8.00 g, 41.88 mmol, 1.00 eq), Pd(PPh3)4 (484.00 mg, 418.80 μmol, 0.01 eq), and CuI (79.77 mg, 418.80 μmol, 0.01 eq) in toluene (40.00 mL) at 20°C under a N2 atmosphere. After addition, the mixture was stirred at this temperature for 30 min, and then ethynyl(trimethyl)silane (4.94 g, 50.26 mmol, 6.96 mL, 1.20 eq) was added at 20°C. The resulting mixture was stirred at 60°C for 11.5 h. The reaction mixture was filtered. The filtrate was diluted with 250 mL of water and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (500 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50:1 to 5:1) to give the title compound (6.40 g, 27.65 mmol, 66.02% yield, 90% purity) as a yellow solid.

[0593] Step 2: 5-Fluoro-1H-pyrrolo[2,3-b]pyridine

[0594] A mixture of 5-fluoro-3-(2-trimethylsilylethynyl)pyridine-2-amine (6.40 g, 30.72 mmol, 1.00 eq) and t-BuOK (5.72 g, 51.00 mmol, 1.66 eq) in NMP (60.00 mL) was stirred at 130 °C for 12 h. The reaction mixture was diluted with 200 mL of water and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (300 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10:1 to 5:1) to give the title compound (3.20 g, 23.04 mmol, 74.99% yield, 98% purity) as a yellow solid.

[0595] Step 3: 1-(benzenesulfonyl)-5-fluoro-pyrrolo[2,3-b]pyridine

[0596] NaH (1.41 g, 35.26 mmol, 60% purity, 1.50 eq) was added dropwise to a solution of 5-fluoro-1H-pyrrolo[2,3-b]pyridine (3.20 g, 23.51 mmol, 1.00 eq) in THF (36.00 mL) and DMF (4.00 mL) at 0°C. After the addition, the mixture was stirred at this temperature for 30 min, and then benzenesulfonyl chloride (6.23 g, 35.26 mmol, 4.51 mL, 1.50 eq) was added dropwise at 0°C. The resulting mixture was stirred at 20°C for 1 h. The reaction mixture was quenched by adding 20 mL of H₂O. A solid formed and was filtered to give the title compound (6.20 g, 21.99 mmol, 93.55% yield, 98% purity) as a white solid.

[0597] Step 4: 1-(benzenesulfonyl)-3-bromo-5-fluoro-pyrrolo[2,3-b]pyridine

[0598] A solution of 1-(benzenesulfonyl)-5-fluoro-pyrrolo[2,3-b]pyridine (6.20 g, 22.44 mmol, 1.00 eq) in DCM (20 mL) was added dropwise to a solution of 1-bromopyrrolidine-2,5-dione (4.43 g, 49.78 mmol, 1.11 eq) in DCM (40 mL) at 20°C. After the addition, the mixture was stirred at this temperature for 12 h. After 12 h, 1-bromopyrrolidine-2,5-dione (4.43 g, 49.78 mmol, 1.11 eq) was added back to the mixture, and the mixture was stirred at 20°C for 24 h. The reaction mixture was diluted with 100 mL of water and extracted with DCM (50 mL x 2). The combined organic layers were washed with brine (200 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, PE / EtOAc = 20:1 to 10:1) to give the title compound (6.24 g, 14.23 mmol, 63.41% yield, 81% purity) as a yellow solid.

[0599] Step 5: 1-(benzenesulfonyl)-5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrrolo[2,3-b]pyridine

[0600] A mixture of 1-(benzenesulfonyl)-3-bromo-5-fluoro-pyrrolo[2,3-b]pyridine (2.00 g, 5.63 mmol, 1.00 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1,3,2-dioxaborhecyclopentane (1.86 g, 7.32 mmol, 1.30 eq), Pd(dppf)Cl2 (412.02 mg, 563.09 μmol, 0.10 eq), and AcOK (1.11 g, 11.26 mmol, 2.00 eq) in DME (10.00 mL) was degassed and purged three times with N2. The mixture was then stirred at 90 °C under N2 atmosphere for 3 h. The reaction mixture was diluted with 100 mL of water and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (200 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, PE / EtOAc = 30:1 to 3:1) to give the title compound (1.04 g) as a yellow solid.

[0601] Step 6: (3S)-3-[[2-[1-(benzenesulfonyl)-5-fluoro-pyrrolo[2,3-b]pyridin-3-yl]-5-chloro-pyrimidin-4-yl]amino]piperidine-1-carboxylic acid tert-butyl ester

[0602] A mixture of 1-(benzenesulfonyl)-5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)pyrrolo[2,3-b]pyridine (1.04 g, 2.59 mmol, 1.00 eq), (3S)-3-[(2,5-dichloropyrimidin-4-yl)amino]piperidine-1-carboxylic acid tert-butyl ester (899.35 mg, 2.59 mmol, 1.00 eq), K3PO4 (1.10 g, 5.18 mmol, 2.00 eq), and di-tert-butyl(cyclopentyl)phosphine; palladium dichloride; iron (168.80 mg, 259.00 μmol, 0.10 eq) in THF (10.00 mL) and H2O (2.00 mL) was degassed and purged three times with N2. The mixture was then heated at 80 °C. The mixture was stirred at °C under a N2 atmosphere for 16 h. The reaction mixture was diluted with 50 mL of water and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, PE / EtOAc = 10:1 to 5:1) to give the desired product as a yellow oil (970 mg). The residue was then purified by preparative HPLC (TFA conditions) to give the desired product as a solution. The pH of the eluent was adjusted to 8 with saturated NaHCO3 aqueous solution and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (400.00 mg, 681.35 μmol, 26.31% yield, 100% purity) as a yellow solid.

[0603] Step 7: (3S)-3-[[2-[1-(benzenesulfonyl)-5-fluoro-pyrrolo[2,3-b]pyridin-3-yl]-5-vinyl-pyrimidin-4-yl]amino]piperidine-1-carboxylic acid tert-butyl ester

[0604] Potassium trifluoro-potassio-vinyl-boron(1-) (342.26 mg, 2.56 mmol, 5.00 eq), (3S)-3-[[2-[1-(benzenesulfonyl)-5-fluoro-pyrrolo[2,3-b]pyridin-3-yl]-5-chloro-pyrimidin-4-yl]amino]piperidin-1-carboxylic acid tert-butyl ester (300.00 mg, 511.01 μmol, 1.00 eq), di(1-adamantyl)-butylphosphine (36.64 mg, 102.20 μmol, 0.20 eq), Cs₂CO₃ (333.00 mg, 1.02 mmol, 2.00 eq) and Pd(OAc)₂ (11.47 mg, 51.10 μmol, 0.10 eq) were prepared in toluene (5.00 mmol, 5.00 eq). The mixture was degassed in 1 mL of water and H2O (1.00 mL) and purged three times with N2. The mixture was then stirred at 120 °C under N2 atmosphere for 12 h. The reaction mixture was diluted with 20 mL of water and extracted with EtOAc (10 mL * 3). The combined organic layers were washed with brine (50 mL * 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, PE / EtOAc = 10:1 to 3:1) to give the title compound (190 mg) as a yellow solid.

[0605] Step 8: (3S)-3-[[2-[1-(benzenesulfonyl)-5-fluoro-pyrrolo[2,3-b]pyridin-3-yl]-5-ethyl-pyrimidin-4-yl]amino]piperidine-1-carboxylic acid tert-butyl ester

[0606] Pd-C (10%, wet, 10 mg) was added to a solution of (3S)-3-[[2-[1-(benzenesulfonyl)-5-fluoro-pyrrolo[2,3-b]pyridin-3-yl]-5-vinyl-pyrimidin-4-yl]amino]piperidin-1-carboxylic acid tert-butyl ester (190.00 mg, 328.34 μL, 1.00 eq) and TEA (99.68 mg, 985.03 μL, 136.54 μL, 3.00 eq) in MeOH (2.00 mL) under N2. The suspension was degassed under vacuum and washed three times with H2. The mixture was stirred in H2 (15 psi) at 20°C for 30 min. The reaction mixture was diluted with 20 mL of water and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO₂, PE / EtOAc = 5:1 to 2:1) to give the title compound (150.00 mg, 255.74 μmol, 77.89% yield, 99% purity) as a yellow solid.

[0607] Step 9: (3S)-3-[[5-ethyl-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]piperidin-1-carboxylic acid tert-butyl ester

[0608] A mixture of (3S)-3-[[2-[1-(benzenesulfonyl)-5-fluoro-pyrrolo[2,3-b]pyridin-3-yl]-5-ethyl-pyrimidin-4-yl]amino]piperidin-1-carboxylic acid tert-butyl ester (150.00 mg, 258.32 μL, 1.00 eq) and NaOH (5 M, 516.64 μL, 10.00 eq) in dioxane (2.00 mL) was stirred at 90 °C for 12 h. The reaction mixture was diluted with 20 mL of water and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (110.00 mg, crude substance) as a yellow solid.

[0609] Step 10: 5-Ethyl-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-[(3S)-3-piperidinyl]pyrimidin-4-amine

[0610] A mixture of (3S)-3-[[5-ethyl-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]piperidin-1-carboxylic acid tert-butyl ester (110.00 mg, 249.71 μmol, 1.00 eq) and HCl / EtOAc (4 M, 2.00 mL) in EA (2.00 mL) was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue (80 mg HCl salt). The residue was purified by preparative HPLC (FA conditions) to the title compound (9.40 mg, 24.08 μmol, 9.64% yield, 99% purity, FA) as a yellow solid. (Purified in combination with another batch. Scale: 30 mg).

[0611] Example 62 7-Methylsulfonyl-3-[2-[[(3S)-3-piperidinyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]-1H-indole-6-carboxynitrile (compound 232).

[0612] Step 1: 1-Bromo-2-methylthio-3-nitro-benzene

[0613] An aqueous solution of NaSMe (10.35 g, 29.55 mmol, 20% purity) was added to a solution of 1-bromo-2-fluoro-3-nitrobenzene (5.00 g, 22.73 mmol) in DMF (50 mL) over 10 minutes at 0°C. The mixture was stirred at 15°C for 1 h 50 min. The reaction mixture was added dropwise to water (200 mL) and stirred for 30 min. The mixture was filtered and the solid was dried under reduced pressure to give the title compound (5.00 g, 79.81%) as a white solid.

[0614] Step 2: 1-Bromo-2-methylsulfonyl-3-nitro-benzene

[0615] m-CPBA (14.90 g, 60.45 mmol, 70% purity, 2.50 eq) was added in a single addition to a mixture of 1-bromo-2-methylthio-3-nitrobenzene (6.00 g, 24.18 mmol, 1.00 eq) in DCM (100.00 mL) at 20 °C under N2. The mixture was stirred at 20 °C for 2 h. The mixture was poured into water (300 mL) and extracted with EtOAc (150 mL x 2). The combined organic phases were washed with aqueous Na2SO3 solution (200 mL x 3) and brine (200 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / DCM = 20 / 1, 0 / 1) to give the title compound (4.40 g, crude substance) as a yellow solid.

[0616] Step 3: 6-Bromo-7-methylsulfonyl-1H-indole

[0617] Magnesium bromide (1 M, 78.55 mL, 5.00 eq) was added fractionally to a mixture of 1-bromo-2-methylsulfonyl-3-nitrobenzene (4.40 g, 15.71 mmol, 1.00 eq) in THF (100.00 mL) at -78 °C under N2. The mixture was stirred at -78 °C for 2 h. The mixture was poured into water (300 mL) and extracted with EtOAc (150 mL x 2). The combined organic phases were washed with brine (200 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EtOAc = 20 / 1, 0 / 1) to give the title compound (1.80 g, 6.57 mmol, 41.80% yield) as a yellow solid.

[0618] Step 4: 7-Methylsulfonyl-1H-indole-6-carboxynitrile

[0619] CuCN (685.13 mg, 7.65 mmol, 1.67 mL, 3.00 eq) was added in a single addition to a mixture of 6-bromo-7-methylsulfonyl-1H-indole (700.00 mg, 2.55 mmol, 1.00 eq) in DMF (20.00 mL) at 15°C under N2. The mixture was stirred at 140°C for 1 h. The residue was poured into water (100 mL) and extracted with EtOAc (50 mL x 2). The combined organic phases were washed with brine (100 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EtOAc = 10 / 1, 3 / 1) to give the title compound (450.00 mg, crude) as a yellow solid.

[0620] Step 5: 3-Bromo-7-methylsulfonyl-1H-indole-6-carboxynitrile

[0621] NBS (399.39 mg, 2.24 mmol, 1.10 eq) was added in a single addition to a mixture of 7-methylsulfonyl-1H-indole-6-carboxynitrile (450.00 mg, 2.04 mmol, 1.00 eq) in DMF (20.00 mL) at 20 °C under N2. The mixture was stirred at 20 °C for 2 h. The mixture was poured into water (100 mL) and extracted with EtOAc (50 mL x 2). The combined organic phases were washed with brine (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EtOAc = 10 / 1, 2 / 1) to give the title compound (400.00 mg, 1.34 mmol, 65.55% yield) as a white solid.

[0622] Step 6: tert-butyl 3-bromo-6-cyano-7-methylsulfonyl-indole-1-carboxylate

[0623] DMAP (32.67 mg, 267.43 μL, 0.20 eq) and DIPEA (345.63 mg, 2.67 mmol, 467.07 μL, 2.00 eq) were added in a single dose to a mixture of 3-bromo-7-methylsulfonyl-1H-indole-6-carboxynitrile (400.00 mg, 1.34 mmol, 1.00 eq) and Boc₂O (437.75 mg, 2.01 mmol, 460.79 μL, 1.50 eq) in THF (20.00 mL) at 20°C under N₂. The mixture was stirred at 80°C for 4 h. The residue was poured into water (50 mL) and extracted with EtOAc (30 mL x 2). The combined organic phases were washed with brine (50 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EtOAc = 10 / 1, 2 / 1) to give the title compound (400.00 mg, crude substance) as a white solid.

[0624] Step 7: 6-Cyano-7-methylsulfonyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)indole-1-carboxylic acid tert-butyl ester

[0625] Pd(dppf)Cl2 (64.14 mg, 87.66 μmol, 0.10 eq) and KOAc (172.06 mg, 1.75 mmol, 2.00 eq) were added in a single dose to a mixture of tert-butyl 3-bromo-6-cyano-7-methylsulfonyl-indole-1-carboxylate (350.00 mg, 876.62 μmol, 1.00 eq) and BPD (267.13 mg, 1.05 mmol, 1.20 eq) in dioxane (10.00 mL) at 15°C under N2. The mixture was stirred at 80°C for 4 h. The residue was poured into water (20 mL) and extracted with EtOAc (10 mL x 2). The combined organic phases were washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (TFA) to give the title compound (100.00 mg, 178.46 μmol, 20.36% yield, TFA salt), which was a yellow oil.

[0626] Step 8: (3S)-3-[[4-(6-cyano-7-methylsulfonyl-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidine-1-carboxylic acid tert-butyl ester

[0627] Pd(PPh3)4 (24.60 mg, 21.29 μmol, 0.10 eq) and Na2CO3 (45.12 mg, 425.70 μmol, 2.00 eq) were added in a single dose to a mixture of 6-cyano-7-methylsulfonyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyl-2-yl)indole-1-carboxylic acid tert-butyl ester (95.00 mg, 212.85 μmol, 1.00 eq) and (3S)-3-[[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidine-1-carboxylic acid tert-butyl ester (121.58 mg, 319.27 μmol, 1.50 eq) in dioxane (10.00 mL) and H2O (2.00 mL) at 15°C under N2. The mixture was stirred at 100 °C for 4 h. The residue was poured into water (30 mL) and extracted with EtOAc (20 mL x 2). The combined organic phases were washed with brine (20 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EtOAc = 10 / 1, 2 / 1) to give the title compound (80.00 mg, crude) as a yellow solid.

[0628] Step 9: 7-Methylsulfonyl-3-[2-[[(3S)-3-piperidinyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]-1H-indole-6-carboxynitrile

[0629] TFA (400.00 μL) was added in portions to a mixture of (3S)-3-[[4-(6-cyano-7-methylsulfonyl-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidin-1-carboxylic acid tert-butyl ester (60.00 mg, 106.27 μol, 1.00 eq) in DCM (2.00 mL). The mixture was stirred at 20 °C for 30 min. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA) to the title compound (14.00 mg, 27.42 μol, 25.80% yield, FA) as a white solid (Note: purified in combination with another batch. Scale: 60 mg). Example 63 4-[3-[2-[[(3S)-3-piperidinyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]-1H-indol-6-yl]-1H-pyrrole-2-carboxynitrile (compound 233).

[0630] Step 1: 1-(2-Trimethylsilylethoxymethyl)pyrrole-2-carboxynitrile

[0631] NaH (195.44 mg, 4.89 mmol, ...

Claims

1. Compounds of Formula I: ， Or its pharmaceutically acceptable salt, stereoisomer, or isotopically labeled derivative, wherein ring A is X is C(R) 6 Each Y is independently C(R) 7 Z is C(R) 8 ); R 1 It is hydrogen or -C1-C6 alkyl, wherein R 1 Any alkyl moiety may be optionally substituted with a monovalent substituent -(CH2). 0-4 OR°, where R° is C 1-6 alkyl; Each R 2 If present, it is independently a halogen, -OH, methyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, sec-pentyl, isopentyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, sec-hexyl, -(C0-C6 alkylene)-heteroaryl or -NH-C(O)-C1-C4 alkyl, or two R 2 One or more atoms bonded to them, together with any inserted ring atoms, form a phenyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl ring, which is fused, spirofused, or bridged to a piperidine ring, wherein R 2 Any heterocyclic or heteroaryl moiety may be optionally substituted with one or more independently selected from -(CH2). 0-4 R°、-(CH2) 0-4 OR° and (CH2) 0-4 The monovalent substituent of S(O)2R°, where R° is hydrogen or C 1-6 alkyl; R 3 It is hydrogen; R 4 It is hydrogen, halogen, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl or -SC1-C6 alkyl, wherein R 4 Any alkyl moiety is optionally substituted and has one or more independently selected from halogens and -(CH2). 0-4 OR° is a monovalent substituent, where R° is hydrogen or C. 1-6 Alkyl; R 5’ It is hydrogen; Each R 1’ Independently hydrogen or C1-C6 alkyl; or Two Rs 1’ The nitrogen atoms that are optionally bonded to them can form a 4-6 membered heterocyclic group or heteroaryl ring, wherein the heterocyclic group or heteroaryl ring is optionally substituted with a monovalent substituent -(CH2). 0-4 OR°, where R° is hydrogen; R 6 For hydrogen; each R 7 Independently hydrogen or R 5 ; Each R 5 Independently halogen, C1-C6 alkyl, -CN, -(C0-C6 alkylene)-C(O)(C1-C4 alkyl), -(C0-C6 alkylene)-S(O)2-(C1-C4 alkyl), -(C0-C6 alkylene)-S(O)2-N(R) 1’ )2、-(C0-C6 alkylene)-P(O)-O-(C1-C4 alkyl)2、-(C0-C6 alkylene)P(O)-(C1-C4 alkyl)(O-C1-C4 alkyl),-(C0-C6 alkylene)P(O)(C1-C4 alkyl)2、-(C0-C6 alkylene)-cyclopropyl、-(C0-C6 alkylene)-cyclobutyl、-(C0-C6 alkylene)-cyclopentyl、-(C0-C6 alkylene)-cyclohexyl、-(C0-C6 alkylene)-heterocyclic、-(C0-C6 alkylene)-heteroaryl、phenyl、-(C2-C4 alkenyl)-phenyl、-S(O)-(C1-C4 alkyl),-S-(C1-C4 alkyl),-S(O)-OH、or-S(O)2-OH、where R 5 Any alkyl, carbocyclic, heterocyclic, phenyl, or heteroaryl moiety may be optionally substituted with one or more independently selected from halogens, -(CH2) 0-4 R°、-(CH2) 0-4 OR°, -CN, -(CH2) 0-4 N(R°)2、-(CH2) 0-4 C(O)N(R°)2, -S(O)2NR°2, and -(CH2) 0-4 The monovalent substituent of N(R°)C(O)NR°2, where R° is hydrogen, C° is carbon, and C° is carbon. 1-6 An aliphatic group, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the C 1-6 Aliphatic group substitutions include halogenated groups or -(CH2). 0-2 OH; or R 5’ And any R 5 Together with the ring atoms they bind to, they form optionally substituted heterocyclic groups, wherein each heterocyclic group is fused to ring A; Wherein (i) each heteroaryl group is a monocyclic or bicyclic ring, wherein the monocyclic ring contains 5 or 6 ring atoms and each ring of the bicyclic ring contains 5 or 6 ring atoms and 1, 2, 3 or 4 ring atoms are independently N, O or S; and (ii) each heterocyclic group is a monocyclic or bicyclic ring, wherein each ring of the monocyclic and bicyclic rings contains 3-7 ring atoms and 1, 2, 3 or 4 ring atoms are independently N, O or S; R 8 It is hydrogen; and n is 0, 1, or 2, wherein the compound is not hydrogen. or its pharmaceutically acceptable salt, stereoisomer, or isotopically labeled derivative.

2. The compound of claim 1, wherein the compound has the structure of formula I, but is not a pharmaceutically acceptable salt or isotopically labeled derivative thereof.

3. The compound of claim 1, wherein the compound is in its pharmaceutically acceptable salt form.

4. The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, or isotopically labeled derivative thereof, wherein R 1 It is hydrogen or -C1-C6 alkyl.

5. The compound of claim 1, wherein the compound is in a pharmaceutically acceptable isotopically labeled derivative form.

6. The compound of claim 4, wherein the compound is in its pharmaceutically acceptable salt form.

7. The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, or isotopically labeled derivative thereof, wherein R 1 It is hydrogen, -CH3, -CH2CH3, -CH2CH2OCH3, -CH(CH3)2 or -CH2CH(CH3)2.

8. The compound of claim 7 or a pharmaceutically acceptable salt, stereoisomer, or isotopically labeled derivative thereof, wherein R 1 It is hydrogen.

9. The compound of claim 1 or claim 4, or a pharmaceutically acceptable salt, stereoisomer, or isotopically labeled derivative thereof, wherein each R 2 If present, it is independently a halogen, -OH, methyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, heteroaryl, or -NH-C(O)-C1-C4 alkyl, wherein R 2 The methyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, any heteroaryl or heterocyclic moiety may be optionally substituted, with one or more independently selected from -(CH2). 0-4 R°、-(CH2) 0-4 OR° and (CH2) 0-4 The monovalent substituent of S(O)2R°, where R° is hydrogen or C 1-6 Alkyl groups, or (a) two R groups bonded to different ring atoms. 2 (a) The atoms that are optionally bonded to them, together with any inserted ring atoms, form a phenyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group, which is fused or bridged to the piperidine ring; or (b) two R atoms bonded to the same ring atom 2 The atoms that are optionally bonded to them together form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups with one or more independently chosen monovalent substituents, which are fused with piperidine cyclospiro.

10. The compound of claim 9 or a pharmaceutically acceptable salt, stereoisomer, or isotopically labeled derivative thereof, wherein each R 2 If present, independently fluorine, =O, -CH3, -OH, -CH(CH3)2, -NHC(O)CH2CH3, 3-methyl-1,2,4-oxadiazol-5-yl, 1,2,4-triazolo[4,3-a]pyridin-3-yl, 8-methylsulfonyl-1,2,4-triazolo[4,3-a]pyridin-3-yl, pyrrolidine-1-ylcarbonyl, 3-hydroxypyrrolidine-1-ylcarbonyl or unsubstituted phenyl, or two Rs on different atoms. 2 The atoms bonded to them, along with any inserted ring atoms, form a ring, which is connected to two R atoms. 2 The combined piperidine ring together is ; or two R atoms bound to the same ring atom 2 The atoms that bond with them form a ring, which is connected to two R atoms. 2 The combined piperidine rings together form: , ,or .

11. The compound of claim 1 or claim 4, or a pharmaceutically acceptable salt, stereoisomer, or isotopically labeled derivative thereof, wherein n is 0 and / or R. 3 It is hydrogen.

12. The compound of claim 1 or claim 4, or a pharmaceutically acceptable salt, stereoisomer, or isotopically labeled derivative thereof, wherein R 4 It is hydrogen, halogen, -CN, C1-C4 alkyl or C2-C4 alkynyl.

13. The compound of claim 12 or a pharmaceutically acceptable salt, stereoisomer, or isotopically labeled derivative thereof, wherein R 4 It can be chlorine, fluorine, bromine, iodine, -CN, -CF3, -CH2CF3, -CH2CH2F, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -OCH3, -CH(OH)CH3, -CH=CH2, -C(O)CH3, -S-CH3, -S-CHF2, -S-CF3 or -C≡CH.

14. The compound of claim 13 or a pharmaceutically acceptable salt, stereoisomer, or isotopically labeled derivative thereof, wherein R 4 It is -CF3, -CH2CH3, or -CH2CH2F.

15. The compound of claim 1 or claim 4, or a pharmaceutically acceptable salt, stereoisomer, or isotopically labeled derivative thereof, wherein each R 7 Independently, it is hydrogen, halogen, -C1-C6 alkyl, -CN, -C(O)(C1-C4 alkyl), -S(O)2-(C1-C4 alkyl), -CH2-S(O)2-(C1-C4 alkyl), -S(O)2-N(R) 1’ )2、-P(O)(C1-C4 alkyl)-O-C1-C4 alkyl、-P(O)(O-(C1-C4 alkyl))2、cyclopropyl、cyclobutyl、cyclopentyl、cyclohexyl、heterocyclic、heteroaryl、-(C1-C4 alkylene)-S(O)2-(C1-C4 alkyl),-O-(C0-C6-alkylene)-cyclopropyl、-O-(C0-C6-alkylene)-cyclobutyl、-O-(C0-C6) -alkylene)-cyclopentyl, -O-(C0-C6-alkylene)-cyclohexyl, phenyl, -(C2-C4-enyl)-phenyl, -S(O)-(C1-C4 alkyl), -S-(C1-C4 alkyl), -S(O)-OH or -S(O)2-OH, wherein any alkyl, alkylene, enyl, carbocyclic, phenyl, heterocyclic or heteroaryl group is optionally substituted with one or more substituted groups independently selected from halogens, -(CH2)-... 0-4 R°、-(CH2) 0-4 OR°, -CN, -(CH2) 0-4 N(R°)2、-(CH2) 0-4 C(O)N(R°)2, -S(O)2NR°2, and -(CH2) 0-4 The monovalent substituent of N(R°)C(O)NR°2, where R° is hydrogen, C° is carbon, and C° is carbon. 1-6 Aliphatic group, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur, wherein C 1-6 Aliphatic group substitutions include halogenated groups or -(CH2). 0-2 OH.

16. The compound of claim 15 or a pharmaceutically acceptable salt, stereoisomer, or isotopically labeled derivative thereof, wherein R 7 It is hydrogen, fluorine, chlorine, bromine, -CN, -CH3, -CH2CH2C(CH3)2OH, -C(O)-CH3, -P(=O)(OCH2CH3)2, -P(=O)(OCH2CH3)CH3, -S(O)2CH3, -P(O)-(CH3)2, -P(O)-(CH2CH3)2, -S(O)2N(CH3)2, -S(O)2CH(CH3)2, -S(O)2CH2F, -S(O)2CHF2, -SCHF2, -S(O)CHF2, -S(O)OH, -S(O)2OH, -S(O)2NHCH3, -(CH2)4CH3, -CH2S(O)2CH3 , -S(O)2-CH2CH3, 1H-pyrazole-4-yl, 1-methylpyrazole-4-yl, 1,3-dimethyl-pyrazole-4-yl, 5-methyl-1H-pyrazole-4-yl, 1-methyl-2-oxoimidazolidine-3-yl, 4-methylimidazol-1-yl, morpholin-4-yl, pyridin-4-yl, pyridazin-4-yl, 4-hydroxycyclohexyl, 4-hydroxy-4-methylcyclohexyl, 5-methyl-1,2,4-triazol-3-yl, 5-methyl-1,2,4-oxadiazol-3-yl, 1,3-dimethylpyridazin-4-yl, 1,5-dimethylpyridazin-4-yl, 3-methyl-1H-pyridazin-4-yl, 1-(2-methyl-2-hydroxypropyl)pyridazin-4-yl, imidazole-1 -yl, 1-methyl-5-cyanopyrrolo-3-yl, 5-cyano-1H-pyrrolo-3-yl, and pyridazin-4-yl, 1H-pyrazole-3-yl, 1-difluoromethyl-pyrazole-3-yl, 1-difluoromethyl-pyrazole-4-yl, 1-methylpyrazole-3-yl, 3-methyl-1H-pyrazole-4-yl, 3-methyl-3-hydroxypyrrolidine-1-ylcarbonyl, 3-hydroxypyrrolidine-1-ylcarbonyl, 4-hydroxycyclohexyl, 4-hydroxycyclohexyl-1-enyl, 1,1-dioxothiomorpholino-4-yl, 4-cyano-1H-imidazol-1-yl, 2,3-dimethyl-1,2,4-triazol-5-yl, 1,5-dimethyl-pyrazole-4-yl, pyridin-3-yl, 1-(2-methyl- 2-Hydroxypropyl-1-yl)pyrazole-4-yl, pyrrolidine-1-yl, pyrrolidine-1-ylcarbonyl, 1H-pyrazole-2-yl, 3-hydroxy-3-trifluoromethylpyrrolidine-1-ylcarbonyl, 3-methoxypyrrolidine-1-ylcarbonyl, 3-cyanopyrrolidine-1-ylcarbonyl, 4-hydroxy-4-methylpiperidin-1-ylcarbonyl, 3-oxopyrrolidine-1-ylcarbonyl, 3-(pyrrolidine-1-ylcarbonyl)phenyl, 3-phenoxyphenyl, thiazol-2-yl, pyrazin-2-yl, 2,4-dioxo-1H,3H-pyrimidin-5-yl, 3-methyl-3-hydroxypyrrolidine-1-ylsulfonyl, 5-fluoropyridin-3-yl, 2-hydroxypyridin-3-yl, 3,3-difluoro-4-hydroxy, 3,5-Dimethyloxazol-4-yl, 3-fluorophenyl, 4-methylpyridin-3-yl, 2-hydroxymethylpyridin-3-yl, 6-hydroxymethylpyridin-2-yl, 5-hydroxymethylpyridin-3-yl, 1-methyl-6-oxopyridin-3-yl, 4-aminosulfonylphenyl, 3-aminosulfonylphenyl, 3-hydroxy-3-ethylpyrrolidine-1-ylcarbonyl, 3-cyano-4-hydroxyphenyl, benzo[, d ]Thiazol-6-yl, 2H-indazole-6-yl, 1H-benzimidazole-5-yl, 2-oxo-3-cyano-4-methylpyridin-5-yl, 2-aminobenzo[ d Thiazol-2-yl, 3-aminocarbonylphenyl, 6-trifluoromethyl-1H-pyrrolo[3,2-c]pyridin-3-yl, 2-aminoquinazoline-8-yl, styrylyl, 1-methyl-1H-indazole-6-yl, 2,3-dihydrobenzo[b][1,4]dioxanediene-7-yl, 2-ethoxyphenyl, 3-(2-hydroxyethyl)phenyl, 3-(methylcarbonylaminomethyl)phenyl, 1-methyl-6-trifluoromethyl-1H-pyrrolo[3,2-c]pyridin-3-yl, quinoline-4-yl, isoquinoline-5-yl, isoquinoline-7-yl or 2-oxo-3,4-dihydroquinoline-7-yl.

17. The compound of claim 16 or a pharmaceutically acceptable salt, stereoisomer, or isotopically labeled derivative thereof, wherein R 7 It is hydrogen, fluorine, -CN, -S(O)2CH3, -S(O)2NHCH3, 3-hydroxy-pyrrolidine-1-ylcarbonyl, 3-hydroxy-3-methyl-pyrrolidine-1-ylcarbonyl or 1H-imidazol-2-yl.

18. The compound of claim 1 or claim 4, or a pharmaceutically acceptable salt, stereoisomer, or isotopically labeled derivative thereof, wherein the compound is a compound of formula (II): (II), where: Y 3 It is C(R) 7e ); R 2a and R 2b Each is independently hydrogen, methyl, n-propyl, or isopropyl; or R 2a and R 2b Together they form a C3-C6 cycloalkyl or heterocyclic ring fused with piperidine cyclospiro, wherein the cycloalkyl or heterocyclic ring is optionally substituted with one or more independently selected C1-C4 alkyl or C1-C4 haloalkyl rings; R 7d It is a hydrogen, -C(O)-(C1-C4 alkyl), -CN, or optionally substituted with one or more independently selected C1-C4 alkyl or C1-C4 haloalkyl groups; R 7e If present, it is hydrogen, halogen, -CN, -S(O)2-(C1-C4 alkyl), -P(O)(C1-C4 alkyl)2, -S(O)2NH-(C1-C4 alkyl), -S(O)2N-(C1-C4 alkyl)2, or optionally a heteroaryl group having one or more independently selected C1-C4 alkyl or C1-C4 haloalkyl groups; and R 14 It is a C1-C3 alkyl or a C1-C3 haloalkyl.

19. A pharmaceutically acceptable salt of the compound of claim 3 or an isotopically labeled derivative of the compound of claim 5, wherein the compound is of formula (II): (II), where: Y 3 For C(R) 7e ); R 2a and R 2b Each is independently hydrogen, methyl, n-propyl, or isopropyl; or R 2a and R 2b Together they form a cycloalkyl or heterocyclic ring fused with piperidine cyclospiro, wherein the cycloalkyl or heterocyclic ring is optionally substituted with one or more independently selected C1-C4 alkyl or C1-C4 haloalkyl rings; R 7d It is a hydrogen, -C(O)-(C1-C4 alkyl), -CN, or optionally substituted with one or more independently selected C1-C4 alkyl or C1-C4 haloalkyl groups; R 7e It is hydrogen, halogen, -S(O)2-(C1-C4 alkyl), -P(O)(C1-C4 alkyl)2, -S(O)2NH-(C1-C4 alkyl), -S(O)2N-(C1-C4 alkyl)2, or optionally a heteroaryl group substituted with one or more independently selected C1-C4 alkyl or C1-C4 haloalkyl groups; and R 14 It is a C1-C3 alkyl or a C1-C3 haloalkyl.

20. The compound of claim 1 or claim 4, or a pharmaceutically acceptable salt, stereoisomer, or isotopically labeled derivative thereof, wherein the compound is a compound of formula (III): (III), where: Y 3 It is C(R) 7e ); R 2a and R 2b Each is independently hydrogen, methyl, n-propyl, or isopropyl; or R 2a and R 2b Together they form a C3-C6 cycloalkyl or heterocyclic ring fused with piperidine cyclospiro, wherein the cycloalkyl or heterocyclic ring is optionally substituted with one or more independently selected C1-C4 alkyl or C1-C4 haloalkyl rings; R 7d It is a hydrogen, -C(O)-(C1-C4 alkyl), -CN, or optionally substituted with one or more independently selected C1-C4 alkyl or C1-C4 haloalkyl groups; R 7e If present, it is hydrogen, halogen, -CN, -S(O)2-(C1-C4 alkyl), -P(O)(C1-C4 alkyl)2, -S(O)2NH-(C1-C4 alkyl), -S(O)2N-(C1-C4 alkyl)2, or optionally a heteroaryl group substituted with one or more independently selected C1-C4 alkyl or C1-C4 haloalkyl groups; and R 14 It is a C1-C3 alkyl or a C1-C3 haloalkyl.

21. A pharmaceutically acceptable salt or stereoisomer of the compound of claim 3 or an isotopically labeled derivative of the compound of claim 5, wherein the compound is of formula (III): (III), where: Y 3 It is C(R) 7e ); R 2a and R 2b Each is independently hydrogen, methyl, n-propyl, or isopropyl; or R 2a and R 2b Together they form a C3-C6 cycloalkyl or heterocyclic ring fused with piperidine cyclospiro, wherein the cycloalkyl or heterocyclic ring is optionally substituted with one or more independently selected C1-C4 alkyl or C1-C4 haloalkyl rings; R 7d It is a hydrogen, -C(O)-(C1-C4 alkyl), -CN, or optionally substituted with one or more independently selected C1-C4 alkyl or C1-C4 haloalkyl groups; R 7e If present, it is hydrogen, halogen, -CN, -S(O)2-(C1-C4 alkyl), -P(O)(C1-C4 alkyl)2, -S(O)2NH-(C1-C4 alkyl), -S(O)2N-(C1-C4 alkyl)2, or optionally a heteroaryl group substituted with one or more independently selected C1-C4 alkyl or C1-C4 haloalkyl groups; and R 14 It is a C1-C3 alkyl or a C1-C3 haloalkyl.

22. The compound of claim 18 or the pharmaceutically acceptable salt or isotope-labeled derivative of claim 19, wherein: R 2a It is hydrogen or -CH3; R 2b It is hydrogen or -CH3; R 7d It is hydrogen, -CN, pyrazin-2-yl, thiazo-2-yl, or 3,5-dimethylisoxazol-4-yl; R 7e It is hydrogen, fluorine, -P(O)(CH3)2, -S(O)2CH3, -S(O)2N(CH3)2, 1,3-dimethylpyrazol-4-yl, or pyridazin-4-yl; and R 14 It is -CH2CH3 or -CF3.

23. The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, or isotopically labeled derivative thereof, wherein the compound is:

24. A pharmaceutical composition comprising a compound of any one of claims 1, 4 or 27, or a pharmaceutically acceptable salt, stereoisomer or isotopically labeled derivative thereof, and a pharmaceutically acceptable excipient.

25. The pharmaceutical composition of claim 24, wherein the composition is optically enriched for the enantiomer of the compound.

26. Use of the compound of any one of claims 1, 4 or 23, or the pharmaceutical composition of claim 24 or 25, in the preparation of a medicament for treating cancer, benign growths, angiogenesis, inflammatory diseases, autoimmune diseases, or infectious diseases.

27. The use according to claim 26, wherein the use is for preparing a medicament for treating cancer, and the cancer is a blood cancer, melanoma, bone cancer, breast cancer, brain cancer, or lung cancer.

28. The use according to claim 27, wherein the hematologic malignancy is: chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML), lymphoma, or multiple myeloma.

29. The use according to claim 27, wherein the bone cancer is osteosarcoma or Ewing sarcoma and the hematologic malignancy is mantle cell lymphoma.

30. The use according to claim 27, wherein the breast cancer is triple-negative breast cancer (TNBC).

31. The use according to claim 27, wherein the brain cancer is a neuroblastoma.

32. The use according to claim 27, wherein the lung cancer is small cell lung cancer (SCLC).

33. The use of claim 27, wherein the composition comprises one or more other agents independently selected from antiproliferative agents, anticancer agents, immunosuppressants, and analgesics, or the compound or composition is used in combination with one or more other agents independently selected from antiproliferative agents, anticancer agents, immunosuppressants, and analgesics.

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