Heteroaryl compounds as modulators of AKT activity

Abstract

Provided herein are compounds of Formula (I) or a stereoisomer, a mixture of stereoisomers, a tautomer, or a pharmaceutically acceptable salt thereof, which may be used as modulators of AKT signaling. Also provided are pharmaceutical compositions comprising the compounds and methods of treating a cell proliferative disease (e.g., cancer) using the compounds.

Description

Attorney Docket No. 14709-051-228HETEROARYL COMPOUNDS AS MODULATORS OF AKT ACTIVITY1. CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority of U. S. Provisional Application Nos. 63 / 737,221, filed December 20, 2024, and 63 / 843,856, filed July 14, 2025, the entirety of each of which is incorporated herein by reference.2. BACKGROUND

[0002] AKT, also known as protein kinase B, plays a pivotal role in cancer development and progression due to its involvement in various cellular processes. One of its primary functions is to promote cell survival and inhibit apoptosis, or programmed cell death, thereby allowing cancer cells to evade destruction. AKT achieves this by phosphorylating and inactivating pro-apoptotic proteins while activating anti-apoptotic factors, creating an environment conducive to tumor survival and proliferation. AKT also regulates cell growth and proliferation by stimulating the mammalian target of rapamycin (mTOR) pathway, promoting protein synthesis and cell cycle progression, and is involved in angiogenesis, the process by which tumors develop new blood vessels to sustain their growth. Additionally, AKT plays a critical role in cancer metabolism by promoting glucose uptake and glycolysis, providing cancer cells with the energy and building blocks necessary for their rapid proliferation.

[0003] Aberrant AKT signaling is a hallmark feature of cancer, contributing significantly to tumorigenesis and disease progression. Dysregulated AKT activation can arise from various genetic alterations, including mutations in upstream regulators such as PI3K (phosphoinositide 3-kinase), PTEN (phosphatase and tensin homolog), and growth factor receptors, as well as amplification or overexpression of AKT itself. In cancer cells, aberrant AKT activation promotes cell survival, proliferation, and metastasis by disrupting the balance between cell growth and death signals. Furthermore, aberrant AKT signaling confers resistance to apoptosis induced by chemotherapy and radiation therapy, making cancer cells more resilient and challenging to eradicate. The most common mutation is AKT1 E17K, which has been reported in 6-8% of breast cancers, 2-6% of colorectal cancers, and in 6% of meningiomas, in humans (Yu, Y., et al. PloS One 2015, 10 (10) No. e0140479). Therefore, targeting aberrant AKT signaling pathways with AKT inhibitors provides a promising therapeutic strategy in cancer treatment.NAI-5008634746v1 -1-Attorney Docket No. 14709-051-2283. SUMMARY

[0004] In one aspect, provided herein is a compound of Formula (I):(I),or a stereoisomer, a mixture of stereoisomers, a tautomer, or a pharmaceutically acceptable salt thereof, wherein Ring A, X1, X2, X3, X4, X5, X6, L’, Ra, and n are as defined herein or elsewhere.

[0005] In one embodiment, provided that: when L’ comprises optionally substituted 3- to 12-membered ring moiety, then (i) two of X1, X2, X3, and X4are N or NRxn; or (ii) X4is C(=O), X3is NRxn, and Rxnis not hydrogen; or both (i) and (ii).

[0006] In one embodiment, Ring A is phenyl.

[0007] In one embodiment, CN. In one embodiment,

[0008] In one embodiment, without being bound by a particular theory, certain compounds provided herein exhibit one or more of the following properties: improved potency (e.g., against AKT1 E17K mutant); improved selectivity (e.g., over wild-type AKT1); improved solubility; improved permeability; and / or improved metabolic stability.

[0009] In another aspect, provided herein is a pharmaceutical composition comprising a compound as provided herein and a pharmaceutically acceptable excipient.

[0010] In another aspect, provided herein is a method of treating a disease or condition associated with aberrant activity of AKT, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as provided herein or a pharmaceutical composition thereof. In one embodiment, the disease or condition is cancer. In one embodiment, the cancer is breast cancer, colorectal cancer, meningioma, ovarian cancer, cervical cancer, pancreatic cancer, glioma, glioblastoma, prostate cancer, leukemia, lymphoma, non-Hodgkin’s lymphoma, lung cancer, hepatocellular cancer, gastric cancer, gastrointestinal stromal tumor (GIST), thyroid cancer, bile duct cancer, endometrial cancer, renal cancer, anaplastic large cellNAI-5008634746v1 -2-Attorney Docket No. 14709-051-228lymphoma, acute myeloid leukemia (AML), multiple myeloma, melanoma, or mesothelioma. In one embodiment, administration modulates activity of a mutant AKT in the subject. In one embodiment, the mutant AKT is AKT E17K. In one embodiment, the mutant AKT is AKT1 E17K. In one embodiment, the mutant AKT is AKT2 E17K. In one embodiment, the mutant AKT is AKT3 E17K.4. DETAILED DESCRIPTION4.1 Definitions

[0011] Headings and subheadings are used for convenience and / or formal compliance only, do not limit the subject technology, and are not referred to in connection with the interpretation of the description of the subject technology. Features described under one heading, or one subheading may be combined, in some embodiments, with features described under other headings or subheadings. Further it is not necessarily the case that all features under a single heading or a single subheading are used together in embodiments.

[0012] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art. The following references provide one of skill with a general definition of many of the terms used herein: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings ascribed to them below, unless specified otherwise.

[0013] As used herein, the terms “comprising” and “including” can be used interchangeably. The terms “comprising” and “including” are to be interpreted as specifying the presence of the stated features or components as referred to but do not preclude the presence or addition of one or more features, or components, or groups thereof. Additionally, the terms “comprising” and “including” are intended to include examples encompassed by the term “consisting of’. Consequently, the term “consisting of’ can be used in place of the terms “comprising” and “including” to provide for more specific embodiments.

[0014] As used herein, the term “or” is to be interpreted as an inclusive “or” meaning any one or any combination. Therefore, “A, B or C” means any of the following: “A; B; C; A and B; A and C; B and C; A, B and C”. An exception to this definition will occur only when a combination of elements, functions, steps, or acts are in some way inherently mutually exclusive.

[0015] The term “and / or” as used in a phrase such as “A and / or B” herein is intended to include both A and B; A or B; A (alone); and B (alone). Likewise, the term “and / or” as used in aNAI-5008634746v1 -3-Attomey Docket No. 14709-051-228phrase such as “A, B, and / or C” is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0016] When a range of values is listed, it is intended to encompass each value and subrange within the range. For example, “Cue” is intended to encompass, Ci, C2, C3, C4, Cs, Ce, Ci-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6.

[0017] Unless specifically stated or obvious from context, as used herein, the term “or” is understood to be inclusive. Unless specifically stated or obvious from context otherwise, as used herein, the terms “a”, “an”, and “the” are understood to be singular or plural.

[0018] As used herein, and unless otherwise specified, the term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term “about” or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0019] It should be noted that if there is a discrepancy between a depicted structure and a name for that structure, the depicted structure is to be accorded more weight.

[0020] It is meant to be understood that proper valences are maintained for all moieties and combinations thereof.

[0021] It is also meant to be understood that a specific embodiment of a variable moiety herein can be the same or different as another specific embodiment having the same identifier.

[0022] Suitable groups for the variables in the compounds and formulas provided herein, as applicable, are independently selected. Non-limiting useful groups for the variables in the compounds and formulas provided herein, as applicable, include any of the respective groups, individually or in any combination, as shown in the Examples or in the specific compounds described herein. Using variable Rxas an example, in some embodiments, any formula provided herein can include an Rxgroup according to any of the Rxgroups shown in the Examples or in the specific compounds described herein, without regard to the other variables shown in the specific compounds. In some embodiments, the compounds and formulas provided herein can include an Rxgroup according to any of the Rxgroups shown in the Examples or in the specific compounds described herein in combination with at least one other variable (e.g., L) according to the Examples or the specific compounds described herein, wherein the Rxand at least one other variable can derive from the same compound or a different compound. Any of suchNAI-5008634746v1 -4-Attorney Docket No. 14709-051-228combinations are contemplated and within the scope of the present application. Unless otherwise specified, a description of a variable in connection with a formula also applies to any other overlapping formulas (e.g., sub-formulas) where said variable is present.

[0023] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March ’s Advanced Organic Chemistry, 5thEdition, 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, 3rdEdition, Cambridge University Press, Cambridge, 1987. The disclosure is not intended to be limited in any manner by the exemplary listing of substituents provided herein.

[0024] As used herein, and unless otherwise specified, the term “alkyl” as used by itself or as part of another group refers to a straight- or branched-chain aliphatic saturated hydrocarbon. In some embodiments, the alkyl can include one to twelve carbon atoms (i.e., C1-12 alkyl) or the number of carbon atoms designated. In some embodiments, the alkyl group is a straight chain Ci-10 alkyl group. In another embodiment, the alkyl group is a branched chain C3-10 alkyl group. In another embodiment, the alkyl group is a straight chain C1-6 alkyl group. In another embodiment, the alkyl group is a branched chain C3-6 alkyl group. In another embodiment, the alkyl group is a straight chain Ci-4 alkyl group. For example, a Ci-4 alkyl group includes methyl, ethyl, propyl (e.g., n-propyl), isopropyl, butyl (e.g., n-butyl, sec-butyl, tert-butyl, iso-butyl). Unless otherwise specified, an alkyl group is optionally substituted. In some embodiments, an alkyl group is unsubstituted. In some embodiments, an alkyl group is substituted.

[0025] As used herein, and unless otherwise specified, the term “alkylene” as used by itself or as part of another group refers to a straight or branched multivalent (e.g., divalent or trivalent) hydrocarbon chain linking the rest of the molecule to a radical group (or groups), consisting solely of carbon and hydrogen, which is saturated. For example, non-limiting straight chain alkylene groups include -CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-, and the like. Unless otherwise specified, an alkylene group is optionally substituted. In some embodiments, an alkylene group is unsubstituted. In some embodiments, an alkylene group is substituted.

[0026] As used herein, and unless otherwise specified, the term “alkenyl” as used by itself or as part of another group refers to a straight- or branched-chain aliphatic hydrocarbonNAI-5008634746v1 -5-Attomey Docket No. 14709-051-228containing one or more (e.g., 1, 2, or 3) carbon-to-carbon double bonds. In some embodiments, the alkenyl group is a C2-6 alkenyl group. In another embodiment, the alkenyl group is a C2-4 alkenyl group. Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl. Unless otherwise specified, an alkenyl group is optionally substituted. In some embodiments, an alkenyl group is unsubstituted. In some embodiments, an alkenyl group is substituted.

[0027] As used herein, and unless otherwise specified, the term “alkynyl” as used by itself or as part of another group refers to a straight- or branched-chain aliphatic hydrocarbon containing one or more (e.g., 1, 2, or 3) carbon-to-carbon triple bonds. In some embodiments, the alkynyl has one carbon-carbon triple bond. In some embodiments, the alkynyl group is a C2-6 alkynyl group. In another embodiment, the alkynyl group is a C2-4 alkynyl group. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups. Unless otherwise specified, an alkynyl group is optionally substituted. In some embodiments, an alkynyl group is unsubstituted. In some embodiments, an alkynyl group is substituted.

[0028] As used herein, and unless otherwise specified, the term “aryl” as used by itself or as part of another group refers to a monocyclic aromatic group and / or multicyclic monovalent aromatic group that contain at least one aromatic hydrocarbon ring. In some embodiments, an aryl group has 6-14 ring carbon atoms (“Ce-14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“Ce aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“Cioaryl”; e.g., naphthyl such as 1 -naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“Cuaryl”; e.g., anthracyl). The term “aryl” also refers to bicyclic, tricyclic, or other multicyclic hydrocarbon rings, where at least one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl). As used herein, and unless otherwise specified, the term “arylene” as used by itself or as part of another group refers to a multivalent (e.g., divalent) radical derived from the aryl group defined herein. Unless otherwise specified, an aryl / arylene group is optionally substituted. In some embodiments, an aryl / arylene group is unsubstituted. In some embodiments, an aryl / arylene group is substituted.

[0029] As used herein, and unless otherwise specified, the term “carbocyclyl” or “carbocyclic” as used by itself or as part of another group refers to a radical of a non-aromatic cyclic hydrocarbon group having at least 3 carbon atoms, e.g., from 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”), and zero heteroatoms in the non-aromatic ring system. The carbocyclylNAI-5008634746v1 -6-Attomey Docket No. 14709-051-228group can be either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) and can be saturated or can be partially unsaturated. Non-limiting exemplary carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbomyl, decalin, adamantyl, cyclopentenyl, and cyclohexenyl. As used herein, the term “carbocyclylene” as used by itself or as part of another group refers to a multivalent (e.g., divalent) radical derived from the carbocyclyl group defined herein. Unless otherwise specified, a carbocyclyl group is optionally substituted. In some embodiments, a carbocyclyl group is unsubstituted. In some embodiments, a carbocyclyl groups is substituted. In some embodiments, “carbocyclyl” is fully saturated, which is also referred to as “cycloalkyl.” In some embodiments, the cycloalkyl can have from 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In some embodiments, the cycloalkyl is a monocyclic ring.

[0030] As used herein, and unless otherwise specified, the term “halo” or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0031] As used herein, and unless otherwise specified, the term “heteroalkyl” as used by itself or in combination with another term refers to a stable straight or branched-chain alkyl group, e.g., having from 2 to 14 carbons, such as 2 to 10 carbons in the chain, wherein one or more of the carbon(s) has been replaced by a heteroatom selected from S, O, P and N, and wherein the N, P, and S atoms can optionally be oxidized and the nitrogen heteroatom can optionally be quaternized. The heteroatom(s) S, O, P and N may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. When the heteroalkyl is said to be substituted, the substituent(s) can replace one or more hydrogen atoms attached to the carbon atom(s) and / or the heteroatom(s) of the heteroalkyl. In some embodiments, the heteroalkyl is a Ci-4 heteroalkyl, which refers to the heteroalkyl defined herein having 1-4 carbon atoms. Examples of Ci-4 heteroalkyl include, but are not limited to, C4 heteroalkyl such as -CH2-CH2-N(CH3)-CH3, C3 heteroalkyl such as -CH2-CH2-0-CH3, -CH2-CH2-NH-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, and -CH2-CH2-S(O)2-CH3, C2 heteroalkyl such as -CH2-CH2-OH, -CH2-CH2-NH2, -CH2-NH(CH3), -and O-CH2-CH3, and Ci heteroalkyl such as, -CH2-OH, -CH2-NH2, and -O-CH3. In some embodiments, the Ci-4 heteroalkyl has 1 or 2 heteroatoms, such as those having one oxygen, one oxygen and one nitrogen, two oxygen atoms, or two nitrogen atoms. Unless otherwise specified, a heteroalkyl group is optionally substituted. In some embodiments, a heteroalkyl group is unsubstituted. In some embodiments, a heteroalkyl groups is substituted.NAI-5008634746v1 -7-Attomey Docket No. 14709-051-228

[0032] The term “heteroalkylene” as used by itself or as part of another substituent means a multivalent (e.g., divalent) radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-O-CH2-CH2- and -O-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. Unless otherwise specified, a heteroalkylene group is optionally substituted. In some embodiments, a heteroalkylene group is unsubstituted. In some embodiments, a heteroalkylene group is substituted.

[0033] As used herein, and unless otherwise specified, the term “heteroaryl” as used by itself or as part of another group refers to a radical of a monocyclic aromatic group and / or multicyclic aromatic group that contains at least one aromatic ring, wherein at least one aromatic ring contains one or more (e.g., 1, 2, 3, or 4) heteroatoms independently selected from O, S, and N. In one embodiment, the heteroaryl has, for example, 5 to 18 ring atoms (5- to 18-membered heteroaryl), 5 to 15 ring atoms (5- to 15-membered heteroaryl), 5 to 10 ring atoms (5- to 10-membered heteroaryl), or 5 to 8 ring atoms (5- to 8-membered heteroaryl). The heteroaryl may be attached to the main structure at any heteroatom or carbon atom. For example, in heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. In bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, and the like), the point of attachment can be on either ring, e.g., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). The term “heteroaryl” also refers to bicyclic, tricyclic, or other multicyclic rings, where at least one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S, and N. Unless otherwise specified, a heteroaryl group is optionally substituted. In some embodiments, a heteroaryl group is unsubstituted. In some embodiments, a heteroaryl groups is substituted.

[0034] Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation,NAI-5008634746v1 -8-Attomey Docket No. 14709-051-228tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl and pyri dinonyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotri azolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadi azolyl, benzthiazolyl, benzisothiazolyl, benzthiadi azolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0035] As used herein, and unless otherwise specified, “heteroatom”, refers to an atom of any element other than carbon or hydrogen, such as nitrogen, oxygen, and sulfur.

[0036] As used herein, and unless otherwise specified, the term “heterocyclyl” or “heterocyclic” as used by itself or as part of another group refers to a radical of a 3 -membered or larger, such as 3- to 18-membered, non-aromatic ring system having ring carbon atoms and at least one ring heteroatom (e.g., 1, 2, 3, or 4 ring heteroatoms), wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, wherein the N, P, and S atoms can optionally be oxidized and the nitrogen heteroatom can optionally be quaternized. In one embodiment, the heterocyclyl has, for example, 3 to 18 ring atoms (3- to 18-membered heterocyclyl), 4 to 18 ring atoms (4- to 18-membered heterocyclyl), 5 to 18 ring atoms (5- to 18-membered heterocyclyl), 4 to 8 ring atoms (4- to 8-membered heterocyclyl), or 5 to 8 ring atoms (5- to 8-membered heterocyclyl). The heterocyclyl may be attached to the main structure at any heteroatom or carbon atom. For example, in heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged, or spiro ring system, such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Saturated heterocyclyl groups can be termed “heterocycloalkyl”. Partially unsaturated heterocyclyl groups can be termed “heterocycloalkenyl” if the heterocyclyl contains at least one double bond, or “heterocycloalkynyl” if the heterocyclyl contains at least one triple bond. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings, and the point of attachment can be on any ring. Unless otherwise specified, a heterocyclyl group is optionallyNAI-5008634746v1 -9-Attomey Docket No. 14709-051-228substituted. In some embodiments, a heterocyclyl group is unsubstituted. In some embodiments, a heterocyclyl groups is substituted.

[0037] Exemplary 3 -membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a Ce aryl ring include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0038] As used herein and unless otherwise specified, a “cycloalkylalkyl” group is a radical of the formula: -alkyl-cycloalkyl, wherein alkyl and cycloalkyl are defined above.Substituted cycloalkylalkyl groups may be substituted at the alkyl, the cycloalkyl, or both the alkyl and the cycloalkyl portions of the group. Representative cycloalkylalkyl groups include but are not limited to cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cyclopentylpropyl, cyclohexylpropyl and the like.

[0039] As used herein and unless otherwise specified, an “aralkyl” group is a radical of the formula: -alkyl-aryl, wherein alkyl and aryl are defined above. Substituted aralkyl groups may be substituted at the alkyl, the aryl, or both the alkyl and the aryl portions of the group.NAI-5008634746v1 -10-Attomey Docket No. 14709-051-228Representative aralkyl groups include but are not limited to benzyl and phenethyl groups and aralkyl groups wherein the aryl group is fused to a cycloalkyl group such as indan-4-yl ethyl.

[0040] As used herein and unless otherwise specified, other similar composite terms mirror the above description for “cycloalkylalkyl” and “aralkyl”. For example, a “heterocyclylalkyl” group is a radical of the formula: -alkyl-heterocyclyl, wherein alkyl and heterocyclyl are defined above. A “heteroarylalkyl” group is a radical of the formula: -alkyl-heteroaryl, wherein alkyl and heteroaryl are defined above. A “heterocycloalkylalkyl” group is a radical of the formula: -alkyl-heterocycloalkyl, wherein alkyl and heterocycloalkyl are defined above.

[0041] The term “lower” when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer non-hydrogen atoms in the substituent, e.g., six or fewer. A “lower alkyl”, for example, refers to an alkyl group that contains ten or fewer non-hydrogen (e.g., carbon) atoms, e.g., six or fewer. In certain embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents.

[0042] As used herein, and unless otherwise specified, an “optionally substituted” group, such as an optionally substituted alkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl groups, refers to the respective group that is unsubstituted or substituted. In general, the term “substituted”, whether preceded by the term “optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent can be the same or different at each position. In some embodiments, when substituted, the optionally substituted groups provided herein can be substituted with 1-5 substituents. Substituents can be a carbon atom substituent, a nitrogen atom substituent, an oxygen atom substituent or a sulfur atom substituent, as applicable. Two of the optional substituents can join to form a ring structure, such as an optionally substituted cycloalkyl, heterocylyl, aryl, or heteroaryl ring. Substitution can occur on any available carbon, oxygen, or nitrogen atom, and can form a spirocycle.NAI-5008634746vl -11-Attomey Docket No. 14709-051-228

[0043] As used herein, and unless otherwise specified, the permissible substituents provided herein include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. The heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a cycloalkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, an aryl, or a heteroaryl, each of which can be substituted, if appropriate

[0044] Exemplary substituents include, but not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, -alkylene-aryl, -arylene-alkyl, -alkylene-heteroaryl, -alkenyl ene-heteroaryl, -alkynylene-heteroaryl, -OH, hydroxyalkyl, haloalkyl, -O-alkyl, -O-haloalkyl, -alkylene-O-alkyl, -O-aryl, -O-alkylene-aryl, acyl, -C(O)-aryl, halo, -NO2, -CN, -SFs, -C(O)OH, -C(O)O-alkyl, -C(O)O-aryl, -C(O)O-alkylene-aryl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)-aryl, -S(O)2-aryl, -S(O)-heteroaryl, -S(O)2-heteroaryl, -S-alkyl, -S-aryl, -S-heteroaryl, -S-alkylene-aryl, -S-alkylene-heteroaryl, -S(O)2-alkylene-aryl, -S(O)2-alkylene-heteroaryl, cycloalkyl, heterocyclyl, -O-C(O)-alkyl, -O-C(O)-aryl, -O-C(O)-cycloalkyl, -C(=N-CN)-NH2, -C(=NH)-NH2, -C(=NH)-NH(alkyl), -N(YI)(Y2), -alkylene-N(Yi)(Y2), -C(O)N(YI)(Y2) and -S(O)2N(YI)(Y2), wherein Yi and Y2 can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and -alkylene-aryl.

[0045] Some examples of suitable substituents include, but not limited to, (Ci-e)alkyl groups, (C2-Cs)alkenyl groups, (C2-Cs)alkynyl groups, (C3-Cio)cycloalkyl groups, halogen (F, Cl, Br or I), halogenated (Ci-e)alkyl groups (for example but not limited to -CF3), -O-(Ci-e)alkyl groups, -OH, -S-(Ci-e)alkyl groups, -SH, -NH(Ci-e)alkyl groups, -N((Ci-e)alkyl)2 groups, -NH2, -C(O)NH2, -C(O)NH(Ci-6)alkyl groups, -C(O)N((Ci-6)alkyl)2, -NHC(O)H, -NHC(O) (Ci-6)alkyl groups, -NHC(O) (C3-Cs)cycloalkyl groups, -N((Ci-6)alkyl)C(O)H, -N((Ci-6)alkyl)C(O)(Ci-e)alkyl groups, -NHC(0)NH2, -NHC(O)NH(Ci-e)alkyl groups, -N((Ci-e)alkyl)C(O)NH2 groups, -NHC(O)N((Ci-e)alkyl)2 groups, -N((Ci-6)alkyl)C(O)N((Ci-e)alkyl)2 groups,-N((Ci-6)alkyl)C(O)NH((Ci-6)alkyl), -C(O)H, -C(O)(Ci-6)alkyl groups, -CN, -NO2, -S(O)(Ci-e)alkyl groups, -S(O)2(Ci-e)alkyl groups, -S(O)2N((Ci-e)alkyl)2 groups, -S(O)2NH(Ci-6)alkylNAI-5008634746vl -12-Attomey Docket No. 14709-051-228groups, -S(O)2NH(C3-Cs)cycloalkyl groups, -S(O)2NH2 groups, -NHS(O)2(Ci-e)alkyl groups, -N((Ci-6)alkyl)S(O)2(Ci-e)alkyl groups, -(Ci-6)alkyl-O-(Ci-e)alkyl groups, -O-(Ci-e)alkyl-O-(Ci-e)alkyl groups, -C(O)OH, -C(O)O(Ci-e)alkyl groups, NHOH, NHO(Ci-e)alkyl groups, -O-halogenated (Ci-e)alkyl groups (for example but not limited to -OCF3), -S(O)2-halogenated (Ci-e)alkyl groups (for example but not limited to -S(O)2CF3), -S -halogenated (Ci-e)alkyl groups (for example but not limited to -SCF3), 3-6-membered heterocycle (for example but not limited to pyrrolidine, tetrahydrofuran, pyran or morpholine), 5-6-membered heteroaryl (for example but not limited to tetrazole, imidazole, furan, pyrazine or pyrazole), -phenyl, -NHC(O)O-(Ci-e)alkyl groups, -N((Ci-6)alkyl)C(O)O-(Ci-e)alkyl groups, -C(=NH)-(Ci-6)alkyl groups, -C(=NOH)-(Ci-e)alkyl groups, or -C(=N-O-(Ci-6)alkyl)-(Ci-6)alkyl groups.

[0046] Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -NO2, -N3, hydroxyl, alkoxy, cycloalkoxy, aryloxy, amino, monoalkyl amino, dialkyl amino, amide, sulfonamide, thiol, acyl, carboxylic acid, ester, sulfone, sulfoxide, alkyl, haloalkyl, alkenyl, alkynyl, C3-10 carbocyclyl, Ce-io aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, etc. For example, exemplary carbon atom substituents can include -F, -Cl, -CN, -SO2H, -SO3H, -OH, -OC1-6 alkyl, -NH2, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), -SH, -SC1-6 alkyl, -C(=O)(Ci-6alkyl), -CO2H, -CO2(Ci-6 alkyl), -OC(=O)(Ci-6 alkyl), -OCO2(Ci-6alkyl), -C(=O)NH2, -C(=O)N(CI-6alkyl)2, -OC(=O)NH(CI-6 alkyl), -NHC(=O)(CI-6 alkyl), -N(CI-6 alkyl)C(=O)(Ci-6alkyl), -NHCO2(CI-6alkyl), -NHC(=O)N(CI-6 alkyl)2, -NHC(=O)NH(CI-6 alkyl), -NHC(=0)NH2, -NHSO2(CI-6 alkyl), -SO2N(CI-6alkyl)2, -SO2NH(CI-6 alkyl), -SO2NH2,-SO2C1-6 alkyl, -SO2OC1-6 alkyl, -OSO2C1-6 alkyl, -SOC1-6 alkyl, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl, Ce-io aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal substituents can be joined to form =0.

[0047] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, acyl groups, esters, sulfone, sulfoxide, C1-10 alkyl, Ci-10 haloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl, or two substituent groups attached to a nitrogen atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl can be further substituted as defined herein. In certain embodiments, the substituent present on a nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group). Nitrogen protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, JohnNAI-5008634746vl -13-Attomey Docket No. 14709-051-228Wiley & Sons, 1999, incorporated by reference herein. Exemplary nitrogen protecting groups include, but not limited to, those forming carbamates, such as Carbobenzyloxy (Cbz) group, p-Methoxybenzyl carbonyl (Moz or MeOZ) group, tert-Butyloxycarbonyl (BOC) group, Troc, 9-Fluorenylmethyloxycarbonyl (Fmoc) group, etc., those forming an amide, such as acetyl, benzoyl, etc., those forming a benzylic amine, such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, etc., those forming a sulfonamide, such as tosyl, nosyl, etc., and others such as p-methoxyphenyl.

[0048] Exemplary oxygen atom substituents include, but are not limited to, acyl groups, esters, sulfonates, Ci-io alkyl, Ci-io haloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl can be further substituted as defined herein. In certain embodiments, the oxygen atom substituent present on an oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Oxygen protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis^. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference. Exemplary oxygen protecting groups include, but are not limited to, those forming alkyl ethers or substituted alkyl ethers, such as methyl, allyl, benzyl, substituted benzyls such as 4-methoxybenzyl, methoxylmethyl (MOM), benzyloxymethyl (BOM), 2-methoxy ethoxymethyl (MEM), etc., those forming silyl ethers, such as trymethylsilyl (TMS), triethylsilyl (TES), triisopropyl silyl (TIPS), t-butyldimethylsilyl (TBDMS), etc., those forming acetals or ketals, such as tetrahydropyranyl (THP), those forming esters such as formate, acetate, chloroacetate, di chloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, etc., those forming carbonates or sulfonates such as methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts), etc.

[0049] Unless expressly stated to the contrary, combinations of substituents and / or variables are allowable only if such combinations are chemically allowed and result in a stable compound. A “stable” compound is a compound that can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic administration to a subject).

[0050] In some embodiments, the “optionally substituted” alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, carbocyclic, carbocyclylene, cycloalkyl, cycloalkylene, alkoxy, cycloalkoxy, aryl, arylene, phenyl, heteroaryl, heteroarylene, heterocyclyl, or heterocyclylene herein can each be independently unsubstituted or substituted with 1, 2, 3, or 4 instances of Rp,NAI-5008634746vl -14-Attomey Docket No. 14709-051-228wherein each instance of Rpis independently selected from halogen (e.g., -F, -Cl, Br-, or I), -OH, oxo (as applicable), -NO2, -CN, -NH2, -NH(CI-4 alkyl), -N(Ci-4alkyl)2, C1-6 alkyl, C2-4 alkenyl, C2-4alkynyl, C1-6 alkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, phenyl, 5- or 6-membered heteroaryl containing 1, 2, or 3 ring heteroatoms independently selected from O, S, and N, or 3- to 7-membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, and wherein each of the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy, phenyl, heteroaryl, and heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from halogen, -NO2, -CN, -NH2, -NH(CI-4 alkyl), -N(Ci-4alkyl)2, oxo (as applicable), Ci-4 alkyl, Ci-4haloalkyl, Ci-4 alkoxy, C2-4 alkenyl, C2-4 alkynyl, phenyl, 5- or 6-membered heteroaryl, and 3- to 7-membered heterocyclyl. In some embodiments, the “optionally substituted” aryl, arylene, heteroaryl or heteroarylene group herein can each be independently unsubstituted or substituted with 1, 2, 3, or 4 instances of Rp, wherein each instance of Rpis independently selected from halogen (e.g., -F, -Cl, Br-, or I), -OH, -NO2, -CN, -NH2, -NH(CI-4 alkyl), -N(CI-4 alkyl)2, C1-6 alkyl, C3-6 cycloalkyl, phenyl, 5- or 6-membered heteroaryl containing 1, 2, or 3 ring heteroatoms independently selected from O, S, and N, or 3- to 7-membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, and wherein each of the alkyl, cycloalkyl, phenyl, heteroaryl, and heterocyclyl, is optionally substituted with 1, 2, or 3 substituents independently selected from halogen, -NO2, -CN, -NH2, -NH(CI-4 alkyl), -N(CI-4 alkyl)2, Ci-4 alkyl, Ci-4haloalkyl, Ci-4 alkoxy, phenyl, 5- or 6-membered heteroaryl, and 3- to 7-membered heterocyclyl, wherein the heteroaryl contains 1, 2 or 3 ring heteroatoms independently selected from O, S, and N, and the heterocyclyl contains 1 or 2 ring heteroatoms independently selected from O, S, and N.

[0051] As used herein and unless otherwise specified, “cancer” refers to any malignant and / or invasive growth or tumor caused by abnormal cell growth, including solid tumors named for the type of cells that form them, cancer of blood, bone marrow, or the lymphatic system. Examples of solid tumors include but not limited to sarcomas and carcinomas. Examples of cancers of the blood include but not limited to leukemias, lymphomas and myeloma. Cancer includes, but not limited to a primary cancer that originates at a specific site in the body, a metastatic cancer that has spread from the place in which it started to other parts of the body, a recurrence from the original primary cancer after remission, and a second primary cancer that is a new primary cancer in a person with a history of previous cancer of different type from latter one. In some embodiments, the cancer is a solid tumor.

[0052] As used herein and unless otherwise specified, “abnormal cell growth” refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition).NAI-5008634746vl -15-Attomey Docket No. 14709-051-228Abnormal cell growth may be benign (not cancerous), or malignant (cancerous). In some embodiments of the methods provided herein, the abnormal cell growth is cancer. In some embodiments, the abnormal cell growth is cancer associated with aberrant activity of AKT. In some embodiments, the abnormal cell growth is cancer associated with a mutant AKT.

[0053] As used herein, and unless otherwise specified, the terms “treat,” “treating,” “treatment,” and the like refer to eliminating, reducing, or ameliorating a disease or condition, and / or symptoms associated therewith. Although not precluded, treating a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated.

[0054] As used herein, and unless otherwise specified, the terms “prevent,” “preventing,” “prevention,” and the like refer to reducing the probability of the onset of a disease or condition, of redeveloping a disease or condition, or of a recurrence of a previously-controlled disease or condition, in a subject who does not have, but is at risk of or is susceptible to, developing or redeveloping a disease or condition or a recurrence of the disease or condition.

[0055] As used herein, and unless otherwise specified, the terms “manage,” “managing,” and “management” refer to the beneficial effects that a subject derives from a therapy (e.g., a prophylactic or therapeutic agent), which does not result in a cure of the disease. In certain embodiments, a subject is administered one or more therapies to “manage” a disease, one or more symptoms thereof, so as to prevent the progression or worsening of the disease.

[0056] As used herein, and unless otherwise specified, the term “effective amount” refers to that amount of a compound or combination of compounds provided herein that is sufficient to affect the intended application including, but not limited to, prophylaxis or treatment of diseases. A therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated (e.g., the weight, age, and gender of the subject), the severity of the disease condition, the manner of administration, etc. which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells and / or tissues. The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether the compound is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which the compound is carried.

[0057] A “response” to a method of treatment can include a decrease in or amelioration of negative symptoms, a decrease in the progression of a disease or symptoms thereof, anNAI-5008634746vl -16-Attomey Docket No. 14709-051-228increase in beneficial symptoms or clinical outcomes, a lessening of side effects, stabilization of disease, partial or complete remedy of disease, among others.

[0058] As used herein, and unless otherwise specified, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. As used herein, and unless otherwise specified, the term “pharmaceutically acceptable salt” includes both acid and base addition salts.

[0059] Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, salts formed with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-di chloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthal ene-2-sulfonic acid, 1 -hydroxy -2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like.

[0060] Examples of pharmaceutically acceptable base addition salt include, but are not limited to, salts prepared from addition of an inorganic base or an organic base to a free acid compound. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. In some embodiments, the inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine,NAI-5008634746vl -17-Attomey Docket No. 14709-051-228ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like.

[0061] As used herein, and unless otherwise specified, the term “isomer” refers to different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A mixture of a pair of enantiomers in any proportion can be known as a “racemic” mixture. “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry can be specified according to the Cahn-Ingold-Prelog R-S system. When a compound is an enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. However, the sign of optical rotation, (+) and (-), is not related to the absolute configuration of the molecule, R and S. Certain compounds provided herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry at each asymmetric atom, as (R)- or (S)-. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic mixtures, optically substantially pure forms, and intermediate mixtures.Optically active (R)- and (5)- isomers can be prepared, for example, using chiral synthons or chiral reagents, or resolved using conventional techniques.

[0062] Stereoisomers” can also include E and Z isomers, or a mixture thereof, and cis and trans isomers or a mixture thereof. In certain embodiments, a compound provided herein is isolated as either the E or Z isomer. In other embodiments, a compound provided herein is a mixture of the E and Z isomers.

[0063] Tautomers” refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution. For example, in aqueous solution, pyrazoles and naphthyridinones may exhibit the following isomeric forms, which are referred to as tautomers of each other:NAI-5008634746vl -18-Attomey Docket No. 14709-051-2284.2 Compounds

[0064] In one aspect, provided herein is a compound of Formula (I):(I),or a stereoisomer, a mixture of stereoisomers, a tautomer, or a pharmaceutically acceptable salt thereof,wherein:Ring A is phenyl or 5- to 10-membered heteroaryl;each of X1, X2, X3, and X4is independently CRX, C(=O), N, or NRxn, as valency permits; X5is CRxor N;X6is CRxor N;each instance of Rxis independently hydrogen, CN, halogen, -NRn2Rn3, -OR01, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted 5- to 10-membered heterocyclyl, or optionally substituted 5- to 10-membered heteroaryl; or two Rxtogether with the atoms to which they are attached form an optionally substituted 5- to 6-membered heterocyclyl or an optionally substituted 5- to 6-membered heteroaryl;each instance of Rxnis independently hydrogen, optionally substituted C1-3 alkyl, optionally substituted C3-4 cycloalkyl, or optionally substituted 4- to 6-membered heterocyclyl;each instance of RO1is independently hydrogen or optionally substituted C1-6 alkyl; L’ is optionally substituted C1-12 alkylene, wherein one or more -CH2- in the alkylene is independently optionally replaced by -C(=O)-NRn1-, -NRnl-C(=O)-, -NRn1-, -O-, -C(=O)-, or optionally substituted 3- to 12-membered ring moiety, as valency permits;each instance of Rais independently halogen, -ORC, optionally substituted C1-6 alkyl, -C(=O)H, -NRn4Rn5, or optionally substituted 3- to 8-membered heterocyclyl;each instance of Rcis independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C3-6 cycloalkyl, optionally NAI-5008634746vl -19-Attomey Docket No. 14709-051-228substituted 3- to 6-membered heterocyclyl, optionally substituted phenyl, or optionally substituted 5- to 6-membered heteroaryl;each instance of Rnl, Rn2, Rn3, Rn4, and Rn5is independently hydrogen, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, -C(=O)Rd, or -C(=O)ORd;or Rn2and Rn3together with the nitrogen to which they are attached form an optionally substituted 3- to 6-membered heterocyclyl or an optionally substituted 5- to 6-membered heteroaryl;or Rn4and Rn5together with the nitrogen to which they are attached form an optionally substituted 3- to 6-membered heterocyclyl or an optionally substituted 5- to 6-membered heteroaryl;each instance of Rdis independently hydrogen or optionally substituted Ci-6 alkyl; and n is 0, 1, 2, 3, 4, 5, 6, 7, or 8 as valency permits.

[0065] In one embodiment, provided that: when L’ comprises optionally substituted 3- to 12-membered ring moiety, then (i) two of X1, X2, X3, and X4are N or NRxn; or (ii) X4is C(=O), X3is NRxn, and Rxnis not hydrogen; or both (i) and (ii). In one embodiment, condition (i) is met. In one embodiment, condition (ii) is met. In one embodiment, both conditions (i) and (ii) are met.

[0066] In one embodiment, the compound is a compound of Formula (I-A), (I-B), or (I- C):or a stereoisomer, a mixture of stereoisomers, a tautomer, or a pharmaceutically acceptable salt thereof.NAI-5008634746vl -20-Attomey Docket No. 14709-051-228

[0067] In one embodiment, the compound is a compound of Formula (I-A):(I-A),or a stereoisomer, a mixture of stereoisomers, a tautomer, or a pharmaceutically acceptable salt thereof,wherein:Ring A is phenyl or 5- to 10-membered heteroaryl;each of X1, X2, X3, and X4is independently CRX, C(=O), N, or NRxn, as valency permits; each instance of Rxis independently hydrogen, halogen, -NRn2Rn3, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, or optionally substituted 5- to 10-membered heteroaryl;each instance of Rxnis independently hydrogen, optionally substituted C1-3 alkyl, optionally substituted C3-4 cycloalkyl, or optionally substituted 4- to 6-membered heterocyclyl;L’ is optionally substituted C1-12 alkylene, wherein one or more -CH2- in the alkylene is independently optionally replaced by -C(=O)-NRn1-, -NRnl-C(=O)-, -NRn1-, -O-, or optionally substituted 3- to 12-membered ring moiety, as valency permits;each instance of Rais independently halogen, -ORC, optionally substituted C1-6 alkyl, -C(=O)H, -NRn4Rn5, or optionally substituted 3- to 8-membered heterocyclyl;each instance of Rcis independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C3-6 cycloalkyl, optionally substituted 3- to 6-membered heterocyclyl, optionally substituted phenyl, or optionally substituted 5- to 6-membered heteroaryl;each instance of Rnl, Rn2, Rn3, Rn4, and Rn5is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, or -C(=O)Rd;or Rn2and Rn3together with the nitrogen to which they are attached form an optionally substituted 3- to 6-membered heterocyclyl or an optionally substituted 5- to 6-membered heteroaryl;NAI-5008634746vl -21-Attomey Docket No. 14709-051-228or Rn4and Rn5together with the nitrogen to which they are attached form an optionally substituted 3- to 6-membered heterocyclyl or an optionally substituted 5- to 6-membered heteroaryl;each instance of Rdis independently hydrogen or optionally substituted Ci-6 alkyl; and n is 0, 1, 2, 3, 4, 5, 6, 7, or 8 as valency permits.

[0068] In one embodiment, L’ is -X-Q-L-, wherein:X is a bond, -NRn1-, -O-, optionally substituted C1-3 alkylene, or optionally substituted Ci-3 heteroalkylene;Q is -C(=O)-NRn1-, -NRnl-C(=O)-, or optionally substituted 3- to 12-membered ring moiety; andL is a bond, -NRn1-, -O-, -C(=O)-, optionally substituted C1-6 alkylene, or optionally substituted C1-6 heteroalkylene.

[0069] In one embodiment, L’ is -X-Q-L-, wherein:X is a bond, -NRn1-, -O-, optionally substituted C1-3 alkylene, or optionally substituted Ci-3 heteroalkylene;Q is -C(=O)-NRn1-, -NRnl-C(=O)-, or optionally substituted 3- to 12-membered ring moiety; andL is a bond, -NRn1-, -O-, optionally substituted C1-3 alkylene, or optionally substituted C1-3 heteroalkylene.

[0070] Unless otherwise specified, X is toward the direction of the phenyl ring in Formula (I), and L is toward the direction of the cyanopyrimidine in Formula (I).

[0071] In one embodiment, X is a bond. In one embodiment, X is optionally substituted C1-3 alkylene. In one embodiment, X is -CR1R2-, wherein each of R1and R2is independently hydrogen, halogen, optionally substituted C1-6 alkyl, or optionally substituted C1-6 heteroalkyl.

[0072] In one embodiment, Q is optionally substituted C3-6 cycloalkylene (e.g., cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, or cycloheptylene). In one embodiment, Q is optionally substituted 3- to 8-membered heterocyclylene (e.g., piperidinylene, piperazinylene, morpholinylene, or pyrrolidinylene). In one embodiment, Q is -C(=O)-NRn1-. In one embodiment, Q is -NRnl-C(=O)-. Unless otherwise specified, in these embodiments, the left side is toward the direction of the phenyl ring in Formula (I), and the right side is toward the direction of the cyanopyrimidine in Formula (I).

[0073] In one embodiment, the compound is a compound of Formula (II-A-1), (II-A-2), or (ILA-3):NAI-5008634746vl -22-Attorney Docket No. 14709-051-228or a stereoisomer, a mixture of stereoisomers, a tautomer, or a pharmaceutically acceptable salt thereof.NAI-5008634746vl -23-Attorney Docket No. 14709-051-228

[0077] In one embodiment, the compound is a compound of Formula (II-B-1), (II-B-2), or (n-B-3):(II-B-1),NAI-5008634746vl -24-Attorney Docket No. 14709-051-228or a stereoisomer, a mixture of stereoisomers, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:each of R1and R2is independently hydrogen, halogen, optionally substituted Ci-6 alkyl, or optionally substituted Ci-6 heteroalkyl;Ring C is 4- to 12-membered heterocyclyl;each instance of R° is independently hydrogen, deuterium, CN, halogen, hydroxy, or optionally substituted Ci-6 alkyl; or two instances of R°, together with the intervening atom(s), form an optionally substituted 3- to 6-membered ring; andp is 0, 1, 2, 3, 4, 5, 6, 7, or 8 as valency permits.

[0078] In one embodiment, the compound is a compound of Formula (II-B-l-a), (II-B-1-b), (II-B-l-c), (II-B-l-d), (II-B-2-a), (II-B-2-b), (II-B-2-c), (II-B-3-d), (II-B-3-a), (II-B-3-b), (II-B-3-c), or (II-B-3-d):(II-B-l-c), (II-B-l-d),NAI-5008634746vl -25-Attorney Docket No. 14709-051-228RxnI(II-B-2-b), RxnI(II-B-2-c), (II-B-2-d), Rxn RxnI(II-B-3-a), (II-B-3-b), RxnRxn(II-B-3-c), or or a stereoisomer, a mixture of stereoisomers, a tautomer, or a pharmaceutically acceptable salt thereof.

[0079] In one embodiment, each instance of R° is independently hydrogen, deuterium, or optionally substituted Ci-6 alkyl; or two instances of R°, together with the intervening atom(s), form an optionally substituted 3- to 6-membered ring. In one embodiment, R° is halogen (e.g., F). In one embodiment, R° is hydroxy. In one embodiment, R° is C1-3 alkyl (e.g., methyl).NAI-5008634746vl -26-Attorney Docket No. 14709-051-228

[0080] In one embodiment, Ring C is 4- to 6-membered heterocyclyl. In one embodiment, the 4- to 6- membered heterocycle comprises 1 heteroatom. In one embodiment, the 4- to 6- membered heterocycle comprises 2 heteroatoms. In one embodiment, the heteroatom(s) are selected from N, O, and S. In one embodiment, Ring C is piperidinyl. In one embodiment, Ring C is piperazinyl. In one embodiment, Ring C is morpholinyl. In one embodiment, Ring C is pyrrolidinyl.HN^)t

[0081] In one embodiment,(Ris (R\ wherein Y is C, CH, orN, as valency permits; s is 0, 1, or 2; and t is 0, 1, or 2. In one embodiment, Y is C. In one embodiment, Y is CH. In one embodiment, Y is N. In one embodiment, two instances of R°, together with the intervening atom(s), form an optionally substituted 3- to 6-membered ring (e.g., the ring formed by R° and Ring C together is fused ring or bridged ring).

[0082] In one embodiment,

[0083] In one embodiment, the compound is a compound of Formula (II-C-1), (II-C-2), or (n-C-3):NAI-5008634746vl -27-Attorney Docket No. 14709-051-228or a stereoisomer, a mixture of stereoisomers, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:each of R1and R2is independently hydrogen, halogen, optionally substituted Ci-6 alkyl, or optionally substituted C1-6 heteroalkyl.

[0084] In one embodiment, at least one of X1, X2, X3, X4, X5, and X6is N or NRxn, as valency permits. In one embodiment, at least one of X1, X2, X3, and X4is N or NRxn, as valency permits. In one embodiment, at least one of X5and X6is N. In one embodiment, at least one of X1, X2, X3, and X4is N or NRxn, as valency permits; and at least one of X5and X6is N. In one embodiment, at least one of X1, X2, X3, and X4is N or NRxn, as valency permits; at least one of X5and X6is N; and Rxnis optionally substituted C1-3 alkyl, optionally substituted C3-4 cycloalkyl, or optionally substituted 4- to 6-membered heterocyclyl. In one embodiment, at least one of X1, X2, X3, and X4is N or NRxn, as valency permits; at least one of X5and X6is N; and Rxnis optionally substituted C1-3 alkyl.

[0085] As used herein and unless otherwise specified, the bicyclic fused ring^X, X4DIC X1b), wherein a indicates the point of attachment to the phenyl ring connected to L’ and b indicates the point of attachment to Ring A, is a bicyclic ring system, including cases where one or more adjacent pairs of X1, X2, X3, and X4together is C(=O)-NRxn, with the remainder of the ring system aromatic or conjugated. For example, in oneNAI-5008634746vl -28-Attorney Docket No. 14709-051-228does not include those cases where one or more adjacent pairs of X1, X2, X3, and X4together is C(=O)-NRxn, and the remainder of the ring system is saturated or partiallyNAI-5008634746vl -29-Attomey Docket No. 14709-051-228NAI-5008634746vl -30-Attorney Docket No. 14709-051-228attachment to the phenyl ring connected to L’ and b indicates the point of attachment to Ring A.

[0087] In one embodiment, X1is C(=O). In one embodiment, X1is CRX. In one embodiment, X1is CH. In one embodiment, X1is NRxn. In one embodiment, X1is N. In one embodiment, X2is C(=O). In one embodiment, X2is CRX. In one embodiment, X2is CH. In one embodiment, X2is NRxn. In one embodiment, X2is N. In one embodiment, X3is C(=O). In one embodiment, X3is CRX. In one embodiment, X3is CH. In one embodiment, X3is NRxn. In one embodiment, X3is N. In one embodiment, X4is C(=O). In one embodiment, X4is CRX. In one embodiment, X4is CH. In one embodiment, X4is NRxn. In one embodiment, X4is N.

[0088] In one embodiment, one adjacent pair of X1, X2, X3, and X4together is C(=O)-NRxn. In one embodiment, X1and X2together is C(=O)-NRxn. In one embodiment, X1and X2together is *C(=O)-NRxn. In one embodiment, X1and X2together is *NRxn-C(=O). In one embodiment, X2and X3together is C(=O)-NRxn. In one embodiment, X2and X3together is *C(=O)-NRxn. In one embodiment, X2and X3together is *NRxn-C(=O). In one embodiment, X3and X4together is C(=O)-NRxn. In one embodiment, X3and X4together is *C(=O)-NRxn. In one embodiment, X3and X4together is *NRxn-C(=O). Unless otherwise specified, * in these embodiments refers to the direction of X1.NAI-5008634746vl -31-Attomey Docket No. 14709-051-228

[0089] In one embodiment, two adjacent pairs of X1, X2, X3, and X4together is C(=O)-NRxn. In one embodiment, X1and X2together is C(=O)-NRxn, and X3and X4together is C(=O)-NRxn.

[0090] In one embodiment, X1is C(=O), X2is NRxn, X3is CRX, and X4is CRX. In one embodiment, X1is CRX, X2is CRX, X3is NRxn, and X4is C(=O). In one embodiment, X1is CRX, X2is CRX, X3is C(=O), and X4is NRxn. In one embodiment, X1is CRX, X2is NRxn, X3is C(=O), and X4is CRX. In one embodiment, X1is CRX, X2is C(=O), X3is NRxn, and X4is CRX. In one embodiment, X1is NRxn, X2is C(=O), X3is CRX, and X4is CRX. In one embodiment, X1is C(=O), X2is NRxn, X3is N, and X4is CRXIn one embodiment, X1is CRX, X2is N, X3is NRxn, and X4is C(=O). In one embodiment, at least one CRXis CH. In one embodiment, NRxnis NH. In one embodiment, Rxnis optionally substituted C1-3 alkyl, optionally substituted C3-4 cycloalkyl, or optionally substituted 4- to 6-membered heterocyclyl. In one embodiment, Rxnis optionally substituted C1-3 alkyl. In one embodiment, NRxnis NC1-3 alkyl. In one embodiment, NRxnis NCH3. In one embodiment, NRxnis NCD3. In one embodiment, NRxnis NCHF2. In one embodiment, NRxnis NCF3.

[0091] In one embodiment, X1is N, X2is CRX, X3is CRX, and X4is CRX. In one embodiment, X1is CRX, X2is N, X3is CRX, and X4is CRX. In one embodiment, X1is CRX, X2is CRX, X3is N, and X4is CRX. In one embodiment, X1is CRX, X2is CRX, X3is CRX, and X4is N. In one embodiment, X1is CRX, X2is N, X3is CRX, and X4is N. In one embodiment, X1is CRX, X2is N, X3is N, and X4is CRX. In one embodiment, X1is N, X2is CRX, X3is N, and X4is CRX.

[0092] In one embodiment, X5is CRX. In one embodiment, X5is CH. In one embodiment, X5is N. In one embodiment, X6is CRX. In one embodiment, X6is CH. In one embodiment, X6is N.

[0093] In one embodiment, at least one of X5and X6is N. In one embodiment, X5is N and X6is CRX(e.g., CH). In one embodiment, X5is CRX(e.g., CH) and X6is N. In one embodiment, X5is N and X6is N.

[0094] In one embodiment, Ring A is phenyl.

[0095] In one embodiment, Ring A is 5- to 10-membered heteroaryl. In one embodiment, Ring A is 5- to 6-membered heteroaryl. In one embodiment, Ring A comprises 1 heteroatom. In one embodiment, Ring A comprises 2 heteroatoms. In one embodiment, the heteroatom(s) of Ring A are selected from N, O, and S.

[0096] In one embodiment, Ring A is 5-membered heteroaryl. In one embodiment, Ring A is thiazolyl, pyrazolyl, pyrrolyl, pyrrol onyl, pyrazolonyl, or isothiazolonyl. In one embodiment, Ring A is thiazolyl (e.g., 5-thiazolyl). In one embodiment, Ring A is pyrazolylNAI-5008634746vl -32-Attomey Docket No. 14709-051-228(e.g., 3-pyrazolyl or 4-pyrazolyl). In one embodiment, Ring A is thiophenyl (e.g., 5-thiophenyl). In one embodiment, Ring A is pyrrolyl (e.g., 5-pyrrolyl). In one embodiment, Ring A is furyl e.g., 5-furyl). In one embodiment, Ring A is imidazolyl e.g., 5-imidazolyl). In one embodiment, Ring A is oxazolyl e.g., 5-oxazolyl). In one embodiment, Ring A is imidazolyl e.g., 2-imidazolyl). In one embodiment, Ring A is pyrazolyl e.g., 4-pyrazolyl). In one embodiment, Ring A is pyrrolonyl. In one embodiment, Ring A is pyrazolonyl. In one embodiment, Ring A is isothiazolonyl.

[0097] In one embodiment, Ring A is 6-membered heteroaryl. In one embodiment, Ring A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridinonyl. In one embodiment, Ring A is pyridinyl. In one embodiment, Ring A is 2-pyridinyl. In one embodiment, Ring A is 3-pyridinyl. In one embodiment, Ring A is 4-pyridinyl. In one embodiment, Ring A is pyrimidinyl. In one embodiment, Ring A is 5-pyrimidinyl. In one embodiment, Ring A is pyranyl e.g., 5-pyranyl). In one embodiment, Ring A is pyridazinyl e.g., 5-pyridazinyl). In one embodiment, Ring A is pyrazinyl. In one embodiment, Ring A is oxazinyl e.g., 1, 2-oxaziyl, 1,3-oxazinyl, 1,4-oxazinyl). In one embodiment, Ring A is thiopyranyl e.g., 4-thiopyranyl). In one embodiment, Ring A is pyridinonyl. In one embodiment, n is 0 or 1. In one embodiment, Rais -NRn4Rn5e.g., -NH2).

[0098] In one embodiment, the Ring A described herein is unsubstituted i.e., n is 0). In one embodiment, the Ring A described herein is substituted (i.e., n is 1, 2, 3, 4, 5, 6, 7, or 8 as valency permits). In one embodiment, the Ring A described herein is monosubstituted (i.e., n is 1). In one embodiment, the Ring A described herein is disubstituted i.e., n is 2).

[0099] In one embodiment, the compound is a compound of Formula (III-A-1), (III-A-2), (ni-A-3), (III-A-4), (III-A-5), (ni-B-1), (III-B-2), (III-B-3), (III-B-4), (III-B-5), (III-B-6), (III-B-7), (III-B-8), (III-B-9), (III-B-10), (III-B-11), (III-B-12), (III-B-13), (III-B-14), (III-B-15), or (III-NAI-5008634746vl -33-Attomey Docket No. 14709-051-228Rx(III-A-3), _ (III-A-4),RXnRxI_ (III-A-5), _ (in-B-1), RxnRx(in-B-2), _ (in-B-3),Rxn(in-B-4), (in-B-5),NAI-5008634746vl -34-Attomey Docket No. 14709-051-228NAI-5008634746vl -35-Attomey Docket No. 14709-051-228or a stereoisomer, a mixture of stereoisomers, a tautomer, or a pharmaceutically acceptable salt thereof, whereinA1is CH or N.

[0100] In one embodiment, A1is CH. In one embodiment, A1is N.

[0101] In one embodiment, L is a bond, -NRl1-, -O-, -C(=O)-, or optionally substituted Ci-3 alkylene. In one embodiment, L is a bond, -NR111-, -O-, or optionally substituted C1-3 alkylene. In one embodiment, L is a bond. In one embodiment, L is -O-. In one embodiment, L is -C(=O)-. In one embodiment, L is -NR111-. In one embodiment, L is -NH-. In one embodiment, L is -N(CH3)-. In one embodiment, L is -N(CD3)-. In one embodiment, L is -N(C(=O)Rd)-. In one embodiment, L is -N(C(=O)ORd)-.

[0102] In one embodiment, L is optionally substituted C1-6 alkylene. In one embodiment, L is C1-6 alkylene optionally substituted with 1 to 3 instances of Rp, wherein Rpis defined herein. In one embodiment, L is C1-6 alkylene optionally substituted with 1 to 3 instances of Rp, wherein Rpis independently halogen, CN, NO2, -OH, NH2, N(CI-3 alkyl)2, C1-5 alkyl, or C1-5 haloalkyl. In some embodiments, Rpis C1-5 alkyl. In one embodiment, L is C1-6 alkylene optionally substituted with 1 to 3 instances of Rp, wherein Rpis halogen, C1-5 alkyl, or C3-5 cycloalkyl. In one embodiment, L is substituted C1-6 alkylene. In one embodiment, L is unsubstituted C1-6 alkylene. In one embodiment, L is optionally substituted C1-3 alkylene. In one embodiment, L is substituted C1-3 alkylene. In one embodiment, L is unsubstituted C1-3 alkylene.

[0103] In one embodiment, L is -(CR3R4)I-6-. In one embodiment, L is -CR3R4-. In one embodiment, L is -(CR3R4)2-. In one embodiment, L is -(CR3R4)3-. In one embodiment, L isNAI-5008634746vl -36-Attorney Docket No. 14709-051-228-(CR3R4)4-. In instances where R3and R4are different, each instance of CR3R4may independently exhibit R or S stereochemistry.

[0104] In one embodiment, L is methylene (i.e., -CH2-). In one embodiment, L is ethylene i.e., -CH2CH2-). In one embodiment, L is -CH(CH )-. In one embodiment, L is -CH(CH3)- and exhibits R stereochemistry. In one embodiment, L is -CH(CH )- and exhibits S stereochemistry. In one embodiment, L is -CH(CF3)-. In one embodiment, L is -CH(CF3)- and exhibits R stereochemistry. In one embodiment, L is -CH(CF3)- and exhibits S stereochemistry. In one embodiment, L is -C(CH3)2-. In one embodiment, L is -CH(isopropyl)-. In one embodiment, L is -CH(isopropyl)- and exhibits S stereochemistry. In one embodiment, L is -CH(isopropyl)- and exhibits R stereochemistry. In one embodiment, L is, wherein thewavy line represents attachment to the rest of the molecule. In one embodiment, L iswherein the wavy line represents attachment to the rest of the molecule.

[0105] In one embodiment, L is an optionally substituted C1-6 heteroalkylene (e.g., optionally substituted with 1 to 3 instances of Rp). In one embodiment, L is a substituted C1-6 heteroalkylene. In one embodiment, L is an unsubstituted C1-6 heteroalkylene. In one embodiment, the heteroalkylene comprises 1 heteroatom. In one embodiment, the heteroalkylene comprises 2 heteroatoms. In one embodiment, the heteroatom(s) of the heteroalkylene are selected from N, O, and S. In one embodiment, the heteroatom is N.

[0106] In one embodiment, L is -O(CR3R4)I-6-*, wherein * is to the direction of the cyanopyrimidine in Formula (I), and each instance of R3and R4is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, orR3andR4are taken together with the carbon they are attached to form an optionally substituted C3-6 cycloalkyl or optionally substituted 3- to 6-membered heterocyclyl.

[0107] In one embodiment, L is -OCR3R4-*. In one embodiment, L is -O(CR3R4)2-*. In one embodiment, L is -O(CR3R4)3-*. In one embodiment, L is -O(CR3R4)4-*. In instances where R3and R4are different, each instance of CR3R4may independently exhibit R or S stereochemistry.

[0108] In one embodiment, L is -OCH2-*. In one embodiment, L is -OCH2CH2-*. In one embodiment, L is -0CH(CH3)-*. In one embodiment, L is -0CH(CH3)-* and exhibits R stereochemistry. In one embodiment, L is -0CH(CH3)-* and exhibits S stereochemistry. In one embodiment, L is-OC(CH3)2-*. In one embodiment, L is -OCH(isopropyl)-*. In one embodiment, L is -NAI-5008634746vl -37-Attorney Docket No. 14709-051-228OCH(isopropyl)-* and exhibits R stereochemistry. In one embodiment, L is -OCH(isopropyl)-*and exhibits S stereochemistry. In one embodiment, L is. In one embodiment, L is

[0109] In one embodiment, each instance of R3and R4is independently hydrogen, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, orR3andR4are taken together with the carbon they are attached to form an optionally substituted C3-6 cycloalkyl or optionally substituted 3- to 6-membered heterocyclyl. In one embodiment, the C1-6 alkyl, C1-6 heteroalkyl, C3-6 cycloalkyl, or 3- to 6-membered heterocyclyl are optionally substituted with 1 to 5 instances of Rp, wherein Rpis as defined herein. In one embodiment, the C1-6 alkyl, C1-6 heteroalkyl, C3-6 cycloalkyl, or 3- to 6-membered heterocyclyl are optionally substituted with 1 to 5 instances of Rp, wherein Rpis halogen or C1-3 alkyl.

[0110] In one embodiment, each instance of R3and R4is independently hydrogen or optionally substituted C1-6 alkyl. In one embodiment, each instance of R3and R4is independently hydrogen or C1-6 alkyl optionally substituted with 1 to 3 instances of Rp, wherein Rpis as defined herein. In some embodiments, Rpis halogen or C1-3 alkyl. In one embodiment, each instance of R3and R4is independently hydrogen or substituted C1-6 alkyl. In one embodiment, each instance of R3and R4is independently hydrogen or unsubstituted C1-6 alkyl.

[0111] In one embodiment, R3is hydrogen. In one embodiment, R3is unsubstituted C1-6 alkyl. In one embodiment, R3is substituted C1-6 alkyl. In one embodiment, R3is unsubstituted C1-3 alkyl. In one embodiment, R3is substituted C1-3 alkyl. In one embodiment, R3is methyl. In one embodiment, R3is ethyl. In one embodiment, R3is propyl. In one embodiment, R3is isopropyl. In one embodiment, R3is unsubstituted C1-6 heteroalkyl. In one embodiment, R3is substituted C1-6 heteroalkyl.

[0112] In one embodiment, R4is hydrogen. In one embodiment, R4is unsubstituted C1-6 alkyl. In one embodiment, R4is substituted C1-6 alkyl. In one embodiment, R4is unsubstituted C1-3 alkyl. In one embodiment, R4is substituted C1-3 alkyl. In one embodiment, R4is methyl. In one embodiment, R4is ethyl. In one embodiment, R4is propyl. In one embodiment, R4is isopropyl. In one embodiment, R4is unsubstituted C1-6 heteroalkyl. In one embodiment, R4is substituted C1-6 heteroalkyl.

[0113] In one embodiment, one of R3and R4is optionally substituted C1-6 alkyl and the other is hydrogen. In one embodiment, one of R3and R4is substituted C1-6 alkyl and the other isNAI-5008634746vl -38-Attomey Docket No. 14709-051-228hydrogen. In one embodiment, one of R3and R4is unsubstituted Ci-6 alkyl and the other is hydrogen.

[0114] In one embodiment, each instance of R3and R4is independently hydrogen or optionally substituted C1-3 alkyl. In one embodiment, each instance of R3and R4is independently hydrogen or substituted C1-3 alkyl. In one embodiment, each instance of R3and R4is independently hydrogen or unsubstituted C1-3 alkyl.

[0115] In one embodiment, R3is substituted C1-3 alkyl and R4is hydrogen. In one embodiment, R3is unsubstituted C1-3 alkyl and R4is hydrogen. In one embodiment, R3is methyl, ethyl, propyl, or isopropyl, and R4is hydrogen. In one embodiment, R3is methyl or isopropyl and R4is hydrogen. In one embodiment, R3is methyl and R4is hydrogen. In one embodiment, R3is ethyl and R4is hydrogen. In one embodiment, R3is isopropyl and R4is hydrogen.

[0116] In one embodiment, R3is hydrogen and R4is optionally substituted C1-3 alkyl. In one embodiment, R3is hydrogen and R4is substituted C1-3 alkyl. In one embodiment, R3is hydrogen and R4is unsubstituted C1-3 alkyl. In one embodiment, R4is methyl, ethyl, propyl, or isopropyl, and R3is hydrogen. In one embodiment, R4is methyl and R3is hydrogen. In one embodiment, R4is ethyl and R3is hydrogen. In one embodiment, R4is isopropyl and R3is hydrogen. In one embodiment, each of R3and R4are hydrogen.

[0117] In one embodiment, R3and R4are taken together with the carbon they are attached to form an optionally substituted C3-6 cycloalkyl (e.g., optionally substituted with 1 to 3 instances of Rp). In one embodiment, R3and R4are taken together with the carbon they are attached to form C3-6 cycloalkyl optionally substituted with 1 to 3 instances of Rp, wherein each instance of Rpis independently halogen, -NH2, -OH, -NO2, cyano, or C1-5 alkyl. In one embodiment, each instance of Rpis independently halogen, CN, C1-5 alkyl, or C1-5 haloalkyl. In one embodiment, R3and R4are taken together with the carbon they are attached to form a substituted C3-6 cycloalkyl. In one embodiment, R3and R4are taken together with the carbon they are attached to form unsubstituted C3-6 cycloalkyl.

[0118] In one embodiment, R3and R4are taken together with the carbon they are attached to form an optionally substituted cyclopropyl (e.g., optionally substituted with 1 to 3 instances of Rp). In one embodiment, R3and R4are taken together with the carbon they are attached to form substituted cyclopropyl. In one embodiment, R3and R4are taken together with the carbon they are attached to form cyclopropyl optionally substituted with 1 to 3 instances of Rp, wherein each instance of Rpis independently halogen, -NH2, -OH, -NO2, cyano, or C1-5 alkyl. In one embodiment, each instance of Rpis independently halogen, CN, C1-5 alkyl, or C1-5NAI-5008634746vl -39-Attomey Docket No. 14709-051-228haloalkyl. In one embodiment, R3and R4are taken together with the carbon they are attached to form unsubstituted cyclopropyl.

[0119] In one embodiment, R3and R4are taken together with the carbon they are attached to form an optionally substituted cyclobutyl (e.g., optionally substituted with 1 to 3 instances of Rp). In one embodiment, R3and R4are taken together with the carbon they are attached to form substituted cyclobutyl. In one embodiment, R3and R4are taken together with the carbon they are attached to form cyclobutyl optionally substituted with 1 to 3 instances of Rp, wherein each instance of Rpis independently halogen, -NH2, -OH, -NO2, cyano, or C1-5 alkyl. In one embodiment, each instance of Rpis independently halogen, CN, C1-5 alkyl, or C1-5 haloalkyl. In one embodiment, R3and R4are taken together with the carbon they are attached to form unsubstituted cyclobutyl.

[0120] In one embodiment, R3and R4are taken together with the carbon they are attached to form an optionally substituted 3- to 6-membered heterocyclyl (e.g., optionally substituted with 1 to 3 instances of Rp). In one embodiment, R3and R4are taken together with the carbon they are attached to form 3- to 6-membered heterocyclyl optionally substituted with 1 to 3 instances of Rp, wherein each instance of Rpis independently halogen, -NH2, -OH, -NO2, cyano, or C1-5 alkyl. In one embodiment, each instance of Rpis independently halogen, CN, C1-5 alkyl, or C1-5 haloalkyl. In one embodiment, R3and R4are taken together with the carbon they are attached to form a substituted 3- to 6-membered heterocyclyl. In one embodiment, R3and R4are taken together with the carbon they are attached to form an unsubstituted 3- to 6-membered heterocyclyl. In one embodiment, R3and R4are taken together with the carbon they are attached to form an unsubstituted oxiranyl. In one embodiment, R3and R4are taken together with the carbon they are attached to form a substituted oxiranyl. In one embodiment, R3and R4are taken together with the carbon they are attached to form an unsubstituted oxetanyl. In one embodiment, R3and R4are taken together with the carbon they are attached to form a substituted oxetanyl.

[0121] In one embodiment, each of R3and R4is independently optionally substituted with 1 to 3 instances of Rp. In one embodiment, each instance of Rpis independently selected from halogen, -NH2, -OH, -NO2, cyano, or C1-5 alkyl.

[0122] In one embodiment, each of R1and R2is independently hydrogen or optionally substituted C1-6 alkyl. In one embodiment, at least one of R1and R2is hydrogen. In one embodiment, each of R1and R2is hydrogen.

[0123] In one embodiment (of -NRnlRnl, e.g., in Formula (II-A-1), (II-A-2), or (II-A-3)), at least one Rnlis hydrogen. In one embodiment, both Rnlare hydrogen. In one embodiment, atNAI-5008634746vl -40-Attomey Docket No. 14709-051-228least one Rnlis substituted or unsubstituted Ci-6 alkyl. In one embodiment, Rnlis Ci-6 alkyl optionally substituted with 1 to 3 instances of Rp, wherein Rpis as defined herein. In one embodiment, Rnlis Ci-6 alkyl optionally substituted with 1 to 3 instances of Rpwherein each instance of Rpis independently halogen, -NH2, -OH, -NO2, cyano, or C1-5 alkyl. In one embodiment, each instance of Rpis independently halogen, CN, C1-5 alkyl, or C1-5 haloalkyl. In one embodiment, at least one Rnlis unsubstituted C1-6 alkyl. In one embodiment, at least one Rnlis substituted C1-6 alkyl. In one embodiment, at least one Rnlis substituted or unsubstituted C1-3 alkyl. In one embodiment, at least one Rnlis unsubstituted C1-3 alkyl. In one embodiment, at least one Rnlis substituted C1-3 alkyl. In one embodiment, at least one Rnlis methyl. In one embodiment, at least one Rnlis ethyl. In one embodiment, at least one Rnlis propyl or isopropyl.

[0124] In one embodiment (of -NRnlRnl, e.g., in Formula (II-A-1), (II-A-2), or (II-A-3)), one of Rnlis hydrogen and one of Rnlis substituted or unsubstituted C1-6 alkyl. In one embodiment, one of Rnlis hydrogen and one of Rnlis unsubstituted C1-6 alkyl. In one embodiment, one of Rnlis hydrogen and one of Rnlis unsubstituted C1-3 alkyl. In one embodiment, one of Rnlis hydrogen and one of Rnlis methyl. In one embodiment, one of Rnlis hydrogen and one of Rnlis ethyl. In one embodiment, both of Rnlare hydrogen. In one embodiment, both of Rnlare unsubstituted C1-3 alkyl. In one embodiment, both of Rnlare methyl.

[0125] In one embodiment (of -NR111-), Rnlis hydrogen. In one embodiment, Rnlis substituted or unsubstituted C1-6 alkyl. In one embodiment, Rnlis substituted or unsubstituted Ci-3 alkyl. In one embodiment, Rnlis -CH3. In one embodiment, Rnlis -CD3. In one embodiment, Rnlis -C(=O)Rd. In one embodiment, Rnlis -C(=O)ORd.

[0126] In one embodiment, each instance of Rxis independently hydrogen, CN, halogen, optionally substituted C1-3 alkyl, optionally substituted C1-3 heteroalkyl, -NRn2Rn3, -OR01, or 5- to 6-membered heteroaryl. In one embodiment, each instance of Rxis independently hydrogen, halogen, -NRn2Rn3, or 5- to 6-membered heteroaryl. In one embodiment, each instance of Rxis independently hydrogen, -NH2, -F, -Cl, CN, -NHCH3, -NHCH(CH3)2, -CH3, -CD3, -CF3,l-l / 3isopropyl, -OH, -O(CH3), -O-(isopropyl), pyrazolyl, or5\ — / . In one embodiment, each instance of Rxis independently hydrogen, -NH2, -F, -NHCH3, -NHCH(CH3)2, pyrazolyl, orNZS

[0127] In one embodiment, Rxis 5-membered heteroaryl (e.g., thiazolyl, thiophenyl, pyrrolyl, furyl, imidazolyl, oxazolyl, or pyrazolyl). In one embodiment, Rxis -NRn2Rn3. In one embodiment, Rxis NH2. In one embodiment, Rxis NHCH3. In one embodiment, Rxis pyrazolyl.NAI-5008634746vl -41-Attomey Docket No. 14709-051-228

[0128] In one embodiment, each instance of Rxis independently hydrogen, halogen, -NRn2Rn3, or optionally substituted 5- to 6-membered heteroaryl. In one embodiment, each instance of Rxis independently hydrogen, halogen, -NRn2Rn3, or 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally substituted with 1 to 4 instances of Rp, wherein Rpis as defined herein. In one embodiment, each instance of Rxis independently hydrogen, halogen, -NRn2Rn3, or 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally substituted with 1 to 4 instances of Rp, wherein each instance of Rpis independently halogen, -NH2, -OH, -NO2, cyano, or C1-5 alkyl. In one embodiment, each instance of Rpis independently halogen, -CN, C1-5 alkyl, or C1-5 haloalkyl. In one embodiment, each instance of Rxis independently hydrogen, -NRn2Rn3, or 5- to 6-membered heteroaryl. In one embodiment, each instance of Rn2and Rn3is independently hydrogen or optionally substituted C1-6 alkyl. In one embodiment, each instance of Rn2and Rn3is independently hydrogen or methyl.

[0129] In one embodiment, each instance of Rxis independently hydrogen, halogen, -NH2,-NHCH3, -N(CH3)2, or pyrazolyl. In one embodiment, each instance of Rxis independently hydrogen, -NH2, -NHCH3, or pyrazolyl.

[0130] In one embodiment, only one instance of Rxis hydrogen. In one embodiment, only two instances of Rxare hydrogen. In one embodiment, only three instances of Rxare hydrogen. In one embodiment, all instances of Rxare hydrogen.

[0131] In one embodiment, one instance of Rxis halogen, -NRn2Rn3or 5- to 6-membered heteroaryl optionally substituted with 1 to 4 instances of Rpand the other instances of Rxare hydrogen. In one embodiment, one instance of Rxis -NRn2Rn3or 5- to 6- membered heteroaryl optionally substituted with 1 to 4 instances of Rpand the other instances of Rxare hydrogen. In one embodiment, one instance of Rx is -NH2or 5- to 6-membered heteroaryl optionally substituted with 1 to 4 instances of Rpand the other instances of Rxare hydrogen. In some embodiments, each instance of Rpis independently selected from halogen, CN, NO2, -OH, NH2, N(CI-3 alkyl)2, C1-5 alkyl, or C1-5 haloalkyl. In one embodiment, one instance of Rx is -F, -NH2or 5- to 6- membered heteroaryl and the other instances of Rxare hydrogen. In one embodiment, one instance of Rx is -NH2and the other instances of Rxare hydrogen. In one embodiment, one instance of Rxis 5- to 6- membered heteroaryl and the other instances of Rxare hydrogen. In one embodiment, one instance of Rxis -F and the other instances of Rxare hydrogen.NAI-5008634746vl -42-Attomey Docket No. 14709-051-228

[0132] In one embodiment, Rxis halogen. In one embodiment, Rxis -F. In one embodiment, Rxis -Cl. In one embodiment, Rxis -Br. In one embodiment, Rxis -I. In one embodiment, Rxis CN.

[0133] In one embodiment, Rxis -NRn2Rn3, wherein each instance of Rn2and Rn3is independently hydrogen or optionally substituted Ci-6 alkyl (e.g., optionally substituted with 1 to 4 instances of Rp). In one embodiment, each instance of Rn2and Rn3is independently hydrogen or substituted Ci-6 alkyl. In one embodiment, each instance of Rn2and Rn3is independently hydrogen or unsubstituted Ci-6 alkyl. In one embodiment, each instance of Rn2and Rn3is independently hydrogen or methyl.

[0134] In one embodiment, one or both of Rn2and Rn3are hydrogen. In one embodiment, one or both of Rn2and Rn3are optionally substituted Ci-6 alkyl (e.g, optionally substituted with 1 to 4 instances of Rp). In one embodiment, one or both of Rn2and Rn3are unsubstituted Ci-6 alkyl. In one embodiment, one or both of Rn2and Rn3are methyl. In one embodiment, one or both of Rn2and Rn3are ethyl. In one embodiment, one or both of Rn2and Rn3are propyl. In one embodiment, one or both of Rn2and Rn3are isopropyl. In one embodiment, one or both of Rn2and Rn3are optionally substituted Ci-6 heteroalkyl (e.g, optionally substituted with 1 to 4 instances of Rp). In one embodiment, one or both of Rn2and Rn3are substituted Ci-6 heteroalkyl. In one embodiment, one or both of Rn2and Rn3are unsubstituted Ci-6 heteroalkyl. In one embodiment, one or both of Rn2and Rn3are -C(=O)Rd. In one embodiment, Rdis hydrogen. In one embodiment, Rdis optionally substituted Ci-6 alkyl (e.g., optionally substituted with 1 to 4 instances of Rp). In one embodiment, Rdis substituted Ci-6 alkyl. In one embodiment, Rdis unsubstituted Ci-6 alkyl. In one embodiment, Rdis methyl. In one embodiment, Rdis ethyl. In one embodiment, Rdis propyl. In one embodiment, each of Rn2and Rn3are hydrogen. In one embodiment, one of Rn2and Rn3is hydrogen and the other is methyl. In one embodiment, one of Rn2and Rn3is hydrogen and the other is isopropyl.

[0135] In some embodiments, each instance of Rpis independently selected from halogen, CN, NO2, -OH, NH2, N(CI-3 alkyl)2, C1-5 alkyl, or C1-5 haloalkyl.

[0136] In one embodiment, each instance of Rxis independently an optionally substituted 5- to 6- membered heteroaryl comprising 1 heteroatom (e.g., optionally substituted with 1 to 5 instances of Rp). In one embodiment, Rxcomprises 2 heteroatoms. In one embodiment, the heteroatom(s) of Rxare selected from N, O, and S.

[0137] In one embodiment, each instance of Rxis independently optionally substituted 5-membered heteroaryl (e.g., optionally substituted with 1 to 5 instances of Rp). In one embodiment, at least one Rxis thiazolyl (e.g., 5-thiazolyl). In one embodiment, at least one RxisNAI-5008634746vl -43-Attomey Docket No. 14709-051-228thiophenyl (e.g., 5-thiophenyl). In one embodiment, at least one Rxis pyrrolyl (e.g., 5-pyrrolyl). In one embodiment, at least one Rxis furyl (e.g., 5-furyl). In one embodiment, at least one Rxis imidazolyl (e.g., 5-imidazolyl). In one embodiment, Rxis oxazolyl (e.g., 5-oxazolyl). In one embodiment, at least one Rxis imidazolyl (e.g., 2-imidazolyl). In one embodiment, at least one Rxis pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl).

[0138] In one embodiment, each instance of Rxis independently optionally substituted 6-membered heteroaryl (e.g., optionally substituted with 1 to 5 instances of Rp). In one embodiment, at least one Rxis pyridinyl. In one embodiment, at least one Rxis 2-pyridinyl. In one embodiment, at least one Rxis 3-pyridinyl. In one embodiment, at least one Rxis 4-pyridinyl. In one embodiment, at least one Rxis pyrimidinyl. In one embodiment, at least one Rxis 5-pyrimidinyl. In one embodiment, at least one Rxis 5-pyranyl. In one embodiment, at least one Rxis pyridazinyl (e.g., 5-pyridazinyl). In one embodiment, at least one Rxis pyrazinyl. In one embodiment, at least one Rxis oxazinyl (e.g., 1, 2-oxaziyl, 1,3-oxazinyl, 1,4-oxazinyl). In one embodiment, at least one Rxis thiapyranyl (e.g., 4-thiopyranyl). In one embodiment, at least one Rxis morpholinyl (e.g., 4-morpholinyl). In one embodiment, at least one Rxis diazinyl.

[0139] In one embodiment, two Rxtogether with the atoms to which they are attached form an optionally substituted 5- to 6-membered heterocyclyl. In one embodiment, two Rxtogether with the atoms to which they are attached form an optionally substituted 5- to 6-membered heteroaryl.

[0140] In one embodiment, X1is CRX, wherein the Rxis optionally substituted 5- to 6-membered heteroaryl (e.g., optionally substituted with 1 to 5 instances of Rp) as described herein. In one embodiment, X2is CRX, wherein the Rxis optionally substituted 5- to 6-membered heteroaryl (e.g., optionally substituted with 1 to 5 instances of Rp) as described herein. In one embodiment, X3is CRX, wherein the Rxis optionally substituted 5- to 6-membered heteroaryl (e.g., optionally substituted with 1 to 4 instances of Rp) as described herein. In one embodiment, X4is CRX, wherein the Rxis optionally substituted 5- to 6-membered heteroaryl (e.g., optionally substituted with 1 to 5 instances of Rp) as described herein.

[0141] In one embodiment, X1is CRX, wherein Rxis pyrazolyl. In one embodiment, X2is CRX, wherein Rxis pyrazolyl. In one embodiment, X3is CRX, wherein Rxis pyrazolyl. In one embodiment, X4is CRX, wherein Rxis pyrazolyl. In one embodiment, Rxis 4-pyrazoyl. In one embodiment, X1is CRX, wherein Rxis imidazolyl. In one embodiment, X2is CRX, wherein Rxis imidazolyl. In one embodiment, X3is CRX, wherein Rxis imidazolyl. In one embodiment, X4is CRX, wherein Rxis imidazolyl. In one embodiment, Rxis 2-imidazolyl. In one embodiment, X1is CRX, wherein Rxis morpholinyl. In one embodiment, X2is CRX, wherein Rxis morpholinyl. InNAI-5008634746vl -44-Attomey Docket No. 14709-051-228one embodiment, X3is CRX, wherein Rxis morpholinyl. In one embodiment, X4is CRX, wherein Rxis morpholinyl. In one embodiment, Rxis 4-morpholinyl.

[0142] In one embodiment, X1is CRX, wherein the Rxis -NRn2Rn3. In one embodiment, X2is CRX, wherein the Rxis -NRn2Rn3. In one embodiment, X3is CRX, wherein the Rxis -NRn2Rn3. In one embodiment, X4is CRX, wherein the Rxis -NRn2Rn3. In one embodiment, the -NRn2Rn3 is -NHCH3. In one embodiment, the -NRn2Rn3is -NH2.

[0143] In one embodiment, X1is CRX, wherein the Rxis halogen. In one embodiment, X2is CRX, wherein the Rxis halogen. In one embodiment, X3is CRX, wherein the Rxis halogen. In one embodiment, X4is CRX, wherein the Rxis halogen. In one embodiment, the halogen is -F. In one embodiment, the halogen is -Cl. In one embodiment, the halogen is -Br. In one embodiment, the halogen is -I.

[0144] In one embodiment, each instance of Rxnis independently hydrogen, optionally substituted C1-3 alkyl (e.g., optionally substituted with 1 to 5 instances of Rp), or optionally substituted C3-4 cycloalkyl (e.g., optionally substituted with 1 to 5 instances of Rp). In some embodiments (e.g., any of Formula (II-B-l-a), (II-B-l-b), (II-B-l-c), (II-B-l-d), (II-B-2-a), (II-B-2-b), (II-B-2-c), (II-B-3-d), (II-B-3-a), (II-B-3-b), (II-B-3-c), (II-B-3-d), (IILA-1), (IILA-2), (III-A-3), (III-A-4), (in-A-5), (III-B-1), (III-B-2), (III-B-3), (III-B-4), (III-B-5), (III-B-6), (III-B-7), (ni-B-8), (III-B-9), (III-B-10), (III-B-11), (III-B-12), (III-B-13), (III-B-14), (III-B-15), or (III-B-16)), each instance of Rxnis independently optionally substituted C1-3 alkyl (e.g., optionally substituted with 1 to 5 instances of Rp), or optionally substituted C3-4 cycloalkyl (e.g., optionally substituted with 1 to 5 instances of Rp). In some embodiments (e.g., any of Formula (II-B-l-a), (II-B-l-b), (II-B-l-c), (II-B-l-d), (II-B-2-a), (II-B-2-b), (II-B-2-c), (II-B-3-d), (II-B-3-a), (II-B-3-b), (II-B-3-c), (II-B-3-d), (III-A-1), (IILA-2), (III-A-3), (III-A-4), (III-A-5), (III-B-1), (III-B-2), (III-B-3), (III-B-4), (III-B-5), (III-B-6), (III-B-7), (III-B-8), (III-B-9), (III-B-10), (III-B-11), (III-B-12), (III-B-13), (III-B-14), (III-B-15), or (III-B-16)), each instance of Rxnis independently optionally substituted C1-3 alkyl (e.g., optionally substituted methyl)). In one embodiment, at least one instance of Rxnis hydrogen. In one embodiment, at least one instance of Rxnis substituted C1-3 alkyl (e.g., substituted with 1 to 5 instances of Rp). In one embodiment, at least one instance of Rxnis unsubstituted C1-3 alkyl. In one embodiment, at least one instance of Rxnis methyl. In one embodiment, at least one instance of Rxnis substituted C3-4 cycloalkyl (e.g., substituted with 1 to 5 instances of Rp). In one embodiment, at least one instance of Rxnis unsubstituted C3-4 cycloalkyl. In one embodiment, at least one instance of Rxnis cyclopropyl. In one embodiment, at least one instance of Rxnis cyclobutyl.NAI-5008634746vl -45-Attomey Docket No. 14709-051-228

[0145] In one embodiment, X1is NRxn, wherein the Rxnis optionally substituted C1-3 alkyl (e.g., optionally substituted with 1 to 5 instances of Rp). In one embodiment, X2is NRxn, wherein the Rxnis optionally substituted C1-3 alkyl (e.g., optionally substituted with 1 to 5 instances of Rp). In one embodiment, X3is NR™, wherein the Rxnis optionally substituted C1-3 alkyl (e.g., optionally substituted with 1 to 5 instances of Rp). In one embodiment, X4is NRxn, wherein the Rxnis optionally substituted C1-3 alkyl (e.g., optionally substituted with 1 to 5 instances of Rp).

[0146] In one embodiment, X1is NRxn, wherein the Rxnis unsubstituted C1-3 alkyl. In one embodiment, X2is NRxn, wherein the Rxnis unsubstituted C1-3 alkyl. In one embodiment, X3is NRxn, wherein the Rxnis unsubstituted C1-3 alkyl. In one embodiment, X4is NRxn, wherein the Rxnis unsubstituted C1-3 alkyl.

[0147] In one embodiment, X1is NRxn, wherein the Rxnis optionally substituted C3-4 cycloalkyl (e.g., optionally substituted with 1 to 5 instances of Rp). In one embodiment, X2is NRxn, wherein the Rxnis optionally substituted C3-4 cycloalkyl (e.g., optionally substituted with 1 to 5 instances of Rp). In one embodiment, X3is NRxn, wherein the Rxnis optionally substituted C3-4 cycloalkyl (e.g., optionally substituted with 1 to 5 instances of Rp). In one embodiment, X4is NRxn, wherein the Rxnis optionally substituted C3-4 cycloalkyl (e.g., optionally substituted with 1 to 5 instances of Rp).

[0148] In one embodiment, X1is NRxn, wherein the Rxnis unsubstituted C3-4 cycloalkyl. In one embodiment, X2is NRxn, wherein the Rxnis unsubstituted C3-4 cycloalkyl. In one embodiment, X3is NR™, wherein the R™ is unsubstituted C3-4 cycloalkyl. In one embodiment, X4is NR™, wherein the R™ is unsubstituted C3-4 cycloalkyl.

[0149] In one embodiment, X1is NRxn, wherein the R™ is hydrogen. In one embodiment, X2is NR™, wherein the R™ is hydrogen. In one embodiment, X3is NR™, wherein the R™ is hydrogen. In one embodiment, X4is NR™, wherein the R™ is hydrogen.NAI-5008634746vl -46-Attomey Docket No. 14709-051-228NAI-5008634746vl -47-Attorney Docket No. 14709-051-228indicates the point of attachment to the phenyl ring connected to L’ and b indicates the point of attachment to Ring A.

[0151] In one embodiment, n is 0. In one embodiment, n is not 0. In one embodiment, n is 1. In one embodiment, n is 2.

[0152] In one embodiment, each instance of Rais independently halogen, -ORC, optionally substituted Ci-6 alkyl (e.g., optionally substituted with 1 to 3 instances of Rp), - C(=O)H, -NRn4Rn5, or optionally substituted 3- to 8-membered heterocyclyl. In one embodiment, each instance of Rais independently halogen, -ORC, substituted Ci-6 alkyl (e.g., NAI-5008634746vl -48-Attorney Docket No. 14709-051-228substituted with 1 to 3 instances of Rp),-C(=O)H, or -NRn4Rn5. In one embodiment, each instance of Rais independently halogen, -ORC, unsubstituted Ci-6 alkyl, -C(=O)H, or -NRn4Rn5. In one embodiment, each instance of Rais independently -F, -OH, -C(=O)H, or -NH2. In one embodiment, Rais -NRn4Rn5(e.g., -NH2).

[0153] In one embodiment, at least one instance of Rais halogen. In one embodiment, at least one instance of Rais optionally substituted C1-6 alkyl (e.g., optionally substituted with 1 to 3 instances of Rp). In one embodiment, at least one instance of Rais substituted C1-6 alkyl (e.g., substituted with 1 to 3 instances of Rp). In one embodiment, at least one instance of Rais unsubstituted C1-6 alkyl. In one embodiment, at least one instance of Rais -ORC. In one embodiment, at least one instance of Rais -OH. In one embodiment, at least one instance of Rais -C(=O)H. In one embodiment, at least one instance of Rais -NRn4Rn5. In one embodiment, at least one instance of Rais -NH2.

[0154] In one embodiment, at least one Rais substituted at the ortho position. In one embodiment, at least one Rais substituted at the meta position. In one embodiment, at least one Rais substituted at the para position.

[0155] In one embodiment, n is i and Rais -NRn4Rn5. In one embodiment, one or both of Rn4and Rn5are hydrogen. In one embodiment, one or both of Rn4and Rn5are optionally substituted C1-6 alkyl (e.g., optionally substituted with 1 to 3 instances of Rp). In one embodiment, one or both of Rn4and Rn5are unsubstituted C1-6 alkyl. In one embodiment, one or both of Rn4and Rn5are methyl. In one embodiment, one or both of Rn4and Rn5are ethyl. In one embodiment, one or both ofRn4andRn5are optionally substituted C 1-6 heteroalkyl (e.g., optionally substituted with 1 to 3 instances of Rp). In one embodiment, one or both of Rn4and Rn5are substituted C1-6 heteroalkyl. In one embodiment, one or both of Rn4and Rn5are unsubstituted C1-6 heteroalkyl. In one embodiment, one or both of Rn4and Rn5are -C(=O)Rd. In one embodiment, each of Rn4and Rn5are hydrogen. In one embodiment, one of Rn4and Rn5is hydrogen and the other is methyl.In one embodiment,In one embodiment,In one embodiment,In one embodiment,NAI-5008634746vl -49-Attorney Docket No. 14709-051-228

[0157] In one embodiment, CN. In one embodiment,

[0158] In one embodiment, the compound is a compound in Table 1, or a tautomer, or a pharmaceutically acceptable salt thereof.Table 1:w>'°fl 7 >=N XYXS'N”XX1 lXNHNOOO\NA 1HNx / \X\X\ HN^IJL^H Nr u s uCompound 1 Compound 2 Compound 30 NN'X,iC^xx XX L x x XN1 IH- A ^ XXXX XX Of ZXXNCJ Xj K JrI u oNUCompound 4 Compound 5 Compound 6..v / raxADX JLNXXCL XX j? JOCO. JX jXr HN^N [QDXxCCX HN*XNiQCompound 7 Compound 8 Compound 9 u nru jfxY HnX NJXX HN^N > J r XY M M TjCompound 10 Compound 11 Compound 12O XNo IYN-" AX.NJXX,H NNJUVX,Nu Xj XjCompound 13 Compound 14 Compound 15NAI-5008634746vl -50-Attomey Docket No. 14709-051-228° rXXN”X tX UJLUN™XCu *N*A NJUL^H NLJNH2N JO NCompound 16 Compound 17 Compound 18 o r:Xx^N'X XN0XX^N”X iXNHN'XfN^Y / X / AANXNX^. XX^N / XI CNAQX ^AN<A NJUU^H NNxO HNUUU\1H2N N H2N JU N I uCompound 19 Compound 20 Compound 21 H 1. N^O / N^OMX¥u axrN^ u axrNX IXNCJ U u uCompound 22 Compound 23 Compound 240iUXNU iXNo ifXX'N'X iXNN A N AH NA A / .H NH2XZN NiCompound 25 Compound 26 Compound 27- X N XAul XX.x L IIN / rax H xX AAJUU^ A H XNX XNx^ «N^ uCompound 28 Compound 29 Compound 30 o rfXXN'ZXsi X'N-A" O CtNX AL II J H SANXN: ‘. UarXCompound 31 Compound 32 Compound 33 ° AXA'A CiA'N / 'XV'7 JI 1 H N I cFn JCTNQNHXXN^NNH2N JO N XJCompound 34 Compound 35 Compound 36 LN JO^Q XIN^U raxx t Xju^ " CN NA>N HNAUXH NNuQ I uCompound 37 or 38 Compound 38 or 37 Compound 39" OCCx " "n^nNCompound 40 Compound 41 Compound 42NAI-5008634746vl -51-Attomey Docket No. 14709-051-228o r^Nneo JQ HN LXU IINU^ I NXXGX ^XAQX M U — O xJUUx A m I UH NCo pound 43 Compound 44 Compound 45 u fYn Ci" AIY^ NJAA - M XAUnIl A O O'‘ ^'0Compound 46 Compound 47 Compound 48HN |'' XAA / ^''^ H N'' ^^ N UQCompound 49 Compound 50 Compound 51 ° xee teN— ■A'N'A'hT >&.1 II 1 H N< A ANA0N H2N"'Y>H2N NCompound 52 Compound 53 Compound 54[j^N OJYN XXCX XX ovb JCXQ XX x. J I A X X 1 x r H N N XXXX HNO X X jX HNM L II Hnu1uCompound 55 Compound 56 Compound 57, N. JI L A JL A neu CN ^X ^N, A^. JJ k A ''N A < AiN X>T J \ HH NiQCompound 58 Compound 59 Compound 600YY^NXY iT^N0X-AN-A ITN^AN\^ NJUU.H NNJUU.H NXX XXCompound 61 Compound 62 or 63 Compound 63 or 62 JJ L A A A \ ^f\L XxX L X X X UJ 1 r r L H II N H N x.UH N1X HN^N XX1uCompound 64 Compound 65 Compound 660f|x5*N0lf^NXN\ NJUOH NNJUU^H NNJXXHXJ XX XXCompound 67 Compound 68 Compound 69° r5ArxXV'N^T*FlA^N. A-rOr-OXA.Y / n® \ NJUOH NNJUU^H NMUX,HXX XX XXCompound 70 Compound 71 Compound 72NAI-5008634746vl -52-Attomey Docket No. 14709-051-2280kAk^NXY'FIYN° YJT^N'YXFIYAA*NAN-AX^ ^NA^N'YYA YANANAN^NJUL^H NMCompound 73 Compound 74 Compound 75 o\ IYYNY>0HYNN A Ax J I A A Af'J 4v* VxH N,]Q N^AYAA ]QXXH NA °A Compound 76 Compound 77 Compound 78 ° YAY YNI ° CNoAy-NyAsxA —? XX \ Ax JxA k kA A IY ANxH NNJUL^ NJUAM XXCompound 79 Compound 80 Compound 81 or 82 o YJA^^AY lYN0IYN\klA _ N. Ax Jl k Af A A s AX^NXYSA kY Y Ax N Y XXN N" Xx^ N y Y N N A,, x Y qA.H N4d- LJ 133 Compound 82 or 81 Compound 83 Compound 84 o IY1'1YY'''N”Y IYNYAY [YN, N., N, A^ AY A A Ox^x. N. A A kA A A ^N'Y^AY^k— YYrr >&. f JiN NAM k X A / sH NN N P |1 / NXJUL^HAJUL-YN^YQ I UCompound 85 Compound 86 Compound 87 or 88•X-A OXs Y JN YNAANAAY[ANH2NY / NYN'NHCompound 88 or 87 Compound 89 Compound 90i ° CNX A^hk L A A -A Y A Y XS,,~AYY1XANL L II H ''N U F HN^NN^T>^NHN^ON^0Compound 91 Compound 92 Compound 93 A Y Q IAA A-NN=V N'NHCompound 94 Compound 95° IYNo rXr 'N>Y YNA'YXAYX^ YYN NA^N< AA^XHNJUUY,H NxoY ' X J H2N N^ sQ XjCompound 97 Compound 98 Compound 99 o AAYNY'''' (YNo YJT^N'Y> ZIYN\ A^-N~ Ax. Jl k A., A Ax JO^CCXX -XA AY jfYNA J A AH NU ”n^n0N^OCompound 100 Compound 101 Compound 102NAI-5008634746vl -53-Attorney Docket No. 14709-051-228 f Q ZI\ A0^-X As JI k A, A iX ANs s A x AJ A A A A9NANXY A ^ ”n^nA k A^ A O AXHA ompound 103 Compound 104N^ CuNC pom bpound 105 x-s,. OH, / s / -s _> OH / s° r ifN1 ||N° r ifN| ||\ A^x AsJl k A A A \ A^N0b XX^NXP> OHIJ^NN X^ T — N N X> x As Ji k A, A A ^NY^NSPXJ k — ANANA.^ i 1 II H N k A A ^ ”n^nk A AH NNo^ONXXQCompound 106 Compound 107 Compound 108 / s A0^xA k»X. Jir^Nk'XAxFA iO -AN\ ( Z — A0x A AXJx^Nk'XA>*FA IA ANL A H " A k A JL Q P5 t (KzCi—-NA^^ 10 ^' iQCompound 109 Compoun Ad 1 °10 Compound 111 / X x-s.xF / Ss. doO i ll 1 1 ]J 1'p / jlNA A '°A -N^N^N' yN"^ IQ H2N'X|\r AIZCompound 112 zz- Compound 113

[0159] In one embodime / nt, the compound is a compound in Table 1 A, or a tautomer, or a X / pharmaceutically acceptable salt thereof.Table 1A:X / / yo- ifAAN'Af rA lONHNY ° / IAY^'N'X CNCXzAA XANANA^ HNJUUXH NNJXXH NI u b op bOzA -X^ XXNi A A H N Pzz- < A / ~. IZXQ_H2t\At\r MQ Qo f o lXN / / / X JLj5!!br^ de d idx^ dNx \klA _ N. / z A AYOXA N Y XA JJ kAJ N A N A A Xsh N> r HNNOUVXH2N X N JHul- / rax\ AAAp O-X NJOLXH NJQ MOHitAA~N^> (A’N _X raxxNCIXLNAU k A A AH N''JOLxH NMo rXO'NX YNifNT5^J LO^NANJk^L A AH NNxQNAI-5008634746vl -54-Attomey Docket No. 14709-051-228X NJX CXXX AX Y YN V fTQ N X tlXX ^ NJX CXXJX NJUUXH NN^AAA\x^\h nUUXxH Nw uX'NX., N. A J L X A A xA axxQ / AA^N" A CN\AY'NY / AAC I HN^N NAAU\H NMUXNIQ IQH NU° rY^NA XNCI^XN XJ XAXN^NJ iJfAA'NA'AANA PNAN^ N I’Vl HNAJUX,H NNXNJUXHXNXXNN I U,_FAkA^N^Y ACIAX^N'A ICNo IUA~N'A A'N XvX X A x YXN< XX^ N" X^HNXNUA ^X / ANXX NXXH NNJX XHL JI JL 1NM uAAY^N'X A^N AQy^OXX" ^ r \ TAU X U X N X N A' A XA AIhXS-,XJU u^NNUX \HuXrXX JrX ''OO^XX^A l 9 AAA AN XXNUX AAXNX ZNUCU L A. AH Nu u ^IsTcA AANA IXNN<X ^X \U.?: AaA0iXNHN / Vj ^ H H^xX XX " LVA ^N^Nn" u I uNA)I<AA'''N’’"'*A HN’XfAX^ X'N^NX A, J L A A IA ANX X x MNHA L XNA r J n N I 'NHN JUXSHJ X O^N^^XYNu u1u° fXX’i^X ifXr r^N Y r X II ^XN HXX(5otx ”n^n^ATO-Ax^N A I xQ O^N'^5syr< A1u0i iQAJ ° rAr^N" Ax°HrfU oXxxoxx k — A N A N A^ x> / MUU^.H NA A AH N'AN'UU’AA AAXXNu X^XQ U x / rox \ JL / X JJ L J>» X < X" XUhSJOA ~ A A j* N JOXIX° HXNAn« A Xu 1Q uNAI-5008634746vl -55-Attorney Docket No. 14709-051-228

[0160] As described herein and unless otherwise specified, when the structure of a compound provided herein shows only straight bonds ( - ) at the chiral center (or the chemical name of a compound provided herein mentions (±)-mixture, racemic mixture, or does not mention stereochemistry), it means the compound is a racemic mixture at the chiral center. As described herein and unless otherwise specified, when the structure of a compound provided herein shows a wedge bondor dash bond (111111 ) at those chiral center(s) and without the notation of an “or” label such as “orl” (or R- or S- stereochemistry at those chiral center(s) is specified in the chemical name of a compound provided herein), it means those chiral center(s) has the stereochemistry as displayed or described. As described herein and unless otherwise specified, when the structure of a compound provided herein has the notation of an “or” label such as “orl” at a chiral center, it means the compound is an enantiomer at the chiral center, but the stereochemistry is not specified. This is the case even if the chiral center also shows a wedge bond (*^^®) or dash bond (HI|H) (or R- or S- stereochemistry at the chiral center is specified in the chemical name). When multiple same “or” labels are present (e.g., when there are two “orl” in a structure), it means the multiple chiral centers may only change in tandem. A person of ordinary skill in the art can understand whether the absolute stereochemistry has been determined at those chiral center(s) based on the description provided herein, e.g., the synthetic Examples for the compound.

[0161] Compounds provided herein can exist in various stereoisomeric forms, such as individual isomer, an individual enantiomer and / or diastereomer, as applicable, or a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. In some embodiments, when applicable, a compound provided herein can have an enantiomeric excess (“ee”) of greater than about 60%, such as having greater than about 80% ee, greater than about 90% ee, greater than about 95% ee, greater than about 98% ee, greater than about 99% ee, or with the other enantiomer in a non-detectable amount. In some embodiments, whenNAI-5008634746vl -56-Attomey Docket No. 14709-051-228applicable, a compound provided herein can also exist as a mixture of stereoisomers in any ratio, such as a racemic mixture.

[0162] As described herein and unless otherwise specified, when the structure of a compound provided herein shows a wedge bondor dash bond (1111II ) at those chiral center(s) at a pseudoasymmetric center (or r- or s- stereochemistry at those chiral center(s) is specified in the chemical name of a compound provided herein), it means the pseudoasymmetric center has the absolute configuration as displayed or described.

[0163] In some embodiments, to the extent applicable, the genus of compounds provided herein also excludes any specifically known single compounds prior to this application. In some embodiments, to the extent applicable, any sub-genus or species of compounds prior to this application that are entirely within a genus of compounds provided herein can also be excluded from such genus provided herein.

[0164] The compounds provided herein can be readily synthesized by those skilled in the art in view of the information provided herein and synthetic knowledge in the art. Exemplified syntheses are also shown in the Examples section.

[0165] As will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in “Protective Groups in Organic Synthesis”, 4thed. P. G. M. Wuts; T. W. Greene, John Wiley, 2007, and references cited therein. The reagents for the reactions described herein are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the reagents are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Sigma (St. Louis, Missouri, USA). Others may be prepared by procedures, or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March’s Advanced Organic Chemistry, (Wiley, 7thEdition), and Larock’s Comprehensive Organic Transformations (Wiley-VCH, 1999), and any available updates as of this filing.

[0166] In one embodiment, without being bound by a particular theory, certain compounds provided herein exhibit one or more of the following properties: improved potencyNAI-5008634746vl -57-Attomey Docket No. 14709-051-228(e.g., against AKT1 E17K mutant); improved selectivity (e.g., over wild-type AKT1); improved solubility (e.g., aqueous solubility); improved permeability; and / or improved metabolic stability.

[0167] Compounds provided herein possess one or more structural features e.g., the presence or absence of an amide group in the ring containing X1to X4, the location of such amide group, whether the amide is N-alkylated, the number of nitrogen atoms in the ring containing X1to X4, etc.). In one embodiment, without being bound by a particular theory, certain compounds provided herein possessing a structural feature exhibit improved potency (e.g., against AKT1 E17K mutant) when compared to compounds lacking said structural feature or possessing a different structural feature. In one embodiment, without being bound by a particular theory, certain compounds provided herein possessing a structural feature exhibit improved selectivity (e.g., over wild-type AKT1) when compared to compounds lacking said structural feature or possessing a different structural feature. In one embodiment, without being bound by a particular theory, certain compounds provided herein possessing a structural feature exhibit improved solubility (e.g., aqueous solubility) when compared to compounds lacking said structural feature or possessing a different structural feature. In one embodiment, without being bound by a particular theory, certain compounds provided herein possessing a structural feature exhibit improved permeability when compared to compounds lacking said structural feature or possessing a different structural feature. In one embodiment, without being bound by a particular theory, certain compounds provided herein possessing a structural feature exhibit improved metabolic stability when compared to compounds lacking said structural feature or possessing a different structural feature.

[0168] Without being bound by a particular theory, certain compounds having an amide group at X3and X4positions (e.g., X4is C(=O), X3is NRxn; or X3is C(=O), X4is NRxn) showed improvement of potency compared to certain compounds having an amide group at X1and X2positions (e.g., see Example Table B).

[0169] Without being bound by a particular theory, certain compounds having an N-alkylated (e.g., N-methylated) amide group in the ring containing X1to X4(e.g., X4is C(=O), X3is NRxn, and R™ is not hydrogen) showed improved permeability and / or improved solubility compared to certain compounds having an N-H amide group at the same positions e.g., see Example Table D).

[0170] Without being bound by a particular theory, introduction of a second nitrogen in the ring containing X1to X4had the advantage of improving potency and selectivity while maintaining a favorable permeability profile (e.g., see Example Tables B and D).NAI-5008634746vl -58-Attomey Docket No. 14709-051-2284.3 Pharmaceutical Compositions

[0171] Also provided herein is a pharmaceutical composition comprising one or more compounds provided herein and a pharmaceutically acceptable excipient.

[0172] In one embodiment, provided herein is a pharmaceutical preparation suitable for use in a human subject, comprising any of the compounds shown above (e.g., a compound provided herein, such as a compound of Formula (I)), and one or more pharmaceutically acceptable excipients. In one embodiment, the pharmaceutical preparations may be for use in treating or preventing a condition or disease as described herein. Any of the compounds provided herein may be used in the manufacture of medicaments for the treatment of any diseases or conditions provided herein.

[0173] The compositions and methods provided herein may be utilized to treat a subject in need thereof. In one embodiment, the subject is a mammal such as a human, or a non-human mammal. In one embodiment, when administered to a subject, such as a human, the composition or the compound is administered as a pharmaceutical composition comprising, for example, a compound provided herein and a pharmaceutically acceptable excipient.

[0174] Formulation can be modified depending upon the route of administration chosen. A compound or salt as described herein may be formulated in any suitable pharmaceutical formulation. A pharmaceutical formulation provided herein typically contains an active ingredient (e.g., a compound of Formula (I) or any sub-formula, or a pharmaceutically acceptable salt thereof), and one or more pharmaceutically acceptable excipients or carriers, including but not limited to: inert solid diluents and fillers, diluents, sterile aqueous solution and various organic solvents, permeation enhancers, antioxidants, solubilizers, and adjuvants. The pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, suspension, cream, gel, ointment, aerosol infusion, powder, solution, syrup, suppository, injection, or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as an eye drop.

[0175] In some embodiments, the dosage form is formulated for oral administration. For example, the pharmaceutical composition can be formulated in the form of a pill, a tablet, a capsule, an inhaler, a liquid suspension, a liquid emulsion, a gel, or a powder. In some embodiments, the pharmaceutical composition can be formulated as a unit dosage in liquid, gel, semi-liquid, semi-solid, or solid form. Preparations for such pharmaceutical compositions are well-known in the art. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G,NAI-5008634746vl -59-Attomey Docket No. 14709-051-228eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingstone, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 2003; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001;Remington’s Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000;Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999).4.4 Therapeutic Methods

[0176] Without being limited by a particular theory, compounds provided herein have various utilities. For example, compounds provided herein can be used as therapeutically active substances for the treatment and / or prophylaxis of a disease or disorder associated with aberrant activity of AKT. Such a method may comprise administering to a subject in need thereof a therapeutically effective amount of a compound provided herein, or a pharmaceutical composition provided herein.

[0177] In one aspect, provided herein is a method of treating a cell proliferative disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or a pharmaceutical composition as described herein. In some embodiments, the cell proliferative disease or disorder is cancer. In some embodiments, the cancer is associated with aberrant activity of AKT.

[0178] In one aspect, provided herein is a method of protecting against a cell proliferative disease or disorder in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or a pharmaceutical composition as described herein. The cell proliferative disease or disorder can be cancer or a precancerous condition.

[0179] As used herein, the term “cell proliferative disorder” or “cell proliferative disease” refers to conditions in which unregulated or abnormal growth, or both, of cells can lead to the development of an unwanted condition, disorder, or disease, which may or may not be cancerous. Exemplary cell proliferative disorders and diseases encompass a variety of conditions wherein cell division is deregulated. Exemplary cell proliferative diseases or disorders include, but are not limited to, neoplasms, benign tumors, malignant tumors, precancerous conditions, in situ tumors, encapsulated tumors, metastatic tumors, liquid tumors, solid tumors, immunological tumors, hematological tumors, cancers, carcinomas, leukemias, lymphomas, sarcomas, and rapidly dividing cells. The term “rapidly dividing cell” as used herein is defined as any cell that divides at a rate that exceeds or is greater than what is expected or observed among neighboringNAI-5008634746vl -60-Attomey Docket No. 14709-051-228or juxtaposed cells within the same tissue. A cell proliferative disease or disorder includes a precancer or a precancerous condition. A cell proliferative disease or disorder includes cancer. Preferably, the methods provided herein are used to treat or alleviate a symptom of cancer. The term “cancer” includes solid tumors as well as hematologic tumors and / or malignancies. A “precancer cell” or “precancerous cell” is a cell manifesting a cell proliferative disorder that is a precancer or a precancerous condition. A “cancer cell” or “cancerous cell” is a cell manifesting a cell proliferative disease or disorder that is a cancer. Any reproducible means of measurement may be used to identify cancer cells or precancerous cells. Cancer cells or precancerous cells can be identified by histological typing or grading of a tissue sample (e.g., a biopsy sample). Cancer cells or precancerous cells can be identified through the use of appropriate molecular markers.

[0180] Exemplary non-cancerous diseases or disorders include, but are not limited to, rheumatoid arthritis; inflammation; autoimmune disease; lymphoproliferative conditions; acromegaly; rheumatoid spondylitis; osteoarthritis; gout, other arthritic conditions; sepsis; septic shock; endotoxic shock; gram-negative sepsis; toxic shock syndrome; asthma; adult respiratory distress syndrome; chronic obstructive pulmonary disease; chronic pulmonary inflammation; inflammatory bowel disease; Crohn’s disease; psoriasis; eczema; ulcerative colitis; pancreatic fibrosis; hepatic fibrosis; acute and chronic renal disease; irritable bowel syndrome; pyresis; restenosis; cerebral malaria; stroke and ischemic injury; neural trauma; Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; acute and chronic pain; allergic rhinitis; allergic conjunctivitis; chronic heart failure; acute coronary syndrome; cachexia; malaria; leprosy; leishmaniasis; Lyme disease; Reiter’s syndrome; acute synovitis; muscle degeneration, bursitis; tendonitis; tenosynovitis; herniated, ruptures, or prolapsed intervertebral disk syndrome; osteopetrosis; thrombosis; restenosis; silicosis; pulmonary sarcosis; bone resorption diseases, such as osteoporosis; graft-versus-host reaction; Multiple Sclerosis; lupus; fibromyalgia; AIDS and other viral diseases such as Herpes Zoster, Herpes Simplex I or II, influenza virus, and cytomegalovirus; and diabetes mellitus.

[0181] Exemplary cancers include, but are not limited to, adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphoma, anal cancer, anorectal cancer, cancer of the anal canal, appendix cancer, childhood cerebellar astrocytoma, childhood cerebral astrocytoma, basal cell carcinoma, skin cancer (non-melanoma), biliary cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, bladder cancer, urinary bladder cancer, bone and joint cancer, osteosarcoma and malignant fibrous histiocytoma, brain cancer, brain tumor, brain stem glioma, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors, visual pathway and hypothalamic glioma,NAI-5008634746vl -61-Attomey Docket No. 14709-051-228breast cancer, bronchial adenomas / carcinoids, carcinoid tumor, gastrointestinal, nervous system cancer, nervous system lymphoma, central nervous system cancer, central nervous system lymphoma, cervical cancer, childhood cancers, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorders, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, lymphoid neoplasm, mycosis fungoides, Sezary syndrome, endometrial cancer, esophageal cancer, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer, intraocular melanoma, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, ovarian germ cell tumor, gestational trophoblastic tumor, glioma, head and neck cancer, hepatocellular (liver) cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, ocular cancer, islet cell tumors (endocrine pancreas), Kaposi sarcoma, kidney cancer, renal cancer, kidney cancer, laryngeal cancer, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, lip and oral cavity cancer, liver cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, AIDS-related lymphoma, non-Hodgkin lymphoma, primary central nervous system lymphoma, Waldenstrom’s macroglobulinemia, medulloblastoma, melanoma, intraocular (eye) melanoma, Merkel cell carcinoma, mesothelioma malignant, mesothelioma, metastatic squamous neck cancer, mouth cancer, cancer of the tongue, multiple endocrine neoplasia syndrome, mycosis fungoides, myelodysplastic syndromes, myelodysplastic / myeloproliferative diseases, chronic myelogenous leukemia, acute myeloid leukemia, multiple myeloma, chronic myeloproliferative disorders, nasopharyngeal cancer, neuroblastoma, oral cancer, oral cavity cancer, oropharyngeal cancer, ovarian cancer, ovarian epithelial cancer, ovarian low malignant potential tumor, pancreatic cancer, islet cell pancreatic cancer, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumor, plasma cell neoplasm / multiple myeloma, pleuropulmonary blastoma, prostate cancer, rectal cancer, renal pelvis and ureter, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Ewing family of sarcoma tumors, Kaposi sarcoma, soft tissue sarcoma, uterine cancer, uterine sarcoma, skin cancer (non-melanoma), skin cancer (melanoma), Merkel cell skin carcinoma, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer, supratentorial primitive neuroectodermal tumors, testicular cancer, throat cancer, thymoma, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter and other urinary organs, gestationalNAI-5008634746vl -62-Attomey Docket No. 14709-051-228trophoblastic tumor, urethral cancer, endometrial uterine cancer, uterine sarcoma, uterine corpus cancer, vaginal cancer, vulvar cancer, and Wilms Tumor.

[0182] In one aspect, provided herein is a method of treating a cell proliferative disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or a pharmaceutical composition as described herein. In one embodiment, the cell proliferative disease or disorder is characterized by dysregulated or abnormal cell growth, dysregulated or abnormal cell proliferation, altered cell survival, altered cell metabolism, and dysregulated or abnormal apoptosis. In one embodiment, the cell proliferative disease or disorder is cancer. In one embodiment, the cancer is associated with aberrant activity of AKT.

[0183] In another aspect, provided herein is a method of treating a disease or disorder associated with aberrant activity of AKT, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or a pharmaceutical composition as described herein. As used herein, aberrant AKT signaling refers to dysregulated or abnormal activation of the AKT pathway within cells. In certain embodiments, aberrant AKT signaling results in dysregulated or abnormal cell growth, dysregulated or abnormal cell proliferation, altered cell survival, altered cell metabolism, and dysregulated or abnormal apoptosis. In certain embodiments, aberrant AKT signaling results in development and progression of cancer.

[0184] In some embodiments, the aberrant AKT activity is associated with overactivity of AKT. In some embodiments, the overactivity of AKT occurs either from a direct change within the kinase itself such as may occur following a mutation within any of its subunits or from increased upstream activity, but not restricted to increased PI3K or PDK activity. In some embodiments, the aberrant AKT activity is associated with a mutation of an AKT gene. In one embodiment, the AKT mutation is of AKT1. In one embodiment, the AKT1 mutation is AKT1 E17K. In one embodiment, the AKT mutation is of AKT2. In one embodiment, the AKT mutation is of AKT3. In one embodiment, the AKT mutation is AKT gene amplification (e.g., amplification of AKT1). In one embodiment, the AKT mutation is an AKT3 mutation. In one embodiment, the AKT mutation is a gene fusion mutation. In one embodiment, the aberrant AKT activity results from mutations affecting upstream regulators of AKT (e.g., PI3K, PTEN). In some embodiments, the compounds as described here may selectivity inhibit one or two of the AKT protein family over the other AKT isoform(s). In some embodiments, the compounds as described here may selectively inhibit one or two of AKT1, AKT2, or AKT3 over the other isoform(s) of AKT. In some embodiments, the compounds may selectively inhibit AKT1 and / or AKT2 over AKT3. In some embodiments, the compounds as described here may selectivelyNAI-5008634746vl -63-Attomey Docket No. 14709-051-228inhibit AKT1 over AKT2 and / or AKT3. In some embodiments, the compounds as described here may selectively inhibit AKT1 mutant (e.g., E17K) over AKT2 and / or AKT3. In some embodiments, the compounds as described here may selectively inhibit AKT1 mutant (e.g., E17K) over AKT1 wild-type. In some embodiments, the compounds as described herein may interact with AKT at an allosteric site. In some embodiments, the compounds as described herein may interact with AKT1 mutant (e.g., E17K) at an allosteric site.

[0185] Further provided herein is a method of modulating AKT activity, comprising administering to a subject in need thereof a compound or a pharmaceutically acceptable salt or pharmaceutical composition as described herein. In one embodiment, the administration of the compound or pharmaceutical composition to the subject modulates the aberrant activity of the AKT in the subject. In one embodiment, the administration of the compound to the subject inhibits the activity of AKT in the subject. In one embodiment, the AKT1 mutation is AKT1 E17K. In one embodiment, the administration of the compound to the subject inhibits the activity of AKT1 in the subject. In one embodiment, the administration of the compound to the subject inhibits the activity of AKT mutant in the subject. In one embodiment, the administration of the compound to the subject inhibits the activity of AKT1 E17K in the subject.

[0186] In certain embodiments, aberrant AKT signaling results in development and progression of tumors. Accordingly, in one embodiment, the disease or disorder associated with aberrant activity of AKT is cancer. Accordingly, provided herein is a method for treating cancer, the method comprising administering to a subject a therapeutically effective amount of a compound or a pharmaceutical composition provided herein. In some embodiments, provided herein is use of a compound or a pharmaceutical composition provided herein in the manufacture of a medicament for treating cancer. In some embodiments, provided herein is use of a compound or a pharmaceutical composition provided herein for treating cancer. In some embodiments, provided herein is a compound or a pharmaceutical composition provided herein for use in the treatment of cancer. In some embodiments, provided herein is a compound or a pharmaceutical composition provided herein for use in a method of treating cancer, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound or a pharmaceutical composition provided herein.

[0187] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is selected from breast cancer, colorectal cancer, meningioma, ovarian cancer, cervical cancer, pancreatic cancer, glioma, glioblastoma, prostate cancer, leukemia, lymphoma, nonHodgkin’s lymphoma, lung cancer, hepatocellular cancer, gastric cancer, gastrointestinal stromal tumor (GIST), thyroid cancer, bile duct cancer, endometrial cancer, renal cancer, anaplastic largeNAI-5008634746vl -64-Attomey Docket No. 14709-051-228cell lymphoma, acute myeloid leukemia (AML), multiple myeloma, melanoma, and mesothelioma.

[0188] In one embodiment, the cancer is selected from adrenal tumors, bile duct cancer, bladder cancer, blood cancer, bone and / or connective tissue cancer, brain and / or central nervous system cancer, breast cancer, cervical cancer, colon and / or rectal cancer, colorectal cancer, endometrial cancer, esophageal cancer, gallbladder cancer, head and neck cancer, Hodgkin’s lymphoma, hypopharyngeal cancer, kidney cancer, laryngeal cancer, leukemia(s), liver cancer, lung cancer, lymphoma, mediastinal tumors, melanoma (including malignant melanoma), mesothelioma, multiple myeloma, nasal cavity cancer, nasopharyngeal cancer, neuroendocrine tumors, non-Hodgkin’s lymphoma, oral cancer, esophagus cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, paranasal sinus cancer, parathyroid cancer, penile cancer, pituitary tumors, prostate cancer, salivary gland cancer, sarcoma, skin cancer, spine cancer, stomach cancer, testicular cancer, thyroid cancer, urethral cancer, uterine cancer, vaginal cancer and vulvar cancer.

[0189] In one embodiment, the cancer is selected from breast cancer, lung cancer, bladder cancer (e.g., bladder urothelial cancer), ovarian cancer, colorectal cancer, endometrial uterine cancer, cervical cancer, prostate cancer, salivary cancer, appendiceal cancer, esophagogastric cancer, head and neck cancer, melanoma cancer, thyroid cancer, embryonal tumor, hepatobiliary cancer, pancreatic cancer, soft tissue sarcoma, sex cord stromal tumor, CNS cancer, B-lymphoblastic leukemia, gallbladder cancer, lymphoma, and mature T and NK neoplasms. In certain embodiments, the cancer is selected from breast cancer, lung cancer, bladder cancer, ovarian cancer, colorectal cancer, endometrial uterine cancer, cervical cancer, and prostate cancer. In one embodiment, the cancer is breast cancer. In one embodiment, the cancer is lung cancer. In one embodiment, the cancer is bladder urothelial cancer. In one embodiment, the cancer is ovarian cancer. In one embodiment, the cancer is colorectal cancer. In one embodiment, the cancer is endometrial uterine cancer. In one embodiment, the cancer is cervical cancer. In one embodiment, the cancer is prostate cancer.

[0190] The administering in the methods provided herein is not limited to any particular route of administration. For example, in some embodiments, the administering can be orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, and parenterally. In some embodiments, the administering is orally. In some embodiments, the administering is a parenteral injection, such as an intravenous injection.NAI-5008634746vl -65-Attomey Docket No. 14709-051-228

[0191] Compounds provided herein can be used as a monotherapy or in a combination therapy. In one embodiment, provided herein is a method of treating a disease or condition associated with aberrant activity of AKT (e.g., AKT1), comprises administering a compound provided herein as the only therapeutic agent. In one embodiment, provided herein is a method of treating a disease or condition associated with aberrant activity of AKT (e.g., AKT1), comprises administering a compound or pharmaceutical composition as provided herein together with an additional therapeutic agent to the subject.

[0192] In one embodiment, a compound as provided herein is administered to the subject concurrently (e.g., at the same time as) with the additional therapeutic agent. In one embodiment, a compound as provided herein is co-administered to the subject in sequence (and in any order) with the additional therapeutic agent. Where administration is sequential, the delay in administering the later therapeutic agent should retain the beneficial effect of administering the combination.

[0193] In one embodiment, a compound as provided herein and the additional therapeutic agent are present and administered to the subject in a single pharmaceutical composition comprising the compound, the additional therapeutic agent, and a pharmaceutically acceptable excipient, as provided herein. In one embodiment, a compound as provided herein, and the additional therapeutic agent are present and administered to the subject in separate pharmaceutical compositions.

[0194] The additional therapeutic agent may be any agent, such as an anticancer therapeutic agent. Non-limiting examples of anticancer therapeutic agents include mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, anti-angiogenesis agents, topoisomerase I and II inhibitors, plant alkaloids, hormonal agents and antagonists, growth factor inhibitors, radiation, signal transduction inhibitors, such as inhibitors of protein tyrosine kinases and / or serine / threonine kinases, cell cycle inhibitors, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxics, immunooncology agents, and the like.

[0195] In some embodiments, the additional therapeutic agent is an androgen receptor signaling modulator. In some embodiments, the androgen receptor signaling modulator is selected from the group consisting of MDV-3100 (“enzalutamide”, 4-(3-[4-cyano-3-(trifluoromethyl)-phenyl]-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl )-2-fluoro-N-methylbenzamide); AZD3514 (l-(4-[2-(4-(l-[3-(trifhioromethyl)-7,8-dihydro[l,2,4]triazolo[4,3-b]pyrid-azin-6-yl]piperidin-4-yl)phenoxy) ethyl]piperazin-l-yl)ethanone); abiraterone, or an ester prodrug thereof ((3P)-17-(pyridin-3-yl)androsta-5,16-dien-3-ol “abiraterone”, or “abirateroneNAI-5008634746vl -66-Attomey Docket No. 14709-051-228acetate”); and bicalutamide (N-[4-cyano-3-(trifluoromethyl)-phenyl]-3-[(4-fluorophenyl)-sulfonyl]-2-hydroxy-2-methylpropanamide, or a pharmaceutically acceptable salt thereof.

[0196] In some embodiments, the additional therapeutic agent is a taxane. In some embodiments, the taxane is selected from docetaxel and paclitaxel.

[0197] In some embodiments, the additional therapeutic agent is an estrogen receptor modulator. Non-limiting examples of estrogen receptor modulators include tamoxifen, raloxifene, toremifene, and fulvestrant.

[0198] In some embodiments, the additional therapeutic agent is an aromatase inhibitor. Non-limiting examples of aromatase inhibitors include Anastrozole, Letrozole, and Exemestane.

[0199] In some embodiments, the additional therapeutic agent is a modulator of at least one of CDK2, CDK4 and CDK6. Non-limiting examples of such modulators include palbociclib, ribociclib, abemaciclib, INX-315, and flavopiridol.

[0200] In some embodiments, the additional therapeutic agent is a HER2 -targeting antibody-drug conjugates (ADC). Non-limiting examples of HER2 -targeting ADCs include trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), disitamab vedotin (RC48), and ARX-788.

[0201] In some embodiments, the additional therapeutic agent is a TROP2 ADC. Nonlimiting examples of TROP2 ADCs include sacituzumab govitecan (TRODELVY) and datopotamab deruxtecan (Dato-DXd).

[0202] In some embodiments, the additional therapeutic agent is a HER3 -targeting ADC. Non-limiting examples of HER3 -targeting ADCs include patritumab deruxtecan (HER3-DXd).

[0203] In some embodiments, the additional therapeutic agent is a LIV1 -targeting ADC.Non-limiting examples of a LIV1 -targeting ADCs include ladiratuzumab vedotin.

[0204] In some embodiments, the additional therapeutic agent is an immunomodulator. Non-limiting examples of immunomodulators (e.g., immuno-oncology agents) include afutuzumab (available from ROCHE®); pegfilgrastim (NEULASTA®); lenalidomide (CC-5013, REVLIMID®); thalidomide (THALOMID®); actimid (CC4047); and IRX-2 (mixture of human cytokines including interleukin 1, interleukin 2, and interferon y, CAS 951209-71-5, available from IRX Therapeutics).

[0205] In certain embodiments, the immunomodulators are chimeric antigen receptor T-cell (CAR-T) therapies, such as tisagenlecleucel (Novartis), axicabtagene ciloleucel (Kite), and tocilizumab (atlizumab; Roche).NAI-5008634746vl -67-Attomey Docket No. 14709-051-228

[0206] In certain embodiments, the immunomodulators are immune checkpoint inhibitors, such as PD-1 inhibitors, PD-L1 inhibitors, cytotoxic T-lymphocyte-associated modulators (e.g., CTLA-4 inhibitors), LAG-3 inhibitors, TIM-3 inhibitors.

[0207] In certain embodiments, the immunomodulators are PD-1 inhibitors, such as pembrolizumab (also known as lambrolizumab, MK-3475, MK03475, SCH-900475, or KEYTRUDA®) and other anti-PD-1 antibodies (as described in Hamid, O. et al. (2013) New England Journal of Medicine 369 (2): 134-44, US 8,354,509, and WO 2009 / 114335, incorporated by reference in their entirety), nivolumab (also known as MDX-1106, MDX-1106-04, ONO-4538, BMS-936558, or OPDIVO®) and other anti-PD-1 antibodies (as described in US 8,008,449 and WO 2006 / 121168, incorporated by reference in their entirety), cemiplimab (LIBTAYO®), sintilimab, spartalizumab (PDR001), pidilizumab (CureTech), MEDI0680 (Medimmune), dostarlimab (TSR-042), PF-06801591 (Pfizer), sintilimab, toripalimab, tislelizumab (BGB-A317), camrelizumab (INCSHR1210, SHR-1210), AMP-224 (Amplimmune), CBT-501 (CBT Pharmaceuticals), CBT-502 (CBT Pharmaceuticals), JS001 (Junshi Biosciences), IB 1308 (Innovent Biologies), INCSHR1210 (Incyte), also known as SHR-1210 (Hengrui Medicine), BGBA317 (Beigene), BGB-108 (Beigene), BAT-1306 (Bio-Thera Solutions), GLS-010 (Gloria Pharmaceuticals; WuXi Biologies), AK103, AK104, AK105 (Akesio Biopharma; Hangzhou Hansi Biologies; Hanzhong Biologies), LZM009 (Livzon), HLX-10 (Henlius Biotech), MEDI0680 (Medimmune), PDF001 (Novartis), PF-06801591 (Pfizer), pidilizumab (CureTech) also known as CT-011 and other anti-PD-1 antibodies (as described in Rosenblatt, J. et al. (2011) J Immunotherapy 34(5): 409-18, US 7,695,715, US 7,332,582, and US 8,686,119, incorporated by reference in their entirety), REGN2810 (Regeneron) and TSR-042 (Tesaro), also known as ANB011, or CS1003 (CStone Pharmaceuticals). MEDI0680 (Medimmune), is also known as AMP-514. MEDI0680 and other anti-PD-1 antibodies are described in US 9,205,148 and WO 2012 / 145493, incorporated by reference in their entireties. Further known anti-PD-1 antibody molecules include those described, e.g., in WO 2015 / 112800, WO 2016 / 092419, WO 2015 / 085847, WO 2014 / 179664, WO 2014 / 194302, WO 2014 / 209804, WO 2015 / 200119, US 8,735,553, US 7,488,802, US 8,927,697, US 8,993,731, and US 9,102,727, incorporated by reference in their entireties. In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody molecule, as described in US 2015 / 0210769, published on July 30, 2015, entitled “Antibody Molecules to PD-1 and Uses Thereof,” incorporated by reference in its entirety. In one embodiment, the anti-PD-1 antibody molecule comprises the CDRs, variable regions, heavy chains and / or light chains of BAP049-Clone-E or BAP049-Clone-B described in US 2015 / 0210769. The antibody molecules described herein can be made by vectors, host cells,NAI-5008634746vl -68-Attomey Docket No. 14709-051-228and methods described in US 2015 / 0210769, incorporated by reference in its entirety. In one embodiment, the PD-1 inhibitor is a peptide that inhibits the PD-1 signaling pathway, e.g., as described in US 8,907,053, incorporated by reference in its entirety. In one embodiment, the PD-1 inhibitor is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region (e.g., an Fc region of an immunoglobulin sequence)). In one embodiment, the PD-1 inhibitor is AMP-224 (B7-DCIg (Amplimmune), e.g., described in WO 2010 / 027827 and WO 2011 / 066342, incorporated by reference in their entireties).

[0208] In certain embodiments, the immunomodulators are PD-L1 inhibitors, such as atezolizumab (also known as MPDL3280A, RG7446, RO5541267, YW243.55. S70, or TECENTRIQ®) and other anti-PD-Ll antibodies as described in US 8,217,149, incorporated by reference in its entirety, avelumab (BAVENCIO®, also known as MSB0010718C) and other anti-PD-Ll antibodies as described in WO 2013 / 079174, incorporated by reference in its entirety, durvalumab (IMFINZI® or MED 14736) and other anti-PD-Ll antibodies as described in US 8,779,108, incorporated by reference in its entirety), FAZ053 (Novartis), and BMS-936559 (Bristol-Myers Squibb). In certain embodiments, the PD-L1 inhibitor is KN035 (Alphamab; 3DMed; Ascletis Pharma), envafolimab (TRACON Pharmaceuticals), BMS 936559 (Bristol-Myers Squibb), CS1001 (CStone Pharmaceuticals, Ligand Pharmaceuticals), CX-072 (CytomX Therapeutics), FAZ053 (Novartis), SHR-1316 (Hengrui Medicine), TQB2450 (Chiatai Tianqing), STLA1014 (Zhaoke Pharm; Lee’s Pharm, Lonza, Sorrento Therapeutics, NantWorks), LYN00102 (Lynkcell), A167 (Harbour BioMed, Kelun Group), BGB-A333 (Beigene), MSB2311 (Mabspace Biosciences), or HLX-20 (Henlius Biotech). In one embodiment, the anti-PD-Ll antibody molecule is BMS-936559 (Bristol-Myers Squibb), also known as MDX-1105 or 12A4. BMS-936559 and other anti-PD-Ll antibodies are described in US 7,943,743 and WO 2015 / 081158, incorporated by reference in their entireties. In certain embodiments, the PD-L1 inhibitor is cosibelimab (Fortress Biotech), LY3300054 or iodapolimab (Eli Lilly), GS-4224 (Gilead Sciences), STLA1015 (Yuhan, Sorrento Therapeutics), BCD-135 (BIOCAD), cosibelimab (Dana-Farber Cancer Institute, TG Therapeutics), APL-502 (Apollomics), AK106 (Akeso Biopharma), MSB2311 (Transcenta Holding), TG-1501 (TG Therapeutics) orFAZ053 (Novartis). In certain embodiments, the PD-L1 inhibitor is MT-6035 (Molecular Templates), icaritin or ZKAB001 (Lonza, Lee’s Pharmaceutical Holdings, Sorrento Therapeutics, Shenogen Pharma Group), TRIDENT Antibody (MacroGenics, Zai Lab), YBL-007 (Anh-Gook Pharmaceutical, Y-Biologics), HTI-1316 (Hengrui Therapeutics), PD-L1 Oncology Project (Weizmann Institute of Sciences), JS003 (Shanghai Junshi Biosciences), ND021 (NumabNAI-5008634746vl -69-Attomey Docket No. 14709-051-228Therapeutics, CStone Pharmaceuticals), Toca 521 (Tocagen) or STT01 (STCube). In certain embodiments, the PD-L1 inhibitor is DB004 (DotBio), MT-5050 (Molecular Templates), KD036 (Kadmon). In one embodiment, the PD-L1 inhibitor is an anti-PD-Ll antibody molecule. In one embodiment, the PD-L1 inhibitor is an anti-PD-Ll antibody molecule as described in US 2016 / 0108123, published on April 21, 2016, entitled “Antibody Molecules to PD-L1 and Uses Thereof,” incorporated by reference in its entirety. In one embodiment, the anti-PD-Ll antibody molecule comprises the CDRs, variable regions, heavy chains and / or light chains of BAP058-Clone O or BAP058-Clone N described in US 2016 / 0108123, incorporated by reference in its entirety. Further known anti-PD-Ll antibodies include those described, e.g., in WO 2015 / 181342, WO 2014 / 100079, WO 2016 / 000619, WO 2014 / 022758, WO 2014 / 055897, WO 2015 / 061668, WO 2013 / 079174, WO 2012 / 145493, WO 2015 / 112805, WO 2015 / 109124, WO 2015 / 195163, US 8,168,179, US 8,552,154, US 8,460,927, and US 9,175,082, incorporated by reference in their entireties.

[0209] In certain embodiments, the immunomodulators are CTLA-4 inhibitors, such as ipilimumab (YERVOY®), tremelimumab, ALPN-202 (Alpine Immune Sciences), RP2 (Replimune), BMS-986249 (Bristol-Myers Squibb), BMS-986218 (Bristol-Myers Squibb), zalifrelimab (Agenus, Ludwig Institute for Cancer Research, UroGen Pharma, Recepta Biopharma), BCD-217 (BIOCAD), Onc-392 (Pfizer, Oncolmmune), IBB 10 (Innovent Biologies), KN046 (Alphamab), MK-1308 (Merck & Co), REGN4659 (Regeneron Pharmaceuticals), XmAb20717 (Xencor), XmAb22841 (Xencor), Anti-CTLA-4 NF (Bristol-Myers Squibb), MEDI5752 (AstraZeneca), AGEN1181 (Agenus), MGD019 (MacroGenics), ATOR-1015 (Alligator Bioscience), BCD-145 (BIOCAD), PSB205 (Sound Biologies), CS1002 (CStone Pharmaceuticals), ADU-1604 (Aduro Biotech), PF-06753512 (Pfizer), Biolnvent-Transgene Research Program (Transgene), AGEN2041 (Agenus, Recepta Biopharam), ATOR-1144 (Alligator Bioscience), CTLA-4 Research Project (Sorrento Therapeutics), PD-L1 / CTLA-4 Research Project (Sorrento Therapeutics), HLX13 (Shanghai Henlius Biotech), ISA203 (ISA Pharmaceuticals), PRS-300 Series A (Pieris Pharmaceuticals), BA3071 (BioAtla), CTLA4 Cancer Research Program (Biosortia Pharmaceuticals), RP3 (Replimune), CG0161 (Cold Genesys), APL-509 (Apollomics, JSR), AGEN2041 (Ludwig Institute for Cancer Research), APC 101 (Advanced Proteome), CTLA-4 Inhibitor (Advanced Proteome), BA3071 (BeiGene), BPL002 (BeyondSpring Pharmaceuticals), CTLA-4 Antibody (Tikcro Technologies), ImmunoOncology Research Program II (OliPass), PBP1701 (Prestige BioPharma), DB002 (DotBio), DB003 (DotBio), OR-2299 (OncoResponse) and NK044 (Alphamab).NAI-5008634746vl -70-Attomey Docket No. 14709-051-228

[0210] In some embodiments, the immunomodulators are LAG-3 inhibitors, such as LAG525 (Novartis), BMS-986016 (Bristol-Myers Squibb), and TSR-033 (Tesaro). In one embodiment, the LAG-3 inhibitor is an anti-LAG-3 antibody molecule. In one embodiment, the LAG-3 inhibitor is an anti-LAG-3 antibody molecule as described in US 2015 / 0259420, published on September 17, 2015, entitled “Antibody Molecules to LAG-3 and Uses Thereof,” incorporated by reference in its entirety. In one embodiment, the anti-LAG-3 antibody molecule comprises the CDRs, variable regions, heavy chains and / or light chains of BAP050-Clone I or BAP050-Clone J described in US 2015 / 0259420. In one embodiment, the anti-LAG-3 antibody molecule is BMS-986016 (Bristol-Myers Squibb), also known as BMS986016. BMS-986016 and other anti-LAG-3 antibodies are described in WO 2015 / 116539 and US 9,505,839, incorporated by reference in their entireties. In one embodiment, the anti-LAG-3 antibody molecule is TSR-033 (Tesaro). In one embodiment, the anti-LAG-3 antibody molecule is IMP731 or GSK2831781 (GSK and Prima BioMed). IMP731 and other anti-LAG-3 antibodies are described in WO 2008 / 132601 and US 9,244,059, incorporated by reference in their entireties. In one embodiment, the anti-LAG-3 antibody molecule is IMP761 (Prima BioMed). Further known anti-LAG-3 antibodies include those described, e.g., in WO 2008 / 132601, WO 2010 / 019570, WO 2014 / 140180, WO 2015 / 116539, WO 2015 / 200119, WO 2016 / 028672, US 9,244,059, US 9,505,839, incorporated by reference in their entireties. In one embodiment, the anti-LAG-3 inhibitor is a soluble LAG-3 protein, e.g., IMP321 (Prima BioMed), e.g., as described in WO 2009 / 044273, incorporated by reference in its entirety.

[0211] In some embodiments, the immunomodulators are TIM-3 inhibitors, such as MGB453 (Novartis) and TSR-022 (Tesaro). In one embodiment, the TIM-3 inhibitor is an anti-TIM-3 antibody molecule. In one embodiment, the TIM-3 inhibitor is an anti-TIM-3 antibody molecule as described in US 2015 / 0218274, published on August 6, 2015, entitled “Antibody Molecules to TIM-3 and Uses Thereof,” incorporated by reference in its entirety. In one embodiment, the anti-TIM-3 antibody molecule comprises the CDRs, variable regions, heavy chains and / or light chains of ABTIM3-huml 1 or ABTIM3-hum03 described in US 2015 / 0218274, incorporated by reference in its entirety. In one embodiment, the anti-TIM-3 antibody molecule is TSR-022 (AnaptysBio / Tesaro). In one embodiment, the anti-TIM-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of APE5137 or APE5121. APE5137, APE5121, and other anti-TIM-3 antibodies are described in WO 2016 / 161270, incorporated by reference in its entirety. In one embodiment, the anti-TIM-3 antibody molecule is the antibody clone F38-2E2. Further known anti-TIM-3NAI-5008634746vl -71-Attomey Docket No. 14709-051-228antibodies include those described, e.g., in WO 2016 / 111947, WO 2016 / 071448, WO 2016 / 144803, US 8,552,156, US 8,841,418, and US 9,163,087, incorporated by reference in their entireties.

[0212] In some embodiments, a platinum analogue can be used in combination with compounds provided herein. In certain embodiments, a platinum analogue (e.g., cisplatin, paclitaxel, carboplatin) and combination therapy comprising a platinum analogue e.g., docetaxel and carboplatin; paclitaxel and carboplatin; carboplatin and liposomal doxorubicin (dox)) can be used in combination with compounds provided herein.

[0213] In some embodiments, exemplified chemotherapeutic agents that may be conjointly administered with compounds provided herein include: l-amino-4-phenylamino-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (acid blue 25), l-amino-4-[4-hydroxyphenyl-amino]- 9.10-dioxo-9,10-dihydroanthracene-2-sulfonate, l-amino-4-[4-aminophenylamino]-9,10-dioxo- 9.10-dihydroanthracene-2-sulfonate, 1 -amino-4-[ 1 -naphthylamino]-9, 10-dioxo-9, 10-dihydroanthracene-2-sulfonate, 1 -amino-4-[4-fluoro-2-carboxyphenylamino]-9, 10-dioxo-9, 10-dihydroanthracene-2-sulfonate, l-amino-4-[2-anthracenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, ABT-263, ado-trastuzumab emtansine, afatinib dimaleate, axitinib, aminoglutethimide, amsacrine, anastrozole, APCP, asparaginase, AZD5363, Bacillus Calmette-Guerin vaccine (beg), bicalutamide, bleomycin, bortezomib, P-methylene-ADP (AOPCP), buserelin, busulfan, cabazitaxel, cabozantinib, campothecin, capecitabine, carboplatin, carfilzomib, carmustine, ceritinib, chlorambucil, chloroquine, cisplatin, cladribine, clodronate, cobimetinib, colchicine, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, demethoxyviridin, dexamethasone, di chloroacetate, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, epirubicin, eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, fam-trastuzumab deruxtecan, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, gefitinib, gemcitabine, genistein, goserelin, GSK1120212, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, ixabepilone, lenalidomide, letrozole, leucovorin, leuprolide, levamisole, lomustine, lonidamine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, metformin, methotrexate, miltefosine, mitomycin, mitotane, mitoxantrone, MK-2206, mutamycin, N-(4-sulfamoylphenylcarbamothioyl) pivalamide, NF279, NF449, nilutamide, nocodazole, octreotide, olaparib, oxaliplatin, paclitaxel, pamidronate, pazopanib, pemexetred, pentostatin, perifosine, PF-04691502, plicamycin, pomalidomide, porfimer, PP DS, procarbazine, quercetin, raltitrexed, ramucirumab, reactive blue 2, rituximab, rolofylline, romidepsin, rucaparib, selumetinib, sirolimus, sodium 2,4-dinitrobenzenesulfonate, sorafenib,NAI-5008634746vl -72-Attomey Docket No. 14709-051-228streptozocin, sunitinib, suramin, talazoparib, tamoxifen, temozolomide, temsirolimus, teniposide, testosterone, thalidomide, thioguanine, thiotepa, titanocene dichloride, tonapofylline, topotecan, trametinib, trastuzumab, tretinoin, veliparib, vinblastine, vincristine, vindesine, vinorelbine, and vorinostat (SAHA). In other embodiments, chemotherapeutic agents that may be conjointly administered with compounds provided herein include: ABT-263, dexamethasone, 5-fluorouracil, PF-04691502, romidepsin, and vorinostat (SAHA). In other embodiments, chemotherapeutic agents that may be conjointly administered with compounds provided herein include: l-amino-4-phenylamino-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (acid blue 25), 1 -amino-4-[4-hydroxyphenyl-amino]-9, 10-dioxo-9, 10-dihydroanthracene-2-sulfonate, 1 -amino-4-[4-aminophenylamino]-9, 10-dioxo-9, 10-dihydroanthracene-2-sulfonate, 1 -amino-4-[ 1 -naphthylamino]-9, 10-dioxo-9, 10-dihydroanthracene-2-sulfonate, l-amino-4-[4-fluoro-2-carboxyphenylamino]-9,10-di oxo-9, 10-dihydroanthracene-2-sulfonate, l-amino-4-[2-anthracenylamino]-9,10-di oxo-9, 10-dihydroanthracene-2-sulfonate, APCP, P-methylene-ADP (AOPCP), capecitabine, cladribine, cytarabine, fludarabine, doxorubicin, gemcitabine, N-(4-sulfamoylphenylcarbamothioyl) pivalamide, NF279, NF449, PP DS, quercetin, reactive blue 2, rolofylline sodium 2,4-dinitrobenzenesulfonate, sumarin, and tonapofylline.5. EXAMPLESGeneral Synthetic Procedures

[0214] The compounds provided herein can be prepared by a variety of synthetic methods, as further described and illustrated herein. It will be understood by those with skill in the art that the following general synthetic methods are representative and not intended to be limiting. For clarity, the exemplified compounds can be prepared by one or more exemplified methods as described here using standard chemical conversion techniques as within the skill of those in the art. Racemic compounds can be enantiomerically enriched via chiral, preparative, SFC, or HPLC separation. Diastereomeric mixtures can be similarly enriched using the same separation techniques. Stereogenic sp3centers drawn without up- or down-wedge annotation represent an unquantified mixture of configurations at that position. Stereogenic sp3centers drawn with up- or down-wedge annotations represent a stereo-enrichment for the configuration drawn. Stereogenic sp3centers drawn with up- or down-wedge further annotated with “orl” represent stereo-enrichment for a single, unknown configuration.Abbreviations DefinitionSolventsEA, EtOAc Ethyl acetateNAI-5008634746vl -73-Attomey Docket No. 14709-051-228Abbreviations DefinitionPE, pet. ether Petroleum etherTHF TetrahydrofuranDCM DichloromethaneDMF N, N-dimethylformamideDMA N, N-dimethylacetamideNMP N -methyl -2-py rroli doneDMSO Dimethyl sulfoxideIPA Isopropyl alcoholDME Dimethoxy ethaneMeCN, ACN AcetonitrileDCE DichloroethaneDioxane 1,4-Dioxanen-Butanol 1 -ButanolTert-Butanol Tert-butyl alcoholReagentsDPPA Diphenylphosphoryl azideDIAD Diisopropyl azodi carb oxy late DEAD Diethyl azodi carb oxy late CS2CO3 Cesium carbonateDIPEA, DIEA 7V,7V-diisopropylethylamine TEA, Et3N TriethylamineATP Adenosine triphosphateTFA Trifluoroacetic acidFA Formic acidK2CO3 Potassium carbonateNa2CO3Sodium carbonateKOH Potassium hydroxideKOAc Potassium acetateHC1 Hydrochloric acidLiCl Lithium chlorideNH₄Cl Ammonium chlorideTf2O Trifluoromethanesulfonic anhydrideNAI-5008634746vl -74-Attomey Docket No. 14709-051-228Abbreviations DefinitionNH3AmmoniaDMAP 4-DimethylaminopyridinepTSA p-Toluenesulfonic acidDEA DiethylamineNaH Sodium hydrideNaOH Sodium hydroxidel-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- HATUb]pyridinium 3 -oxide hexafluorophosphatePOCh Phosphoryl chloridePhNTf2A-Phenyl-trifluoromethanesulfonimidePd(PPh3)4Palladium-tetrakis(triphenylphosphine)[1,1'- Pd(dppf)C12Bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(OAc)2Palladium(II) acetatePd2(dba)3 Tris(dibenzylideneacetone)dipalladium(0)MOM Methoxymethyl etherMOMC1 Chloromethyl methyl etherNBS N-BromosuccinimideNIS N-IodosuccinimidePPh3TriphenylphosphineAcCl Acetyl chlorideXPhos 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene RuPhos 2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl DMA DimethylacetamideMeONa Sodium methoxideNaBEU Sodium borohydrideOtherHPLC high-pressure liquid chromatographyPrep preparativewt wild-typert, r.t., RT room-temperatureNAI-5008634746vl -75-Attorney Docket No. 14709-051-228Abbreviations DefinitionSFC supercritical fluid chromatographyv / v volume / volumeLC / MS, LC-MS,liquid chromatography-mass spectrometryLCMS MS mass spectrometryESI, ES+, ES- electrospray ionizationNMR nuclear magnetic resonancePPm parts per millionsat saturatedaq aqueousBoc tert-butoxycarbonylBOC2O Di -tert-butyl di carb onateGeneral Methods of Synthesizing Compound Cores and IntermediatesScheme 1A-vi A-xi A-xii Z = Cl, OTfNAI-5008634746vl -76-Atorney Docket No. 14709-051-228(4) Cs2CO3, DMF A-xiiiPd(dppf)CI2, Na2CO3, dioxane / H2O, 90°C Z = Cl, OTf(5) (Ra)NH2A-xx o (6) (Ra)n-(Ak A A-xx A-xxv A-xxvi Z = Cl, OTf o A-xxvii POCI3 or PhNTf2CS2CO3, DMF CS2CO3, DMF (Ra)n Z = Cl, OTfNAI-5008634746vl -77-Atorney Docket No. 14709-051-228POCI3or PhNTf2K2CO3, MeCNA-xxxviiZ = Cl, OTfA-xxxvCS2CO3, DMF Pd(dppf)CI2, Na2CO3,dioxane / H2O, heatedNaBH4, MeOHAppel Reaction or SOCI2A-xxxv Pd(dppf)CI2, Na2CO3, dioxane / H2O, heatedZ = Cl, Br or INAI-5008634746vl -78-Attorney Docket No. 14709-051-228Appel Reaction or SOCI2DCMZ = Cl, BrorA-LXviii A-LXX A-LXXiZ = Cl, Bror lNAI-5008634746vl -79-Attorney Docket No. 14709-051-228

[0215] According to Scheme 1-(1), compound A-i reacts with aldehyde A-ii in the presence of a base (e.g., CS2CO3) to generate compound A-iii, which undergoes nucleophilic aromatic substitution in the presence of a base (e.g, MeONa) to yield intermediate A-iv.Derivatization of compound A-iv in the presence of POCI3 or PhNTf? or TfzO provides bicyclic compound A-v. In some embodiments, X4and X3are each independently CRX(e.g, in Scheme 1-(2)).

[0216] Similar to Scheme 1-(1), Scheme l-(7) provides the synthetic process to prepare compound A-xxix.

[0217] In Scheme l-(2), compound A-vi reacts with aldehyde A-vii to give bicyclic intermediate A-viii. Subsequent treatment of intermediate A-viii with POCI3 or PhNTt'2 or TfzO provides compound A-ix. In some embodiments, X4and X3are each independently CRX.

[0218] Similar to Scheme l-(2), Scheme l-(3), Scheme l-(5) and Scheme l-(6) provide the synthetic process to prepare compound A-xii, A-xxiii, and A-xxvi. In some embodiments, X2and X1are each independently CRX(e.g., in Scheme l-(3)). In some embodiments, X2is N and X1is CRX(e.g., in Scheme l-(3)). In some embodiments, X1is N and X2is CRX.

[0219] In Scheme l-(4), compound A-xiii reacts with aldehyde A-xiv in the presence of a base (e.g., CS2CO3) to generate compound A-xv. Subsequent nucleophilic aromatic substitution of compound A-xv in the presence of a base (e.g., MeONa) leads to compound A-xvi. Compound A-xvi undergoes a coupling reaction with boronic acid A-xvii in the presence of a metal catalyst (e.g., Pd(dppf)C12) provides intermediate A-xviii. Derivatization of compound A-xviii in the presence of POCI3 or PhNTf2 or Tf2O generates compound A-xix.NAI-5008634746vl -80-Attomey Docket No. 14709-051-228

[0220] In Scheme l-(8), commercially available compound A-xxx reacts with boronic acid A-xxxi to provide naphthyridine A-xxxii.

[0221] In Scheme l-(9), compound A-xiii reacts with aldehyde A-xxxiii to give bicyclic intermediate A-xxxiv. Subsequent coupling of intermediate A-xxxiv with boronic acid A-xxxv in the presence of a metal catalyst (e.g., Pd(dppf)C12) provides intermediate A-xxxvi. Derivatization of compound A-xxxvi in the presence of POCh or PhNTt'2 generates compound A-xxxvii.

[0222] In Scheme l-(10), compound A-xxxviii reacts with aldehyde A-xxxiii to give bicyclic intermediate A-xxxix. Subsequent coupling of intermediate A-xxxix with boronic acid A-xxxv in the presence of a metal catalyst (e.g., Pd(dppf)C12) provides intermediate A-xxxx. Intermediate A-xxxx undergoes a deprotection reaction to deprotect the acetal group in the presence of an acid (e.g., HC1, TFA, etc.) to give aldehyde intermediate A-xxxxi. Reduction of aldehyde A-xxxxi by a reducing agent e.g., NaBH4, Li Al FL, etc.) provides intermediate A-xxxxii. Derivatization of compound A-xxxxii by an Appel reaction (e.g., PPhs and C(Halide)4) or in the presence of SOCI2 generates compound A-xxxxiii. Following a similar approach, Scheme l-(ll) can be used to prepare compound A-xxxxix.

[0223] In Scheme 1-(12), coupling of intermediate A-xxxxv with an amine in the presence of a metal catalyst (e.g., a Pd complex like an XPhos-ligated Pd complex) provides intermediate A-L. Intermediate A-L undergoes a deprotection reaction in the presence of an acid (e.g., HC1, TFA, etc.) to give aldehyde intermediate A-Li. Reduction of aldehyde A-Li by a reducing agent (e.g., NaBFL, LiAlLh, etc.) provides intermediate A-Lii. Derivatization of compound A-Lii by an Appel reaction (e.g., PPhs and C(Halide)4) or in the presence of SOCI2 generates compound A-Liii.

[0224] In Scheme 1-(13), compound A-Liv reacts with di-amine, A-Lv to give bicyclic intermediates A-Lvi or A-Lvii.

[0225] Similar to Schemes 1-(1) to 1 -(4), in Schemes 1-(14) and 1-(15), intermediate A-Lviii reacts with aldehyde A-Lix or A-Lxi in the presence of a base (e.g., CS2CO3) to provide intermediate A-LX or A-LXii respectively.

[0226] In Scheme 1-(16), compound A-LXiii is treated with a base (e.g., CS2CO3, TMEDA, n-BuLi, etc.) in the presence of DMF to yield aldehyde A-LXiv. Subsequent coupling of intermediate A-LXiv with boronic acid A-LXv in the presence of a metal catalyst (e.g, Pd(PPh3)4 or Pd(dppf)C12) provides intermediate A-LXvi, followed by acetylation to give intermediate A-LXvii. Subsequent treatment of intermediate A-LXvii with NBS provides compound A-LXviii. Coupling of intermediate A-LXviii with boronic acid A-LXix in the presence of a metal catalyst (e.g, Pd(PPh3)4 or Pd(dppf)C12) provides intermediate A-LXX,NAI-5008634746vl -81-Attorney Docket No. 14709-051-228followed by olefin formation to yield intermediate A-LXXi. Compound A-LXXi undergoes cyclization in the presence of a base (e.g., CS2CO3, EtONa, etc.) to provide intermediate A- LXXii. Nucleophilic substitution of intermediate A-LXXii in the presence of a base (e.g., CS2CO3, K2CO3, etc.) generates compound A-LXXiii. Derivatization of compound A-LXXiii by an Appel reaction (e.g., PPI13 and C(Halide)4) or in the presence of SOCI2 generates compound A-LXXiv.

[0227] In Scheme 1-(17), compound A-xxxviii-b reacts with aldehyde A-LXXv to give bicyclic intermediate A-LXXvi. Subsequent deprotection under acidic conditions (e.g., HC1, TFA, etc.) yields intermediate A-LXXvii. Nucleophilic substitution of intermediate A-LXXvii gives intermediate A-LXXviii. Reduction of compound A-LXXviii provides intermediate A- LXXix, which can be transformed to compound A-LXXX using Appel conditions (e.g., PPI13 and C(Halide)4). Alternatively, Compound A-LXXviii can be transformed to intermediate A-LXXXi by a Grignard reaction. Derivatization of intermediate A-LXXXi using Appel conditions (e.g., PPhs and C(Halide)4) or in the presence of SOCI2 generates compound A-LXXXii.

[0228] As used in the schemes provided herein and unless otherwise specified, Ra, Rx, Rn2, Rn3, n, Ring A, Rxn, and Xx-X4are as defined herein. In some embodiments, Z is Cl, Br, I, or OTf. In some embodiments, Z is Cl. In some embodiments, Z is Br. In some embodiments, Z is I. In some embodiments, Z is OTf. As used herein, Z1is H or C1-3 alkyl. In some embodiments, Z1is H. In some embodiments, Z1is C1-3 alkyl. In some embodiments, Z1is CH3.Scheme 2a

[0229] Scheme 2a shows the synthesis of intermediates A, B, C and D. Compound 1-i undergoes a Grignard reaction with compound 1-ii to give intermediate 1-iii. Subsequent nitrile hydrolysis of compound 1-iii provides intermediate 1-iv. Curtius rearrangement of intermediate 1-iv with DPPA generates cyclic carbamate 1-v. Subsequent hydrolysis of carbamate 1-v givesNAI-5008634746vl -82-Attomey Docket No. 14709-051-228cyclobutyl alcohol 1-vi. Intermediate 1-vi undergoes a nitrogen protecting reaction (e.g., Boc-protection with BOC2O in MeOH) to give intermediate 1-vii, which is subject to boronic ester formation to provide intermediate 1-viii. Coupling of intermediate 1-viii with naphthyridine A-v, A-ix, or A-xii or A-xix, or A-xxiii from Scheme 1 in the presence of a metal catalyst with an appropriate ligand (e.g., Pd(dppf)C12) produces intermediate A, B, C, or D. As used herein, Rsnrefers to a nitrogen protecting group e.g., Boc).Scheme 2bIntermediate A-2 Intermediate A-3Z = Cl, Br or I(2) NaBH4, MeOHIntermediate B-2 Intermediate B-3Z = Cl, Br or I

[0230] As shown in Scheme 2b, intermediates A-l, A-2, A-3, B-l, B-2 and B-3 can be synthesized based on two approaches. From Scheme 2b-(l), compound 1-i e.g., compound A-ix, A-xxiv) undergoes the Suzuki coupling with boronic acid 1-ii to give Intermediate A-l.Reduction of aldehyde in intermediate A-l gives intermediate A-2. Subsequent nucleophilic substitution of intermediate A-2 provides intermediate A-3. Intermediates B-l, B-2 and B-3 can be synthesized in a similar manner.NAI-5008634746vl -83-Attorney Docket No. 14709-051-228General Methods of Synthesizing Compound ProductsScheme 3a

[0231] From Scheme 3a, Compound B-i can be prepared from intermediate A by two approaches: i) a nucleophilic substitution, or n) a coupling reaction in the presence of a metal catalyst (e.g., Cu, Pd, etc.), an appropriate ligand (e.g., XPhos, PPhs, RuPhos, Xantphos, etc.), and a base (EtsN, CS2CO3, K2CO3, etc.). If a protecting group is present, a subsequent deprotection reaction (e.g., treatment with an acid such as TFA, HC1, etc.) is necessary to give intermediate B-i. Alternatively, a Lewis acid (H3BO3, BF3, etc.) can be used to substitute the base in the nucleophilic substitution or coupling reaction. Demethylation of intermediate B-i in the presence of a salt (e.g., LiCl, etc.) and an acid (e.g., PTSA, HC1, etc.) gives compound Bl.Following this approach, compounds B2, B3, and B4 can be generated. B5 can also be generated by using the same approach followed by a subsequent methylation reaction. In some embodiments, Lxis a bond, optionally substituted C1-3 alkylene, or optionally substituted C1-3 heteroalkylene.NAI-5008634746vl -84-Attorney Docket No. 14709-051-228

[0232] The naphthyridine products can be prepared using two approaches as shown in Scheme 3b. In Scheme 3b-( 1 ), intermediate 3A-i undergoes reductive amination in the presence of a base (e.g., DIEA, TEA, etc.) to give naphthyridine 3B-i. In Scheme 3b-(2), naphthyri dines 3B-i can be formed via nucleophilic substitution of 3 A-ii with an appropriate amine in the presence of a base (e.g., DIEA, TEA, etc.). Naphthyri dines 3B-ii to 3B-iv can be prepared using similar approaches.3B-ii 3B-iii 3B-iv Synthetic ExamplesI. Synthesis of IntermediatesSynthesis of tert-butyl (2-cyanopyrimidin-4-yl)(l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzyl)piperidin-4-yl)carbamate-Vo o-V- " Xo o-y~ N NNAI-5008634746vl -85-Attomey Docket No. 14709-051-228

[0233] Step 1: To a solution of tert-butyl piperidin-4-ylcarbamate (3.00 g, 15.0 mmol) in DCM (30 mL) were added 4-bromo-l-(bromomethyl)benzene (4.50 g, 18.0 mmol) and TEA (4.15 mL, 30.0 mmol). Then the reaction was stirred at 80°C for 18 h. LCMS showed the reaction was completed. The reaction mixture was cooled to 0°C and a white precipitate appeared. The mixture was filtered, the filter cake was collected and dried in vacuo to give tertbutyl (l-(4-bromobenzyl)piperidin-4-yl)carbamate (3.7 g). LC / MS ESI (m / z): 369 / 371 [M+H]+.

[0234] Step 2: To a solution of tert-butyl (l-(4-bromobenzyl)piperidin-4-yl)carbamate (300 mg, 0.81 mmol) in DCM (4 mL) was added HCl / dioxane (2 mL, 8.00 mmol, 4.0 M in 1,4-dioxane). Then the resulting mixture was stirred at r.t for 1 h. LCMS showed the reaction was completed. The reaction mixture was concentrated to give l-[(4-bromophenyl)methyl]hexahydropyridin-4-amine (220 mg, crude) as a white solid. The crude product was directly used in the next step without any further purification. LC / MS ESI (m / z): 269 / 271 [M+H]+.

[0235] Step 3: To a solution of l-(4-bromobenzyl)piperidin-4-amine (220 mg, crude) in THF (6 mL) were added 4-chloropyrimidine-2-carbonitrile (124 mg, 0.89 mmol) and K2CO3 (336 mg, 2.43 mmol). Then the reaction was stirred at r.t for 2 h. LCMS showed the reaction was completed. The reaction mixture was diluted with sat. aq. NH4CI solution (10 mL) and extracted with EtOAc (15 mL x 3). The combined organic phases were washed with brine (15 mL), dried over anhydrous Na2SC>4, filtered and concentrated to give a residue. The residue was purified by flash column chromatography on silica gel with MeOH in DCM + 1% NH4OH (0— >5%, V / V) to give 4-((l-(4-bromobenzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile (165 mg). LC / MS ESI (m / z): 372 / 374 [M+H]+.

[0236] Step 4: To a solution of 4-((l-(4-bromobenzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile (165 mg, 0.44 mmol) in THF (4 mL) were added di-tert-butyl dicarbonate (145 mg, 0.66 mmol), DMAP (5 mg, 0.04 mmol) and DIEA (172 mg, 1.33 mmol). Then the reaction was stirred at r.t for 1 h. LCMS showed the reaction was completed. The reaction mixture was diluted with sat. aq. NH₄Cl solution (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The residue was purified by flash column chromatography on silica gel with MeOH in DCM (0— >5%, V / V) to give tert-butyl (l-(4-bromobenzyl)piperidin-4-yl)(2-cyanopyrimidin-4-yl)carbamate (203 mg). LC / MS ESI (m / z): 472 / 474 [M+H]+.

[0237] Step 5: To a solution of tert-butyl (l-(4-bromobenzyl)piperidin-4-yl)(2-cyanopyrimidin-4-yl)carbamate (203 mg, 0.43 mmol) in 1,4-di oxane (10 mL) were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (218 mg, 0.86 mmol), Pd(dppf)C12 (47NAI-5008634746vl -86-Attomey Docket No. 14709-051-228mg, 0.064 mmol) and KO Ac (126 mg, 1.29 mmol). Then the resulting mixture was degassed with N2 for 3 times and stirred at 80°C for 18 h. LCMS showed the reaction was completed. The reaction mixture was cooled to r.t and filtered. The filtrate was concentrated to give a residue. The residue was purified by flash column chromatography on silica gel with MeOH in DCM (0— >5%, V / V) to give tert-butyl (2-cyanopyrimidin-4-yl)(l-(4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzyl)piperidin-4-yl)carbamate (190 mg). LC / MS ESI (m / z): 520 [M+H]+.

[0238] The following compounds were synthesized using a similar protocol.Intermediates CharacterizationLC / MS ESI (m / z): 434 [M+H]+. / T°1Synthesis of 4-(piperidin-4-ylamino)pyrimidine-2-carbonitrile

[0239] Step 1: A solution of 4-chloropyrimidine-2-carbonitrile (500 mg, 3.58 mmol), tertbutyl 4-aminopiperidine-l -carboxylate (788 mg, 3.94 mmol) and CS2CO3 (1.75 g, 5.37 mmol) in DMF (20 mL) was stirred at 80 °C for 2 h. Upon completion of the reaction based on LC-MS analysis, the reaction mixture was quenched with ice cooled water (120 mL), extracted with EtOAc (30 mL x 3) and washed with brine (50 mL x 2). The organic phase was dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to yield 1 g of crude tertbutyl 4-((2-cyanopyrimidin-4-yl)amino)piperidine-l -carboxylate, which was directly used for the next step without further purification. LC-MS (ESI+): m / z 304.2 [M+H]+.

[0240] Step 2: To a solution of tert-butyl 4-((2-cyanopyrimidin-4-yl)amino)piperidine-l- carboxylate (70 mg, 0.23 mmol) in DCM (5 mL) at RT was added TFA (3 mL). The reaction was stirred at RT for 1 h. Upon completion of the reaction based on LC-MS analysis, DCM and TFA were removed under reduced pressure to yield 25 mg of crude 4-(piperidin-4-ylamino)pyrimidine-2-carbonitrile TFA salt, which was directly used for the next step without further purification. LC-MS (ESI+): m / z 204.2 [M+H]+.

[0241] The following compounds were synthesized using a similar protocol.Intermediates CharacterizationH LC / MS ESI (m / z): 176.2 [M+H]+.HN-J Ij^jNAI-5008634746vl -87-Attomey Docket No. 14709-051-228H LC / MS ESI (m / z): 216.2 [M+H]+. „. X TXLC / MS ESI (m / z): 230.3 [M+H]+.H / NLC / MS ESI (m / z): 216.2 [M+H]+...x xrH LC / MS ESI (m / z): 230.3 [M+H]+. x xrLC / MS ESI (m / z): 218.2 [M+H]+. " A XAHLC / MS ESI (m / z): 218.2 [M+H]+. " A X AHLC / MS ESI (m / z): 218.2 [M+H]+. " A X AHI (RJ). k II LC / MS ESI (m / z): 218.2 [M+H]+.''N N k$>HHN^-"Ff^NI (RJ) k II LC / MS ESI (m / z): 222.1 [M+H]+.'N N XAHLC / MS ESI (m / z): 222.1 [M+H]+. ”® X H ALC / MS ESI (m / z): 222.1 [M+H]+. " A XAH"®X LC / MS ESI (m / z): 222.1 [M+H]+.H A LC / MS ESI (m / z): 220.1 [M+H]+. " A XAHNAI-5008634746vl -88-Attorney Docket No. 14709-051-228LC / MS ESI (m / z): 220.1 [M+H]+.■« X\HLC / MS ESI (m / z): 220.1 [M+H]+.H HN r^NI (ty. k II LC / MS ESI (m / z): 220.1 [M+H]+.'N NHHN (R) / ; X-U- LC / MS ESI (m / z): 216.2 [M+H]+.\ / 'N N >^KI— H NLC / MS ESI (m / z): 216.2 [M+H]+.X~A CXHN LC / MS ESI (m / z): 230.1 [M+H]+.HN LC / MS ESI (m / z): 230.1 [M+H]+.Synthesis of 4-(piperazine-l-carbonyI)pyrimidine-2-carbonitrileCN CN

[0242] Step 1: To a solution of 2-cyanopyrimidine-4-carboxylic acid (90 mg, 0.60 mmol), tert-butyl piperazine- 1 -carboxylate (134.9 mg, 0.72 mmol) and DIPEA (235 mg, 1.81 mmol) in DMA (5 mL) at RT was added HATU (550 mg, 1.45 mmol). The reaction mixture was stirred at RT for 2 h. Upon completion of the reaction based on LC-MS analysis, the reaction mixture was quenched with water (30 mL) and extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography to yield 340 mgNAI-5008634746vl -89-Attomey Docket No. 14709-051-228of tert-butyl 4-(2-cyanopyrimidine-4-carbonyl)piperazine-l -carboxylate as yellow oil. LC-MS (ESI+): m / z 318.2 [M+H]+.

[0243] Step 2: Similar to the TFA deprotection described in Step 2 of synthesis of 4-(piperidin-4-ylamino)pyrimidine-2-carbonitrile. LC-MS (ESI+): m / z 218.2 [M+H]+.Synthesis of 4-(piperidin-4-yloxy)pyrimidine-2-carbonitrile

[0244] Step 1: A solution of tert-butyl 4-hydroxypiperidine-l -carboxylate (200 mg, 1.0 mmol), 4-chloropyrimidine-2-carbonitrile (153.5 mg, 1.1 mmol) and CS2CO3 (488 mg, 1.5 mmol) in DMF (3 mL) was stirred at 80 °C for 2 h. Upon completion of the reaction based on LC-MS analysis, the reaction mixture was quenched with water (25 mL) and extracted with EtOAc (30 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography to yield 23 mg of tert-butyl 4-((2-cyanopyrimidin-4-yl)oxy)piperidine-l-carboxylate. LC-MS (ESI+): m / z 305.2 [M+H]+.

[0245] Step 2: To a solution of tert-butyl 4-((2-cyanopyrimidin-4-yl)oxy)piperidine-l-carboxylate (23 mg, 0.076 mmol) in DCM (2 mL) at RT was added TFA (0.5 mL). Upon completion of the reaction, DCM and TFA were removed under reduced pressure to yield 28 mg of 4-(piperidin-4-yloxy)pyrimidine-2-carbonitrile TFA salt, which was directly used for the next step without further purification. LC-MS (ESI+): m / z 205.2 [M+H]+.Synthesis of 2-chloro-3-phenyl-l,6-naphthyridine

[0246] Step 1: To a solution of 4-aminonicotinaldehyde (5.0 g, 40.9 mmol) in DMF (10 mL) were added ethyl 2-phenylacetate (8.1 g, 45.0 mmol) and CS2CO3 (40 g, 0.12 mol). The reaction was stirred at 120°C for 18 h. The reaction mixture was cooled to r.t, diluted with water (50 mL) and EtOAc (10 mL). The precipitate was collected by filtration and triturated with water to give 3-phenyl-l,6-naphthyridin-2(U7)-one (6.4 g). LC / MS ESI (m / z): 223 [M+H]+.

[0247] Step 2: A mixture of 3-phenyl-l,6-naphthyridin-2(U7)-one (2.0 g, 8.99 mmol) in POCI3 (24 mL) was stirred at 100°C for 2.5 h. LCMS showed the reaction was completed. The reaction mixture was cooled to r.t, concentrated to dryness. The residue was diluted with EtOAcNAI-5008634746vl -90-Attorney Docket No. 14709-051-228(20 mL), basified with sat. aq. NaHCO3to pH 7, and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SC>4, filtered, and concentrated to give a residue. The residue was purified by flash column chromatography on silica gel with EtOAc in PE (0— >40%, V / V) to give 2-chl oro-3 -phenyl- 1,6- Z— Anaphthyridine (1 / . A / 5 g). LC / MS ESI (m / z): 241 / 243 [M+H]+.

[0248] The following intermediates were synthesized using a similar protocol.A / / Intermediates Characterization( / = - > z / / / LC / MS ESI (m / z): 241 / 243 [M+H]+.LC / MS ESI (m / z): 241 / 243 [M+H]+.0 0 LC / MS ESI (m / z): 242 / 244 [M+H]+.Synthesis of 8-((4-methoxybenzyl)oxy)-3-phenyl-l,7-naphthyridin-2-yl / \\z A / —i l o o e hJ / tr f u r m t anesulfonateK2OsO4’2H2O, NMO, PMB-OH ^BF3’K+NalO4, acetone / H2O NaH, DMF Pd(dppf)CI2, K2CO3, dioxane / H2O, 60°CPd2(dba)3, XantPhos, Cs2CO3, toluene

[0249] Step 1: To a solution of (4-methoxyphenyl)methanol (1.51 g, 10.93 mmol) in DMF (30 mL) was added NaH (0.48 g, 11.93 mmol, 60% dispersion in mineral oil) at 0°C in portions at 0°C. After stirring at 0°C for 0.5 h, 3-bromo-2-fluoro-4-iodopyridine (3.00 g, 9.94 mmol) was added and the reaction was stirred at r.t for 2 h. LCMS showed the reaction was completed. The reaction mixture was quenched with sat. aq. NH₄Cl (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The residue was purified byNAI-5008634746vl -91-Attomey Docket No. 14709-051-228column chromatography on silica gel with EtOAc in PE (0— >45%, V / V) to give 3-bromo-4-iodo-2-((4-methoxybenzyl)oxy)pyridine (3.60 g). LC / MS ESI (m / z): 420 / 422 [M+H]+.

[0250] Step 2: To a mixture of 3-bromo-4-iodo-2-((4-methoxybenzyl)oxy)pyridine (3.20 g, 7.62 mmol), potassium vinyltrifluoroborate (2.03 g, 15.2 mmol), Pd(dppf)C12 (0.56 g, 0.76 mmol) and K2CO3 (3.16 g, 22.85 mmol) in 1,4-dioxane (30 mL), was added water (6 mL). Then the resulting mixture was degassed with N2 for 3 times and stirred at 60°C for 18 h. LCMS showed the reaction was completed. The reaction mixture was cooled to r.t and filtered. The filtrate was concentrated to give a residue. The residue was purified by column chromatography on silica gel with EtOAc in PE (0— >30%, V / V) to give 3-bromo-2-((4-methoxybenzyl)oxy)-4-vinylpyridine (1.82 g). LC / MS ESI (m / z): 320 / 322 [M+H]+.

[0251] Step 3: To a solution of 3-bromo-2-((4-methoxybenzyl)oxy)-4-vinylpyridine (1.82 g, 5.68 mmol) in acetone (20 mL), were added potassium osmate (VI) dihydrate (0.21 g, 0.57 mmol), 4-methylmorpholine N-oxide (2.00 g, 8.53 mmol) and water (5 mL). After stirring at r.t for 1 h, sodium periodate (4.86 g, 22.7 mmol) was added, and the resulting mixture was stirred at r.t for 2 h. LCMS showed the reaction was completed. The reaction mixture was filtered, the filtrate was diluted with sat. aq. NH4CI (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography on silica gel with EtOAc in PE (0— >45%, V / V) to give 3-bromo-2-((4-methoxybenzyl)oxy)isonicotinaldehyde (1.50 g). LC / MS ESI (m / z): 322 / 324 [M+H]+.

[0252] Step 4: To a mixture of 3-bromo-2-((4-methoxybenzyl)oxy)isonicotinaldehyde (1.00 g, 3.10 mmol) in toluene (6 mL), were added 2-phenylacetamide (503 mg, 3.72 mmol), Pd2(dba)3 (284 mg, 0.31 mmol), XantPhos (538 mg, 0.93 mmol) and CS2CO3 (3.03 g, 9.31 mmol). Then the resulting mixture was degassed with N2 for 3 times and stirred at 100°C for 2 h. LCMS showed the reaction was completed. The reaction mixture was cooled to r.t and filtered. The filtrate was concentrated to give a residue. The residue was purified by column chromatography on silica gel with MeOH in DCM (0— >10%, V / V) to give 8-((4-methoxybenzyl)oxy)-3-phenyl-l,7-naphthyridin-2(177)-one (1.05 g). LC / MS ESI (m / z): 359 [M+H]+.

[0253] Step 5: To a solution of 8-((4-methoxybenzyl)oxy)-3-phenyl-l,7-naphthyridin-2(177)-one (400 mg, 1.12 mmol) in DMF (1 mL), were added CS2CO3 (909 mg, 2.79 mmol) and TV-phenyl-bis(trifluoromethanesulfonimide) (598 mg, 1.67 mmol) at 0°C. Then the reaction was stirred at r.t for 1 h. LCMS showed the reaction was completed. The reaction mixture was quenched with NH4CI (10 mL) and extracted with EtOAc (10 mL x 3). The combined organicNAI-5008634746vl -92-Attomey Docket No. 14709-051-228phases were washed with brine (10 mL x 2), dried over anhydrous Na2SC>4, filtered and concentrated to give a residue. The residue was purified by column chromatography on silica gel with EtOAc in PE (0— >45%, V / V) to give 8-((4-methoxybenzyl)oxy)-3-phenyl-l,7-naphthyridin-2-yl trifluoromethanesulfonate (380 mg). LC / MS ESI (m / z): 491 [M+H]+.z—

[0254] The " H — / following intermediates were synthesized using a similar protocol.Inter (m\ediates CharacterizationA / / LC / MS ESI (m / z): 373 [M+H]+.Synthesis of 2-(4-(l,3-dioxolan-2-yl)phenyl)-7-chloro-3-phenyl-l,6-naphthyridine

[0255] Step 1: To a solution of 4-formylbenzonitrile (20.0 g, 0.15 mol) in toluene (60 mL) were added ethylene glycol (42.6 mL, 0.76 mol) and / i-toluenesulfonic acid (2.63 g, 15.2 mmol). Then the reaction was stirred at 120°C for 48 h. The reaction mixture was cooled to r.t, diluted with sat. aq. NaHCO3(250 mL) and extracted with EtOAc (100 mL x 3). The combined organic phases were washed with brine (100 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The residue was purified by flash column chromatography on silica gel with EtOAc in PE (0— >10%, V / V) to give 4-(l,3-dioxolan-2-yl)benzonitrile (22.0 g).LC / MS ESI (m / z): 176 [M+H]+.

[0256] Step 2: To a stirred solution of 4-(l,3-dioxolan-2-yl)benzonitrile (4.0 g, 22.8 mmol) in THF (40 mL) was added BnMgCl (34.2 mL, 34.2 mmol, 1.0 M in THF) dropwise at 0°C. Then the reaction was stirred at r.t for 18 h. LCMS showed the reaction was completed. The reaction mixture was cooled to 0°C, quenched with sat. aq. NFLCl (80 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The residue was purified by flash column chromatography on silica gel with EtOAc in PE (0— >20%, V / V) to give l-(4-(l,3-dioxolan-2-yl)phenyl)-2-phenylethan-l-one (6.44 g). LC / MS ESI (m / z): 269 [M+H]+.

[0257] Step 3: To a solution of l-(4-(l,3-dioxolan-2-yl)phenyl)-2-phenylethan-l-one (2.00 g, 7.45 mmol) in DMF (20 mL) were added 4-amino-6-chloronicotinaldehyde (1.17 g, 7.45 mmol) and K2CO3 (4.12 g, 29.84 mmol). Then the resulting mixture was stirred at 120°C for 18 h. LCMS showed the reaction was completed. The reaction mixture was cooled to r.t and filtered.NAI-5008634746vl -93-Attomey Docket No. 14709-051-228The filtrate was concentrated to give a residue. The residue was purified by flash column chromatography on silica gel with EtOAc in PE (0— >50%, V / V) to give 2-(4-(l,3-dioxolan-2-yl)phenyl)-7-chloro-3-phenyl-l,6-naphthyridine (2.80 g). LC / MS ESI (m / z): 389 [M+H]+.

[0258] The following intermediates were synthesized using a similar protocol.Intermediates Characterization (\A / \ / \ / ==zBrLC / MS ESI (m / z): 433 / 435 [M+H]+. NOOCQ ° ° \ / LC / MS ESI (m / z): 385 [M+H]+.( °—LC / MS ESI (m / z): 386 [M+H]+.LC / MS ESI (m / z): 386 [M+H]+.0"^0LC / MS ESI (m / z): 372 [M+H]+. ANA IQ0 / N. As, LC / MS ESI (m / z): 372 [M+H]+. HN -VNAI-5008634746vl -94-Attomey Docket No. 14709-051-228o O LC / MS ESI (m / z): 388 [M+H]+.? \ I / Y zz-zz \—> z? Co=p z z#\ \( ~Z\ / - / A / A / / / ) z y y / LC / MS ESI (m / z): 389 [M+H]+. / / \ / A _° ° / ° ° / / / LC / MS ESI (m / z): 389 [M+H]+.(o— / \ cG h co( b — 'LC / MS ESI (m / z): 386 [M+H]+.z AA / '' / ZZ-LC / MS ESI (m / z): 416 [M+H]+.LC / MS ESI (m / z): 386 [M+H]+.Synthesis of 3-(3-(4-(l,3-dioxolan-2-yl)phenyl)-5-methoxypyrido[2,3-d]pyridazin-2-yl)pyridin-2-amineNAI-5008634746vl -95-Attomey Docket No. 14709-051-228

[0259] Step 1: A solution of 5-amino-3-methoxypyridazine-4-carbaldehyde (600 mg, 2.59 mmol), methyl 2-(4-(l,3-dioxolan-2-yl)phenyl)acetate (576 mg, 2.59 mmol) and CHsONa (1.5 mL, 7.79 mmol, 5.4 N in MeOH) in MeOH (10 mL) was heated to 65 °C for 3 h. Upon completion of the reaction based on TLC analysis, the reaction mixture was cooled to RT, acidified with diluted HC1 aqueous solution to pH 7 and extracted with EtOAc (10 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography to yield 536 mg of 3-(4-(l,3-dioxolan-2-yl)phenyl)-5-methoxypyrido[2,3-d]pyridazin-2-ol as yellow solid. LC-MS (ESI+): m / z 326.1 [M+H]+.

[0260] Step 2: A solution of 3-(4-(l,3-dioxolan-2-yl)phenyl)-5-methoxypyrido[2,3-d]pyridazin-2-ol (420 mg, 1.29 mmol), 1,1,1 -tri fluoro-N-pheny 1-N-((trifluoromethyl)sulfonyl)methanesulfonamide (920 mg, 2.58 mmol) and K2CO3 (535 mg, 3.87 mmol) in DMAC (10 mL) was stirred at RT overnight. Upon completion of the reaction based on LC-MS analysis, the reaction mixture was quenched with water (30 mL) and extracted with EtOAc (60 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica-gel chromatography to yield 505 mg of 3-(4-(l,3-dioxolan-2-yl)phenyl)-5-methoxypyrido[2,3-d]pyridazin-2-yl trifluorom ethanesulfonate as yellow solid. LC-MS (ESI+): m / z 458.3 [M+H]+.

[0261] Step 3: A solution of 3-(4-(l,3-dioxolan-2-yl)phenyl)-5-methoxypyrido[2,3-d]pyridazin-2-yl trifluoromethanesulfonate (300 mg, 0.66 mmol), (2-aminopyridin-3-yl)boronic acid (433 mg, 1.97 mmol), Pd(dppf)Ch (48 mg, 0.065 mmol) and AcOK (321 mg, 3.28 mmol) in dioxane (10 mL) and H2O (3 mL) was stirred under N2 atmosphere at 100 °C for 2.5 h. Upon completion of the reaction based on LC-MS analysis, the reaction mixture was cooled to RT, quenched with water (20 mL) and filtered through a pad of Celite. The filtrate was extracted with EtOAc (50 mL x 5). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography to yield 220 mg of 3-(3-(4-(l,3-dioxolan-2-yl)phenyl)-5-methoxypyrido[2,3-d]pyridazin-2-yl)pyridin-2-amine as red solid. LC-MS (ESI+): m / z 402.2 [M+H]+.

[0262] The following intermediates were synthesized using a similar protocol.NAI-5008634746vl -96-Attorney Docket No. 14709-051-228Synthesis of 7-chloro-6-iodo-3-methylpyrido [2, 3-d] pyrimidin-4(3H)-one

[0263] Step 1: To a solution of 2-amino-6-chloropyridine-3-carboxylic acid (5.0 g, 29.0 mmol) in MeCN (60 mL) was added A-iodosuccinimide (9.78 g, 43.5 mmol) at 0°C. The reaction was stirred at room temperature for 18 h. LCMS showed the reaction was completed. The reaction mixture was concentrated to give a residue. The residue was triturated with water, filtered and dried azeotropically with toluene to give 2-amino-6-chloro-5-iodonicotinic acid (5.3 g, 61.3% yield) as a brown solid. The crude product was directly used in the next step without any further purification. LC / MS ESI (m / z): 299 / 301 [M+H]+.

[0264] Step 2: To a mixture of 2-amino-6-chloro-5-iodopyridine-3-carboxylic acid (2.0 g, 6.70 mmol) in DCM (30 mL) were added methylamine hydrochloride (540 mg, 8.04 mmol), DIEA (6.06 g, 46.9 mmol), EDCI (1.93 g, 10.0 mmol) and DMAP (40 mg, 0.34 mmol). The reaction was stirred at room temperature for 5 h. LCMS showed the reaction was completed. The reaction mixture was quenched with sat. aq. NELCl (30 mL) and extracted with DCM (15 mL x 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SC>4, filtered and concentrated. The residue was purified by flash column chromatography on silica gel with EtOAc in DCM (0— >30%, V / V) to give 2-amino-6-chloro-5-iodo-7V-methylnicotinamide (400 mg, 19.2% yield) as a yellow solid. LC / MS ESI (m / z): 312 / 314 [M+H]+.NAI-5008634746vl -97-Attorney Docket No. 14709-051-228

[0265] Step 3: To a mixture of 2-amino-6-chloro-5-iodo-A-methylnicotinamide (400 mg, 1.29 mmol) in triethyl orthoformate (8 mL) was added TFA (7 mg, 0.064 mmol). The reaction stirred at 120°C for 18 h. LCMS showed the reaction was completed. After cooling down to room temperature, the reaction mixture was concentrated and filtered. The filter cake was rinsed / with EtOH (3 mL x 3) and dried azeotropically with toluene to give 7-chloro-6-iodo-3- ° z= / methylpyrido[2,3- ]pyrimidin-4(3J7)-one (310 mg, 75.1% yield) as a white solid. LC / MS ESI (m / z): 322 / 324 [M+H]+. zA / /

[0266] The following in in —termediate was synthesized using a similar protocol.Intermediates CharacterizationLC / MS ESI (m / z): 322 / 324 [M+H]+.LC-MS ESI m / z: 366 / 368 [M+H]+.0OL LC-MS ESI m / z: 378 / 380 [M+H]h.T / 1 °OLX LC-MS ESI m / z: 392 / 394 [M+H]+.Synthesis of 6-bromo-7-phenylpyrido[3,2-d]pyrimidin-4(3H)-oneOHK2CO3, H2O2 DMSO

[0267] Step 1: To a mixture of 3-amino-5-bromopicolinonitrile (1.00 g, 5.08 mmol), phenylboronic acid (651 mg, 5.33 mmol), Pd(dppf)C12 (371 mg, 0.51 mmol) and K2CO3 (2.10 g, 15.2 mmol) in 1,4-dioxane (15 mL) was added water (1.5 mL). Then the resulting mixture was degassed under N2 for 3 times and stirred at 80°C for 18 h. LCMS showed the reaction wasNAI-5008634746vl -98-Attomey Docket No. 14709-051-228completed. The reaction mixture was cooled to room temperature, filtered and concentrated. The residue was purified by flash column chromatography on silica gel with EtOAc in PE (0— >30%, V / V) to give 3-amino-5-phenylpicolinonitrile (980 mg, 98.8% yield) as a yellow solid. LC / MS ESI (m / z): 196 [M+H]+.

[0268] Step 2: To a solution of 3-amino-5-phenylpicolinonitrile (500 mg, 2.56 mmol) in MeCN (10 mL) was added NBS (456 mg, 2.56 mmol). Then the resulting mixture was degassed with N23 times and stirred at room temperature for 3 h. LCMS showed the reaction was completed. The reaction mixture was quenched with sat. aq. NEUCl (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography on silica gel with EtOAc in PE (0— >20%, V / V) to give 3-amino-6-bromo-5-phenylpicolinonitrile (520 mg, 74.4% yield) as a brown solid. LC / MS ESI (m / z): 274 / 276 [M+H]+.

[0269] Step 3: To a solution of 3-amino-6-bromo-5-phenylpicolinonitrile (520 mg, 1.90 mmol) in DMSO (5 mL) was added K2CO3 (263 mg, 1.90 mmol) and hydrogen peroxide (1.0 mL, 30 wf / o in water) at room temperature. Then the resulting mixture was stirred at room temperature for 2 h. LCMS showed the reaction was completed. The reaction mixture was quenched with sat. aq. NH₄Cl (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated to give 3-amino-6-bromo-5-phenylpicolinamide (550 mg, crude) as a brown solid. LC / MS ESI (m / z): 292 / 294 [M+H]+.

[0270] Step 4: A mixture of 3-amino-6-bromo-5-phenylpicolinamide (550 mg, crude) in tri ethyl orthoformate (3.0 mL) was heated to reflux and stirred for 18 h. LCMS showed the reaction was completed. The reaction mixture was cooled to room temperature and concentrated to give 6-bromo-7-phenylpyrido[3,2- ]pyrimidin-4(3J7)-one (500 mg, crude) as a brown solid.LC / MS ESI (m / z): 302 / 304 [M+H]+.Synthesis of 2-(4-(l,3-dioxolan-2-yl)phenyl)-5-methoxy-3-phenylpyrido[3,4-b]pyrazine and 3-(4-(l,3-dioxolan-2-yl)phenyl)-5-methoxy-2-phenylpyrido[3,4-b]pyrazineNAI-5008634746vl -99-Attomey Docket No. 14709-051-228

[0271] Step 1: To a solution of l-(4-( 1,3 -di oxolan-2-yl)phenyl)-2-phenylethane- 1,2-dione (200 mg, 0.71 mmol) in MeOH (5 mL) were added 2-chloropyridine-3,4-diamine (122 mg, 0.85 mmol) and sodium methoxide (191 mg, 3.52 mmol). Then the resulting mixture was stirred at r.t T I Ifor 18 h. LCM Z— AS showed the reaction was completed. The reaction mixture was poured into water / O°=(1 ) f ° zm n lz= / 0 L a d i te \red. The filter cake was collected and dried azeotropically with toluene to give a z z z z z z Imixture of 2-(4-(l,3-di\\ / / \ \ / / oxolan-2-yl)phenyl)-5-methoxy-3-phenylpyrido[3,4-Z>]pyrazine and 3-(4-(l,3-dioxolan-2-yl)phenyl)-5-methoxy-2-phenylpyrido[3,4-Z>]pyrazine (149 mg, 54.6% yield) as ) () z / \ / a yellow solid. LC / MS ESI (m / \ / / / \ \ / z): 386 [M+H]+.

[0272] The following inter ° ° °m / / / ediates were synthesized using a similar protocol.J °\Intermediates LC / MS CharacterizationLC / MS ESI (m / z): 373 [M+H]+. o / —\ / \zZ Z T v vLC / MS ESI (m / z): 373 [M+H]+.# \ °z— "TLC / MS ESI (m / z): 388 [M+H]+.LC / MS ESI (m / z): 388 [M+H]+.NAI-5008634746vl -100-Attorney Docket No. 14709-051-228LC / MS ESI (m / z): 373 [M+H]+.I Tzz zz-- ^^0 0==z z z z\\ / / \ \ / / LC / MS ESI (m / z): 373 [M+H]+.00 / / Synthesis of 5-methoxy-3-phenyl-l,6-naphthyridin-2-yl trifluoromethanesulfonate

[0273] Step 1: To a stirred solution of 4-bromo-2-methoxypyridine (4.0 g, 21.3 mmol) in THF (20 mL) was added LDA (16.0 mL, 32.0 mmol, 2.0 M in THF) dropwise at -78°C. After stirring at -78°C for 0.5 h, DMF (3.11 g, 42.5 mmol) was added, and the resulting mixture was stirred at the same temperature for 1 h. LCMS showed the reaction was completed. The reaction mixture was quenched with sat. aq. NH₄Cl (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SC>4, filtered and concentrated to give a residue. The residue was purified by flash column chromatography on silica gel with EtOAc in PE (0— >50%, V / V) to give 4-bromo-2-methoxynicotinaldehyde (2.00 g). LC / MS ESI (m / z): 216 / 218 [M+H]+.

[0274] Step 2: To a solution of 4-bromo-2-methoxynicotinaldehyde (2.0 g, 9.26 mmol) in toluene (20 mL) were added 2-phenylacetamide (1.88 g, 13.9 mmol), Pd2(dba)3 (848 mg, 0.93 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.07 g, 1.85 mmol) and CS2CO3 (9.05 g, 27.8 mmol). Then the resulting mixture was degassed with N2 for 3 times and stirred at 100°C for 2 h. LCMS showed the reaction was completed. The reaction mixture was cooled to r.t, filtered and concentrated to give a residue. The residue was purified by flash column chromatography on silica gel with EtOAc in PE (0— >100%, V / V) to give 5-methoxy-3-phenyl-l,6-naphthyridin-2(177)-one (500 mg). LC / MS ESI (m / z): 253 [M+H]+.

[0275] Step 3: To a stirred mixture of 5-methoxy-3-phenyl-l,6-naphthyridin-2(177)-one (500 mg, 1.98 mmol) and CS2CO3 (1.94 g, 5.95 mmol) in DMF (10 mL) was added 1,1,1-trifluoro-7V-phenyl-7V-((trifluoromethyl)sulfonyl)methanesulfonamide (1.06 g, 2.97 mmol). Then the reaction was stirred at r.t for 1 h. LCMS showed the reaction was completed. The reactionNAI-5008634746vl -101-Attomey Docket No. 14709-051-228mixture was quenched with water (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine (10 mL x 2), dried over anhydrous Na2SC>4, filtered and concentrated to give a residue. The residue was purified by flash column chromatography on silica gel with EtOAc in PE (0— >50%, V / V) to give 5-methoxy-3-phenyl-l,6-naphthyridin-2-yl I I^ z Zz zz--trifluoromethanesulfonate (500 mg). LC / MS ESI (m / z): 385 [M+H]+.)°=\

[0276] The ' C) f°=ollowing intermediates were synthesized using a similar protocol.( (z z\\Interme A A / / A / / / / diates LC / MS Characterization / / O O / = / =\ / HLC / MS ESI (m / z): 385 [M+H]+.BrJx^ -N^OTfLC / MS ESI (m / z): 462 [M+H]+.OO7 ZLC / MS ESI (m / z): 491 [M+H]+. tn z—JCLLC / MS ESI (m / z): 371 [M+H]+.OX^ N OTfOCC. LC / MS ESI (m / z): 385 [M+H]+.oLC / MS ESI (m / z): 372 [M+H]+.LC / MS ESI (m / z): 386 [M+H]+.NAI-5008634746vl -102-Attorney Docket No. 14709-051-228Synthesis of 8-bromo-5-methoxy-3-phenyl-l,6-naphthyridin-2(lH)-one

[0277] Step 1: To a stirred mixture of 4-amino-2-chloronicotinaldehyde (600 mg, 3.83 mmol) in DMF (15 mL) was added NBS (784 mg, 4.41 mmol) at 0°C. Then the reaction was stirred at r.t for 5 h. LCMS showed the reaction was completed. The reaction mixture was quenched with water (30 mL) and filtered. The filter cake was rinsed with water (5 mL x 3) and dried azeotropically with toluene to give 4-amino-5-bromo-2-chloronicotinaldehyde (400 mg). LC / MS ESI (m / z): 235 / 237 / 239 [M+H]+.

[0278] Step 2: To a stirred mixture of 4-amino-5-bromo-2-chloronicotinaldehyde (300 mg, 1.27 mmol) and methyl 2-phenylacetate (230 mg, 1.53 mmol) in THF (10 mL) was added lithium bis(trimethylsilyl)amide (3.82 mL, 3.82 mmol, 1.0 M in THF) at 0°C. Then the reaction was stirred at r.t for 18 h. LCMS showed the reaction was completed. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SC>4, filtered and concentrated to give a residue. The residue was purified by flash column chromatography on silica gel with MeOH in DCM (0— >7%, V / V) to give 8-bromo-5-chloro-3-phenyl-l,6-naphthyridin-2(U7)-one (385 mg). LC / MS ESI (m / z): 335 / 337 / 339 [M+H]+.

[0279] Step 3: To a stirred mixture of 8-bromo-5-chloro-3-phenyl-l,6-naphthyridin-2(U7)-one (385 mg, 1.15 mmol) in MeOH (10 mL) was added sodium methoxide (10 mL, 16.2 mmol, 30% solution in MeOH). Then the reaction was stirred at 80°C for 18 h. LCMS showed the reaction was completed. The reaction mixture was concentrated to give a residue. The residue was purified by flash column chromatography on silica gel with MeOH in DCM (0— >5%, V / V) to give 8-bromo-5-methoxy-3-phenyl-l,6-naphthyridin-2(U7)-one (308 mg). LC / MS ESI (m / z): 331 / 333 [M+H]+.Synthesis of 3-(4-bromophenyl)-6-methoxy-2-phenylpyrido [2, 3-b] pyrazine and 2-(4-bromophenyl)-6-methoxy-3-phenylpyrido [2, 3-b] pyrazineNAI-5008634746vl -103-Attorney Docket No. 14709-051-228

[0280] Step 1: A solution of 6-chloropyridine-2,3-diamine (2 g, 13.93 mmol), l-(4-bromophenyl)-2-phenylethane- 1,2-dione (4 g, 13.93 mmol) and aq. NaOH (8 mL, 48 mmol, 6 N) in MeOH (60 mL) was stirred at 70 °C for 1 h. Upon completion of the reaction based on LC-MS analysis, the reaction mixture was cooled to RT and quenched with water (180 mL). The precipitated solid was collected by filtration and dried to yield 5.26 g of 3-(4-bromophenyl)-6-methoxy-2-phenylpyrido[2,3-b]pyrazine and 2-(4-brom ophenyl)-6-m ethoxy-3 -phenylpyrido[2, 3-b]pyrazine as white solid. LC / MS ESI (m / z): 392.1 / 394.1 [M+H]+.

[0281] The following intermediates were synthesized using a similar protocol.Intermediates m LC / MS CharacterizationLC / MS ESI (m / z): 392.1 / 394.1 [M+H]+. z zo—jj j A LC / MS ESI (m / z): 392.1 / 394.1 [M+H]+.1II JLBr^^, BrLC / MS ESI (m / z): 379.1 / 389.1 [M+H]+. Tnv nLC / MS ESI (m / z): 379.1 / 389.1 [M+H]+. TNY n0Vk BrSynthesis of 6-bromo-7-chloro-3-methylpyrido [2, 3-d] pyrimidin-4(3H)-oneMel, DMFNAI-5008634746vl -104-Attomey Docket No. 14709-051-228

[0282] Step 1: To a solution of 2-amino-6-chloronicotinic acid (2 g, 12 mmol) in HO Ac (25 mL) was added NBS (2.27 g, 13 mmol). The reaction mixture was stirred at RT for 2 h. Upon completion of the reaction based on LC-MS analysis, the reaction mixture was quenched with water (50 mL) and filtered. The filter cake was dissolved in THF (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure yield 2.3 g of crude 2-amino-5-bromo-6-chloronicotinic acid, which was used for the next step without further purification. LC-MS (ESI+): m / z 251.1, 253.1 [M+H]+.

[0283] Step 2: To a solution of 2-amino-5-bromo-6-chloronicotinic acid (1 g, 4 mmol) in THF (15 mL) was added CDI (0.97 g, 6 mmol). The reaction mixture was stirred at RT for 2 h. To the above mixture was added a solution of NH3 H2O (5 mL) in dioxane (20 mL). Upon completion of the reaction based on LC-MS analysis, the reaction mixture was quenched with saturated Na₂CO₃ solution (5 mL) and extracted with EtOAc (50 mL x 3). The combined organic phase was washed with brine (5 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to yield 840 mg of 2-amino-5-bromo-6-chloronicotinamide as gray solid. LC-MS (ESI+): m / z 250.2, 252.2 [M+H]+.

[0284] Step 3: A solution of 2-amino-5-bromo-6-chloronicotinamide (400 mg, 1.59 mol) in tri ethyl orthoformate (5 mL) was stirred at 140 °C for overnight. Upon completion of the reaction based on LC-MS analysis, the reaction mixture was cooled to rt and filtered. The filter cake was purified by silica-gel column chromatography to yield 350 mg of 6-bromo-7-chloropyrido[2,3-d]pyrimidin-4(3H)-one as yellow solid. LC-MS (ESI+): m / z 260.1, 262.1 [M+H]+.

[0285] Step 4: A solution of 6-bromo-7-chloropyrido[2,3-d]pyrimidin-4(3H)-one (200 mg, 0.77 mmol), K2CO3 (181.5 mg, 1.54 mmol) and Mel (218.7 mg, 1.54 mmol) in DMF (5 mL) was stirred at RT for 1 h. Upon completion of the reaction based on LC-MS analysis, the reaction mixture was quenched with water (40 mL) and extracted with EtOAc (30 mL x 3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography to yield 150 mg of 6-bromo-7-chloro-3-methylpyrido[2,3-d]pyrimidin-4(3H)-one as white solid. LC-MS (ESI+): m / z 274.2, 276.2 [M+H]+.Synthesis of 4-(3-(2-aminopyridin-3-yl)-8-oxo-7,8-dihydropyrazino [2, 3-d] pyridazin-2-yl)benzaldehyde and 4-(3-(2-aminopyridin-3-yl)-5-oxo-5,6-dihydropyrazino [2,3-d] pyridazin-2-yl)benzaldehyde.NAI-5008634746vl -105-Attomey Docket No. 14709-051-228

[0286] Step 1: A solution of 4-formylbenzonitrile (10.0 g, 76.26 mmol), ethylene glycol (19 g, 304.8 mmol) and p-TsOH (720 mg, 3.82 mmol) in toluene (200 mL) was heated to 110 °C overnight. Upon completion of the reaction based on TLC analysis, the reaction mixture was cooled to RT, neutralized with 2 M aqueous Na₂CO₃ solution to pH = 10 and extracted with EtOAc (50 mL x 3). The combined organic phase was dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography to yield 12.7 g of 4-(l,3-dioxolan-2-yl)benzonitrile. LC-MS (ESI+): m / z 176.1 [M+H]+.

[0287] Step 2: To a solution of tert-butyl (3-methylpyridin-2-yl)carbamate (3.4 g, 16 mmol) in THF (40 mL) under N2 atmosphere at -78 °C was added t-BuLi (24 mL, 32 mmol, 1.3 M in THF) dropwise. After stirred at -78 °C for 2 h, a solution of 4-(l,3-dioxolan-2-yl)benzonitrile (2.86 g, 16 mmol) in THF (15 mL) was then added in dropwise to the above solution. The reaction mixture was stirred at -78 °C for 2 h. Upon completion of the reaction based on LC-MS analysis, the reaction mixture was quenched with water (200 mL) and extracted with EtOAc (50 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography to yield 560 mg of tert-butyl (3-(2-(4-(l,3-dioxolan-2-yl)phenyl)-2-oxoethyl)pyridin-2-yl)carbamate. LC-MS (ESI+): m / z 385.2 [M+H]+.

[0288] Step 3: A solution of tert-butyl (3-(2-(4-(l,3-dioxolan-2-yl)phenyl)-2-oxoethyl)pyridin-2-yl)carbamate (500 mg, 1.30 mmol) and aq. HBr (0.5 mL, 40%) in DMSO (10 mL) was stirred at 80 °C for 1 h. Upon completion of the reaction based on LC-MS analysis, the reaction mixture was cooled to RT, neutralized with 2 M aqueous Na₂CO₃ solution to pH = 10 and extracted with DCM (10 mL x 5). The combined organic phase was dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by silica-gel NAI-5008634746vl -106-Attomey Docket No. 14709-051-228column chromatography to yield 537 mg of 4-(2-(2-aminopyri din-3 -yl)-2-oxoacetyl)benzaldehyde. LC-MS (ESI+): m / z 255.2 [M+H]+.

[0289] Step 4: A solution of 4-(2-(2-aminopyri din-3 -yl)-2-oxoacetyl)benzaldehy de (400 mg, 1.57 mmol) and 4,5-diaminopyridazin-3(2H)-one (99 mg, 0.78 mmol) in AcOH (0.2 mL) and dioxane (6 mL) was stirred at 90 °C overnight. Upon completion of the reaction based on LC-MS analysis, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography to yield 57 mg of a mixture of 4-(3-(2-aminopyridin-3-yl)-8-oxo-7,8-dihydropyrazino[2,3-d]pyridazin-2-yl)benzaldehyde and 4-(3-(2-aminopyridin-3-yl)-5-oxo-5,6-dihydropyrazino[2,3-d]pyridazin-2-yl)benzaldehyde. LC-MS (ESI+): m / z 345.2 [M+H]+.Synthesis of tert-butyl (l-(2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propan-2-yl)piperidin-4-yl)carbamate

[0290] Step 1: A solution of 2-(4-bromophenyl)propan-2-amine (500 mg, 2.34 mmol), 1-Benzyl-l-methyl-4-oxopiperidinium iodide (773 mg, 2.34 mmol) and K2CO3 (32 mg, 0.23 mmol) in EtOH (12 mL) and H2O (8 mL) was stirred at 90 °C for 20 h. Upon completion of the reaction based on LC-MS analysis, the reaction mixture was cooled to RT, quenched with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic phase was dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography to yield 387 mg of l-(2-(4-bromophenyl)propan-2-yl)piperidin-4-one as yellow oil. LC-MS (ESI+): m / z 296.2, 298.2 [M+H]+.

[0291] Step 2: To a solution of l-(2-(4-bromophenyl)propan-2-yl)piperidin-4-one (287 mg, 0.97 mmol) and ammonium acetate (112 mg, 1.45 mmol) in DCM (10 mL) was added titanium tetraisopropanolate (0.7 mL, 2.91 mmol). After the reaction was stirred at rt for 1 h, NaCNBH₃ (122 mg, 1.94 mmol) was added to the above mixture and the reaction was stirred for 3 h. Upon completion of the reaction based on LC-MS analysis, the reaction mixture was poured into aqueous Na2CC>3 solution (50 mL) and filtered. The filter cake was washed with DCM / MeOH = 5 / 1 (50 mL). The organic layer was separated and dried over anhydrous Na2SC>4, NAI-5008634746vl -107-Attomey Docket No. 14709-051-228filtered and concentrated under reduced pressure to yield 300 mg of l-(2-(4-bromophenyl)propan-2-yl)piperidin-4-amine as colorless oil, which was directly used for the next step without further purification. LC-MS (ESI+): m / z 297.2, 299.2 [M+H]+.

[0292] Step 3: To a solution of l-(2-(4-bromophenyl)propan-2-yl)piperidin-4-amine (300 mg, 1.01 mmol) and saturated Na₂CO₃ aqueous solution (4 mL) in THF (8 mL) at rt was added BOC2O (330 mg, 1.51 mmol). The reaction mixture was stirred atRT overnight. Upon completion of the reaction, the resulting mixture was extracted with EtOAc (10 mL x 3), dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography to yield 142 mg of tert-butyl (l-(2-(4-bromophenyl)propan-2-yl)piperidin-4-yl)carbamate. LC-MS (ESI+): m / z 397.2, 399.2 [M+H]+.

[0293] Step 4: A solution of tert-butyl (l-(2-(4-bromophenyl)propan-2-yl)piperidin-4-yl)carbamate (92 mg, 0.23 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (235 mg, 0.93 mmol), Pd(dppf)C12 (19 mg, 0.02 mmol) and KOAc (68 mg, 0.69 mmol) in dioxane (10 mL) was stirred under N2 atmosphere at 90 °C for 2 h. Upon completion of the reaction based on LC-MS analysis, the reaction mixture was cooled to RT, quenched with water (50 mL) and filtered through a pad of Celite. The filtrate was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography to yield 90 mg of tert-butyl (l-(2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propan-2-yl)piperidin-4-yl)carbamate as colorless oil. LC-MS (ESI+): m / z 445.3 [M+H]+.Synthesis of 6-bromo-3-methyl-7-phenylpyrido[3,2-d]pyrimidin-4(3H)-one0 0 0 0o

[0294] Step 1: To a mixture of methyl 3-amino-5-bromopicolinate (5.00 g, 21.6 mmol), phenylboronic acid (3.96 g, 32.5 mmol), Pd(dppf)C12 (790 mg, 1.08 mmol) and Na₂CO₃ (6.88 g, 64.9 mmol) in 1,4-dioxane (75 mL) was added water (5 mL). Then the resulting mixture was degassed under N2 for 3 times and stirred at 80°C for 18 h. LCMS showed the reaction was completed. The reaction mixture was cooled down to room temperature, filtered and concentrated. The residue was purified by flash column chromatography on silica gel withNAI-5008634746vl -108-Attomey Docket No. 14709-051-228EtOAc in PE (0— >100%, V / V) to give methyl 3-amino-5-phenylpicolinate (3.50 g, 70.9% yield). LC / MS ESI (m / z): 229 [M+H]+.

[0295] Step 2: To a solution of methyl 3-amino-5-phenylpicolinate (4.70 g, 20.6 mmol) in THF (10 mL) was added methylamine (20 mL, 0.43 mol, 40% wt. in water). Then the resulting mixture was stirred at 60°C for 18 h. LCMS showed the reaction was completed. The reaction mixture was cooled down to room temperature and concentrated to give 3-amino-V-methyl-5-phenylpicolinamide (4.50 g, 96.1% yield). LC / MS ESI (m / z): 228 [M+H]+.

[0296] Step 3: To a solution of 3-amino-7V-methyl-5-phenylpicolinamide (4.00 g, 17.6 mmol) in MeCN (50 mL) was added NBS (3.13 g, 17.6 mmol) at 0°C. Then the resulting mixture was stirred at room temperature for 1 h. LCMS showed the reaction was completed. The reaction mixture was quenched with sat. aq. NaHCO3(100 mL) and 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 flash column chromatography on silica gel with EtOAc in PE (0— >50%, V / V) to give 3-amino-6-bromo-7V-methyl-5-phenylpicolinamide (4.70 g, 87.2% yield). LC / MS ESI (m / z): 306 / 308 [M+H]+.

[0297] Step 4: A mixture of 3-amino-6-bromo-7V-methyl-5-phenylpicolinamide (4.70 g, 15.4 mmol) in triethyl orthoformate (80 mL) was heated to 120°C and stirred for 24 h. LCMS showed the reaction was completed. The reaction mixture was cooled down to room temperature and concentrated. The residue was purified by flash column chromatography on silica gel with EtOAc in PE (0— >50%, V / V) to give 6-bromo-3-methyl-7-phenylpyrido[3,2-J]pyrimidin-4(3J7)-one (4.60 g, 94.8% yield). LC / MS ESI (m / z): 316 / 318 [M+H]+.Synthesis of 6-bromo-7-chloro-3-methylpteridin-4(3H)-one

[0298] Step 1: To a stirred solution of methyl 3-amino-6-bromopyrazine-2-carboxylate (5.00 g, 21.6 mmol) in chloroform (50 mL) was added 3 -chloroperoxybenzoic acid (5.58 g, 32.3 mmol). Then the resulting mixture was stirred at 60 °C for 18 h. LCMS showed the reaction was completed. The reaction mixture was quenched with sat. aq. NaHCO3(100 mL) and extracted with DCM (50 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SC>4, filtered and concentrated to give 2-amino-5-bromo-3- NAI-5008634746vl -109-Attomey Docket No. 14709-051-228(methoxycarbonyl)pyrazine 1-oxide (3.50 g, crude) as a yellow solid. The crude product was directly used in the next step without any further purification. LC / MS ESI (m / z): 248 / 250 [M+H]+.

[0299] Step 2: To a solution of 2-amino-5-bromo-3-(methoxycarbonyl)pyrazine 1-oxide (3.50 g, crude) in DMF (35 mL) was slowly added phosphoryl trichloride (4.27 g, 27.8 mmol) at 0°C. Then the resulting mixture was stirred at room temperature for 18 h. LCMS showed the reaction was completed. The reaction mixture was diluted with EtOAc (50 mL), cooled down to 0°C and carefully quenched with sat. aq. NaHCO3to pH = 7. Then the mixture 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 flash column chromatography on silica gel with EtOAc in PE (0— >70%, V / V) to give methyl 3-amino-6-bromo-5-chloropyrazine-2-carboxylate (1.1 g, 19.2% yield over two steps). LC / MS ESI (m / z): 266 / 268 / 270 [M+H]+.

[0300] Step 3: To a solution of methyl 3-amino-6-bromo-5-chloropyrazine-2-carboxylate (700 mg, 2.63 mmol) in THF (10 mL) was added potassium trimethylsilanolate (672 mg, 5.25 mmol) at 0°C. Then the resulting mixture was stirred at room temperature for 0.5 h. LCMS showed the reaction was completed. The reaction mixture was quenched with 2M HC1 to pH = 3 ~ 4 at 0 °C and extracted with EtOAc (5 mL x 3). The combined organic phases were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated to give 3-amino-6-bromo-5-chloropyrazine-2-carboxylic acid (450 mg, crude). LC / MS ESI (m / z): 252 / 254 / 256 [M+H]+.

[0301] Step 4: To a mixture of 3-amino-6-bromo-5-chloropyrazine-2-carboxylic acid (450 mg, crude), 1 -methyl- UT-imidazole (511 mg, 6.25 mmol) and methylamine hydrochloride (145 mg, 2.15 mmol) in THF (10 mL) was added 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (2.27 g, 3.57 mmol, 50% wt. in EtOAc) at 0 °C. Then the resulting mixture was stirred at room temperature for 18 h. The reaction mixture was quenched with sat. aq. NaHCO3(20 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography on silica gel with EtOAc in PE (0— >50%, V / V) to give 3-amino-6-bromo-7V-methyl-5-phenylpicolinamide (203 mg, 32.7% yield over two steps). LC / MS ESI (m / z): 265 / 267 / 269 [M+H]+.

[0302] Step 5: A mixture of 3-amino-6-bromo-7V-methyl-5-phenylpicolinamide (200 mg, 0.75 mmol) in triethyl orthoformate (10 mL) was heated to 120 °C and stirred for 18 h. LCMS showed the reaction was completed. The reaction mixture was cooled down to room temperature and concentrated. The residue was purified by flash column chromatography on silica gel withNAI-5008634746vl -110-Attomey Docket No. 14709-051-228EtOAc in PE (0— >50%, V / V) to give 6-bromo-7-chloro-3-methylpteridin-4(3rt)-one (150 mg, 72.3% yield). LC / MS ESI (m / z): 275 / 277 / 279 [M+H]+.II. Synthesis of Compounds

[0303] Some compounds prepared below have one or more basic amine groups (e.g., -NH2 or a piperidine ring). They can be prepared as free base form or a salt form (e.g., a TFA or formate salt when a compound was purified with HPLC using either 0.1% TFA or 0.1% formic acid). A salt form can be converted to the free base form using standard chemical conversion techniques, and vice versa.Example 1: 5-((ls,3s)-3-amino-3-(4-(5-oxo-3-phenyl-5,6-dihydro-l,6-naphthyridin-2-yl)phenyl)cyclobutoxy)pyrimidine-2-carbonitrile1) TFA’DCMx^yL^XX JL Cs2CO3, DMF I IIN—2). LiCI, PTSA, DMF HN JLxXN—( T r il T r ii n r ilcy cyN°N

[0304] Step 1: To a solution of tert-butyl ((l,3 )-3-hydroxy-l-(4-(5-methoxy-3-phenyl- I,6-naphthyridin-2-yl)phenyl)cyclobutyl)carbamate (100 mg, 0.20 mmol) in DMF (2 mL), were added 5-fluoropyrimidine-2-carbonitrile (25 mg, 0.20 mmol) and CS2CO3 (197 mg, 0.60 mmol). Then the resulting mixture was stirred at 70°C for 4 h. LCMS showed the reaction was completed. The reaction mixture was cooled to r.t and filtered. The filtrate was diluted with sat. aq. NH₄Cl (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The residue was purified by prep-TLC (EtOAc / DCM = 1 / 3, V / V) to give tert-butyl ((ls,3s)-3-((2-cyanopyrimidin-5-yl)oxy)-l-(4-(5-methoxy-3-phenyl-l,6-naphthyridin-2-yl)phenyl)cyclobutyl)carbamate (50 mg). LC / MS ESI (m / z): 601 [M+H]+.

[0305] Step 2: To a stirred solution of tert-butyl ((l,3 )-3-((2-cyanopyrimidin-5-yl)oxy)-l-(4-(5-methoxy-3-phenyl-l,6-naphthyridin-2-yl)phenyl)cyclobutyl)carbamate (15 mg, 0.025 mmol) in DCM (2 mL) was added TFA (1 mL, 13.1 mmol). After stirring at r.t for 1 h, the reaction mixture was concentrated to remove the solvent. Then DMF (2 mL), lithium chloride (6 mg, 0.14 mmol) and / >-toluenesulfonic acid (21 mg, 0.12 mmol) were added. The resulting mixture was heated to 120°C and stirred for 0.5 h. LCMS showed the reaction was completed. The reaction mixture was cooled to r.t and filtered. The filtrate was purified by prep-HPLC (Column: YMC-Actus Triart C18 150* 15mm, 20— >95% MeCN in H2O with 0.1% TFA) to give the desired product (5.9 mg). LC / MS ESI (m / z): 487 [M+H]+. 'H NMR (400 MHz, DMSO-tfc) 6 II.63 (d, J = 5.7 Hz, 1H), 8.74 (s, 2H), 8.40 (s, 1H), 7.62 - 7.58 (m, 2H), 7.54 - 7.50 (m, 3H),NAI-5008634746vl -111-Attomey Docket No. 14709-051-2287.37 - 7.31 (m, 5H), 6.69 (d, J = 7.3 Hz, 1H), 4.95 - 4.87 (m, 1H), 3.35 - 3.33 (m, 2H), 2.83 - 2.77 (m, 2H).

[0306] The following compounds were prepared in a similar manner.4-(( 1 s,3 s)-3 -amino-3 -(4-(5 -oxo-3 -phenyl - 5,6-dihydro- 1,6-naphthyridin-2- yl)phenyl)cyclobutoxy)pyrimidine-2- carbonitrile _’H NMR (400 MHz DMSO-d6) d 11.58 (s 1H) 8.70 (d J = 5.9 Hz 1H) 8.38 (s 1H) 7.54 - 7.45 (m 4H) 7.41 (d J = 8.4 Hz 2H) 131 - 7.27 (m 7H) 6.69 (d J = 7.3 Hz 1H) 4.94 (p J = 7.0 Hz 1H) 3.06 - 3.01(m 2H) 2.46 - 2.41 (m 2H), _LC / MS (ESI) (m / z): 487 [M+H]+, _ Example 3: 4-((l-(4-(5-oxo-3-phenyl-5,6-dihydro-l,6-naphthyridin-2-yl)benzyl)piperidin-4-

[0307] Step 1: A solution of 2-(4-(l,3-dioxolan-2-yl)phenyl)-5-methoxy-3-phenyl-l,6- naphthyridine (1.0 g, 2.60 mmol) in 6 M aqueous HC1 solution (5 mL) was stirred at RT for 2 h. Upon completion of the reaction based on TLC analysis, the reaction mixture was concentrated under reduced pressure to yield 0.94 g of 4-(5-oxo-3-phenyl-5,6-dihydro-l,6-naphthyridin-2- yl)benzaldehyde, which was directly used for the next step without further purification. LC-MS (ESI+): m / z 327.2 [M+H]+.

[0308] Step 2: To a solution of 4-(5-oxo-3-phenyl-5,6-dihydro-l,6-naphthyridin-2- yl)benzaldehyde (250 mg, 0.77 mmol) in THF (5 mL) under N2 atmosphere at RT was added Lithium tri-tert-butoxyaluminum hydride (1.0 mL, 1.0 mmol, 1 M in THF) dropwise. The mixture was stirred at RT for 1 h. Upon completion of the reaction based on TLC analysis, the reaction mixture was quenched with MeOH (5 mL), concentrated under reduced pressure andNAI-5008634746vl -112-Attomey Docket No. 14709-051-228purified by silica-gel column chromatography to yield 200 mg of 2-(4-(hydroxymethyl)phenyl)-3-phenyl-l,6-naphthyridin-5(6H)-one. LC-MS (ESI+): m / z 329.3 [M+H]+.

[0309] Step 3: A solution of 2-(4-(hydroxymethyl)phenyl)-3 -phenyl- 1,6-naphthyridin-5(6H)-one (200 mg, 0.61 mmol) and SOCh (2 mL) in DCM (4 mL) was stirred at RT for 1 h. Upon completion of the reaction based on LC-MS analysis, the reaction mixture was concentrated under reduced pressure to yield 220 mg of 2-(4-(chloromethyl)phenyl)-3-phenyl-l,6-naphthyridin-5(6H)-one, which was directly used for the next step without further purification. LC-MS (ESI+): m / z 347.1, 349.1 [M+H]+.

[0310] Step 4: A solution of 2-(4-(chloromethyl)phenyl)-3 -phenyl- 1,6-naphthyri din-5(6H)-one (45 mg, 0.13 mmol), 4-(piperidin-4-ylamino)pyrimidine-2-carbonitrile (40 mg, 0.20 mmol) and K2CO3 (89 mg, 0.65 mmol) in DMSO (5 mL) and H2O (1.5 mL) was stirred at 70 °C for 12 h. Upon completion of the reaction based on LC-MS analysis, the reaction mixture was quenched with water (15 mL) and extracted with EtOAc (10 mL x 5). The combined organic phase was washed with brine (15 mL x 3), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC to yield 26 mg of 4-((l-(4-(5-oxo-3-phenyl-5,6-dihydro-l,6-naphthyridin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile. LC-MS (ESI+): m / z 514.4 [M+H]+; 'H-NMR. (400 MHz, CD3OD) t / 8.61 (s, 1H), 7.99 (s, 1H), 7.51-7.44 (m, 1H), 7.40-7.36 (m, 2H), 7.32-7.22 (m, 7H), 6.87 (d, = 7.2 Hz, 1H), 6.62-6.57 (m, 1H), 4.00-3.89 (m, 1H), 3.59 (s, 2H), 2.90 (d, J= 11.6 Hz, 2H), 2.23 (t, J= 11.2 Hz, 2H), 1.98 (d, J= 11.2 Hz, 2H), 1.65-1.42 (m, 2H).

[0311] The following compounds were prepared in a similar manner.4-(( 1 -(4-(5 -oxo-3 -phenyl-5,6-dihydro- 1,6- naphthyridin-2-yl)benzyl)piperidin-4- yl)oxy)pyrimidine-2-carbonitrile’H-NMR (400 MHz, CD3OD+CDCI3) d 8.66 Example 4 (s, 1H), 8.47 (d, J= 6.0 Hz, 1H), 7.40-7.34 (m,2H), 7.33-7.29 (m, 1H), 7.25-7.20 (m, 7H), 1 u 6.91-6.89 (m, 2H), 5.21-5.19 (m,1H), 3.55 (s,2H), 2.78-2.74 (m, 2H), 2.34-2.29 (m, 2H), 2.10-2.00 (m, 2H), 1.85-1.82 (m, 2H).LC-MS (ESI+): m / z 515.5 [M+H]+4-(( 1 -(4-(7 -morpholino-3 -phenyl- 1,6- naphthyridin-2-yl)benzyl)piperidin-4- ON yl)amino)pyrimidine-2-carbonitrile ’HNMR (400 MHz, DMSO-d6) 59.13 (s, 1H), 8.34 (s, 1H), 8.08 (d, J= 6.2 Hz, 1H), 8.02 (d, Example 5 J= 7.4 Hz, 1H), 7.33-7.29 (m, 5H), 7.23-7.19(m, 4H), 7.07 (s, 1H), 6.66 (d, J= 6.0 Hz, 1H), 3.79-3.76 (m, 4H), 3.62-3.59 (m, 4H), 3.47 (s, 2H), 2.77-2.73 (m, 2H), 2.54-2.53 (m, 1H), 2.10-2.04 (m, 2H), 1.88-1.82 (m, 2H), 1.48-1.41 (m, 2H).NAI-5008634746vl -113-Attomey Docket No. 14709-051-228LC / MS ESI (m / z): 583 [M+H]+.4-((l-(4-(6-methyl-5-oxo-2-phenyl-5,6- dihydropyrido [2,3 -d]pyridazin-3 - yl)benzyl)piperidin-4-yl)amino)pyrimidine-2- carbonitrile>irxr-a.yx. ’HNMR (400 MHz, DMSO-J6) 58.59 (s, 1H), Example 6 JI A HXN 8.52 (s, 1H), 8.21 (d, J= 6.9 Hz, 1H), 8.15 (d,J= 6.1 Hz, 1H), 7.48 (d, J= 8.1 Hz, 2H), 7.45 - 7.27 (m, 7H), 6.80 - 6.65 (m, 1H), 4.32 (d, J = 3.8 Hz, 2H), 4.19 - 4.02 (m, 1H), 3.79 (s, 3H), 3.42 - 3.27 (m, 2H), 3.20 - 3.07 (m, 2H), 2.18 - 1.56 (m, 4H).LC / MS ESI (m / z): 529 [M+H]+.4-((l-(4-(7-methyl-8-oxo-3-phenyl-7,8- dihydropyrido [2,3 -d]pyridazin-2- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2- carbonitrile’H-NMR (400 MHz, CD3OD) £8.45 (s, 1H), Example 7 x-xroxHxN8.34 (s, 1H), 8.05-7.97 (m, 1H), 7.45 (d, J= 8.0*0 Hz, 2H), 7.38-7.31 (m, 3H), 7.30-7.25 (m, 4H),6.62-6.57 (m, 1H), 3.96-3.89 (m, 4H), 3.58 (s, 2H), 2.95-2.83 (m, 2H), 2.30-2.18 (m, 2H), 2.04-1.90 (m, 2H), 1.65-1.50 (m, 2H).LC-MS (ESI+): m / z 529.5 [M+H]+4-((l-(4-(7-(methyl-d3)-8-oxo-3-phenyl-7,8- dihydropyrido [2,3 -d]pyridazin-2- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2- carbonitrileExample 8 A N^J iJfxk / XHXXN’H-NMR (400 MHz, CD3OD) £8.46 (s, 1H),8.35 (s, 1H), 8.05-7.95 (m, 1H), 7.46 (d, J= 8.0 Hz, 2H), 7.38-7.31 (m, 3H), 7.30-7.22 (m, 4H), 6.59 (d, J= 6.0 Hz, 1H), 3.96-3.84 (m, 1H), 3.59 (s, 2H), 2.95-2.85 (m, 2H), 2.30-2.18 (m, 2H), 2.04-1.90 (m, 2H), 1.65-1.50 (m, 2H). LC-MS (ESI+): m / z 532.5 [M+H]+4-(( 1 -(4-(5 -oxo-2 -phenyl-5,6- dihydropyrido [2,3 -d]pyridazin-3 - yl)benzyl)piperidin-4-yl)amino)pyrimidine-2- carbonitrile ji JQXQL XX ’H-NMR (400 MHz, CD3OD) £8.62 (s, 1H), Example 9 Jyx ^ « 8.49 (s, 1H), 8.05-7.98 (m, 1H), 7.43 (d, J= 8.0Hz, 2H), 7.38-7.32 (m, 3H), 7.30-7.20 (m, 4H),n^n1Q] 6.62-6.54 (m, 1H), 4.05-3.90 (m, 1H), 3.90- 3.70 (m, 2H), 3.10-2.88 (m, 2H), 2.55-2.20 (m, 2H), 2.10-2.00 (m, 2H), 1.70-1.58 (m, 2H). LC-MS (ESI+): m / z 515.4 [M+H]+NAI-5008634746vl -114-Attomey Docket No. 14709-051-2284-((l-(4-(7-methyl-8-oxo-3-phenyl-7,8- dihydropyrido [2,3 -d]pyridazin-2- yl)benzyl)azetidin-3-yl)amino)pyrimidine-2- carbonitrile’H-NMR (400 MHz, CD3OD) £8.45 (s, 1H), Example 10 8.34 (s, 1H), 8.12-8.02 (m, 1H), 7.45 (d, J= 8.0 zz- Hz, 2H), 7.38-7.31 (m, 3H), 7.30-7.22 (m, 4H), ^ C°= / 6.64 (d, J = 6.0 Hz, 1H), 4.68-4.55 (m, 1H),3.91 (s, 3H), 3.76-3.67 (m, 4H), 3.13-3.09 (m, o2H).LC-MS (ESI+): m / z 501.5 [M+H]+4-((2-(4-(7-methyl-8-oxo-3-phenyl-7,8- dihydropyrido[2,3-d]pyridazin-2-yl)benzyl)-2- Z- ^ azaspiro[3.3]heptan-6-yl)amino)pyrimidine-2- carbonitrileIZ ’H-NMR (400 MHz, CD3OD) £8.45 (s, 1H), Example 11 N if 1V"^'N'A'NX>^ 8.34 (s, 1H), 8.05-7.95 (m, 1H), 7.46 (d, J= 8.0H z Hz, 2H), 7.34-7.33 (m, 3H), 7.30-7.24 (m, 4H), ZI 6.56 (d, J= 6.0 Hz, 1H), 4.61 (s, 1H), 4.35-4.25(m, 1H), 3.91 (s, 3H), 3.67 (s, 2H), 3.50-3.40 z(m, 3H), 2.65-2.60 (m, 2H), 2.20-2.10 (m, 2H). LC-MS (ESI+): m / z 541.6 [M+H| C—+4-(((3aR,5s,6aS)-2-(4-(7-methyl-8-oxo-3- phenyl-7, 8-dihy dropyrido [2,3 -d]pyridazin-2- yl)benzyl)octahydrocyclopenta[c]pyrrol-5- yl)amino)pyrimidine-2-carbonitrileQ z ’H-NMR (400 MHz, CD3OD) £8.43 (s, 1H), Example 12 8.31 (s, 1H), 7.97-7.95 (m, 1H), 7.40 (d, J= 8.0 c# °= Hz, 2H), 7.30-7.22 (m, 7H), 6.57-6.56 (m, 1H), zz- _ _ / 4.60-4.51 (m, 1H), 3.90 (s, 3H), 3.61 (s, 2H),2.74-2.73 (m, 4H), 2.31-2.25 (m, 2H), 1.88- 1.83 (m, 2H), 1.70-1.67 (m, 2H).LC-MS (ESI+): m / z 541.6 [M+H]+4-(((lR,5S,6s)-3-(4-(7-methyl-8-oxo-3- phenyl-7, 8-dihy dropyrido [2,3 -d]pyridazin-2- yl)benzyl) -3 -azabicyclo [3.1. l]heptan-6- yl)amino)pyrimidine-2-carbonitrile’H-NMR (400 MHz, CD3OD) £8.45 (s, 1H),.x-xraxxExample 13 8.34 (s, 1H), 8.10-8.01 (m, 1H), 7.44 (d, J= 8.0U' X %.H NHz, 2H), 7.31-7.28 (m, 7H), 6.80-6.61 (m, 1H),|TJ 4.60-4.45 (s, 1H), 3.91 (s, 3H), 3.68 (s, 2H),3.05-3.02 (m, 2H), 2.86-2.81 (m, 2H), 2.65- 2.58 (m, 2H), 1.89-1.84 (m, 1H), 1.41-1.39 (m, 1H).LC-MS (ESI+): m / z 541.5 [M+H]+NAI-5008634746vl -115-Attomey Docket No. 14709-051-2284-(((lR,5S,6s)-3-(4-(7-methyl-8-oxo-3- phenyl-7, 8-dihydropyrido [2,3 -d]pyridazin-2- yl)benzyl) -3 -azabicyclo [3.1,0]hexan-6- yl)amino)pyrimidine-2-carbonitrile’H-NMR (400 MHz, CD3OD) £8.48 (s, 1H), Example 14 / zz- 8.40 (s, 1H), 8.20-8.11 (m, 1H), 7.61 (d, J= 8.4Hz, 2H), 7.44 (d, J= 8.8 Hz, 2H), 7.37 (d, J = ) Co=2.0 Hz, 3H), 7.35-7.30 (m 2H), 6.80-6.61 (m,1H), 4.40-4.25 (m, 2H), 3.93 (s, 3H), 3.71-3.61 (m, 3H), 3.33-3.32 (m, 1H), 3.11-3.06 (m, 1H), 2.20-2.08 (m, 2H).LC-MS (ESI+): m / z 527.5 [M+H]+;4-((l-(4-(7-methyl-8-oxo-3-phenyl-7,8- dihydropyrido [2,3 -d]pyridazin-2- p, yl)benzyl)piperidin-4-yl)oxy)pyrimidine-2- carbonitrileTZ’H-NMR (400 MHz, CD3OD) £8.54 (d, J= 6.0 Example 15 Hz, 1H), 8.45 (s, 1H), 8.34 (s, 1H), 7.49-7.454 Q \=z: (m, 2H), 7.36-7.27 (m, 7H), 7.05 (d, J= 6.0 Hz, ) oo=> Z. — / / 1H), 5.27-5.18 (m, 1H), 3.91 (s, 3H), 3.60 (s, z2H), 2.81-2.73 (m, 2H), 2.48-2.40 (m, 2H), d z—> 2.11-2.04 (m, 2H), 1.90-1.80 (m, 2H).LC-MS (ESI+): m / z 530.6 [M+H]+4-(4-(4-(7-methyl-8-oxo-3-phenyl-7,8- dihydropyrido [2,3 -d]pyridazin-2- yl)benzyl)piperazine- 1 -carbonyl)pyrimidine- 2-carbonitrileoExample 16 M 'H-NMR (400 MHz, CD3OD) £9.07 (d, J =5.2<(dd o o==zz zz-- Hz, 1H), 8.45 (s, 1H), 8.34 (s, 1H), 8.87 (d, J = _ _ _ _ / / 5.2 Hz, 1H), 7.45 (d, J = 8.0Hz, 2H), 7.35-7.27(m, 7H), 3.91 (s, 3H), 3.81-3.77 (m, 2H), 3.60 (s, 2H), 3.53-3.49 (m, 2H), 2.39-2.47 (m, 4H). LC-MS (ESI+): m / z 543.6 [M+H]+4-(((lR,5S)-8-(4-(7-methyl-8-oxo-3-phenyl- 7, 8-dihydropyrido [2,3 -d]pyridazin-2- yl)benzyl) -8 -azabicyclo [3.2.1] octan-3 - yl)amino)pyrimidine-2-carbonitrile’H-NMR (400 MHz, CD3OD) £8.45 (s, 1H), Example 17.x-xr-axa.8.34 (s, 1H), 8.02-7.99 (m, 1H), 7.43-7.42 (m, 2H), 7.41-7.28 (m, 7H), 6.83-6.80 (m, 0.5H), 6.65-6.60 (m, 0.5H), 3.91 (s, 3H), 3.85 (s, 1H), 3.52 (d, J= 5.2 Hz, 2H), 2.73-2.70 (m,lH), 2.48 (s, 2H), 2.30-2.21 (m, 3H), 1.83-1.79 (m, 4H).LC-MS (ESI+): m / z 555.7 [M+H]+NAI-5008634746vl -116-Attomey Docket No. 14709-051-2284-(( 1 -(4-(2-(2-aminopyridin-3 -y 1) -5 -oxo-5,6- dihydropyrido [2,3 -d]pyridazin-3 - yl)benzyl)piperidin-4-yl)amino)pyrimidine-2- carbonitrile’H-NMR (400 MHz, CD3OD) £8.70 (s, 1H), 8.50 (s, 1H), 8.09 (d, J= 4.8 Hz, 1H), 7.93 (d, Example 18HS zz- jOU HN^N J= 5.6 Hz, 1H), 7.53 (d, J= 8.0 Hz, 2H), 7.46N? C^o=NJO (d, J= 8.0 Hz, 2H), 7.36 (d, J= 7.2 Hz, 1H), H2N N 6.67-6.61 (m, 1H), 6.60-6.58 (m, 1H), 4.32 (s,2H), 4.28-4.18 (m, 1H), 3.52-3.40 (m, 2H), 3.20-3.18 (m, 2H), 2.30-2.20 (m, 2H), 1.90- 1.78 (m, 2H).LC-MS (ESI+): m / z 531.4 [M+H]+4-(( 1 -(4-(2-(2-aminopyridin-3 -yl)-6-methyl-5 - oxo-5, 6-dihydropyrido[2,3-d]pyridazin-3- 0IZ yl)benzyl)piperidin-4-yl)amino)pyrimidine-2- carbonitrile’H-NMR (400 MHz, CD30D) £8.70 (s, 1H), p4 8.50 (s, 1H), 8.08 (d, J= 5.2 Hz, 1H), 7.92 (d, Example 19 / _ o J= 4.8 Hz, 1H), 7.53 (d, J= 8.0 Hz, 2H), 7.44 z(d, J= 7.6 Hz, 2H), 7.36 (d, J= 6.8 Hz, 1H), ZA- ^ 6.66-6.58 (m, 2H), 4.31-4.25 (m, 2H), 4.25- 4.15 (m, 1H), 3.88 (s, 3H), 3.42-3.31 (m, 2H), 3.13-3.11 (m, 2H), 2.21-2.19 (m, 2H), 2.02- 1.93 (m, 2H).LC-MS (ESI+): m / z 545.4 [M+H]+4-(( 1 -(4-(3 -(2-aminopyridin-3 -yl)-8-oxo-7, 8- o dihydropyrido [2,3 -d]pyridazin-2-;z o / = yl)benzyl)piperidin-4-yl)amino)pyrimidine-2- z-f_ z _0iCNcarbonitrile'H-NMR (400 MHz, CD3OD) £8.49 (s, 1H), Example 20 NJUL^H N8.39 (s, 1H), 8.08-8.00 (m, 1H), 7.95 (d, J= 1.6Y J Hz, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.39-7.33 (m, H2N N 3H), 6.71-6.65 (m, 2H), 4.03-3.95 (m, 1H),3.76 (s, 2H), 3.08-3.00 (m, 2H), 2.53-2.39 (m, 2H), 2.10-2.00 (m, 2H), 1.73-1.55 (m, 2H). LC-MS (ESI+): m / z 531.5 [M+H]+rel-4-((3aS,7aR)-5-(4-(3-methyl-4-oxo-7- phenyl-3,4-dihydropyrido[3,2-d]pyrimidin-6- yl)benzyl)octahydro- 1 H-pyrrolo [3,2- clpyridin- 1 -yl)pyrimidine-2 -carbonitrile ’H-NMR (400 MHz, CD3OD) > 8.46 (s, 1H), 8.22-8.15 (m, 1H), 8.13 (s, 1H), 7.56 (d, J= 8.0 Example 37 Hz, 2H), 7.49-7.72 (m, 2H), 7.37-7.33 (m, 3H),7.27-7.22 (m, 2H), 6.85-6.60 (m, 1H), 4.60- 4.25 (m, 3H), 3.70 (s, 3H), 3.68-3.60 (m, 2H), 3.55-3.35 (m, 3H), 3.21-3.10 (m, 1 H), 2.95- 2.60 (m, 2H), 2.40-2.05 (m, 2H), 1.85-1.50 (m, 1H).LC-MS (ESI+): m / z 555.7 [M+H]+NAI-5008634746vl -117-Attorney Docket No. 14709-051-228Rel-4-((3aR,7aS)-5-(4-(3-methyl-4-oxo-7- phenyl-3,4-dihydropyrido[3,2-d]pyrimidin-6- yl)benzyl)octahydro- IH-pyrrolo [3,2- clpyridin- 1 -yl)pyrimidine-2 -carbonitrile ’H-NMR (400 MHz, CD3OD) > 8.46 (s, 1H), 8.22-8.15 (m, 1H), 8.13 (s, 1H), 7.56 (d, J= 8.4 Hz, 2H), 7.47-7.72 (m, 2H), 7.37-7.33 (m, 3H), 7.29-7.23 (m, 2H), 6.85-6.60 (m, 1H), 4.53- 4.25 (m, 3H), 3.70 (s, 3H), 3.68-3.60 (m, 2H), 3.55-3.40 (m, 3H), 3.21-3.10 (m, 1H), 2.95- 2.60 (m, 2H), 2.40-2.05 (m, 2H), 1.72-1.55 (m, 1H).LC-MS (ESI+): m / z 555.7 [M+H]+Example 21: 4-(methyl(l-(4-(5-oxo-3-phenyl-5,6-dihydro-l,6-naphthyridin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile

[0312] Step 1: To a solution of 4-(methyl(l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile (60 mg, crude) in 1,4-di oxane (1 mL) and water (0.1 mL) were added 5-methoxy-3-phenyl-l,6-naphthyridin-2-yl trifluoromethanesulfonate (50 mg, 0.13 mmol), Pd(dppf)C12 (15 mg, 0.02 mmol) and Na₂CO₃ (28 mg, 0.26 mmol). Then the resulting mixture was degassed with N2 for three times and stirred at 80°C for 2 h. LCMS showed the reaction was completed. The reaction mixture was cooled to r.t and filtered. The filtrate was concentrated to give a residue. The residue was purified by flash column chromatography on silica gel with MeOH in DCM (0— >15%, V / V) to give 4-((l-(4-(5-methoxy-3 -phenyl- 1, 6-naphthyri din-2 -yl)benzyl)piperidin-4-yl)(methyl)amino)pyrimidine-2-carbonitrile (40 mg). LC / MS ESI (m / z): 542 [M+H]+.

[0313] Step 2: To a stirred solution of 4-((l-(4-(5-methoxy-3-phenyl-l,6-naphthyridin-2-yl)benzyl)piperidin-4-yl)(methyl)amino)pyrimidine-2-carbonitrile (40 mg, 0.074 mmol) in DMF (1 mL), were added lithium chloride (15 mg, 0.35 mmol) and / >-toluenesulfonic acid (60 mg, 0.35 mmol). Then the reaction was stirred at 120°C for 0.5 h. LCMS showed the reaction was completed. The reaction mixture was cooled to r.t and concentrated to give a residue. The residue was purified by prep-HPLC (Column: YMC Triart Cl 8- 150*20 mm I. D, 5um, 10-95% MeCN in H2O with 0.1% TFA) to give the desired product (11.0 mg). LC / MS ESI (m / z): 528 [M+H]+. 'H NMR(400 MHz, DMSO-tZ6) 5 11.63 (d, J = 6.0 Hz, 1H), 8.43 (s, 1H), 8.31 (d, J = 6.4 Hz, 1H), 7.52 (dd, J= 7.2, 6.1 Hz, 1H), 7.49 - 7.42 (m, 4H), 7.37 - 7.23 (m, 5H), 7.01 (br, 1H), 6.69 (d, J = 7.0 Hz, 1H), 4.32 (s, 2H), 3.31 - 3.06 (m, 5H), 2.88 (s, 3H), 2.07 - 1.93 (m, 2H), 1.91 - 1.76 (m, 2H).NAI-5008634746vl -118-Attomey Docket No. 14709-051-228

[0314] The following compounds were prepared in a similar manner.4-(( 1 -(4-(8-oxo-3 -phenyl-7,8-dihydro- 1,7- naphthyridin-2-yl)benzyl)piperidin-4- Hyl)amino)pyrimidine-2-carbonitrile ’H NMR (400 MHz, DMSO-d6) 5 11.62 (d, J= 5.8 Hz, 1H), 8.25 (d, J= 7.2 Hz, 1H), Example 22 8.20 (s, 1H), 8.14 (d, J= 6.1 Hz, 1H), 7.43(s, 4H), 7.40 - 7.27 (m, 6H), 6.82 - 6.67 (m, 1H), 6.66 (d, J= 7.0 Hz, 1H), 4.38 - 4.26 (m, 2H), 4.19 - 3.96 (m, 1H), 3.45 - 3.24 (m, 2H), 3.23 - 3.06 (m, 2H), 2.20 - 1.91 (m, 2H), 1.78 - 1.52 (m, 2H).LC / MS ESI (m / z): 514 [M+H]+.4-((l-(4-(7-methyl-8-oxo-3-phenyl-7,8- dihydro- 1,7-naphthyridin-2- V yl)benzyl)piperidin-4-, N^O yl)amino)pyrimidine-2-carbonitrile[T T p ’H NMR (400 MHz, DMSO-d6) 58.20 (d, J IZ = 3.3 Hz, 2H), 8.14 (d, J= 6.3 Hz, 1H), 7.66 Example 23 Fh(d, J= 7.3 Hz, 1H), 7.43 (s, 4H), 7.35 (dd, J = 6.4, 3.3 Hz, 3H), 7.28 (dd, J= 6.4, 3.0 Hz, 02H), 6.81 - 6.63 (m, 2H), 4.36 - 4.26 (m, 2H), 4.23 - 3.96 (m, 1H), 3.57 (s, 3H), 3.35 - 3.26 (m, 2H), 3.22 - 3.02 (m, 2H), 2.19 - 1.94 (m, 2H), 1.81 - 1.45 (m, 2H).\ Z\Z== LL LC / MS ESI (m / z): 528 [M+H]+.4-(( 1 -(4-(8-fIuoro-3 -phenyl- 1,6- naphthyridin-2-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile ’H NMR (400 MHz, DMSO-d6) 5 9.34 (s, 1H), 8.78 (d, J= 2.8 Hz, 1H), 8.72 (d, J = 1.7 Hz, 1H), 8.08 (d, J= 6.0 Hz, 1H), 8.03 Example 24 (d, J = 7.8 Hz, 1H), 7.40 - 7.35 (m, 5H),7.34 - 7.30 (m, 2H), 7.26 (d, J = 8.1 Hz, 2H), 6.66 (d, J= 5.9 Hz, 1H), 3.78 (s, 1H), 3.49 (s, 2H), 2.76 (d, J= 11.8 Hz, 2H), 2.12 - 2.05 (m, 2H), 1.85 (d, J= 12.2 Hz, 2H), 1.51 - 1.41 (m, 2H).LC / MS ESI (m / z): 516 [M+H]+.4-(( 1 -(4-(7 -methyl-8-oxo-3 -(pyridin-3 -yl)- 7, 8-dihydropyrido [2,3 -d]pyridazin-2- yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile'H NMR (400 MHz, DMSO-d6) 58.60 (s, 1H), 8.58 (dd, J= 4.9, 1.6 Hz, 1H), 8.53 (s, 1H), 8.51 (d, J=2.4Hz, 1H), 8.22 (d, J = Example 25H N7.6 Hz, 1H), 8.15 (d, J= 6.0 Hz, 1H), 7.85- 7.72 (m, 1H), 7.50 (s, 4H), 7.44 (dd, J= 7.9, 4.9 Hz, 1H), 6.69 (d, J= 6.3 Hz, 1H), 4.33 (m, 2H), 4.12 - 3.98 (m, 1H), 3.81 (s, 3H), 3.44 - 3.35 (m, 2H), 3.27 - 3.10 (m, 2H), 2.21 - 2.05 (m, 2H), 1.77 - 1.55 (m, 2H).LC / MS ESI (m / z): 530 [M+H]+.NAI-5008634746vl -119-Attomey Docket No. 14709-051-2284-(( 1 -(4- (5 -oxo-3 -phenyl-5,6- dihydropyrido [2,3 -d]pyridazin-2- yl)benzyl)piperidin-4- HN'X yl)amino)pyrimidine-2-carbonitrile'H NMR (400 MHz, DMSO-d6) 5 13.05 (s, 1H), 8.50 (s, 1H), 8.49 (s, 1H), 8.18 Example 39 TZZ- (dd, J= 28.4, 6.2 Hz, 2H), 7.50 - 7.45 (m,4H), 7.39 - 7.29 (m, 5H), 6.73 (dd, J = C 39.7, 6.3 Hz, 1H), 4.33 (dd, J= 15.0, 4.4Hz, 2H), 4.04 (s, 1H), 3.41 - 3.26 (m, 2H), M 3.14 (d, J= 10.0 Hz, 2H), 2.15 - 2.00 (m,2H), 1.99- 1.59 (m, 2H).LC / MS ESI (m / z): 515.5 [M+H]+.4-(( 1 -(4-(8-oxo-3 -phenyl-7, 8- dihydropyrido [2,3 -d]pyridazin-2- yl)benzyl)piperidin-4- 3TZ yl)amino)pyrimidine-2-carbonitrile'H NMR (400 MHz, DMSO-d6) 5 12.99 (s, 1H), 8.48 (d, J= 1.4 Hz, 2H), 8.18 (dd, Example 40 0 J= 33.0, 6.5 Hz, 2H), 7.49 - 7.44 (m, 4H), / / z 7.40 - 7.35 (m, 3H), 7.31 (dd, J= 6.5, 2.9 Hz, 2H), 6.73 (dd, J= 39.5, 5.8 Hz, 1H), 4.32 (d, J= 15.4 Hz, 2H), 4.03 (s, 1H), 3.35 - 3.21 (m, 2H), 3.14 (d, J= 11.1 Hz, 2H), 2.18 - 1.93 (m, 2H), 1.79 - 1.52 (m, 2H).LC / MS ESI (m / z): 515.5 [M+H]+.4-((l-(4-(7-isopropyl-8-oxo-3-phenyl-7,8- dihydro- 1,7-naphthyridin-2- yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile i o r^N 'H NMR (400 MHz, DMSO-d6) 58.24 - 1 JLN J J < 1 A x 8.12 (m, 3H), 7.71 (d, J= 7.5 Hz, 1H), Example 41OOy\ " 7.43 (s, 4H), 131 - 133 (m, 3H), 7.29 - 7.25 (m, 2H), 6.79 - 6.64 (m, 2H), 5.27 - 5.19 (m, 1H), 4.35 - 4.27 (m, 2H), 4.21 - 3.92 (m, 1H), 3.30 - 3.09 (m, 4H), 2.14 - 2.01 (m, 2H), 1.71 - 1.53 (m, 2H), 1.37 (d, J= 6.8 Hz, 6H).LC / MS ESI (m / z): 556.4 [M+H]+.4-(( 1 -(4-(7 -methyl-8-oxo-3 -(pyridin-3 -yl)- 7, 8-dihydro- 1,7-naphthyridin-2- yl)benzyl)piperidin-4- O r^N yl)amino)pyrimidine-2-carbonitrile'H NMR (400 MHz, DMSO-d6) 58.55 (d, Example 42 1 II H J=4.4Hz, 1H), 8.48 (s, 1H), 8.31 (s, 1H),8.27 - 8.11 (m, 2H), 7.75 - 7.67 (m, 2H), 7.47 _ 7.40 (m, 5H), 6.81 - 6.65 (m, 2H), 4.36 - 4.29 (m, 2H), 4.13 - 4.00 (m, 1H), 3.58 (s, 3H), 3.33 - 3.11 (m, 4H), 2.13 - 2.00 (m, 2H), 1.73 - 1.55 (m, 2H).LC / MS ESI (m / z): 529.4 [M+H]+.4-((l-(4-(6-methyl-5-oxo-3-phenyl-5,6- Example 43 dihydro- 1,6-naphthyridin-2- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile NAI-5008634746vl -120-Attorney Docket No. 14709-051-228'H NMR (400 MHz, DMSO-d6) 58.47 (s, 1H), 8.31 - 8.11 (m, 2H), 7.83 (d, J= 7.6 Hz, 1H), 7.48 - 7.42 (m, 4H), 7.36 - 7.31 (m, 3H), 7.28 - 7.24 (m, 2H), 6.82 - 6.65 (m, 2H), 4.34 - 4.29 (m, 2H), 4.18 - 3.98 (m, 1H), 3.58 (s, 3H), 3.43 - 3.30 (m, 2H), \ I 3.21 - 3.04 (m, 2H), 2.18 - 2.02 (m, 2H),1.98 - 1.57 (m, 2H).LC / MS ESI (m / z): 528.3 [M+H]+.O 4-(methyl(l-(4-(8-oxo-3-phenyl-7,8- dihydro- 1,7-naphthyridin-2- yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile'H NMR (400 MHz, DMSO-d6) 5 11.60 (d, J= 5.6 Hz, 1H), 8.30 (d, J= 6.4 Hz, Example 44 00 1H), 8.20 (s, 1H), 7.48 - 7.27 (m, 10H), z IZ — 7.01 (s, 1H), 6.65 (dd, J = 6.9, 1.1 Hz, 1H),4.86 (s, 1H), 4.33 (d, J= 3.6 Hz, 2H), 3.45 hh zz- 3.39 (m, 2H), 3.27- 3.12 (m, 2H), 2.88 (s, 3H), 2.11 - 1.89 (m, 2H), 1.88 - 1.69 z z (m, 2H).LC / MS ESI (m / z): 528.3 [M+H]+.4-((l-(4-(6-methyl-5-oxo-3-phenyl-5,6- dihydropyrido [2,3 -d]pyridazin-2- yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile'H NMR (400 MHz, DMSO-d6) 58.56 (s,.^.jx o xy 1H), 8.52 (s, 1H), 8.21 (d, J= 6.5 Hz, 1H), Example 45 8.15 (d, J= 5.9 Hz, 1H), 7.51 - 7.45 (m,4H), 7.38 - 7.29 (m, 5H), 6.82 - 6.63 (m, I U 1H), 4.31 (d, J = 3.9 Hz, 2H), 4.22 - 3.96 (m, 1H), 3.80 (s, 3H), 3.42 - 3.34 (m, 2H), 3.20 - 3.09 (m, 2H), 2.14 - 2.00 (m, 2H), 1.75 - 1.55 (m, 2H).LC / MS ESI (m / z): 529.3 [M+H]+.Example 26: 4-((l-(4-(7-(2-aminopyridin-3-yl)-3-methyl-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrilecataCXium A Pd G3, K3P04, THF / H20, 80 C

[0315] Step 1: To a solution of 7-chloro-6-iodo-3-methylpyrido[2,3-J]pyrimidin-4(3J7)-one (70 mg, 0.22 mmol), / c / 7-butyl (2-cyanopyrimidin-4-yl)(l-(4-(4,4,5,5-tetramethyl-l,3,2-NAI-5008634746vl -121-Attomey Docket No. 14709-051-228dioxaborolan-2-yl)benzyl)piperidin-4-yl)carbamate (113 mg, 0.22 mmol), cataCXium APd G3 (32 mg, 0.044 mmol) and K3PO4 (139 mg, 0.65 mmol) in THF (2 mL) was added water (0.2 mL). Then the resulting mixture was degassed with N2 for 3 times and stirred at 80°C for 3 h. LCMS showed the reaction was completed. The reaction mixture was cooled to room temperature, filtered and concentrated. The residue was purified by prep-TLC (MeOH / DCM = 1 / 15, V / V) to give 75 mg of tert-butyl (l-(4-(7-chloro-3-methyl-4-oxo-3,4-dihydropyrido[2,3-J]pyrimidin-6-yl)benzyl)piperidin-4-yl)(2-cyanopyrimidin-4-yl)carbamate. LC / MS ESI (m / z): 587 / 589 [M+H]+.

[0316] Step 2: To a solution of tert-butyl (l-(4-(7-chloro-3-methyl-4-oxo-3,4-dihydropyrido[2,3-J]pyrimidin-6-yl)benzyl)piperidin-4-yl)(2-cyanopyrimidin-4-yl)carbamate (30 mg, 0.051 mmol), 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-amine (17 mg, 0.077 mmol), Pd(dppf)C12 (4 mg, 0.0055 mmol) and Na₂CO₃ (16 mg, 0.15 mmol) in 1,4-dioxane (1 mL) was added water (0.1 mL). The resulting mixture was degassed with N2 for 3 times and stirred at 65°C for 18 h. LCMS showed the reaction was completed. The reaction mixture was cooled to room temperature, filtered and concentrated. The residue was purified by prep-TLC (MeOH / DCM = 1 / 10, V / V) to give 25 mg of tert-butyl (l-(4-(7-(2-aminopyri din-3 -yl)-3-methyl-4-oxo-3,4-dihydropyrido[2,3-J]pyrimidin-6-yl)benzyl)piperidin-4-yl)(2-cyanopyrimidin-4-yl)carbamate. LC / MS ESI (m / z): 645 [M+H]+.

[0317] Step 3: To a stirred solution of tert-butyl (l-(4-(7-(2-aminopyridin-3-yl)-3-methyl-4-oxo-3,4-dihydropyrido[2,3-J]pyrimidin-6-yl)benzyl)piperidin-4-yl)(2-cyanopyrimidin-4-yl)carbamate (25 mg, 0.039 mmol) in DCM (1 mL) was added TFA (0.5 mL). Then the reaction was stirred at room temperature for 1 h. LCMS showed the reaction was completed. The reaction mixture was concentrated. The residue was purified by prep-HPLC (Column: YMC-Actus Triart C18 150*15 mm, MeCN in H2O with 0.1% TFA) to give 15.9 mg of the desired product. LC / MS ESI (m / z): 545 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 68.72 (s, 1H), 8.54 (s, 1H), 8.29 - 8.07 (m, 2H), 8.00 (d, J= 6.0 Hz, 1H), 7.84 - 7.53 (m, 2H), 7.49 (d, J= 7.9 Hz, 2H), 7.40 (d, J= 8.2 Hz, 2H), 6.84 - 6.65 (m, 2H), 4.30 (s, 2H), 4.04 (s, 1H), 3.58 (s, 3H), 3.20 - 3.07 (m, 4H), 2.14 -2.00 (m, 2H), 1.81 - 1.52 (m, 2H).

[0318] The following compounds were prepared in a similar manner.NAI-5008634746vl -122-Attorney Docket No. 14709-051-2284-((l-(4-(3-methyl-4-oxo-7-phenyl-3,4- dihydropyrido [2,3 -d]pyrimidin-6- yl)benzyl)piperidin-4- -2-carbonitrile'H NMR (400 MHz, DMSO-d6) 5 8.67 (s, Example 27 1H), 8.46 (s, 1H), 8.31 - 8.02 (m, 2H), 7.46(d, J= 8.1 Hz, 2H), 7.40 - 7.31 (m, 7H), 6.88 - 6.60 (m, 1H), 4.36 - 4.29 (m, 2H), 4.16 - 3.97 (m, 1H), 3.55 (s, 3H), 3.33 - 3.24 (m, 2H), 3.18 - 3.04 (m, 2H), 2.15 - 2.00 (m, 2H), 1.81 - 1.40 (m, 2H).LC / MS ESI (m / z): 529 [M+H]+Example 28: 4-((l-(4-(3-methyl-4-oxo-7-phenyl-3,4-dihydropyrido[3,2-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile

[0319] Step 1: To a solution of 6-bromo-7-phenylpyrido[3,2-d]pyrimidin-4(3H)-one (100 mg, crude) in DMF (2 mL) were added K2CO3 (138 mg, 1.00 mmol) and iodomethane (142 mg, 1.00 mmol). Then the resulting mixture was degassed with N2 for 3 times and stirred at 60°C for 1 h. LCMS showed the reaction was completed. The reaction mixture was cooled to room temperature, filtered and concentrated. The residue was purified by flash column chromatography on silica gel with EtOAc in PE (0— >30%, V / V) to give 96 mg of 6-bromo-3-methyl-7-phenylpyrido[3,2-J]pyrimidin-4(3J7)-one. LC / MS ESI (m / z): 316 / 318 [M+H]+.

[0320] Step 2: To a mixture of 6-bromo-3-methyl-7-phenylpyrido[3,2-J]pyrimidin-4(3J7)-one (50 mg, 0.15 mmol), tert-butyl (2-cyanopyrimidin-4-yl)(l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzyl)piperidin-4-yl)carbamate (79 mg, 0.15 mmol), cataCXium APd G3 (22 mg, 0.030 mmol) and K3PO4 (48 mg, 0.22 mmol) in DMF (1.5 mL) was added H2O (0.15 mL). Then the resulting mixture was degassed with N2 for 3 times and stirred at 80°C for 18 h. LCMS showed the reaction was completed. The reaction mixture was cooled to room temperature, filtered and concentrated. The residue was purified by flash column chromatography on silica gel with EtOAc in PE (0— >50%, V / V) to give 80 mg of tert-butyl (2-NAI-5008634746vl -123-Attomey Docket No. 14709-051-228cyanopyrimidin-4-yl)(l-(4-(3-methyl-4-oxo-7-phenyl-3,4-dihydropyrido[3,2-J]pyrimidin-6-yl)benzyl)piperidin-4-yl)carbamate. LC / MS ESI (m / z): 629 [M+H]+.

[0321] Step 3: To a stirred solution of tert-butyl (2-cyanopyrimidin-4-yl)(l-(4-(3-methyl-4-oxo-7-phenyl-3,4-dihydropyrido[3,2-J]pyrimidin-6-yl)benzyl)piperidin-4-yl)carbamate (80 mg, 0.13 mmol) in DCM (2 mL) was added TFA (1 mL). Then the reaction was stirred at room temperature for 2.5 h. LCMS showed the reaction was completed. The reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC (Column: YMC Triart C18 150*20 mm I. D, 5 pm; 20-95% MeCN in H2O + 0.1% FA) to give 20.4 mg of the desired product (formate salt). LC / MS ESI (m / z): 529 [M+H]+. 'HNMR (400 MHz, DMSO-6) 88.51 (s, 1H), 8.12 - 8.07 (m, 2H), 8.07 (s, 1H), 7.35 - 7.28 (m, 9H), 6.67 (d, J= 6.2 Hz, 1H), 3.90 -3.82 (m, 1H), 3.80 - 3.61 (m, 2H), 3.57 (s, 3H), 2.98 - 2.86 (m, 2H), 2.45 - 2.16 (m, 2H), 1.96 -1.86 (m, 2H), 1.57 - 1.47 (m, 2H).

[0322] The following compounds were prepared in a similar manner.4-((2-(4-(3-methyl-4-oxo-7-phenyl-3,4- dihydropyrido [3,2-d]pyrimidin-6- yl)benzyl) -2 -azaspiro [3.3] heptan-6- yl)amino)pyrimidine-2-carbonitrile 0\ A — 1 n N ’H-NMR (400 MHz, CD3OD) 88.44 (s, Example 29 1H), 8.10-8.05 (m, 1H), 8.04-7.97 (m, 1H), A H N 7.47-7.38 (m, 2H), 7.35-7.25 (m, 7H), 6.57(d, J = 6.0Hz, 1H), 4.44-4.28 (m, 1H), 3.99- 3.89 (m, 2H), 3.80-3.73 (m, 2H), 3.72 (s, 3H), 3.68-3.58 (m, 2H), 2.73-2.66 (m, 2H), 2.21-2.14 (m, 2H).LC-MS (ESI+): m / z 541.5 [M+H|+4-(( 1 -(4-(4-oxo-7 -phenyl-3,4- dihydropyrido[3,2-d]pyrimidin-6- yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile'H NMR (400 MHz, DMSO-A) 5 12.64 (s, Example 46 f II 1 H N 1H), 8.23 (s, 1H), 8.23 - 8.19 (m, 1H), 8.14N^ u (d, J = 6.1 Hz, 1H), 8.09 (s, 1H), 7.45 - 7.41(m, 4H), 7.37 - 7.28 (m, 5H), 6.73 (dd, J = 38.7, 6.1 Hz, 1H), 4.30 (d, J= 3.9 Hz, 2H), 4.15 - 3.94 (m, 1H), 3.40 - 3.36 (m, 2H), 3.18 - 3.08 (m, 2H), 2.11 - 1.62 (m, 4H). LC-MS (ESI+): m / z 515.3 [M+H|+tert-butyl (2-cyanopyrimidin-4-yl)(l-(4-(7- Example 47 (methyl-d3)-8-oxo-3-phenyl-7,8- dihydropyrido[2,3-d]pyridazin-2-yl)benzvl)piperidin-4-yl)carbamateNAI-5008634746vl -124-Attorney Docket No. 14709-051-228'H NMR (400 MHz, DMSO-d6) 58.79 (d, J= 5.9 Hz, 1H), 8.50 (s, 1H), 8.44 (s, 1H), 7.82 (d, J= 5.8 Hz, 1H), 7.40 - 7.22 (m, 9H), 4.32 (t, J= 14.2 Hz, 1H), 3.50 (s, 2H), 2.87 (d, J= 11.0 Hz, 2H), 2.22 (dd, J= 22.7, 11.4 Hz, 2H), 2.02 (t, J= 11.2 Hz, 2H), 1.65 (d, J= 11.4 Hz, 2H), 1.48 (s, 9H).LC-MS (ESI+): m / z 632.8 [M+H]+Example 30: 4-((l-(4-(6-methyl-5-oxo-2-phenyl-5,6-dihydropyrido[3,4-b]pyrazin-3-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile

[0323] Step 1: To a stirred solution of 3-(4-(l,3-dioxolan-2-yl)phenyl)-5-methoxy-2-phenylpyrido[3,4-Z>]pyrazine (149 mg, 0.39 mmol) in 1,4-dioxane (2 mL) was added 2M HC1 (2.0 mL). Then the resulting mixture was stirred at room temperature for 18 h. LCMS showed the reaction was completed. The reaction mixture was neutralized with sat. aq. NaHCO3to pH 7 and extracted with EtOAc (5 mL x 3). The combined organic phases were washed with brine (5 mL), dried over anhydrous Na2SC>4, filtered and concentrated. The residue was purified by prep-TLC (MeOH / DCM = 1 / 20, V / V) to give 40 mg of 4-(5-oxo-2-phenyl-5,6-dihydropyrido[3,4-Z»]pyrazin-3-yl)benzaldehyde. LC / MS ESI (m / z): 328 [M+H]+.

[0324] Step 2: To a solution of 4-(5-oxo-2-phenyl-5,6-dihydropyrido[3,4-Z>]pyrazin-3-yl)benzaldehyde (40 mg, 0.12 mmol) in DMF (1 mL) were added K2CO3 (51 mg, 0.37 mmol) and iodomethane (35 mg, 0.24 mmol). Then the resulting mixture was stirred at 50°C for 1 h. LCMS showed the reaction was completed. The reaction mixture was quenched with sat. aq.NH₄Cl (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic phases were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography on silica gel with EtOAc in PE (0— >70%, V / V) to give 30 mg of 4-(6-methyl-5-oxo-2-phenyl-5,6-dihydropyrido[3,4-Z>]pyrazin-3-yl)benzaldehyde.LC / MS ESI (m / z): 342 [M+H]+.

[0325] Step 3: To a solution of 4-(6-methyl-5-oxo-2-phenyl-5,6-dihydropyrido[3,4-Z»]pyrazin-3-yl)benzaldehyde (30 mg, 0.088 mmol) in DCE (1 mL) were added triethylamine (24 NAI-5008634746vl -125-Attorney Docket No. 14709-051-228mg, 0.24 mmol) and 4-(piperidin-4-ylamino)pyrimidine-2-carbonitrile bis(trifluoroacetate) (51 mg, 0.12 mmol). Then the resulting mixture was stirred at room temperature for 0.5 h. Then sodium cyanoborohydride (10 mg, 0.16 mmol) was added and the reaction was stirred at room temperature for 18 h. LCMS showed the reaction was completed. The reaction mixture was \quenched with water (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic phases Q> O=were washed with brine (5 mL), dried over anhydrous Na2SC>4, filtered and concentrated. The z z\ \residue was purified by prep-HPLC (Column: YMC-Actus Triart Cl 8 150*20mm XB, MeCN in H2O with 0.1% TFA) to give 18 mg of the desired product (TFA salt). LC / MS ESI (m / z): 529 [M+H]+. 'HNMR (400 MHz, DMSO-tL) 68.18 (dd, J= 19.9, 5.4 Hz, 2H), 7.94 (d, J= 7.5 Hz, 1H), 7.55 (d, J= 8.1 Hz, 2H), 7.50 (d, J= 8.3 Hz, 4H), 7.43 (d, J= 7.1 Hz, 1H), 7.38 (t, J= 7.2 0Hz, 2H), 6.82 (d, = 7.5 Hz, 1H), 6.68 (d, IZ = 6.0 Hz, 1H), 4.35 (d, J= 16.3 Hz, 2H), 4.11 (d, J = 43.2 Hz, 1H), 3.61 (s, 3H), 3.16 (d, = 12.3 Hz, 2H), 2.13 (d, J= 16.9 Hz, 2H), 2.01 (s, 1H), 1.64 (d, J= 15.3 Hz, 2H). / / z

[0326] The following compounds were prepared in a similar manner.4-((l-(4-(6-methyl-5-oxo-3-phenyl-5,6- dihydropyrido [3,4-b]pyrazin-2- yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile 1H NMR (400 MHz DMSO-d6) 5 8.33 - 8.12 (m, 2H), 7.93 (d, J= 7.6Hz, 1H), 7.58 Example 31 (d, J= 8.2 Hz, 2H), 7.52 - 7.44 (m, 4H),7.42 - 7.35 (m, 3H), 6.79 (d, J = 7.5 Hz, 1H), 6.69 (d, J= 5.6 Hz, 1H), 4.35 (d, J = 15.6 Hz, 2H), 4.10 (d, J = 46.1 Hz, 1H), 3.62 (s, 3H), 3.16 (dd, J= 18.7, 7.4 Hz, 2H), 2.13 (d, J= 12.3 Hz, 2H), 2.01 (s, 1H), 1.65 (dd, J = 24.5, 13.0 Hz, 2H).LC / MS ESI (m / z): 529 [M+H]+.4-((l-(4-(3-methyl-4-oxo-7-phenyl-3,4- dihydropteridin-6-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile ’H NMR (400 MHz, DMSO-d6) 5 8.70 (s, Example 32 f II 1 H 1H), 8.23 - 8.01 (m, 2H), 7.50 - 7.28 (m,9H), 6.71 (m, 1H), 3.78 (s, 1H), 3.58 (s, 3H), 3.50 (s, 2H), 2.76 (d, J = 11.6 Hz, 2H), 2.13 - 2.06 (m, 2H), 1.85 (d, J = 10.9 Hz, 2H), 1.51 - 1.41 (m, 2H).LC / MS ESI (m / z): 530 [M+H]+.NAI-5008634746vl -126-Attomey Docket No. 14709-051-2284-((l-(4-(3-methyl-4-oxo-6-phenyl-3,4- dihydropteridin-7-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile 1HNMR (400 MHz DMSO) 58.72 (s, 1H), 8.18 (dd, J = 26.1, 6.3 Hz, 2H), 7.60 - 7.36 Example 33 (m, 9H), 6.91 - 6.63 (m, 1H), 4.35 (dd, J =\ 15.1, 4.4 Hz, 2H), 4.10 (d, J = 45.3 Hz, 1H),3.59 (s, 3H), 3.41 - 3.30 (m, 2H), 3.24 - 3.11 (m, 2H), 2.15 - 1.99 (m, 2H), 1.82 - z z 1.51 (m, 2H).LC / MS ESI (m / z): 530 [M+H]+.4-(( 1 -(4-(2-(2-aminopyridin-3 -yl)-6- methyl-5-oxo-5,6-dihydro-l,6- naphthyridin-3-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile 'H NMR (400 MHz DMSO) 58.45 (s, 1H), O IZ J 8.05 (dd, J = 20.2, 6.4 Hz, 2H), 7.90 (dd, J. Af v = 4.9, 1.8 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), Example 34 T JI 1 H^> z NZT 7.26 - 7.20 (m, 4H), 7.05 (dd, J = 7.4, 1.7 \=zNjO Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H), 6.66 (d, J H2N N / / z = 5.9 Hz, 1H), 6.39 (dd, J = 7.4, 4.9 Hz, 1H), d5.93 (s, 2H), 3.78 (s, 1H), 3.57 (s, 3H), 3.46 (s, 2H), 2.75 (d, J = 11.1 Hz, 2H), 2.07 (d, J = 9.5 Hz, 2H), 1.84 (s, 2H), 1.45 (d, J = 9.1 Hz, 2H).z z LC / MS ESI (m / z): 544 [M+H]+.4-((l-(4-(7-(difluoromethyl)-8-oxo-3- ^ $ o - phenyl-7, 8-dihydropyrido [2,3 -d]pyridazin- zz- / 2-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile 1 F J oI N A JJAAN xA if. A ’H NMR (400 MHz DMSO-d6) 5 9.69 (s, NExample 36 i H N 1H), 8.71 (s, 1H), 8.40 - 7.88 (m, 3H), 7.45- 7.35 (m, 5H), 7.35 - 7.30 (m, 2H), 7.28 u (d, J = 8.1 Hz, 2H), 6.99 - 6.60 (m, 1H),3.89 - 3.67 (m, 1H), 3.49 (s, 2H), 2.80 - 2.66 (m, 2H), 2.21 - 1.97 (m, 2H), 1.94 - 1.76 (m, 2H), 1.63 - 1.37 (m, 2H).LC / MS ESI (m / z): 565 [M+H]+.4-((l-(4-(7-methyl-8-oxo-3-phenyl-7,8- dihydropyrazino [2,3 -d]pyridazin-2- yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile ’H NMR (400 MHz, DMSO-d6) 5 8.67 (s, Example 48 1H), 8.25 - 8.11 (m, 2H), 7.69 - 7.24 (m,9H), 6.73 (dd, J= 37.6, 6.3 Hz, 1H), 4.40 - 4.33 (m, 2H), 4.23 - 3.97 (m, 1H), 3.83 (s, 3H), 3.33 - 3.26 (m, 2H), 3.20 - 3.13 (m, 2H), 2.22 - 1.95 (m, 2H), 1.71 - 1.59 (m, 2H).LC / MS ESI (m / z): 530 [M+H]+.4-((l-(4-(6-methyl-5-oxo-3-phenyl-5,6- Example 49 dihydropyrazino [2,3 -d]pyridazin-2- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileNAI-5008634746vl -127-Attomey Docket No. 14709-051-228'H NMR (400 MHz, DMSO-d6) 5 8.62 (s, 1H), 8.26 (br, 2H), 7.61 (d, J= 8.1 Hz, 2H), 7.57 - 7.37 (m, 7H), 7.30 (d, J = 7.5 Hz, 1H), 4.37 (d, J= 4.0 Hz, 2H), 3.83 (s, 3H), 3.70 - 3.59 (m, 1H), 3.29 - 3.15 (m, 2H), 3.08 - 2.96 (m, 2H), 2.21 - 1.90 (m, 2H), \ 1.68 - 1.54 (m, 2H).zz- LC / MS ESI (m / z): 530 [M+H]+.^$o= _4-((l-(4-(6-methyl-5-oxo-2-phenyl-5,6- z z\ / \^ dihydro- 1,6-naphthyridin-3 - yl)benzyl)piperidin-4- 0 r^N yl)amino)pyrimidine-2-carbonitrile’H NMR (400 MHz, DMSO-d6) 5 8.47 (s, Example 50 f II 1 H 1H), 8.18 (dd, J= 24.9, 6.6 Hz, 2H), 7.84(d, J = 7.6 Hz, 1H), 7.48 - 7.29 (m, 9H),NAQ 6.81 - 6.66 (m, 2H), 4.35 - 4.28 (m, 2H),0IZ 4.11 - 4.04 (m, 1H), 3.57 (s, 3H), 3.46 - 3.36 (m, 2H), 3.22 - 3.07 (m, 2H), 2.15 - A z 2.00 (m, 2H), 1.90- 1.43 (m, 2H).LC / MS ESI (m / z): 528.3 [M+H]+.Z 4-(( 1 -(4-(5 -oxo-2 -phenyl-5,6-dihydro- 1,6- naphthyridin-3-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile ° AIN’H NMR (400 MHz, DMSO-d6) 5 11.62 (d,J= 5.7 Hz, 1H), 8.43 (s, 1H), 8.18 (dd, J = Example 51 27.4, 6.5 Hz, 2H), 7.54 - 7.50 (m, 1H), 7.47- 7.43 (m, 2H), 7.38 - 7.29 (m, 7H), 6.81 -N^ u 6.66 (m, 2H), 4.34 - 4.29 (m, 2H), 4.13 - 4.08 (m, 1H), 3.43 - 3.34 (m, 2H), 3.20 - 3.08 (m, 2H), 2.16- 1.60 (m, 4H).LC / MS ESI (m / z): 514.3 [M+H]+.4-((l-(4-(6-methyl-5-oxo-2-(pyridin-3-yl)- 5,6-dihydro- 1,6-naphthyridin-3 - yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile ’H NMR (400 MHz, Methanol-J4) 58.83 - 8.64 (m, 3H), 8.31 (d, J= 8.0Hz, 1H), 8.13 Example 52 f II 1 A HAA N - 8.00 (m, 1H), 7.79 - 7.71 (m, 2H), 7.58 - 7.54 (m, 2H), 7.49 - 7.44 (m, 2H), 6.92 (d, N J= 7.6 Hz, 1H), 6.66 (s, 1H), 4.38 (s, 2H),4.23 (s, 1H), 3.68 (s, 3H), 3.64 - 3.51 (m, 2H), 3.29 - 3.12 (m, 2H), 2.31 (d, J= 13.6 Hz, 2H), 1.95 - 1.65 (m, 2H).LC / MS ESI (m / z): 529.3 [M+H]+.Example 53 and 54: 4-((l-(4-(3-(2-aminopyridin-3-yl)-7-methyl-8-oxo-7,8-dihydropyrazino[2,3-d]pyridazin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile and 4-((l-(4-(3-(2-aminopyridin-3-yl)-6-methyl-5-oxo-5,6-dihydropyrazino [2,3-d]pyridazin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileNAI-5008634746vl -128-Attomey Docket No. 14709-051-228

[0327] Step 1: A solution of 4-(3-(2-aminopyridin-3-yl)-8-oxo-7,8-dihydropyrazino[2,3-d]pyridazin-2-yl)benzaldehyde and 4-(3-(2-aminopyridin-3-yl)-5-oxo-5,6-dihydropyrazino[2,3-d]pyridazin-2-yl)benzaldehyde (50 mg, 0.15 mmol), K2CO3 (20 mg, 0.15 mmol) and Me2SC>4 (10 mg, 0.08 mmol) in DMF (1 mL) was stirred at RT for 3 h. Upon completion of the reaction based on LC-MS analysis, the reaction was quenched with NH3. H2O (0.2 mL) and the solution was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography to yield 57 mg of a mixture of 4-(3-(2-aminopyridin-3-yl)-7-methyl-8-oxo-7,8-dihydropyrazino[2,3-d]pyridazin-2-yl)benzaldehyde and 4-(3-(2-aminopyridin-3-yl)-6-methyl-5-oxo-5, 6-dihydropyrazino[2,3-d]pyridazin-2-yl)benzaldehyde. LC-MS (ESI+): m / z 359.2 [M+H]+.

[0328] Step 2: 2-(2-aminopyridin-3-yl)-3-(4-(hydroxymethyl)phenyl)-6-methylpyrazino[2,3-d]pyridazin-5(6H)-one and 3-(2-aminopyridin-3-yl)-2-(4-(hydroxymethyl)phenyl)-6-methylpyrazino[2,3-d]pyridazin-5(6H)-one was prepared from 4-(3-(2-aminopyridin-3-yl)-7-methyl-8-oxo-7,8-dihydropyrazino[2,3-d]pyridazin-2-yl)benzaldehyde and 4-(3-(2-aminopyridin-3-yl)-6-methyl-5-oxo-5,6-dihydropyrazino[2,3-d]pyridazin-2-yl)benzaldehyde according to the procedure reported in Example 3, step 2. LC-MS (ESI+): m / z 361.1 [M+H]+.

[0329] Step 3: 2-(2-aminopyridin-3-yl)-3-(4-(chloromethyl)phenyl)-6-methylpyrazino[2,3-d]pyridazin-5(6H)-one and 3-(2-aminopyridin-3-yl)-2-(4-NAI-5008634746vl -129-Attomey Docket No. 14709-051-228(chloromethyl)phenyl)-6-methylpyrazino[2,3-d]pyridazin-5(6H)-one was prepared from 2-(2-aminopyridin-3-yl)-3-(4-(hydroxymethyl)phenyl)-6-methylpyrazino[2,3-d]pyridazin-5(6H)-one and 3-(2-aminopyridin-3-yl)-2-(4-(hydroxymethyl)phenyl)-6-methylpyrazino[2,3-d]pyridazin-5(6H)-one according to the procedure reported in Example 3, step 3. LC-MS (ESI+): m / z 379.2, 381.2 [M+H]+.

[0330] Step 4: A solution of 2-(2-aminopyri din-3 -yl)-3-(4-(chl orom ethyl)phenyl)-6-methylpyrazino[2,3-d]pyridazin-5(6H)-one and 3-(2-aminopyridin-3-yl)-2-(4-(chloromethyl)phenyl)-6-methylpyrazino[2,3-d]pyridazin-5(6H)-one (8 mg, 0.021 mmol), 4-(piperidin-4-ylamino)pyrimidine-2-carbonitrile (8 mg, 0.041 mmol) and saturated NaHCO3aqueous solution (1.5 mL) in DMAC (2 mL) was stirred at 60 °C for 1 h. Upon completion of the reaction based on LC-MS analysis, the reaction mixture was diluted with water (3 mL) and extracted with DCM / MeOH = 10 / 1 (10 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography and further separated by preparative HPLC to yield 3 mg of 4-((l-(4-(3-(2-aminopyridin-3-yl)-7-methyl-8-oxo-7,8-dihydropyrazino[2,3-d]pyridazin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile and 3 mg of 4-((l-(4-(3-(2-aminopyridin-3-yl)-6-methyl-5-oxo-5,6-dihydropyrazino[2,3-d]pyridazin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile. The structures of both compounds were arbitrarily assigned.

[0331] 4-((l-(4-(3-(2-aminopyridin-3-yl)-7-methyl-8-oxo-7,8-dihydropyrazino[2,3-d]pyridazin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile (53): LC-MS (ESI+): m / z 546.6 [M+H]+; 'H-NMR (400 MHz, CD3OD) 88.55 (s, 1H), 7.99 (d, J= 2.0 Hz, 2H), 7.61 (d, J= 8.0 Hz, 2H), 7.36-7.35 (m, 3H), 6.59-6.56 (m, 2H), 3.96-3.93 (m, 4H), 3.57 (s, 2H), 2.90-2.86 (m, 2H), 2.23-2.16 (m, 2H), 2.03-1.95 (m, 2H), 1.58-1.55 (m, 2H).

[0332] 4-((l-(4-(3-(2-aminopyridin-3-yl)-6-methyl-5-oxo-5,6-dihydropyrazino[2,3-d]pyridazin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile (54): LC-MS (ESI+): m / z 546.6 [M+H]+; 'H-NMR (400 MHz, CD3OD) 68.56 (s, 1H), 7.99-7.97 (m, 2H), 7.58-7.56 (m, 2H), 7.40-7.36 (m, 3H), 6.62-6.55 (m, 2H), 3.94-3.90 (m, 4H), 3.59 (s, 2H), 2.93-2.87 (m, 2H), 2.24-2.16 (m, 2H), 2.10-1.96 (m, 2H), 1.63-1.56 (m, 2H).NAI-5008634746vl -130-Attomey Docket No. 14709-051-228Example 55: 4-((l-(4-(6-methyl-7-oxo-3-phenyl-6,7-dihydro-l,6-naphthyridin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile

[0333] Step 1: A solution of 4-(6-amino-3-bromo-5-formylpyridin-2-yl)benzyl acetate (0.8 g, 3.3 mmol), phenylboronic acid (0.8 g, 6.6 mmol), Pd(PPh3)4 (0.35 g, 0.33 mmol) and K2CO3 (0.91 g, 6.6 mmol) in dioxane (30 mL) and H2O (5 mL) was stirred under N2 atmosphere at 100 °C for 2 h. Upon completion of the reaction based on LC-MS analysis, the reaction mixture was cooled to RT, quenched with water (100 mL) and filtered through a pad of Celite. The filtrate was extracted with EtOAc (30 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography to yield 0.78 g of 4-(6-amino-5-formyl-3-phenylpyridin-2-yl)benzyl acetate as yellow solid. LC-MS (ESI+): m / z 347.2 [M+H]+.

[0334] Step 2: To a solution of ethyl 2-(diethoxyphosphoryl)acetate (0.64 g, 2.86 mmol) in THF (15 mL) at 0 °C was added NaH (0.11 g, 4.4 mmol, 60% in mineral oil). After the reaction was stirred at 0 °C for 4 h, a solution of 4-(6-amino-5-formyl-3-phenylpyridin-2-yl)benzyl acetate (0.76 g, 2.2 mmol) in THF (2 mL)was added. The reaction mixture was stirred at 0 °C for 1 h. Upon completion of the reaction based on LC-MS analysis, the reaction was quenched with saturated NH₄Cl aqueous solution and extracted with EtOAc (30 mL x 3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography to yield 0.4 g of ethyl (E)-3-(2-amino-6-(4-(hydroxymethyl)phenyl)-5-phenylpyri din-3 -yl)acrylate as green oil. LC-MS (ESI+): m / z 375.2 [M+H]+.

[0335] Step 3: To a solution of (E)-3-(2-amino-6-(4-(hydroxymethyl)phenyl)-5-phenylpyri din-3 -yl)acrylate (0.38 g, 1.0 mmol) in EtOH (50 mL) at 0 °C was added EtONa (1 mL, 2.0 mmol). The reaction mixture was stirred at 0 °C for 2.5 h. Upon completion of the reaction based on LC-MS analysis, the reaction mixture was concentrated under reducedNAI-5008634746vl -131-Attomey Docket No. 14709-051-228pressure, diluted with water (10 mL) and extracted with EtOAc (30 mL x 3). The combined organic layer was washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography to yield 60 mg of 7-(4-(hydroxymethyl)phenyl)-6-phenyl-l,8-naphthyridin-2(lH)-one as yellow solid. LC-MS (ESI+): m / z 329.2 [M+H]+.

[0336] Step 4: A solution of 7-(4-(hydroxymethyl)phenyl)-6-phenyl-l,8-naphthyridin-2(lH)-one (30 mg, 0.091 mmol), K2CO3 (21.5 mg, 0.18 mmol) and Mel (20.5 mg, 0.18 mmol) in DMF (1 mL) was stirred at RT for 3 h. Upon completion of the reaction based on LC-MS analysis, the reaction was quenched with water (10 mL) and extracted with EtOAc (5 mL x 3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield 30 mg of 7-(4-(hydroxymethyl)phenyl)-l-methyl-6-phenyl-l,8-naphthyridin-2(lH)-one as white solid. LC-MS (ESI+): m / z 343.2 [M+H]+.

[0337] Step 5: 7-(4-(chloromethyl)phenyl)-l-methyl-6-phenyl-l,8-naphthyridin-2(lH)-one was prepared from 7-(4-(hydroxymethyl)phenyl)-l-methyl-6-phenyl-l,8-naphthyridin-2(lH)-one according to the procedure reported in Example 3, step 3. LC-MS (ESI+): m / z 361.2, 363.2 [M+H]+.

[0338] Step 6: 4-((l-(4-(8-methyl-7-oxo-3-phenyl-7,8-dihydro-l,8-naphthyridin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile was prepared from 7-(4-(chloromethyl)phenyl)-l-methyl-6-phenyl-l,8-naphthyridin-2(lH)-one and 4-(piperidin-4-ylamino)pyrimidine-2-carbonitrile according to the procedure reported in Examples 53 and 54, step 4. LC-MS (ESI+): m / z 528.8 [M+H]+; 'H-NMR (400 MHz, CD3OD) 58.10 (s, 1H), 8.01 (d, J= 6.0 Hz, 2H), 7.42 (d, J= 8.4 Hz, 2H), 7.33-7.21 (m, 7H), 6.76 (d, J= 9.6 Hz, 1H), 6.62-6.57 (m, 1H), 4.00-3.90 (m, 1H), 3.89 (s, 3H), 3.57 (s, 2H), 2.97-2.87 (m, 2H), 2.28-2.19 (m, 2H), 2.02-1.95 (m, 2H), 1.63-1.53 (m, 2H).Example 56 and 57: 4-((l-(4-(5-methyl-6-oxo-2-phenyl-5,6-dihydropyrido[2,3-b]pyrazin-3-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile and 4-((l-(4-(5-methyl-6-oxo-3-phenyl-5,6-dihydropyrido[2,3-b]pyrazin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileNAI-5008634746vl -132-Attomey Docket No. 14709-051-228

[0339] Step 1: 3-(4-bromophenyl)-2-phenylpyrido[2,3-b]pyrazin-6(5H)-one and 2-(4-bromophenyl)-3-phenylpyrido[2,3-b]pyrazin-6(5H)-one was prepared from 3-(4-bromophenyl)-6-methoxy-2-phenylpyrido[2,3-b]pyrazine and 2-(4-bromophenyl)-6-methoxy-3-phenylpyrido[2,3-b]pyrazine according to the procedure reported in Example 3, step 1. LC-MS (ESI+): m / z 378.1, 380.1 [M+H]+.

[0340] Step 2: 3-(4-bromophenyl)-5-methyl-2-phenylpyrido[2,3-b]pyrazin-6(5H)-one and 2-(4-bromophenyl)-5-methyl-3-phenylpyrido[2,3-b]pyrazin-6(5H)-one was prepared from 3-(4-bromophenyl)-2-phenylpyrido[2,3-b]pyrazin-6(5H)-one and 2-(4-bromophenyl)-3-phenylpyrido[2,3-b]pyrazin-6(5H)-one according to the procedure reported in Example 55, step 4. LC-MS (ESI+): m / z 392.1, 394.1 [M+H]+.

[0341] Step 3: A solution of 3-(4-bromophenyl)-2-phenylpyrido[2,3-b]pyrazin-6(5H)-one and 2-(4-bromophenyl)-3-phenylpyrido[2,3-b]pyrazin-6(5H)-one (1.5 g, 3.82 mmol), potassium vinyltrifluoroborate (768 mg, 5.74 mol), XPhos Pd G2 (150 mg, 0.19 mol) and CS2CO3 (2.5 g, 7.65 mol) in dioxane (40 mL) and H2O (10 mL) was stirred under N2 atmosphere at 100 °C for 1.5 h. Upon completion of the reaction based on LC-MS analysis, the reaction mixture was cooled to RT, quenched with water (120 mL) and extracted with EtOAc (30 mL x 3). The combined organic phase was dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography to yield 5.2 g of 5-methyl-2-phenyl-3-(4-vinylphenyl)pyrido[2,3-b]pyrazin-6(5H)-one and 5-methyl-3-phenyl-2-(4-vinylphenyl)pyrido[2,3-b]pyrazin-6(5H)-one. LC-MS (ESI+): m / z 340.1 [M+H]+.NAI-5008634746vl -133-Attomey Docket No. 14709-051-228

[0342] Step 4: To a solution of 5-methyl-2-phenyl-3-(4-vinylphenyl)pyrido[2,3-b]pyrazin-6(5H)-one and 5-methyl-3-phenyl-2-(4-vinylphenyl)pyrido[2,3-b]pyrazin-6(5H)-one (1.2 g, 3.54 mmol) in THF (36 mL) and water (12 mL) was added K2OSO4 (65 mg, 0.18 mmol) and NaIC>4 (2.3 g, 10.61 mmol). After the reaction was stirred at RT for 1 h, the reaction mixture was diluted with water (50 mL) and filtered. The filtration was extracted with EtOAc (20 mL x 3). The combined organic phase was dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography to yield 920 mg of 4-(5-methyl-6-oxo-2-phenyl-5,6-dihydropyrido[2,3-b]pyrazin-3-yl)benzaldehyde and 4-(5-methyl-6-oxo-3-phenyl-5,6-dihydropyrido[2,3-b]pyrazin-2-yl)benzaldehyde. LC-MS (ESI+): m / z 342.1 [M+H]+.

[0343] Step 5: 4-((l-(4-(5-methyl-6-oxo-2-phenyl-5,6-dihydropyrido[2,3-b]pyrazin-3-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile and 4-((l-(4-(5-methyl-6-oxo-3-phenyl-5,6-dihydropyrido[2,3-b]pyrazin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile were prepared from 4-(5-methyl-6-oxo-2-phenyl-5,6-dihydropyrido[2,3-b]pyrazin-3-yl)benzaldehyde and 4-(5-methyl-6-oxo-3-phenyl-5,6-dihydropyrido[2,3-b]pyrazin-2-yl)benzaldehyde and 4-(piperidin-4-ylamino)pyrimidine-2-carbonitrile according to the procedure reported in Example 30, step 3, which were separated by preparative TLC. The structures of both compounds were arbitrarily assigned.

[0344] 4-((l-(4-(5-methyl-6-oxo-2-phenyl-5,6-dihydropyrido[2,3-b]pyrazin-3-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile (56): LC-MS (ESI+): m / z 529.6 [M+H]+; 'H-NMR (400 MHz, CD3OD) 8.09 (d, J= 9.6 Hz, 1H), 8.05-7.95 (m, 1H), 7.54-7.52 (m, 2H), 7.46-7.44 (m, 2H), 7.38-7.31 (m, 5H), 7.03 (d, J= 9.6 Hz, 1H), 6.65-6.55 (m, 1H), 4.03-3.91 (m, 1H), 3.99 (s, 3H), 3.64 (s, 2H), 3.00-2.90 (m, 2H), 2.37-2.23 (m, 2H), 2.07-1.98 (m, 2H), 1.70-1.51 (m, 2H).

[0345] 4-((l-(4-(5-methyl-6-oxo-3-phenyl-5,6-dihydropyrido[2,3-b]pyrazin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile (57): LC-MS (ESI+): m / z 529.1 [M+H]+; 'H-NMR (400 MHz, CD3OD) 9.21 (s, 1H), 8.03-8.01 (m, 1H), 7.53-7.45 (m, 6H), 7.36-7.33 (m, 4H), 6.60-6.58 (m, 1H), 4.11 (s, 3H), 4.00-3.90 (s, 1H), 3.60 (s, 2H), 2.92-2.89 (m, 2H), 2.22-2.20 (m, 2H), 2.03-1.98 (m, 2H), 1.60-1.58 (m, 2H).

[0346] The following compounds were prepared in a similar manner.NAI-5008634746vl -134-Atorney Docket No. 14709-051-2284-((l-(4-(6-methyl-7-oxo-3-phenyl-6,7- dihydropyrido [3,4-b]pyrazin-2- yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile 1H-NMR (400 MHz, CD3OD) 8 9.22 (s, Example 58 1H), 8.02-8.00 (m, 1H), 7.52-7.43 (m, 4H),7.42-7.32 (m, 6H), 6.60-6.58 (m, 1H), 4.11 (s, 3H), 4.00-3.90 (m, 1H), 3.60 (s, 2H), 2.97-2.94 (m, 2H), 2.34-2.28 (m, 2H), 2.03- z z 2.00 (m, 2H), 1.64-1.59 (m, 2H).LC-MS (ESI+): m / z 529.14-((l-(4-(6-methyl-7-oxo-2-phenyl-6,7- dihydropyrido [3,4-b]pyrazin-3 - yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile ’H-NMR (400 MHz, CD3OD) 89.21 (s, Example 59 1H), 8.03-8.01 (m, 1H), 7.53-7.45 (m, 6H),7.36-7.33 (m, 4H), 6.60-6.58 (m, 1H), 4.11 (s, 3H), 4.00-3.90 (s, 1H), 3.60 (s, 2H), 2.92-2.89 (m, 2H), 2.22-2.20 (m, 2H), 2.03- / / >Z 1.98 (m, 2H), 1.60-1.58 (m, 2H).LC-MS (ESI+): m / z 529.14-(( 1 -(4-(5 -oxo-3 -phenyl-5,6- dihydropyrazino [2,3 -d]pyridazin-2- yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile ’H-NMR (400 MHz, CD3OD) 88.54 (s, Example 60 AH N1H), 8.01-8.00 (m, 1H), 7.59-7.53 (m, 4H),7.38-7.34 (m, 5H), 6.66-6.59 (m, 1H), 3.99-03.90 (m, 1H), 3.60 (s, 2H), 2.93-2.82 (m,2H), 2.30-2.23 (m, 2H), 2.09-2.00 (m, 2H), 1.65-1.58 (m, 2H).LC-MS (ESI+): m / z 516.7 [M+H]+4-((l-(4-(8-oxo-3-phenyl-7,8- dihydropyrazino [2,3 -d]pyridazin-2- yl)benzyl)piperidin-4- o r^Nyl)amino)pyrimidine-2-carbonitrile’H-NMR (400 MHz, CD3OD) 88.54 (s, Example 61 MLh N1H), 8.03-7.96 (m, 1H), 7.58-7.54 (m, 4H),7.46-7.42 (m, 1H), 7.38-7.34 (m, 4H), 6.66-Nu 6.59 (m, 1H), 3.99-3.93 (m, 1H), 3.60 (s,2H), 2.92-2.85 (m, 2H), 2.29-2.21 (m, 2H), 2.01-1.90 (m, 2H), 1.60-1.50 (m, 2H).LC-MS (ESI+): m / z 516.7 [M+H]+Example 62 and 63: (R)-4-((l-(l-(4-(7-methyl-8-oxo-3-phenyl-7,8-dihydropyrido[2,3-d]pyridazin-2-yl)phenyl)ethyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile and (S)-4- ((l-(l-(4-(7-methyl-8-oxo-3-phenyl-7,8-dihydropyrido[2,3-d]pyridazin-2-yl)phenyl)ethyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrileNAI-5008634746vl -135-Attorney Docket No. 14709-051-228

[0347] Step 1: A solution of l-(4-(l,3-dioxolan-2-yl)phenyl)-2-phenylethan-l-one (11.9 g, 44.4 mmol), 5-amino-6-methoxypyridazine-4-carbaldehyde (0.5 g, 4.1 mmol) and aq. NaOH (37 mL, 222 mmol, 6 N) in MeOH (200 mL) was stirred at 65 °C for 12 h. Upon completion of the reaction based on LC-MS analysis, the reaction mixture was cooled to RT, quenched with water (600 mL) and extracted with EtOAc (200 mL x 4). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography to yield 10 g of a mixture of 2-(4-(l,3-dioxolan-2-yl)phenyl)-8-methoxy-3-phenylpyrido[2,3-d]pyridazine and 2-(4-(l,3-dioxolan-2-yl)phenyl)-3-phenylpyrido[2,3-d]pyridazin-8(7H)-one. LC-MS (ESI+): m / z 386.1; 372.1 [M+H]+.

[0348] Step 2: A solution of a mixture of 2-(4-(l,3-dioxolan-2-yl)phenyl)-8-methoxy-3-phenylpyrido[2,3-d]pyridazine and 2-(4-(l,3-dioxolan-2-yl)phenyl)-3-phenylpyrido[2,3-d]pyridazin-8(7H)-one (9.9 g), and 2 M aqueous HC1 solution (35 mL) in THF (100 mL) was stirred at 60 °C for 2 h. Upon completion of the reaction based on TLC analysis, the reaction mixture was neutralized with NaHCOs aqueous solution and extracted with DCM (100 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield 10 g of 4-(8-oxo-3-phenyl-7,8-dihydropyrido[2,3-d]pyridazin-2-yl)benzaldehyde, which was directly used for the next step without further purification. LC-MS (ESI+): m / z 328.2 [M+H]+.NAI-5008634746vl -136-Attomey Docket No. 14709-051-228

[0349] Step 3: 4-(7-methyl-8-oxo-3-phenyl-7,8-dihydropyrido[2,3-d]pyridazin-2-yl)benzaldehyde was prepared from 4-(7-methyl-8-oxo-3-phenyl-7,8-dihydropyrido[2,3-d]pyridazin-2-yl)benzaldehyde according to the procedure reported in Example 55, step 4. LC-MS (ESI+): m / z 342.2 [M+H]+.

[0350] Step 4: To a solution of 4-(7-methyl-8-oxo-3-phenyl-7,8-dihydropyrido[2,3-d]pyridazin-2-yl)benzaldehyde (1 g, 2.93 mmol) in THF (15 mL) under N2 atmosphere at 0 °C was added MeMgBr (5 mL, 15 mmol, 3 M in THF) in dropwise. After stirred at 0 °C for 2h, the reaction mixture was quenched with saturated NH₄Cl solution (8 mL), extracted with EtOAc (30 mL x 3) and washed with brine (10 mL). The combined organic phase was dried over anhydrous Na2SC>4, and concentrated. The residue was purified by silica column chromatography to yield 520 mg of 2-(4-(l-hydroxyethyl)phenyl)-7-methyl-3-phenylpyrido[2,3-d]pyridazin-8(7H)-one. LC-MS (ESI+): m / z 358.1 [M+H]+

[0351] Step 5: 2-(4-(l-hydroxyethyl)phenyl)-7-methyl-3-phenylpyrido[2,3-d]pyridazin-8(7H)-one was prepared from 2-(4-(l -hydroxy ethyl)phenyl)-7-methyl-3-phenylpyrido[2, 3-d]pyridazin-8(7H)-one according to the procedure reported in Example 3, step 3. LC-MS (ESI+): m / z 376.1, 378.1 [M+H]+.

[0352] Step 6: 4-((l-(l-(4-(7-methyl-8-oxo-3-phenyl-7,8-dihydropyrido[2,3-d]pyridazin-2-yl)phenyl)ethyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile was prepared from 2-(4-(l-chloroethyl)phenyl)-7-methyl-3-phenylpyrido[2,3-d]pyridazin-8(7H)-one and 4-(piperidin-4-ylamino)pyrimidine-2-carbonitrile according to the procedure reported in Examples 53 and 54, step 4. LC-MS (ESI+): m / z 543.8 [M+H]+.

[0353] Step 7: The racemate 4-((l-(l-(4-(7-methyl-8-oxo-3-phenyl-7,8-dihydropyrido[2,3-d]pyridazin-2-yl)phenyl)ethyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile was separated by SFC. The early eluting peak was arbitrarily assigned as (R)-4-((l-(l-(4-(7-methyl-8-oxo-3-phenyl-7,8-dihydropyrido[2,3-d]pyridazin-2-yl)phenyl)ethyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile and the later eluting peak was arbitrarily assigned as (S)-4-((l-(l-(4-(7-methyl-8-oxo-3-phenyl-7,8-dihydropyrido[2,3-d]pyridazin-2-yl)phenyl)ethyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile. The stereoconfigurations were arbitrarily assigned.

[0354] (R)-4-((l-(l-(4-(7-methyl-8-oxo-3-phenyl-7,8-dihydropyrido[2,3-d]pyridazin-2-yl)phenyl)ethyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile (62): LC-MS (ESI+): m / z 543.8 [M+H]+; 'H-NMR (400 MHz, CD3OD) 8.45 (s, 1H), 8.35 (s, 1H), 8.02-7.95 (m, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.40-7.31 (m, 3H), 7.29-7.25 (m, 4H), 6.65-6.60 (m, 1H), 3.92 (s, 3H), 3.90-3.82NAI-5008634746vl -137-Attomey Docket No. 14709-051-228(m, 1H), 3.60-3.50 (m, 1H), 3.15-3.04 (m, 1H), 2.85-2.78 (m, 1H), 2.20-1.85 (m, 4H), 1.65-1.56 (m, 1H), 1.55-1.44 (m,1H), 1.47 (d, J= 6.0 Hz, 3H).

[0355] (S)-4-((l-(l-(4-(7-methyl-8-oxo-3-phenyl-7,8-dihydropyrido[2,3-d]pyridazin-2-yl)phenyl)ethyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile (63). LC-MS (ESI+): m / z 543.8 [M+H]+; ’H-NMR (400 MHz, CD3OD) 8.45 (s, 1H), 8.34 (s, 1H), 8.01-7.95 (m, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.40-7.30 (m, 3H), 7.29-7.25 (m, 4H), 6.65-6.60 (m, 1H), 3.92 (s, 3H), 3.90-3.82 (m, 1H), 3.60-3.50 (m, 1H), 3.15-3.04 (m, 1H), 2.85-2.78 (m, 1H), 2.20-1.85 (m, 4H), 1.65-1.56 (m, 1H), 1.55-1.44 (m,1H), 1.47 (d, J= 6.0 Hz, 3H).Example 64: 4-((l-(4-(6-methyl-7-oxo-3-phenyl-6,7-dihydro-l,6-naphthyridin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile

[0356] Step 1: A solution of 2-(4-(l,3-dioxolan-2-yl)phenyl)-7-chloro-3-phenyl-l,6-naphthyridine (100 mg, 0.26 mmol), KOH (22 mg, 0.39 mmol) and t-BuPhos Pd G3 (41 mg, 0.05 mmol) in dioxane (5 mL) and H2O (1 mL) was stirred under N2 atmosphere at 90 °C for 1.5 h. Upon completion of the reaction based on LC-MS analysis, the reaction mixture was cooled to RT, quenched with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield 95 mg of 2-(4-(l,3-dioxolan-2-yl)phenyl)-3-phenyl-l,6-naphthyridin-7(6H)-one as crude product. LC-MS (ESI+): m / z 371.2 [M+H]+.

[0357] Step 2: 2-(4-(l,3-dioxolan-2-yl)phenyl)-6-methyl-3-phenyl-l,6-naphthyridin-7(6H)-one was prepared from 2-(4-(l,3-dioxolan-2-yl)phenyl)-3-phenyl-l,6-naphthyridin-7(6H)-one according to the procedure reported in Example 55, step 4. LC-MS (ESI+): m / z 385.2 [M+H]+.

[0358] Step 3: 4-(6-methyl-7-oxo-3-phenyl-6,7-dihydro-l,6-naphthyridin-2-yl)benzaldehyde was prepared from 2-(4-(l,3-dioxolan-2-yl)phenyl)-6-methyl-3-phenyl-l,6-NAI-5008634746vl -138-Attorney Docket No. 14709-051-228naphthyridin-7(6H)-one according to the procedure reported in Examples 62 and 63, step 2, which was directly used for the next step without further purification. LC-MS (ESI+): m / z 341.1 [M+H]+.

[0359] Step 4: 4-((l-(4-(6-methyl-7-oxo-3-phenyl-6,7-dihydro-l,6-naphthyridin-2- 0yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile was prepared from 4-(6-methyl-7-oxo- Qz -3-phenyl-6,7-dihydro-l,6-naphthyridin-2-yl)benzaldehyde according to the procedure reported in Example 30, step 3. LC-MS (ESI+): m / z 528.7 [M+H]+; ’H-NMR (400 MHz, CD3OD) 59.13 (s, 1H), 8.46 (s, 1H), 8.05-7.99 (m, 1H), 7.40 (d, J= 8.0 Hz, 2H), 7.33-7.28 (m, 6H), 7.27-7.20 (m, 2H), 6.64-6.55 (m, 1H), 4.08 (s, 3H), 3.99-3.87 (m, 1H), 3.60 (s, 2H), 2.92-2.87 (m, 2H), 2.28-2.19 (m, 2H), 2.01-1.95 (m, 2H), 1.61-1.52 (m, 2H).

[0360] The following compounds were prepared in a similar manner.4-((l-(4-(5-methyl-6-oxo-3-phenyl-5,6- pdihydro- 1,5 -naphthyridin-2- 1' yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile1H-NMR (400 MHz, CD3OD) £8.07 (d, J= Example 65 9.6 Hz, 1H), 8.00 (s, 2H), 7.35-7.26 (m,9H), 6.98 (d, J= 10.0 Hz, 1H), 6.65-6.55 (m, 1H), 4.00-3.89 (m, 1H), 3.80 (s, 3H), 3.62 (s, 2H), 2.95-2.87 (m, 2H), 2.28-2.19 (m, 2H), 2.01-1.94 (m, 2H), 1.62-1.51 (m, 2H).LC-MS (ESI+): m / z 528.7 [M+H]+4-((l-(4-(7-methyl-6-oxo-3-phenyl-6,7- dihydro- 1,7-naphthyridin-2- 1 yl)benzyl)piperidin-4- O^N.yl)amino)pyrimidine-2-carbonitrile ’H-NMR (400 MHz, CD3OD) £ 9.15 (s, Example 66 1H), 8.25 (s, 1H), 8.03-7.95 (m, 1H), 7.40- 7.37 (m, 2H), 7.32-7.24 (m, 8H), 6.67-6.54 (m, 1H), 4.06 (s, 3H), 4.00-3.89 (m, 1H), 3.60 (s, 2H), 2.95-2.87 (m, 2H), 2.29-2.20 0(m, 2H), 2.02-1.96 (m, 2H), 1.63-1.54 (m, 2H).LC-MS (ESI+): m / z 528.7 [M+H]+4-(((3 S,4S)-3 -methyl- 1 -(4-(5 -methyl-6- oxo-3 -phenyl-5,6-dihydro- 1,5- naphthyridin-2-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile ’H-NMR (400 MHz, CD3OD) £8.07 (d, J = Example 9.6 Hz, 1H), 8.03-7.97 (m, 2H), 7.35-7.26(m, 9H), 6.98 (d, J= 10.0 Hz, 1H), 6.59 (d, 100J= 6.0 Hz, 1H), 3.80 (s, 3H), 3.74-3.65 (m, 1H), 3.57 (s, 2H), 2.98-2.85 (m, 2H), 2.17 (t, J = 11.6 Hz, 1H), 2.00-1.92 (m, 1H), 1.90-1.80 (m, 1H), 1.79-1.69 (m, 1H), 1.59- 1.45 (m, 1H), 0.88 (d, J= 6.4 Hz, 3H)LC-MS (ESI+): m / z 542.7 [M+H]+NAI-5008634746vl -139-Attorney Docket No. 14709-051-228Example 67: 4-(((3S,4S)-3-methyl-l-(4-(7-methyl-8-oxo-3-phenyl-7,8-dihydropyrido [2,3-d]pyridazin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile

[0361] Step 1: 2-(4-(hydroxymethyl)phenyl)-7-methyl-3-phenylpyrido[2,3-d]pyridazin-8(7H)-one was prepared from 4-(7-methyl-8-oxo-3-phenyl-7,8-dihydropyrido[2,3-d]pyridazin-2-yl)benzaldehyde according to the procedure reported in Example 3, step 2. LC-MS (ESI+): m / z 344.2 [M+H]+.

[0362] Step 2: 2-(4-(chloromethyl)phenyl)-7-methyl-3-phenylpyrido[2,3-d]pyridazin-8(7H)-one was prepared from 2-(4-(hydroxymethyl)phenyl)-7-methyl-3-phenylpyrido[2,3-d]pyridazin-8(7H)-one according to the procedure reported in Example 3, step 3. LC-MS (ESI+): m / z 362.2, 364.2 [M+H]+.

[0363] Step 3: 4-(((3S,4S)-3-methyl-l-(4-(7-methyl-8-oxo-3-phenyl-7,8-dihydropyrido[2,3-d]pyridazin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile was prepared from 2-(4-(chloromethyl)phenyl)-7-methyl-3-phenylpyrido[2,3-d]pyridazin-8(7H)-one and 4-(((3S,4S)-3-methylpiperidin-4-yl)amino)pyrimidine-2-carbonitrile according to the procedure reported in Examples 53 and 54, step 4. LC-MS (ESI+): m / z 543.8 [M+H]+; 'H-NMR (400 MHz, CD3OD) 8.45 (s, 1H), 8.35 (s, 1H), 7.99 (d, J= 6.4 Hz, 1H), 7.51-7.42 (m, 2H), 7.38-7.25 (m, 7H), 6.59 (d, J= 6.0 Hz, 1H), 3.91 (s, 3H), 3.78-3.62 (m, 1H), 3.60-3.50 (m, 2H), 3.00-2.83 (m, 2H), 2.22-2.12 (m, 1H), 2.00-1.90 (m, 1H), 1.89-1.80 (m, 1H), 1.79-1.69 (m, 1H), 1.58-1.45 (m, 1H), 0.88 (d, J= 6.4 Hz, 3H).

[0364] The following compounds were prepared in a similar manner.4-(((3R,4S)-3-methyl-l-(4-(7-methyl-8- oxo-3 -phenyl-7, 8-dihydropyrido [2,3 - d]pyridazin-2-yl)benzyl)piperidin-4- -2-carbonitrile ’H-NMR (400 MHz, CD3OD) 58.45 (s, Example 68 1H), 8.34 (s, 1H), 8.01 (d, J= 5.6 Hz, 1H),7.50-7.44 (m, 2H), 7.40-7.32 (m, 3H), 7.31- 7.25 (m, 4H), 6.72 (d, J= 6.0 Hz, 1H), 4.25 (s, 1H), 3.91 (s, 3H), 3.60-3.48 (m, 2H), 2.65-2.30 (m, 4H), 2.20-2.10 (m, 1H), 1.90- 1.72 (m, 2H), 0.96 (d, J= 6.4 Hz, 3H).LC-MS (ESI+): m / z 543.8 [M+H]+NAI-5008634746vl -140-Attomey Docket No. 14709-051-2284-(((3R,4R)-3-methyl-l-(4-(7-methyl-8- oxo-3 -phenyl-7, 8-dihydropyrido [2,3 - d]pyridazin-2-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile 9 ’H-NMR (400 MHz, CD3OD) 88.45 (s, x A N JL ji L JL A 1H), 8.35 (s, 1H), 7.99 (d, J= 6.4 Hz, 1H), Example 69 / / N X ''N N N$Jzz- 7.50-7.44 (m, 2H), 7.35-7.25 (m, 7H), 6.59 ft \o=H N(d, J= 6.4 Hz, 1H), 3.91 (s, 3H), 3.75-3.62?o=(m, 1H), 3.60-3.50 (m, 2H), 2.98-2.85 (m,2H), 2.22-2.12 (m, 1H), 2.00-1.92 (m, 1H), M M 1.90-1.82 (m, 1H), 1.80-1.70 (m, 1H), 1.58- 1.48 (m, 1H), 0.88 (d, J= 6.8 Hz, 3H). LC-MS (ESI+): m / z 543.8 [M+H]+4-(((3 S,4R)-3 -methyl- 1 -(4 - (7 -methyl-8- oxo-3-phenyl-7,8-dihydropyrido[2,3- d]pyridazin-2-yl)benzyl)piperidin-4- TZ iz m J yl)amino)pyrimidine-2-carbonitrile’H-NMR (400 MHz, CD3OD) 88.45 (s, Example 70 1H), 8.34 (s, 1H), 8.01 (d, J= 6.0 Hz, 1H), p p 7.48-7.42 (m, 2H), 7.38-7.25 (m, 7H), 6.72 / / ' / / z z (d, J= 6.4 Hz, 1H), 4.25 (s, 1H), 3.91 (s, 3H), 3.60-3.48 (m, 2H), 2.60-2.30 (m, 4H), 2.20-2.10 (m, 1H), 1.90-1.73 (m, 2H), 0.93 (d, J = 6.4 Hz, 3H).LC-MS (ESI+): m / z 543.8 [M+H|+4-(((3R,4R)-3-fluoro-l-(4-(7-methyl-8- wzoxo-3 -phenyl-7, 8-dihydropyrido [2,3 - K^ o= d]pyridazin-2-yl)benzyl)piperidin-4- z z- / yl)amino)pyrimidine-2-carbonitrile’H-NMR (400 MHz, CD3OD) 88.46 (s, 1H), 8.35 (s, 1H), 8.10-8.00 (m, 1H), 7.45 Example 71 (d, J= 8.4 Hz, 2H), 7.39-7.33 (m, 3H), 7.33- 7.25 (m, 4H), 6.70-6.60 (m, 1H), 4.59-4.45 (m, 1H), 4.22-4.10 (m, 1H), 3.91 (s, 3H), 3.69-3.54 (dd, J= 26.4 Hz, J= 9.2 Hz, 2H), 3.15-3.10 (m, 1H), 2.85-2.79 (m, 1H),2.25- 2.18 (m, 2H), 2.10-2.00 (m, 1H), 1.61-1.49 (m, 1H).LC-MS (ESI+): m / z 547.8 [M+H]+4-(((3 S,4R)-3 -fluoro- 1 -(4-(7-methyl-8- oxo-3 -phenyl-7, 8-dihydropyrido [2,3 - d]pyridazin-2-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile ’H-NMR (400 MHz, CD3OD) 88.46 (s, 1H), 8.35 (s, 1H), 8.10-8.00 (m, 1H), 7.45 Example 72 (d, J= 8.4 Hz, 2H), 7.39-7.33 (m, 3H), 7.33- 7.25 (m, 4H), 6.70-6.60 (m, 1H), 4.59-4.45 (m, 1H), 4.22-4.10 (m, 1H), 3.91 (s, 3H), 3.69-3.54 (dd, J = 26.0 Hz, J = 13.2 Hz, 2H), 3.15-3.10 (m, 1H), 2.85-2.79 (m, 1H), 2.25-2.18 (m, 2H), 2.10-2.00 (m, 1H), 1.61- 1.51 (m, 1H).LC-MS (ESI+): m / z 547.8 [M+H]+NAI-5008634746vl -141-Attomey Docket No. 14709-051-2284-(((3S,4S)-3-fluoro-l-(4-(7-methyl-8- oxo-3 -phenyl-7, 8-dihydropyrido [2,3 - d]pyridazin-2-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile ’H-NMR (400 MHz, CD3OD) 8 8.46 (s, 1H), 8.35 (s, 1H), 8.10-8.00 (m, 1H), 7.45 Example 73 / / / zz- (d, J= 8.4 Hz, 2H), 7.39-7.33 (m, 3H), 7.33- ft \ ^oo== 7.25 (m, 4H), 6.70-6.60 (m, 1H), 4.59-4.45?o=(m, 1H), 4.22-4.10 (m, 1H), 3.91 (s, 3H),3.69-3.54 (dd, J= 40.0, J = 13.2 Hz, 2H), M M 3.15-3.10 (m, 1H), 2.85-2.79 (m, 1H),2.25- 2.18 (m, 2H), 2.10-2.00 (m, 1H), 1.61-1.51 (m, 1H).LC-MS (ESI+): m / z 547.8 [M+H]+4-(((3R,4S)-3-fluoro-l-(4-(7-methyl-8- oxo-3 -phenyl-7, 8-dihydropyrido [2,3 - zz o TZ TZ nn T1 d]pyridazin-2-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile\ zO ZI 'H-NMR (400 MHz, CD3OD) 88.46 (s, p p 1H), 8.35 (s, 1H), 8.10-8.00 (m, 1H), 7.45 p / ' / / / / Example 74 z z (d, J= 8.4 Hz, 2H), 7.39-7.33 (m, 3H), 7.33- 7.25 (m, 4H), 6.70 (d, J= 6.4 Hz, 1H), 4.85- 4.70 (m, 1H), 4.22-4.08 (m, 1H), 3.91 (s, 3H), 3.69-3.54 (dd, J= 26.0 Hz, J = 12.8 Hz, 2H), 3.15-3.10 (m, 1H), 2.95-2.88 (m, 1H), 2.35-2.25 (m, 2H), 2.05-1.90 (m, 1H), o 1.80-1.70 (m, 1H).LC-MS (ESI+): m / z 547.8 [M+H]+ / 4-(((3S,4S)-3-hydroxy-l-(4-(7-methyl-8- oxo-3-phenyl-7,8-dihydropyrido[2,3- d]pyridazin-2-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile ’H-NMR (400 MHz, CD3OD) 88.46 (s, Example 75 1H), 8.35 (s 1H), 8.05-7.96 (m, 1H), 7.46(d, J= 8.0 Hz, 2H), 7.38-7.29 (m, 7H), 6.63- 6.62 (m, 1H), 3.91 (s, 3H), 3.91-3.90 (m, 1H), 3.66-3.55 (m, 3H), 3.07-3.00 (m, 1H), 2.90-2.81 (m, 1H), 2.21-2.12 (m, 1H), 2.08- 1.98 (m, 2H), 1.59-1.43 (m, 1H)LC-MS (ESI+): m / z 545.6 [M+H]+4-(((3R,4S)-3-hydroxy-l-(4-(7-methyl-8- oxo-3 -phenyl-7, 8-dihydropyrido [2,3 - d]pyridazin-2-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile ’H-NMR (400 MHz, CD3OD) 88.46 (s, Example 76 1H), 8.35 (s 1H), 8.05-7.96 (m, 1H), 7.46(d, J = 8.0 Hz, 2H), 7.38-7.29 (m, 7H), 6.71- 6.70 (m, 1H), 4.12-4.00 (m, 1H) 3.91 (s, 3H), 3.91-3.90 (m, 1H), 3.61-3.57 (m, 2H), 2.98-2,78 (m, 2H), 2.40-2.29 (m, 2H), 2.01- 1.85 (m, 1H), 1.79-1.66 (m, 1H)LC-MS (ESI+): m / z 545.6 [M+H]+NAI-5008634746vl -142-Attomey Docket No. 14709-051-2284-(((3S,4R)-3-hydroxy-l-(4-(7-methyl-8- oxo-3 -phenyl-7, 8-dihydropyrido [2,3 - d]pyridazin-2-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile 2 r II li i ’H-NMR (400 MHz, CD3OD) 88.45 (s, Example 77 1H), 8.34 (s 1H), 8.05-7.96 (m, 1H), 7.45 / zz-H N(d, J= 8.0 Hz, 2H), 7.38-7.27 (m, 7H), 6.71- ^O= 6.70 (m, 1H), 4.12-4.00 (m, 1H), 3.91 (s,3H), 3.91-3.90 (m, 1H), 3.61-3.57 (m, 2H), 2.98-2,78 (m, 2H), 2.40-2.29 (m, 2H), 2.01- 1.92 (m, 1H), 1.75-1.72 (m, 1H)LC-MS (ESI+): m / z 545.6 [M+H1+4-(((3R,4R)-3-hydroxy-l-(4-(7-methyl-8- oxo-3 -phenyl-7, 8-dihydropyrido [2,3 - d]pyridazin-2-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile o IZ ’H-NMR (400 MHz, CD3OD) 88.46 (s, Example 78 1H), 8.36 (s 1H), 8.09-7.98 (m, 1H), 7.46(d, J= 8.0 Hz, 2H), 7.38-7.25 (m, 7H), 6.69- 6.58 (m, 1H), 3.92 (s, 3H), 3.92-3.90 (m, / ' / z 1H), 3.70-3.55 (m, 3H), 3.09-3.01 (m, 1H), 2.93-2.83 (m, 1H), 2.31-2.17 (m, 1H), 2.14- 2.00 (m, 2H), 1.65-1.49 (m, 1H)LC-MS (ESI+): m / z 545.6 [M+H]+4-((l-(4-(7-ethyl-8-oxo-3-phenyl-7,8- dihydropyrido [2,3 -d]pyridazin-2- yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile 0 AAX AA ’H-NMR (400 MHz, CD3OD) 8 8.48 (s,1H), 8.34 (s, 1H), 8.05-7.95 (m, 1H), 7.45 Example 79 AX ANA^NJUL^H N(d, J = 8.0 Hz, 2H), 7.41-7.30 (m, 7H),6.62-6.55 (m, 1H), 4.45 (q, J= 8.8 Hz, 2H), 3.93-3.85 (m, 1H), 3.57 (s, 2H), 2.95-2.84 (m, 2H), 2.26-2.15 (m, 2H), 2.00-1.90 (m, 2H), 1.61-1.50 (m, 2H), 1.44 (t, J= 6.8 Hz, 3H).LC-MS (ESI+): m / z 543.7 [M+H|+4-((l-(4-(7-isopropyl-8-oxo-3-phenyl-7,8- dihydropyrido[2,3-d]pyridazin-2- yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile i ° AAA AN ’H-NMR (400 MHz, CD3OD) 88.52 (s, J-.NX f<?5Xj kANANAExample 80 1H), 8.33 (s, 1H), 8.05-7.95 (m, 1H), 7.45(d, J = 8.0 Hz, 2H), 7.41-7.30 (m, 7H), MUy^H6.62-6.55 (m, 1H), 5.48-5.40 (m, 2H), 3.93- 3.85 (m, 1H), 3.57 (s, 2H), 2.95-2.82 (m, 2H), 2.26-2.15 (m, 2H), 2.00-1.90 (m, 2H), 1.65-1.50 (m, 2H), 1.46 (d, J= 6.8 Hz, 6H). LC-MS (ESI+): m / z 557.7 [M+HfNAI-5008634746vl -143-Attomey Docket No. 14709-051-228rel-4-(((lS,6S)-3-(4-(7-methyl-8-oxo-3- phenyl -7, 8-dihydropyrido [2,3 -d]pyridazin- 2-yl)benzyl)-3 -azabicyclo [4.1,0]heptan-6- yl)amino)pyrimidine-2-carbonitrile ’H-NMR (400 MHz, CD3OD) 88.44 (s, 1H), 8.33 (s, 1H), 8.22-8.21 (m, 0.5H), Example 81 / / zz zz-- 8.02-8.01 (m, 0.5H), 7.44-7.42 (m, 2H),7.36-7.27 (m, 7H), 7.00-6.98 (m, 0.5H),? C ) Coo==6.57-6.55 (m, 0.5H), 3.91 (s, 3H), 3.60-3.46 Mz (m, 2H), 2.86-2.70 (m, 1H), 2.68-2.42 (m, M 2H), 2.36-2.16 (m, 2H), 2.01-1.89 (m, 1H),1.36-1.31 (m, 1H), 0.99-0.88 (m, 2H). LC-MS (ESI+): m / z 541.6 [M+H]+rel-4-(((lR,6R)-3-(4-(7-methyl-8-oxo-3- pheny 1-7, 8-dihydropyrido [2,3 -d]pyridazin- 2-yl)benzyl)-3-azabicyclo[4.1,0]heptan-6- s0.vIZ yl)amino)pyrimidine-2-carbonitrile o=\ / ’H-NMR (400 MHz, CD3OD) 88.44 (s, 01H), 8.33 (s, 1H), 8.22-8.20 (m, 0.5H), \ N JJ L °x< J p! JLExample 82 p 8.02-8.01 (m, 0.5H), 7.43-7.41 (m, 2H), / H / / / Nz z 7.35-7.32 (m, 3H), 7.31-7.26 (m, 4H), 7.00- 6.98 (m, 0.5H), 6.57-6.55 (m, 0.5H), 3.90 (s, 3H), 3.60-3.59 (m, 1H), 3.47-3.46 (m, 1H), 2.88-2.76 (m, 1H), 2.60-2.34 (m, 2H), 2.29-2.15 (m, 2H), 2.03-1.93 (m, 1H), 1.38- 1.36 (m, 1H), 0.99-0.90 (m, 2H).LC-MS (ESI+): m / z 541.6 [M+H]+4-((l-(4-(7-methyl-8-oxo-3-phenyl-7,8- dihydropyrido[2,3-d]pyridazin-2- yl)benzyl)piperidin-4-yl-4- d)amino)pyrimidine-2-carbonitrile ’H-NMR (400 MHz, CD3OD) 88.45 (s, Example 83. X. XTQXX. 1H), 8.34 (s, 1H), 8.03-7.98 (m, 1H), 7.45H N(d, J= 8.0 Hz, 2H), 7.38-7.30 (m, 3H), 7.30- 7.26 (m, 4H), 6.62-6.58 (m, 1H), 3.91 (s, 3H), 3.58 (s, 2H), 2.93-2.86 (m, 2H), 2.23 (t, J = 11.2 Hz, 2H)„ 2.01-1.94 (m, 2H), 1.61-1.51 (m, 2H).LC-MS (ESI+): m / z 530.5 [M+H]+4-((methyl-d3)(l-(4-(7-methyl-8-oxo-3- phenyl-7, 8-dihydropyrido [2,3 -d]pyridazin- 2-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile ’H-NMR (400 MHz, CD3OD) 8 8.44 (s, Example 84 1H), 8.33 (s, 1H), 8.15 (d, J= 3.6 Hz, 1H),7.45-7.43 (m, 2H), 7.35-7.23 (m, 7H), 6.76- 6.93 (m, 1H), 3.91 (s, 3H), 3.60 (s, 2H), 3.31-3.28 (m, 1H), 3.01-2.98 (m, 2H), 2.25- 2.19 (m, 2H), 1.93-1.87 (m, 2H), 1.67-1.65 (m, 2H).LC-MS (ESI+): m / z 546.4 [M+H]+NAI-5008634746vl -144-Attorney Docket No. 14709-051-2284-((l-(4-(2-methyl-3-oxo-7-phenyl-2,3- dihydropyrido[3,2-c]pyridazin-6- yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile ’H-NMR (400 MHz, CD3OD) 88.10-8.09 Example 85 (m, 1H), 8.04 (s, 1H), 7.59 (d, J= 8.0 Hz,2H), 7.6 (d, J= 8.4 Hz, 2H), 7.33-7.25 (m, 6H), 6.66-6.65 (m, 1H), 4.40-4.32 (m, 2H), 4.22-4.18 (m, 1H), 3.56-3.52 (m, 2H), 3.23- 3.19 (m, 2H), 2.64 (s, 3H), 2.33-2.32 (m, 2H), 1.77-1.74 (m, 2H).LC-MS (ESI+): m / z 529.1 [M+H]+Example 86: 4-((l-(4-(3-methyl-4-oxo-6-phenyl-3,4-dihydropyrido[2,3-d]pyrimidin-7-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile

[0365] Step 1: 6-chloro-3-methyl-7-phenylpyrido[3,2-d]pyrimidin-4(3H)-one was prepared from 6-bromo-7-chloro-3-methylpyrido[2,3-d]pyrimidin-4(3H)-one and phenylboronic acid according to the procedure reported in Example 55, step 1. LC-MS (ESI+): m / z 272.2, 274.2 [M+H]+.

[0366] Step 2: 6-(4-(hydroxymethyl)phenyl)-3-methyl-7-phenylpyrido[3,2-d]pyrimidin-4(3H)-one was prepared from 6-chloro-3-methyl-7-phenylpyrido[3,2-d]pyrimidin-4(3H)-one and (4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)methanol according to the procedure reported in Example 55, step 1. LC-MS (ESI+): m / z 344.1 [M+H]+.

[0367] Step 3: 7-(4-(chloromethyl)phenyl)-3-methyl-6-phenylpyrido[2,3-d]pyrimidin-4(3H)-one was prepared from 7-(4-(hydroxymethyl)phenyl)-3-methyl-6-phenylpyrido[2,3-d]pyrimidin-4(3H)-one according to the procedure reported in Example 3, step 3. LC-MS (ESI+): m / z 362.1, 364.2 [M+H]+.

[0368] Step 4: 4-((l-(4-(3-methyl-4-oxo-6-phenyl-3,4-dihydropyrido[2,3-d]pyrimidin-7-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile was prepared from 7-(4-(chloromethyl)phenyl)-3-methyl-6-phenylpyrido[2,3-d]pyrimidin-4(3H)-one and 4-(piperidin-4-ylamino)pyrimidine-2-carbonitrile according to the procedure reported in Examples 53 and 54,NAI-5008634746vl -145-Attorney Docket No. 14709-051-228step 4. LC-MS (ESI+): m / z 529.5 [M+H]+; 'H-NMR (400 MHz, CD3OD) 8 8.63 (s, 1H), 8.59 (s, 1H), 8.16-8.06 (m, 1H), 7.56 (d, J= 8.0 Hz, 2H), 7.45 (d, J= 8.0 Hz, 2H), 7.36-7.30 (m, 3H), 7.29-7.24 (m, 2H), 6.69-6.60 (m, 1H), 4.38-4.31 (m, 2H), 4.28-4.11 (m, 1H), 3.65 (s, 3H), 3.60-3.50 (m, 2H), 3.25-3.15 (m, 2H), 2.39-2.21 (m, 2H), 1.82-1.65 (m, 2H).

[0369] The following compounds were prepared in a similar manner.rel-4-((( 1 S,6S)-3 -(4-(7-(2-aminopyridin-3 - yl)-3 -methyl -4-oxo-3,4-dihydropyrido [2,3- d]pyrimidin-6-yl)benzyl)-3 - azabicyclo [4.1,0]heptan-6- yl)amino)pyrimidine-2-carbonitrile _ ’H-NMR (400 MHz, CD3OD) 8 8.61 (s, 1H), 8.55 (s, 1H), 8.27-8.20 (m, 0.5H), Example 87 8.06-7.98 (m, 0.5H), 7.92-7.85 (m, 1H),7.35-7.29 (m, 2H), 7.27-7.22 (m, 2H), 7.20- 7.17 (m, 1H), 7.04-6.98 (m, 0.5H), 6.60- 6.52 (m, 0.5H), 6.50-6.42 (m, 1H), 3.64 (s, 3H), 3.61-3.55 (m, 1H), 3.50-3.43 (m, 1H), 2.88-2.75 (m, 1H), 2.59-2.31 (m, 2H), 2.30- 2.18 (m, 2H), 2.01-1.94 (m, 1H), 1.28-1.18 (m, 1H), 1,00-0,90 (m, 2H), _LC-MS (ESI+): m / z 557,6 [M+H]+_ rel-4-((( 1 R,6R)-3 -(4-(7 -(2-aminopyridin-3 - yl)-3 -methyl -4-oxo-3,4-dihydropyrido [2,3- d]pyrimidin-6-yl)benzyl)-3 - azabicyclo [4.1,0]heptan-6- yl)amino)pyrimidine-2-carbonitrile _ ’H-NMR (400 MHz, CD3OD) 8 8.63 (s, 1H), 8.56 (s, 1H), 8.28-8.20 (m, 0.5H), Example 88 8.08-7.97 (m, 0.5H), 7.92-7.87 (m, 1H),7.35-7.29 (m, 2H), 7.28-7.22 (m, 2H), 7.20- H2N 7.16 (m, 1H), 7.02-6.94 (m, 0.5H), 6.60- 6.52 (m, 0.5H), 6.50-6.43 (m, 1H), 3.65 (s, 3H), 3.61-3.55 (m, 1H), 3.50-3.47 (m, 1H), 2.84-2.74 (m, 1H), 2.62-2.35 (m, 2H), 2.29- 2.16 (m, 2H), 2.01-1.95 (m, 1H), 1.28-1.18 (m, 1H), 0,98-0,90 (m, 2H), _LC-MS (ESI+): m / z 557,6 [M+H]+NAI-5008634746vl -146-Attomey Docket No. 14709-051-228Example 89: 4-((l-(4-(7-(lH-imidazol-2-yl)-3-methyl-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile

[0370] Step 1: 7-bromo-3-methyl-6-(4-(4,4,5,5-tetramethyl-l,3-dioxolan-2-yl)phenyl)pyrido[3,2-d]pyrimidin-4(3H)-one was prepared from 7-bromo-6-iodo-3-methylpyrido[3,2-d]pyrimidin-4(3H)-one according to the procedure reported in Example 55, step 1. LC-MS (ESI+): m / z 444.2, 446.2 [M+H]+.

[0371] Step 2: 4-(7-bromo-3-methyl-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidin-6-yl)benzaldehyde was prepared from 7-bromo-3-methyl-6-(4-(4,4,5,5-tetramethyl-l,3-dioxolan-2-yl)phenyl)pyrido[3,2-d]pyrimidin-4(3H)-one according to the procedure reported in Example 3, step 1. LC-MS (ESI+): m / z 344.2, 346.2 [M+H]+.

[0372] Step 3: 7-bromo-6-(4-(hydroxymethyl)phenyl)-3-methylpyrido[3,2-d]pyrimidin-4(3H)-one was prepared from 7-bromo-3-methyl-6-(4-(4,4,5,5-tetramethyl-l,3-dioxolan-2-yl)phenyl)pyrido[3,2-d]pyrimidin-4(3H)-one according to the procedure reported in Example 3, step 2. LC-MS (ESI+): m / z 346.2, 348.2 [M+H]+.

[0373] Step 4: 7-bromo-6-(4-(chloromethyl)phenyl)-3-methylpyrido[3,2-d]pyrimidin-4(3H)-one was prepared from 7-bromo-3-methyl-6-(4-(4,4,5,5-tetramethyl-l,3-dioxolan-2-yl)phenyl)pyrido[3,2-d]pyrimidin-4(3H)-one according to the procedure reported in Example 3, step 3. LC-MS (ESI+): m / z 364.2, 366.2 [M+H]+.

[0374] Step 5: 4-((l-(4-(7-bromo-3-methyl-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile was prepared from 7-bromo-3-methyl-6-(4-(4,4,5,5-tetramethyl-l,3-dioxolan-2-yl)phenyl)pyrido[3,2-d]pyrimidin-4(3H)-one and 4-NAI-5008634746vl -147-Attomey Docket No. 14709-051-228(piperidin-4-ylamino)pyrimidine-2-carbonitrile according to the procedure reported in Examples 53 and 54, step 4. LC-MS (ESI+): m / z 531.2, 533.2 [M+H]+.

[0375] Step 6: A solution of 4-((l-(4-(7-bromo-3-methyl-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile (149 mg, 0.28 mmol), Bis(pinacolato)diboron (285 mg, 1.12 mmol), Pd(dppf)Ch (23 mg, 0.03 mmol) and AcOK (83 mg, 0.84 mmol) in DMF (3 mL) was stirred under N2 atmosphere at 90 °C for 3 h. Upon completion of the reaction based on LC-MS analysis, the reaction mixture was cooled to RT, quenched with water (20 mL) and adjusted to pH = 7. The aqueous solution was washed with DCM (20 mL x 3). The aqueous solution was concentrated under reduced pressure. The residue was purified by reverse HPLC to yield 49 mg of (6-(4-((4-((2-cyanopyrimidin-4-yl)amino)piperidin-l-yl)methyl)phenyl)-3-methyl-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidin-7-yl)boronic acid. LC-MS (ESI+): m / z 497.2 [M+H]+.

[0376] Step 7: A solution of (6-(4-((4-((2-cyanopyrimidin-4-yl)amino)piperidin-l-yl)methyl)phenyl)-3-methyl-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidin-7-yl)boronic acid (49 mg, 0.1 mmol), 2-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazole (39 mg, 0.15 mmol), XPhos Pd G2 (8 mg, 0.01 mmol) and CS2CO3 (64 mg, 0.2 mmol) in dioxane (10 mL) and water (2.5 mL) was stirred under N2 atmosphere at 90 °C for 1 h. Upon completion of the reaction based on LC-MS analysis, the reaction mixture was cooled to RT, quenched with water (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC to yield 9.3 mg of 4-((l-(4-(3-methyl-4-oxo-7-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazol-2-yl)-3,4-dihydropyrido[3,2-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile as yellow solid. LC-MS (ESI+): m / z 649.3 [M+H]+.

[0377] Step 8: To a solution of 4-((l-(4-(3-methyl-4-oxo-7-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazol-2-yl)-3,4-dihydropyrido[3,2-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile (9.3 mg, 0.01 mmol) in DCM (4 mL) at RT was added TFA (1 mL). The reaction was stirred at RT overnight. Upon completion of the reaction based on LC-MS analysis, DCM and TFA were removed under reduced pressure, the residue was neutralized with saturated Na₂CO₃ solution to pH = 8. The aqueous solution was diluted in MeOH and purified by reverse HPLC to yield 2.5 mg of 4-((l-(4-(7-(lH-imidazol-2-yl)-3-methyl-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidin-6-yl)benzyl)piperi din-4-yl)amino)pyrimidine-2-carbonitrile. LC-MS (ESI+): m / z 519.6 [M+H]+; 'H-NMR (400 MHz, CD3OD) 8.50 (d, J= 6.8 Hz, 2H), 8.12-8.05 (m, 1H), 7.57 (s, 4H), 7.51 (s, 2H), 6.70-6.60 (m,NAI-5008634746vl -148-Attomey Docket No. 14709-051-2281H), 4.39 (s, 2H), 4.31-4.12 (m, 1H...

Claims

Attorney Docket No. 14709-051-228WHAT IS CLAIMED IS:

1. A compound of Formula (I):or a stereoisomer, a mixture of stereoisomers, a tautomer, or a pharmaceutically acceptable salt thereof,wherein:Ring A is phenyl or 5- to 10-membered heteroaryl;each of X1, X2, X3, and X4is independently CRX, C(=O), N, or NRxn, as valency permits; X5is CRxor N;X6is CRxor N;each instance of Rxis independently hydrogen, CN, halogen, -NRn2Rn3, -OR01, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted 5- to 10-membered heterocyclyl, or optionally substituted 5- to 10-membered heteroaryl; or two Rxtogether with the atoms to which they are attached form an optionally substituted 5- to 6-membered heterocyclyl or an optionally substituted 5- to 6-membered heteroaryl;each instance of Rxnis independently hydrogen, optionally substituted C1-3 alkyl, optionally substituted C3-4 cycloalkyl, or optionally substituted 4- to 6-membered heterocyclyl;each instance of RO1is independently hydrogen or optionally substituted C1-6 alkyl; L’ is optionally substituted C1-12 alkylene, wherein one or more -CH2- in the alkylene is independently optionally replaced by -C(=O)-NRn1-, -NRnl-C(=O)-, -NRn1-, -O-, -C(=O)-, or optionally substituted 3- to 12-membered ring moiety, as valency permits;each instance of Rais independently halogen, -ORC, optionally substituted C1-6 alkyl, -C(=O)H, -NRn4Rn5, or optionally substituted 3- to 8-membered heterocyclyl;each instance of Rcis independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C3-6 cycloalkyl, optionally substituted 3- to 6-membered heterocyclyl, optionally substituted phenyl, or optionally substituted 5- to 6-membered heteroaryl;NAI-5008634746vl -172-Attomey Docket No. 14709-051-228each instance of Rnl, Rn2, Rn3, Rn4, and Rn5is independently hydrogen, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, -C(=O)Rd, or -C(=O)ORd;or Rn2and Rn3together with the nitrogen to which they are attached form an optionally substituted 3- to 6-membered heterocyclyl or an optionally substituted 5- to 6-membered heteroaryl;or Rn4and Rn5together with the nitrogen to which they are attached form an optionally substituted 3- to 6-membered heterocyclyl or an optionally substituted 5- to 6-membered heteroaryl;each instance of Rdis independently hydrogen or optionally substituted Ci-6 alkyl; and n is 0, 1, 2, 3, 4, 5, 6, 7, or 8 as valency permits.

2. The compound of claim 1, wherein at least one of X1, X2, X3, and X4is N or NRxn, as valency permits.

3. The compound of claim 1 or 2, provided that: when L’ comprises optionally substituted 3- to 12-membered ring moiety, then (i) two of X1, X2, X3, and X4are N or NRxn; or (ii) X4is C(=O), X3is NRxn, and Rxnis not hydrogen; or both (i) and (ii).

4. The compound of any one of claims 1 to 3, wherein at least one of X5and X6is N.

5. The compound of any one of claims 1 to 3, which is a compound of Formula (I-A), (I-B),or a stereoisomer, a mixture of stereoisomers, a tautomer, or a pharmaceutically acceptable salt thereof.NAI-5008634746vl -173-Attomey Docket No. 14709-051-2286. The compound of any one of claims 1 to 5, wherein L’ is -X-Q-L-, wherein:X is a bond, -NRl1-, -O-, optionally substituted C1-3 alkylene, or optionally substituted Ci-3 heteroalkylene;Q is -C(=O)-NRn1-, -NRnl-C(=O)-, or optionally substituted 3- to 12-membered ring moiety; andL is a bond, -NR111-, -O-, -C(=O)-, optionally substituted C1-6 alkylene, or optionally substituted C1-6 heteroalkylene.

7. The compound of claim 6, wherein X is a bond or optionally substituted C1-3 alkylene.

8. The compound of claim 6 or 7, wherein Q is optionally substituted C3-6 cycloalkylene or optionally substituted 3- to 8-membered heterocyclylene.

9. The compound of any one of claims 6 to 8, wherein L is a bond, -NR111-, -O-, -C(=O)-, or optionally substituted C1-3 alkylene.

10. The compound of claim 6, wherein the compound is a compound of Formula (II-B-1), (II-B-2), or (II-B-3):(II-B-1), (II-B-2), or(II-B-3), or a stereoisomer, a mixture of stereoisomers, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:each of R1and R2is independently hydrogen, halogen, optionally substituted C1-6 alkyl, or optionally substituted C1-6 heteroalkyl;Ring C is 4- to 12-membered heterocyclyl;NAI-5008634746vl -174-Attorney Docket No. 14709-051-228each instance of R° is independently hydrogen, deuterium, CN, halogen, hydroxy, or optionally substituted Ci-6 alkyl; or two instances of R°, together with the intervening atom(s), form an optionally substituted 3- to 6-membered ring; andp is 0, 1, 2, 3, 4, 5, 6, 7, or 8 as valency permits.

11. The compound of claim 10, wherein the compound is a compound of Formula (II-B-l-a), (II-B-l-b), (II-B-l-c), (II-B-l-d), (II-B-2-a), (II-B-2-b), (II-B-2-c), (II-B-3-d), (II-B-3-a), (II-B-3-b), (II-B-3-c), or (II-B-3-d):(II-B-l-a), (II-B-l-b), RxnRxn(II-B-l-c), (II-B-l-d),(II-B-2-a), (II-B-2-b),NAI-5008634746vl -175-Attorney Docket No. 14709-051-228(II-B-3-c), or (II-B-3-d), or a stereoisomer, a mixture of stereoisomers, a tautomer, or a pharmaceutically acceptable salt thereof.

12. The compound of claim 10 or 11, whereinwherein Y is C, CH, or N, as valency permits; s is 0, 1, or 2; and t is 0, 1, or 2.

13. The compound of claim 12, wherein Y is CH.

14. The compound of claim 10 or 11, whereinNAI-5008634746vl -176-Attomey Docket No. 14709-051-22815. The compound of claim 6, wherein the compound is a compound of Formula (II-A-1), (II- A-2), or (II-A-3):or a stereoisomer, a mixture of stereoisomers, a tautomer, or a pharmaceutically acceptable salt thereof.NAI-5008634746vl -177-Attorney Docket No. 14709-051-22816. The compound of claim 15, wherein17. The compound of claim 6, wherein the compound is a compound of Formula (II-C-1), (II- C-2), or (II-C-3):or a stereoisomer, a mixture of stereoisomers, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:each of R1and R2is independently hydrogen, halogen, optionally substituted Ci-6 alkyl, or optionally substituted Ci-6 heteroalkyl.

18. The compound of any one of claims 1 to 17, whereinNAI-5008634746vl -178-Attomey Docket No. 14709-051-228to the phenyl ring connected to L’ and b indicates the point of attachment to Ring A.NAI-5008634746vl -179-Attorney Docket No. 14709-051-228a indicates the point of attachment to the phenyl ring connected to L’ and b indicates the point of attachment to Ring A.

20. The compound of any one of claims 1 to 19, wherein Ring A is phenyl.

21. The compound of any one of claims 1 to 19, wherein Ring A is 5- to 6-membered heteroaryl.

22. The compound of claim 21, wherein Ring A is pyridinyl.NAI-5008634746vl -180-Attorney Docket No. 14709-051-22823. The compound of claim 21, wherein Ring A is thiazolyl.

24. The compound of any one of claims 10 to 17, wherein the compound is a compound of Formula (IILA-1), (III-A-2), (III-A-3), (IILA-4), (III-A-5), (III-B-1), (III-B-2), (IILB-3), (III-B-4), (III-B-5), (in-B-6), (in-B-7), (IILB-8), (IILB-9), (IILB-10), (III-B-11), (IILB-12), (IILB-13), (ni-B-14), (ni-B-15), or (IILB-16):(in-B-2), (IILB-3),NAI-5008634746vl -181-Attomey Docket No. 14709-051-228NAI-5008634746vl -182-Attorney Docket No. 14709-051-228or a stereoisomer, a mixture of stereoisomers, a tautomer, or a pharmaceutically acceptable salt thereof, whereinA1is CH or N.

25. The compound of claim 24, wherein A1is CH.

26. The compound of claim 24, wherein A1is N.

27. The compound of any one of claims 6 to 26, wherein L is a bond.

28. The compound of any one of claims 6 to 26, wherein L is -O-.

29. The compound of any one of claims 6 to 26, wherein L is -NH- or -N(CH3)-.

30. The compound of any one of claims 1 to 29, wherein each instance of Rxis independently hydrogen, CN, halogen, optionally substituted C1-3 alkyl, optionally substituted C1-3 heteroalkyl, -NRn2Rn3, -OR01, or 5- to 6-membered heteroaryl.NAI-5008634746vl -183-Attorney Docket No. 14709-051-22831. The compound of claim 30, wherein each instance of Rxis independently hydrogen, -NH2, -F, -Cl, CN, -NHCH3, -NHCH(CH3)2, -CH3, -CD3, -CF3, isopropyl, -OH, -O(CH3), -O-(isopropyl), pyrazolyl, or\.

32. The compound of any one of claims 1 to 31, wherein Rxnis optionally substituted Ci-3alkyl, optionally substituted C3-4 cycloalkyl, or optionally substituted 4- to 6-membered heterocyclyl.

33. The compound of claim 32, wherein Rxnis optionally substituted methyl.NAI-5008634746vl -184-Attomey Docket No. 14709-051-228NAI-5008634746vl -185-Attorney Docket No. 14709-051-228attachment to the phenyl ring connected to L’ and b indicates the point of attachment to Ring A.

35. The compound of any one of claims 1 to 34, wherein n is 0.

36. The compound of any one of claims 1 to 34, wherein n is 1 and Rais -NRn4Rn5.

37. The compound of any one of claims 1 to 34, wherein38. The compound of any one of claims 1 to 37, wherein39. The compound of any one of claims 1 to 37, wherein40. A compound in Table 1 or Table 1 A, or a pharmaceutically acceptable salt thereof.

41. A pharmaceutical composition, comprising a compound of any one of claims 1 to 40 and a pharmaceutically acceptable excipient.

42. A method of treating a cell proliferative disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any of claims 1 to 40 or a pharmaceutical composition of claim 41.

43. The method of claim 42, wherein the cell proliferative disease is cancer.

44. The method of claim 43, wherein the cancer is a cancer associated with aberrant activity of ART.NAI-5008634746vl -186-Attomey Docket No. 14709-051-22845. The method of claim 43, wherein the cancer is breast cancer, colorectal cancer, meningioma, ovarian cancer, cervical cancer, pancreatic cancer, glioma, glioblastoma, prostate cancer, leukemia, lymphoma, non-Hodgkin’s lymphoma, lung cancer, hepatocellular cancer, gastric cancer, gastrointestinal stromal tumor (GIST), thyroid cancer, bile duct cancer, endometrial cancer, renal cancer, anaplastic large cell lymphoma, acute myeloid leukemia (AML), multiple myeloma, melanoma, or mesothelioma.

46. The method of any one of claims 42 to 45, wherein the administration modulates activity of the AKT in the subject.

47. The method of any one of claims 42 to 45, wherein the administration modulates activity of a mutant AKT in the subject.

48. The method of claim 47, wherein the mutant AKT is AKT1 E17K.

49. The method of any one of claims 42 to 48, further comprising administering an additional therapeutic agent to the subject.NAI-5008634746vl -187-

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