Substitutional tricyclic compounds

Abstract

Disclosed herein are substituted tricyclic compounds, including imidazoquinazolines, imidazopyridopyrimidines, triazoloquinazolines, pyridotriazolopyrimidines, triazoloquinoxalines, pyridotriazolopyrazines, thienonaphthyridines, and thienoquinolines, methods for their preparation, and uses thereof.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Application No. 63 / 483,070, filed February 3, 2023, the disclosure of which is incorporated herein by reference in its entirety.

[0002] The present disclosure is directed to substituted tricyclic compounds (including imidazoquinazolines, imidazopyridopyrimidines, triazoloquinazolines, pyridotriazolopyrimidines, triazoloquinoxalines, pyridotriazolopyrazines, thienonaphthyridines, and thienoquinolines), and said compounds are useful for treating diseases or disorders associated with PI3K modulation. [Background technology]

[0003] Cellular activities can be controlled by extracellular signals that stimulate or inhibit intracellular events. The process by which stimulatory or inhibitory signals are transmitted into cells, resulting in an intracellular response, is called signal transduction. Over the past decades, cascades of signal transduction events have been elucidated and found to play a central role in a variety of biological responses. Defects in various components of signal transduction pathways have been found to be key factors in a vast number of diseases, including various forms of cancer, inflammatory diseases, metabolic disorders, vascular diseases, and neurological diseases.

[0004] Kinases are a type of important signal transduction molecule. Kinases can generally be classified as protein kinases and lipid kinases, with some kinases exhibiting dual specificity. Protein kinases are enzymes that phosphorylate other proteins and / or themselves (i.e., autophosphorylation). Protein kinases can generally be classified into three main groups based on substrate utilization: tyrosine kinases that primarily phosphorylate tyrosine residues (e.g., erb2, PDGF receptor, EGF receptor, VEGF receptor, src, abl), serine / threonine kinases that primarily phosphorylate serine and / or threonine residues (e.g., mTORC1, mTORC2, ATM, ATR, DNA-PK, Akt), and dual specificity kinases that phosphorylate tyrosine, serine, and / or threonine residues.

[0005] Lipid kinases are enzymes that catalyze the phosphorylation of intracellular lipids. These enzymes, and the resulting phosphorylated lipids and lipid-derived bioactive organic molecules, play a role in a variety of physiological processes, including cell proliferation, migration, adhesion, and differentiation. A specific group of lipid kinases includes membrane lipid kinases (i.e., kinases that catalyze the phosphorylation of lipids contained in or associated with cell membranes). Examples of such enzymes include phosphoinositide kinases (e.g., PI3-kinase, PI4-kinase), diacylglycerol kinase, and sphingosine kinase.

[0006] Phosphoinositide 3-kinase (PI3K) signaling is one of the most frequently mutated systems in human cancer. PI3K signaling is also involved in numerous other pathologies, including allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, psoriasis, multiple sclerosis, asthma, and disorders associated with diabetic and inflammatory complications of the cardiovascular system (e.g., acute coronary syndromes).

[0007] PI3Ks are members of a unique and conserved family of intracellular lipid kinases that phosphorylate the 3'-OH group of phosphatidylinositols or phosphoinositides. The PI3K family includes 15 kinases with distinct substrate specificities, expression patterns, and modes of regulation. Class I PI3Ks (PI10a, PI10b, PI106, and PI10g) are typically activated by tyrosine kinases or G protein-coupled receptors, generating PIP3 and activating downstream effectors (e.g., downstream effectors in the Akt / PDKl, mTOR, Tec family kinases, and Rho family GTPase pathways). Class II and III PI3Ks play important roles in intracellular trafficking through the synthesis of PI(3)P and PI(3,4)P2.

[0008] PI3K isoforms, for example, are involved in various human cancers and disorders. Mutations in genes encoding PI3K isoforms or mutations that lead to the upregulation of PI3K isoforms are believed to occur in many human cancers. Mutations in the genes encoding PI3K isoforms are point mutations concentrated in several hotspots within the helical and kinase domains. Due to the high incidence of PI3K mutations, targeting this pathway may offer beneficial therapeutic opportunities.

[0009] Mutations in PI3K signaling genes are believed to be involved in a wide range of cancers, including endometrial cancer, breast cancer, esophageal squamous cell carcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, bladder urothelial carcinoma, glioblastoma, ovarian cancer, non-small cell lung cancer, esophagogastric carcinoma, nerve sheath tumor, head and neck squamous cell carcinoma, melanoma, esophagogastric adenocarcinoma, soft tissue sarcoma, prostate cancer, fibrolamellar carcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, cholangiocarcinoma, B-cell lymphoma, mesothelioma, adrenocortical cell carcinoma, renal non-clear cell carcinoma, renal clear cell carcinoma, germ cell carcinoma, thymic tumors, pheochromocytoma, mixed neuroepithelial tumor, thyroid cancer, leukemia, and encapsulating glioma.

[0010] The PI3K alpha (α) isoform, for example, has been implicated in various human cancers. Angiogenesis has been shown to selectively require the PI3K alpha (α) isoform in regulating endothelial cell migration. Mutations in the gene encoding PI3K α or mutations leading to upregulation of PI3K α are believed to occur in numerous human cancers (e.g., lung, gastric, endometrial, ovarian, bladder, breast, colon, brain, prostate, and skin cancers). Mutations in the gene encoding PI3K α are point mutations concentrated in several hotspots within the helical and kinase domains, including E542K, E545K, and H1047R. Many of these mutations have been shown to be oncogenic gain-of-function mutations. Due to the high incidence of PI3K mutations, targeting this pathway may offer valuable therapeutic opportunities. Other PI3K isoforms (eg, PI3Kδ or PI3Kγ) are expressed primarily in hematopoietic cells, whereas PI3Kα, along with PI3Kβ, is constitutively expressed.

[0011] Because PI3Kα plays a central role in regulating biological glucose homeostasis, PI3K inhibition in patients frequently leads to hyperglycemia and / or hyperinsulinemia. High circulating insulin concentrations may confer mitogenic and / or antiapoptotic properties to cancer cells, thus negating the growth-suppressing effects of PI3K inhibition.

[0012] In the setting of mutant PI3Kα cancer, one way to overcome the problem of compensatory insulin and / or glucose production based on systemic PI3Kα inhibition would be to develop inhibitors that are more selective for mutant PI3Kα than for wild-type PI3Kα. This would increase the drug's dosing window and selectively inhibit the pathological signaling of mutant PI3Kα in cancer cells without affecting wild-type PI3Kα in host tissues, which regulates systemic metabolism. This would result in reduced toxicity, allowing for higher doses and more complete inhibition of the drug target.

[0013] Existing PI3Kα inhibitors exhibit roughly equivalent activity against wild-type and mutant PI3Kα. Mutant-selective inhibitors have been difficult to develop because the PI3Kα mutation site is far from the active site. Therefore, inhibitors targeting the secondary binding pocket surrounding the known mutation (e.g., H1047R) may provide a means for selective PI3Kα inhibition. Therefore, targeting the binding pocket surrounding the PI3Kα mutation may provide a promising therapeutic target for drug development.

[0014] Therefore, kinases (eg, lipid kinases such as PI3K) are prime targets for drug development. Summary of the Invention

[0015] In some embodiments, the present disclosure provides a compound of formula (I): [ka] [In formula: R 1 is H, C1-C3 alkyl, or C3-C6 cycloalkyl; R 2 is a phenyl or a 5- or 6-membered heteroaryl group, and each of the phenyl and heteroaryl groups is 12 substituted accordingly; Each R 12 are independently C1-C4 alkyl, -OR A , -C(O)OR A ,(C1-C3 alkyl)-OR A , -C(O)N(R B )2, cyano, tetrazolyl, or halogen; Each R A are independently H, C1-C6 alkyl, or C3-C6 cycloalkyl; Each R B is independently H, —OH, C1-C6 alkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl; and R 3is C1-C3 alkyl optionally substituted, polysubstituted, or fully substituted with fluoro, C3-C6 cycloalkyl, C2-C3 alkenyl, C2-C3 alkynyl, or C5-C6 cycloalkenyl; R 4 is H, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C2-C3 alkenyl, C2-C3 alkynyl, or C5-C6 cycloalkenyl, cyano, or halo, each of which C1-C3 alkyl and C3-C6 cycloalkyl is optionally substituted with 1 to 5 halo groups; T is N or CR 6 and The R 6 is H or C1-C6 alkyl; Formula (Z): [ka] is the formula (E), (G), (J), (K), (L), or (M): [ka] represents each d is a point of attachment to a bridgehead carbon bonded to T; In formula (E), both X and Y are CR 5 , or one of X and Y is CR 5 and the other is N: In formula (J), both X and Y are N; each ring A is a 4- to 8-membered carbocyclic ring or a 3- to 7-membered heterocyclic ring; Each R 5are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogen, haloC1-C6 alkyl, cyano, hydroxy, hydroxyC1-C6 alkyl, amino, mono- or di(C1-C6 alkyl)amino, C3-C6 cycloalkyl, haloC3-C6 cycloalkyl, phenyl, or 5-6 membered heteroaryl, each of which alkyl and cycloalkyl is optionally substituted with one to three hydroxy, C1-C3 alkyl, C1-C3 alkoxy, cyano, amino, or mono- or di(C1-C3)alkylamino, and each of which phenyl and heteroaryl is optionally substituted with one to three halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, cyano, amino, or mono- or di(C1-C3)alkylamino; R 30 is -NR 7 NR 8 or R 31 and R 31 teeth, (i) a 5- to 7-membered heteroaryl, or (ii) A 3- to 8-membered monocyclic heterocyclyl group attached to a tricyclic ring via a carbon atom, the heterocyclyl group being saturated or unsaturated, optionally fused to an aromatic or non-aromatic ring containing 3 to 6 ring members (one or two of which are nitrogen, oxygen, or sulfur atoms, as appropriate, and the remainder are carbon atoms); or the carbon atoms of the monocyclic heterocyclyl group together with the additional carbon or nitrogen atom form a spiro ring system having a total of up to 10 ring members, each of which is carbon or nitrogen; and R 31 Each such heteroaryl and heterocyclyl group in 39 group, and each R 39are independently C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, haloC1-C3 alkyl, hydroxyC1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino, or phenyl, phenyl(C1-C3 alkanoyl), 5- to 7-membered heterocyclyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxy, cyano, amino, or mono- or di-(C1-C3 alkyl)amino; R 7 represents H or C1-C3 alkyl; R 8 represents (i) H, (ii) C1-C6 alkyl optionally substituted with a 5- to 8-membered heterocyclyl, (iii) C3-C6 cycloalkyl, or (iv) C3-C6 cycloalkyl(C1-C3 alkyl); or R 7 and R 8 together with the nitrogen to which it is attached form a ring Q, which ring Q is A 3- to 8-membered monocyclic heterocyclyl group containing one or two ring nitrogens, the heterocyclyl group being optionally fused to an aromatic or non-aromatic ring containing 3 to 6 ring members (one or two of which are nitrogen, oxygen, or sulfur atoms, as appropriate, and the remainder are carbon atoms); or together with the carbon atom of the monocyclic heterocyclyl group and the additional carbon or nitrogen atom, form a spiro ring system having a total of up to 10 ring members, each of which is carbon or nitrogen (the spiro center of the spiro ring system is a carbon atom of the 3- to 7-membered monocyclic heterocyclyl group); and Each ring Q may have 1 to 4 R 9 group, and each R 9are independently C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, haloC1-C3 alkyl, hydroxyC1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino, or phenyl, phenyl(C1-C3 alkanoyl), 5- to 7-membered heterocyclyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxy, cyano, amino, or mono- or di-(C1-C3 alkyl)amino. and pharmaceutically acceptable salts thereof, and prodrugs, solvates, hydrates, isomers, deuterated forms, and tautomers thereof.

[0016] In another aspect, the disclosure provides a pharmaceutical composition comprising a compound or salt as otherwise described herein, together with a pharmaceutically acceptable carrier, excipient, or diluent.

[0017] In another aspect, the present disclosure provides a method for treating a disease or disorder associated with the regulation of phosphoinositide 3-kinase (PI3K), comprising administering to a patient in need thereof a therapeutically effective amount of any compound described elsewhere herein or a pharmaceutical composition described elsewhere herein.

[0018] In another aspect, the disclosure provides a method for inhibiting phosphoinositide 3-kinase (PI3K), comprising administering to a patient in need thereof a therapeutically effective amount of a compound described elsewhere herein or a pharmaceutical composition described elsewhere herein.

[0019] In another aspect, the disclosure provides a method for treating cancer or a disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound described elsewhere herein or a pharmaceutical composition described elsewhere herein.

[0020] The compounds disclosed herein selectively bind to H1047R mutant PI3Kα and not to wild-type PI3Kα.

[0021] In other aspects, the disclosure provides intermediates and synthetic methods useful for preparing compounds of formula (I).

[0022] Other aspects and embodiments of the present disclosure will be apparent from consideration of the detailed description provided herein. DETAILED DESCRIPTION OF THE INVENTION

[0023] The present invention relates to inhibitors of PI3K alpha. In particular, the present invention relates to compounds that inhibit PI3K alpha activity, pharmaceutical compositions containing therapeutically effective amounts of the compounds, and methods of use thereof.

[0024] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. All patents, patent applications, and literature referenced herein are incorporated by reference to the extent consistent with this disclosure. Terms and scopes are subject to the definitions generally defined unless expressly defined otherwise.

[0025] For simplicity, chemical moieties are defined and referred to throughout this specification primarily as monovalent chemical moieties (e.g., alkyl, aryl, etc.). However, such terms may also be used to refer to corresponding multivalent moieties under the appropriate structural circumstances apparent to one of ordinary skill in the art. For example, while an "alkyl" group generally refers to a monovalent group (e.g., CH3-CH2-), in certain circumstances, a divalent linking moiety may be referred to as "alkyl" if one of ordinary skill in the art would understand that the alkyl is a divalent group (e.g., -CH2-CH2-) and is equivalent to the term "alkylene." (Similarly, where a divalent moiety is required to be "aryl," one of ordinary skill in the art would understand the term "aryl" to refer to the corresponding divalent moiety, arylene, under the described circumstances.) All atoms are understood to have normal valencies for bond formation (i.e., carbon is tetravalent, nitrogen is trivalent, oxygen is divalent, and S is divalent, tetravalent, or hexavalent depending on its oxidation state).

[0026] The term "amino" refers to -NH2.

[0027] The term "acetyl" refers to -C(O)CH3.

[0028] As used herein, the term "acyl" refers to an alkylcarbonyl or arylcarbonyl substituent, where the alkyl and aryl groups are defined herein.

[0029] The term "alkyl" as used herein refers to saturated straight- and branched-chain aliphatic groups having 1 to 12 carbon atoms. Thus, "alkyl" includes C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C50, C51, C52, C53, C54, C55, C56, C 10 , C 11 , and C 12 The alkyl group may be branched or unbranched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0030] The term "alkenyl" as used herein refers to an unsaturated straight- or branched-chain aliphatic group having 2 to 12 carbon atoms and having one or more carbon-carbon double bonds. Thus, "alkenyl" includes C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C50, C51, C52, C5 10 , C 11 , and C 12 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

[0031] The term "alkynyl" as used herein refers to an unsaturated straight- or branched-chain aliphatic group having 2 to 12 carbon atoms and having one or more carbon-carbon triple bonds. Thus, "alkynyl" includes C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C50, C51, C52, C5 10 , C 11 , and C 12 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl groups.

[0032] An "alkylene," "alkenylene," or "alkynylene" group is an alkyl, alkenyl, or alkynyl group, as defined hereinabove, that is positioned between and serves to connect two other chemical groups. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene. Representative alkenylene groups include, but are not limited to, ethenylene, propenylene, and butenylene. Representative alkynylene groups include, but are not limited to, ethynylene, propynylene, and butynylene.

[0033] The term "alkoxy" refers to -O(C1-C6 alkyl).

[0034] The term "cycloalkyl" as used herein refers to saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons. Thus, "cycloalkyl" includes C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C50, C51, C52, C53, C54, C55, C56, C57, C58 10 , C 11, and C 12 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0035] The term "heteroalkyl" refers to an alkyl group, as defined hereinabove, wherein one or more carbon atoms in the chain are independently O, S, or NR x is replaced by the R x refers to an alkyl group, which is hydrogen or a C1-C3 alkyl. Examples of heteroalkyl groups include methoxymethyl, methoxyethyl, and methoxypropyl.

[0036] An "aryl" group is a C6-C6 alkyl group containing one to three aromatic rings. 14 It is an aromatic moiety. Thus, "aryl" refers to C6, C 10 , C 13 , and C 14 Contains cyclic hydrocarbon groups. Representative aryl groups are C6-C 10 An aryl group. Particular aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and fluorenyl. "Aryl" groups also include fused polycyclic (e.g., bicyclic) systems, where one or more of the fused rings may be non-aromatic, provided that at least one ring is aromatic (e.g., indenyl).

[0037] An "aralkyl" or "arylalkyl" group comprises an aryl group covalently linked to an alkyl group, which is then linked to another group through the alkyl portion. Representative aralkyl groups include -(C-C)alkyl (C-C 10 ) aryl, including, but not limited to, benzyl, phenethyl, and naphthylmethyl. For example, an arylC1-C3 alkyl is an aryl group covalently linked to a C1-C3 alkyl.

[0038] A "heterocyclyl" or "heterocycle" or "heterocycloalkyl" group is a monocyclic or bicyclic (fused or spiro) ring structure having 3 to 12 atoms (3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 atoms), e.g., 4 to 8 atoms, wherein one or more ring atoms are independently -C(O)-, N, NR 4, O, or S, with the remaining ring atoms being quaternary or carbonyl carbons. Examples of heterocyclic groups include, but are not limited to, epoxy, oxiranyl, oxetanyl, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, thiatanyl, dithianyl, trithianyl, azathianyl, oxathianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidonyl, thiomorpholinyl, dimethyl-morpholinyl, and morpholinyl. Examples of heterocyclic groups that are spirocyclic ring systems include azaspiro[2.5]octan-6-yl, 5-azaspiro[2.4]heptan-5-yl, 6-azaspiro[3.4]octan-6-yl, 5-oxa-7-azaspiro[3.4]octan-7-yl, 5,5-dimethyl-4-oxa-7-azaspiro[2.5]octan-7-yl, and 7,7-dimethyl-5-azaspiro[2.5]octan-5-yl. Compounds with adjacent ring O and / or S atoms are specifically excluded from the scope of this term. Heterocyclic groups can be attached to the parent group (i.e., the point of attachment) through any ring atom, including one heteroatom or one carbon atom on the heterocyclic group. If chemically required, heterocycles can be attached to one or more other groups, for example, when they function as bridging groups. The term "heterocyclyl" also includes fused polycyclic (e.g., bicyclic) systems, in which one or more of the fused rings are aromatic or non-aromatic, provided that at least one ring is non-aromatic and contains an N, O, or S ring atom. Examples of such fused polycyclic systems include indolinyl, indolin-2-yl, 2,3-dihydrobenzofuran-2-yl, and 2,3,4,5-tetrahydrobenzo[d]oxazol-2-yl. Each of these examples is a nine-membered heterocyclyl.

[0039] As used herein, the term "heteroaryl" refers to a group having 5 to 14 ring atoms, preferably 5, 6, 10, 13, or 14 ring atoms; 6, 10, or 14 π electrons shared in a cyclic arrangement; and, in addition to carbon atoms, 1 to 3 heteroatoms, each independently N, O, or S. "Heteroaryl" also includes fused polycyclic (e.g., bicyclic) systems, in which at least one ring is aromatic (e.g., indenyl) and one or more fused rings are non-aromatic, provided that at least one ring contains an N, O, or S ring atom. A heteroaryl group can be bonded to the parent group (i.e., the point of attachment) through any ring atom, including a heteroatom or a carbon atom on the heteroaryl ring group. If chemically required, a heteroaryl can be bonded to one or more other groups, for example, to function as a bridging group.

[0040] Examples of heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzo[d]oxazol-2(3H)-one, 2H-benzo[b][1,4]oxazin-3(4H)-one, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, furanyl, Furazanyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxa Zolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclinyl thiazinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

[0041] An "arylene," "heteroarylene," or "heterocyclylene" group is a divalent aryl, heteroaryl, or heterocyclyl group, respectively, as defined hereinabove, that is positioned between and serves to link two other chemical groups.

[0042] As used herein, when a moiety (e.g., cycloalkyl, aryl, heteroaryl, heterocyclyl, urea, etc.) is described as "optionally substituted" without explicitly listing substituents, it means that the group optionally has any number of non-hydrogen substituents, e.g., 1 to 5, or 1 to 4, or 1 to 3, or 1, or 2 non-hydrogen substituents.

[0043] As used herein, the term "halogen" or "halo" refers to chlorine, bromine, fluorine, or iodine.

[0044] The term "haloalkyl," e.g., haloC1-C6 alkyl, refers to an alkyl chain in which one or more hydrogens have been replaced with halogen. Representative haloalkyls are trifluoromethyl, difluoromethyl, fluorochloromethyl, chloromethyl, fluoromethyl, trifluoroethyl, pentafluoroethyl (perfluoroethyl), heptafluoropropyl (perfluoropropyl), tetrafluorocyclopropyl, and pentafluorocyclopropyl (perfluorocyclopropyl).

[0045] The term "halocycloalkyl," e.g., haloC3-C6 cycloalkyl, refers to a cycloalkyl group in which one or more hydrogens are replaced by halogen. Representative halocycloalkyls are 2,2-difluorocyclopropyl, 2,2,3,3-tetrafluorocyclopropyl, 2,3,4-trifluorocyclobutyl, and 2,4-difluorocyclopentyl.

[0046] The term "hydroxyalkyl" refers to -alkylene-OH.

[0047] In embodiments of Formula (I), groups (e.g., —C(O)OR Aor -C(O)N(R B )2) is R 2 is attached to the nitrogen atom in the alpha or ortho position. 2 It should be understood that when linking to, the following structure is intended: [ka]

[0048] It should be understood that each atom present in formula (I) and the compounds in formula (I) can be in any form of naturally occurring isotopes, but the most abundant isotope is preferred.Thus, for example, each hydrogen atom present in formula (I) or the formulas described later herein can be present as 1H, 2H (deuterium; D) or 3H (tritium; T) atom, but 1H is preferred.Similarly, for example, each carbon atom present in formula (I) or the formulas described later herein can be present as 12C, 13C or 14C atom, but 12C is preferred.

[0049] As used herein, an "effective amount" of a compound is an amount sufficient to negatively modulate or inhibit the activity of PI3K alpha.

[0050] As used herein, a "therapeutically effective amount" of a compound is an amount sufficient to ameliorate or in any way reduce symptoms, or to halt or reverse the progression of a disease state, or to negatively regulate or inhibit the activity of PI3K alpha. Such an amount may be administered as a single dose or according to an effective dosing regimen.

[0051] As used herein, "treatment" refers to any manner in which the symptoms or pathology of a condition, disorder, or disease are alleviated or other beneficial alteration is produced in a patient.

[0052] As used herein, "alleviating the symptoms of a particular disorder by administering a particular compound or pharmaceutical composition" refers to any relief, whether permanent or temporary, lasting or transient, that can result from or be associated with administration of the composition.

[0053] compound In some embodiments, the present disclosure provides a compound of formula (I): [ka] [In the formula, R 1 is H, C1-C3 alkyl, or C3-C6 cycloalkyl; R 2 is a phenyl or a 5- or 6-membered heteroaryl group, and each of the phenyl and heteroaryl groups is 12 substituted accordingly; Each R 12 are independently C1-C4 alkyl, -OR A , -C(O)OR A , (C1-C3 alkyl)-OR A , -C(O)N(R B )2, cyano, or halogen; Each R A are independently H, C1-C6 alkyl, or C3-C6 cycloalkyl; Each R B is independently H, —OH, C1-C6 alkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl; and R 3 is C1-C3 alkyl optionally substituted, polysubstituted, or fully substituted with fluoro, C3-C6 cycloalkyl, C1-C3 alkenyl, C2-C3 alkynyl, or C5-C6 cycloalkenyl; R 4 is H, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkenyl, C2-C3 alkynyl, or C5-C6 cycloalkenyl, cyano, or halo, each of which C1-C3 alkyl and C3-C6 cycloalkyl is optionally substituted with 1 to 5 halo groups; T is N or CR 6 and The R 6 is H or C1-C6 alkyl; Formula (Z): [ka] is the formula (E), (G), (J), (K), (L), or (M): [ka] represents each d represents a point of attachment to a bridgehead carbon bonded to T; In formula (E), both X and Y are CR 5 , or one of X and Y is CR 5 and the other is N: In formula (J), both X and Y are N; each ring A is a 4- to 8-membered carbocyclic ring or a 3- to 7-membered heterocyclic ring; Each R 5 are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogen, haloC1-C6 alkyl, cyano, hydroxy, hydroxyC1-C6 alkyl, amino, mono- or di(C1-C6 alkyl)amino, C3-C6 cycloalkyl, haloC3-C6 cycloalkyl, phenyl, or 5-6 membered heteroaryl, each of which alkyl and cycloalkyl is optionally substituted with 1-3 hydroxy, C1-C3 alkyl, C1-C3 alkoxy, cyano, amino, or mono- or di(C1-C3)alkylamino, and each of which phenyl and heteroaryl is optionally substituted with 1-3 halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, cyano, amino, or mono- or di(C1-C3)alkylamino; R 30 is -NR 7 NR 8 or R 31 represents R 31 teeth, (i) a 5- to 7-membered heteroaryl, or (ii) A 3- to 8-membered monocyclic heterocyclyl group bonded to a tricyclic ring via a carbon atom, and the heterocyclyl group is saturated or unsaturated, optionally fused to an aromatic or non-aromatic ring containing 3 to 6 ring members (one or two of which are nitrogen, oxygen, or sulfur atoms, as appropriate, and the remainder are carbon atoms); or the carbon atoms of the monocyclic heterocyclyl group together with the additional carbon or nitrogen atom form a spiro ring system having a total of up to 10 ring members, each of which is carbon or nitrogen; and The R 31 Each heteroaryl and heterocyclyl group in 39 group, and each R 39 are independently C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, haloC1-C3 alkyl, hydroxyC1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino, or phenyl, phenyl(C1-C3 alkanoyl), 5- to 7-membered heterocyclyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxy, cyano, amino, or mono- or di-(C1-C3 alkyl)amino; R 7 represents H or C1-C3 alkyl; R 8 represents H, or C1-C6 alkyl optionally substituted with a 5-8 membered heterocyclyl, C3-C6 cycloalkyl, or C3-C6 cycloalkyl (C1-C3 alkyl); or R 7 and R 8 together with the nitrogen to which it is attached form a ring Q, which ring Q is A 3- to 8-membered monocyclic heterocyclyl group containing one or two ring nitrogen atoms and only nitrogen heteroatoms, said heterocyclyl group being optionally fused to an aromatic or non-aromatic ring containing 3 to 6 ring members (one or two of which are nitrogen, oxygen, or sulfur atoms, as appropriate, and the remainder are carbon atoms); or the carbon atoms of the monocyclic heterocyclyl group together with the additional carbon or nitrogen atom form a spiro ring system having a total of up to 10 ring members, each of which is carbon or nitrogen (the spiro center of the spiro ring system is a carbon atom of the 3- to 7-membered monocyclic heterocyclyl group); and Each ring Q may contain 1 to 4 R 9 groups, and each R 9 are independently C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, haloC1-C3 alkyl, hydroxyC1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino, or phenyl, phenyl(C1-C3 alkanoyl), 5- to 7-membered heterocyclyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxy, cyano, amino, or mono- or di-(C1-C3 alkyl)amino. and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, deuterated forms, and tautomers thereof.

[0054] In certain embodiments of formula (I) described elsewhere herein, formula (Z) represents formula (E).

[0055] In certain embodiments of formula (I) described elsewhere herein, formula (Z) represents formula (G).

[0056] In certain embodiments of formula (I) described elsewhere herein, formula (Z) represents formula (J).

[0057] In certain embodiments of formula (I) described elsewhere herein, formula (Z) represents formula (K).

[0058] In certain embodiments of formula (I) described elsewhere herein, formula (Z) represents formula (L).

[0059] In certain embodiments of formula (I) described elsewhere herein, formula (Z) represents formula (M).

[0060] In certain embodiments of formula (I) described elsewhere herein, T is CR 6 Represents.

[0061] In certain embodiments of formula (I) described elsewhere herein, R 1 represents H or CH3.

[0062] In certain embodiments of formula (I) described elsewhere herein, R 2 is phenyl, pyridinyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, pyrazinyl, pyridazinyl, or pyrimidinyl, each of which is selected from 1 to 5 R 12 is substituted as appropriate.

[0063] In certain embodiments of formula (I) described elsewhere herein, R 2 is phenyl or pyridinyl, each of which has 1 to 5 R 12 is substituted as appropriate.

[0064] In certain embodiments of formula (I) described elsewhere herein, R 2 is phenyl or a 5- to 7-membered heteroaryl, each of which is substituted with 1, 2, 3, or 4 R 12 The group is substituted.

[0065] In certain embodiments of formula (I) described elsewhere herein, R 2 can contain one, two, or three R 12 It is a phenyl or 5- to 7-membered heteroaryl substituted with a group.

[0066] In certain embodiments of formula (I) described elsewhere herein, R 2 is phenyl or a 5- to 7-membered heteroaryl, each of which is substituted with 1, 2, 3, or 4 R 12 group and at least one R 12 The group is -C(O)OR A is.

[0067] In certain embodiments of formula (I) described elsewhere herein, R 2 can contain one, two, or three R 12 phenyl or 5- to 7-membered heteroaryl substituted with a group, and at least one R 12 The group is -C(O)OR A is.

[0068] In certain embodiments of formula (I) described elsewhere herein, R 2 is one -C(O)OR A and the -C(O)OR A is R 2 is attached to the nitrogen atom in the alpha position (i.e., ortho position) 2 is bonded to.

[0069] In certain embodiments of formula (I) described elsewhere herein, R 2 is phenyl or a 5- to 7-membered heteroaryl, each of which is substituted with 1, 2, 3, or 4 R 12 group and at least one R 12 The group is -C(O)OR A and -C(O)OR A is R 2 is attached to the nitrogen atom at the α-position, and R 2 is bonded to.

[0070] In certain embodiments of formula (I) described elsewhere herein, R 2 can contain one, two, or three R 12phenyl or 5- to 7-membered heteroaryl substituted with a group, and at least one R 12 The group is -C(O)OR A and -C(O)OR A is R 2 is attached to the nitrogen atom in the alpha position (i.e., ortho position) 2 is bonded to.

[0071] In certain embodiments of formula (I) described elsewhere herein, R 3 is a C1-C3 alkyl group, which is unsubstituted, substituted with 1 to 5 halo groups, or fully substituted.

[0072] In certain embodiments of formula (I) described elsewhere herein, R 2 can have 1, 2, 3, or 4 R's 12 and phenyl optionally substituted with a group.

[0073] In certain embodiments of formula (I) described elsewhere herein, R 2 can have 1, 2, 3, or 4 R's 12 and pyridinyl optionally substituted with a group.

[0074] In certain embodiments of formula (I) described elsewhere herein, R 2 can have 1, 2, 3, or 4 R's 12 and thienyl optionally substituted with a group.

[0075] In certain embodiments of formula (I) described elsewhere herein, R 2 can have 1, 2, 3, or 4 R's 12 and thiazolyl optionally substituted with a group.

[0076] In certain embodiments of formula (I) described elsewhere herein, R 2 can have 1, 2, 3, or 4 R's 12 and oxazolyl optionally substituted with a group.

[0077] In certain embodiments of formula (I) described elsewhere herein, R 2 can have 1, 2, 3, or 4 R's 12 is an isoxazolyl optionally substituted with a group.

[0078] In certain embodiments of formula (I) described elsewhere herein, R 2 can have 1, 2, 3, or 4 R's 12 and imidazolyl optionally substituted with a group.

[0079] In certain embodiments of formula (I) described elsewhere herein, R 2 can have 1, 2, 3, or 4 R's 12 and pyrazolyl optionally substituted with a group.

[0080] In certain embodiments of formula (I) described elsewhere herein, R 2 can have 1, 2, 3, or 4 R's 12 and pyrazinyl optionally substituted with a group.

[0081] In certain embodiments of formula (I) described elsewhere herein, R 2 can have 1, 2, 3, or 4 R's 12 and pyridazinyl optionally substituted with a group.

[0082] In certain embodiments of formula (I) described elsewhere herein, R 2 can have 1, 2, 3, or 4 R's 12 and pyrimidinyl optionally substituted with a group.

[0083] In certain embodiments of formula (I) described elsewhere herein, R 2 is one -C(O)OR A is substituted as appropriate.

[0084] In certain embodiments of formula (I) described elsewhere herein, R 4is hydrogen, fluoro, chloro, bromo, methyl, methoxy, ethyl, ethoxy, cyclopropyl, trifluoromethyl, or cyano.

[0085] In certain embodiments of formula (I) described elsewhere herein, R 4 is hydrogen, methyl, ethyl, or cyano.

[0086] In certain embodiments of formula (I) described elsewhere herein, R 4 is methoxy.

[0087] In certain embodiments of formula (I) described elsewhere herein, R 4 is fluoro, chloro, or bromo.

[0088] In certain embodiments of formula (I) described elsewhere herein, R 4 is hydrogen.

[0089] In certain embodiments of formula (I) described elsewhere herein, R 4 is fluoro.

[0090] In certain embodiments of formula (I) described elsewhere herein, R 4 is chloro.

[0091] In certain embodiments of formula (I) described elsewhere herein, R 4 is bromo.

[0092] In certain embodiments of formula (I) described elsewhere herein, R 4 is methyl.

[0093] In certain embodiments of formula (I) described elsewhere herein, R 4 is ethyl.

[0094] In certain embodiments of formula (I) described elsewhere herein, R 4 is cyano.

[0095] In certain embodiments of formula (I) described elsewhere herein, R 4 is cyclopropyl.

[0096] In certain embodiments of formula (I) described elsewhere herein, R 4 is trifluoromethyl.

[0097] In certain embodiments of formula (I) described elsewhere herein, two or more R 5 If there is one R 5 is hydrogen, and other R 5 is hydrogen, halogen, C3-C6 cycloalkyl, phenyl, or 5-6 membered heteroaryl, each of which is optionally substituted with 1-3 halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, cyano, amino, or mono- or di(C1-C3) alkylamino.

[0098] In certain embodiments of formula (I) described elsewhere herein, two or more R 5 If there is one R 5 is hydrogen, and other R 5 is hydrogen, halogen, C3-C6 cycloalkyl, phenyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with one or two halogen, hydroxy, C1-C2 alkyl, C1-C2 alkoxy, cyano, amino, or mono- or di(C1-C2)alkylamino.

[0099] In certain embodiments of formula (I) described elsewhere herein, one R 5 If there is R 5is hydrogen, halogen, C3-C6 cycloalkyl, phenyl, or 5-6 membered heteroaryl, each of which is optionally substituted with 1-3 halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, cyano, amino, or mono- or di(C1-C3) alkylamino.

[0100] In certain embodiments of formula (I) described elsewhere herein, one R 5 If there is R 5 is hydrogen, and other R 5 is halogen, C3-C6 cycloalkyl, phenyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with one or two halogen, hydroxy, C1-C2 alkyl, C1-C2 alkoxy, cyano, amino, or mono- or di(C1-C2)alkylamino.

[0101] In certain embodiments of formula (I) described elsewhere herein, one R 5 If there is R 5 is hydrogen, halogen, hydroxy, cyano, or amino.

[0102] In certain embodiments of formula (I) described elsewhere herein, two or more R 5 If there is one R 5 is hydrogen, and other R 5 is hydrogen, halogen, hydroxy, cyano, or amino.

[0103] In certain embodiments of formula (I) described elsewhere herein, R 2 is optionally substituted with phenyl.

[0104] In certain embodiments of formula (I) described elsewhere herein, R 2 is optionally substituted with pyridinyl.

[0105] In certain embodiments of formula (I) described elsewhere herein, R 7 is hydrogen, and R 8 represents hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkyl(C1-C3 alkyl).

[0106] In certain embodiments of formula (I) described elsewhere herein, R 7 and R 8 together with the nitrogen to which it is attached form a ring Q, which ring Q is a 3- to 7-membered monocyclic heterocyclyl group containing 1 or 2 ring nitrogen atoms (in certain embodiments, only nitrogen heteroatoms), and The heterocyclyl group may be one to four R 9 group, and each R 9 are independently C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, haloC1-C3 alkyl, hydroxyC1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino, or phenyl or phenyl(C1-C3 alkanoyl), each phenyl optionally substituted with C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxy, cyano, amino, or mono- or di-(C1-C3 alkyl)amino.

[0107] In certain embodiments of formula (I) described elsewhere herein, the group: [ka] is the base: [ka] [In the formula, a is 0, 1, 2, or 3; V is CR 14 or N; Each R 12 are independently C1-C4 alkyl, -OR A , -C(O)OR A,(C1-C3 alkyl)-OR A , -C(O)N(R B )2, cyano, or halogen; R 13 is (i) cyano, (ii) tetrazolyl, (iii) -C(O)OR A (In the formula, R A is H, C1-C6 alkyl, or C3-C6 cycloalkyl), or (iv) —C(O)N(R B )2(wherein, R B is H, —OH, C1-C6 alkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl; and R 14 is hydrogen, cyano, halogen, hydroxy, C1-C4 alkoxy, C1-C4 alkyl, -C(O)OR A , (C1-C3 alkyl)-OR A , or -C(O)N(R B )2] Represents.

[0108] In other embodiments of formula (I) described elsewhere herein, the group: [ka] is the base: [ka] [In the formula, V is CR 14 or N; Each R 12 are independently C1-C4 alkyl, -OR A , -C(O)OR A ,(C1-C3 alkyl)-OR A , -C(O)N(R B )2, cyano, or halogen; R 13 is (i) cyano, (ii) tetrazolyl, (iii) -C(O)OR A (In the formula, R Ais H, C1-C6 alkyl, or C3-C6 cycloalkyl), or (iv) —C(O)N(R B )2(wherein, R B is H, —OH, C1-C6 alkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl; and R 14 is hydrogen, cyano, halogen, hydroxy, C1-C4 alkoxy, C1-C4 alkyl, -C(O)OR A , (C1-C3 alkyl)-OR A , or -C(O)N(R B )2] Represents.

[0109] In certain embodiments of formula (I) described elsewhere herein, R 7 and R 8 together with the nitrogen to which it is attached form a ring Q, which ring Q is [ka] represents a nitrogen-containing ring selected from:

[0110] In certain embodiments of formula (I) described elsewhere herein, the nitrogen-containing ring Q contains only nitrogen atoms.

[0111] In certain embodiments of formula (I) described elsewhere herein, the nitrogen-containing ring Q contains one nitrogen atom and one other heteroatom selected from oxygen and sulfur. Examples of such groups include: [ka] wherein each R 39 is defined as for formula (I), and each v represents 0, 1, 2, 3, or 4.

[0112] In certain embodiments, the nitrogen-containing ring is independently substituted with 1, 2, or 3 halogens. In certain embodiments, the halogens are independently fluorine or chlorine atoms.

[0113] In certain embodiments, the nitrogen-containing ring is substituted with phenyl or phenyl(C1-C3 alkanoyl), each of which is optionally substituted with C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxy, cyano, amino, or mono- or di(C1-C3 alkyl)amino.

[0114] In certain embodiments of formula (I) described elsewhere herein, R 7 and R 8 together with the nitrogen to which it is attached form a ring Q, which ring Q is a 3- to 7-membered monocyclic heterocyclyl group optionally containing one or two ring nitrogen atoms and one or two additional heteroatoms selected from oxygen and sulfur, and the heterocyclyl group is fused to an aromatic or non-aromatic ring containing 3 to 6 ring members (one or two of which are optionally nitrogen and the remainder are carbon atoms); The fused heterocyclyl group may have 1 to 4 R 9 group, and each R 9 are independently C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, haloC1-C3 alkyl, hydroxyC1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino, or phenyl or phenyl(C1-C3 alkanoyl), each phenyl optionally substituted with C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxy, cyano, amino, or mono- or di-(C1-C3 alkyl)amino.

[0115] In certain embodiments of formula (I) described elsewhere herein, R 7 and R 8together with the nitrogen to which it is attached form a ring Q, which ring Q is [ka] wherein each v represents 0, 1, 2, 3, or 4; R 9 The group may be present on either ring.

[0116] In certain embodiments, the fused bicyclic group is independently substituted with 1, 2, 3, or 4 C1-C4 alkyl, C3-C6 cycloalkyl, C1-C3 haloalkyl, or halogen.

[0117] In certain embodiments, the fused bicyclic group is independently substituted with 1, 2, 3, or 4 halogen atoms. In certain embodiments, the halogen atoms are independently fluorine atoms or chlorine atoms. In other embodiments, the halogen atoms are fluorine atoms.

[0118] In other embodiments, the fused bicyclic group is substituted with phenyl or phenyl(C1-C3 alkanoyl), each phenyl optionally substituted with C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxy, cyano, amino, or mono- or di(C1-C3 alkyl)amino.

[0119] In certain embodiments of formula (I) described elsewhere herein, R 7 and R 8 together with the nitrogen to which it is attached form a 3- to 7-membered monocyclic heterocyclyl group containing one or two ring nitrogens (in certain embodiments, only nitrogen heteroatoms), and the heterocyclyl group, together with the carbon atom of the monocyclic heterocyclyl group and the additional carbon or nitrogen atom, forms a spiro ring system having up to a total of 10 ring members; The spiro ring system may comprise 1 to 4 R 9 group, and each R 9are independently C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, haloC1-C3 alkyl, hydroxyC1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino, or phenyl or phenyl(C1-C3 alkanoyl), each phenyl optionally substituted with C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxy, cyano, amino, or mono- or di-(C1-C3 alkyl)amino.

[0120] In certain embodiments of formula (I) described elsewhere herein, R 7 and R 8 represents a spiro ring system having, together with the nitrogen to which it is attached, one or two nitrogen atoms and a total of up to 10 ring members. A spiro ring system may have up to four R 9 Examples of such optionally substituted spiro ring systems include: [ka] wherein each v represents 0, 1, 2, 3, or 4; R 9 The group may be present on either ring.

[0121] In certain embodiments, the spiro ring system is independently substituted with 1, 2, 3, or 4 C1-C4 alkyl, C3-C6 cycloalkyl, C1-C3 haloalkyl, or halogen.

[0122] In certain embodiments, the spiro ring system is independently substituted with 1, 2, 3, or 4 halogen atoms. In certain embodiments, the halogen atoms are independently fluorine atoms or chlorine atoms. In other embodiments, the halogen atoms are fluorine atoms.

[0123] In certain embodiments, the spiro ring system is substituted with phenyl or phenyl(C1-C3 alkanoyl), each of which is optionally substituted with C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxy, cyano, amino, or mono- or di(C1-C3 alkyl)amino.

[0124] In certain embodiments of formula (I) described elsewhere herein, T is N.

[0125] In certain embodiments of formula (I) described elsewhere herein, T is CR 6 and R 6 is H or C1-C2 alkyl, especially methyl.

[0126] In certain embodiments of formula (I) described elsewhere herein, T is CR 6 and R 6 is H.

[0127] In certain embodiments of Formula (I) described elsewhere herein, the compound has the formula (II-e), (II-g), (II-j), (II-k), (II-l), or (II-m): [ka] or a pharmaceutically acceptable salt thereof.

[0128] In certain embodiments of formulas (II-e), (II-g), (II-j), (II-k), (II-l), and (II-m) described elsewhere herein, R 1 is H, C1-C3 alkyl, or C3-C6 cycloalkyl; R 2 is phenyl or pyridinyl, and each of the phenyl and pyridinyl groups is selected from 1 to 5 R 12 substituted accordingly; Each R 12 are independently C1-C4 alkyl; -OR A , -C(O)ORA , (C1-C3 alkyl)-OR A , -C(O)N(R B )2, cyano, or halogen; Each R A are independently H, C1-C6 alkyl, or C3-C6 cycloalkyl; Each R B are independently H, —OH, C1-C6 alkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl; and R 3 is C1-C3 alkyl or C3-C6 cycloalkyl; and R 4 is H, C1-C3 alkyl, C3-C6 cycloalkyl, cyano, or halo, each C1-C3 alkyl optionally substituted with 1 to 5 halo groups.

[0129] In certain embodiments of formulas (II-e), (II-g), (II-j), (II-k), (II-l), and (II-m) described elsewhere herein, T is N.

[0130] In certain embodiments of formulas (II-e), (II-g), (II-j), (II-k), (II-l), and (II-m) described elsewhere herein, T is CR 6 and R 6 is H or C1-C2 alkyl, especially methyl.

[0131] In certain embodiments of formulas (II-e), (II-g), (II-j), (II-k), (II-l), and (II-m) described elsewhere herein, T is CR 6 and R 6 is H.

[0132] In certain embodiments of formulas (II-e), (II-g), (II-j), (II-k), (II-l), and (II-m) described elsewhere herein, R 3 is C1-C3 alkyl.

[0133] In certain embodiments of formulas (II-e), (II-g), (II-j), (II-k), (II-l), and (II-m) described elsewhere herein, R 3 is methyl.

[0134] In certain embodiments of formulas (II-e), (II-g), (II-j), (II-k), (II-l), and (II-m) described elsewhere herein, R 4 is H, C1-C3 alkyl, C3-C4 cycloalkyl, or cyano.

[0135] In certain embodiments of formulas (II-e), (II-g), (II-j), (II-k), (II-l), and (II-m) described elsewhere herein, R 2 is one -C(O)OR A is substituted as appropriate.

[0136] In certain embodiments of formulas (II-e), (II-g), (II-j), (II-k), (II-l), and (II-m) described elsewhere herein, the group: [ka] The base: [ka] [In the formula, a is 0, 1, 2, or 3; V is CR 14 or N; Each R 12 are independently C1-C4 alkyl, -OR A , -C(O)OR A , (C1-C3 alkyl)-OR A , -C(O)N(R B )2, cyano, or halogen; R 13 is (i) cyano, (ii) tetrazolyl, (iii) -C(O)OR A (In the formula, R Ais H, C1-C6 alkyl, or C3-C6 cycloalkyl), or (iv) —C(O)N(R B )2(wherein, R B is H, —OH, C1-C6 alkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl; and R 14 is hydrogen, cyano, halogen, hydroxy, C1-C4 alkoxy, C1-C4 alkyl, -C(O)OR A , (C1-C3 alkyl)-OR A , or -C(O)N(R B )2] Represents.

[0137] In certain embodiments of formulas (II-e), (II-g), (II-j), (II-k), (II-l), and (II-m) described elsewhere herein, the group: [ka] The base: [ka] [In the formula, V is CR 14 or N; Each R 12 are independently C1-C4 alkyl, -OR A , -C(O)OR A , (C1-C3 alkyl)-OR A , -C(O)N(R B )2, cyano, or halogen; R 13 is (i) cyano, (ii) tetrazolyl, (iii) -C(O)OR A (In the formula, R A is H, C1-C6 alkyl, or C3-C6 cycloalkyl), or (iv) —C(O)N(R B )2(wherein, R B is H, —OH, C1-C6 alkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl; and R 14is hydrogen, cyano, halogen, hydroxy, C1-C4 alkoxy, C1-C4 alkyl, -C(O)OR A , (C1-C3 alkyl)-OR A , or -C(O)N(R B )2] Represents.

[0138] In certain embodiments of formulas (II-e), (II-g), (II-j), (II-k), (II-l), and (II-m) described elsewhere herein, R 7 is hydrogen and R 8 is hydrogen, C-C alkyl, C-C cycloalkyl, or C-C cycloalkyl (C. In certain embodiments of formulas (II-e), (II-g), (II-j), (II-k), (II-l), and (II-m) described elsewhere herein, R 7 and R 8 together with the nitrogen to which it is attached form a ring Q, and ring Q is a C1-C6 heterocyclyl.

[0139] In certain embodiments of formulas (II-e), (II-g), (II-j), (II-k), (II-l), and (II-m) described elsewhere herein, R 7 and R 8 together with the nitrogen to which it is attached, form a ring Q, and ring Q is aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, or azepanyl, each of which is substituted with one to two R 9 group, and each R 9are independently C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, haloC1-C3 alkyl, hydroxyC1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino, phenyl, 5- to 7-membered heterocyclyl, or 5- to 6-membered heteroaryl, and each of the phenyl, 5- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl is optionally substituted with C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxy, cyano, amino, or mono- or di-(C1-C3 alkyl)amino.

[0140] In certain embodiments of formulas (II-e), (II-g), (II-j), (II-k), (II-l), and (II-m) described elsewhere herein, R 7 and R 8 together with the nitrogen to which it is attached form ring Q, where ring Q is aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, or azepanyl, each of which is optionally substituted with 1, 2, 3, or 4 halogens.

[0141] In certain embodiments of formulas (II-e), (II-g), (II-j), (II-k), (II-l), and (II-m) described elsewhere herein, R 7 and R 8 together with the nitrogen to which it is attached, form ring Q, which is a 5-6 membered monocyclic heterocyclyl group containing 1 or 2 ring nitrogens (in certain embodiments, only nitrogen heteroatoms), and the heterocyclyl group is fused to an aromatic or non-aromatic ring containing 3 to 6 ring members (of which 1 or 2 are optionally nitrogen and the remainder are carbon atoms), and the fused ring system can have 1 to 4 R 9 group, and each R 9 are independently C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, haloC1-C3 alkyl, hydroxyC1-C6 alkyl, amino, or mono- or di-(C1-C6 alkyl)amino.

[0142] In certain embodiments of formulas (II-e), (II-g), (II-j), (II-k), (II-l), and (II-m) described elsewhere herein, the R 7 and R 8 together with the nitrogen to which it is attached form a ring Q, said ring Q having the formula: [ka] [In the formula, each ring A is a 3- to 6-membered carbocyclic ring or a 3- to 6-membered heterocyclic ring; m is 0, 1, 2, 3, or 4; n is 0, 1, or 2; p and r are independently 1 or 2, provided that their sum is 2 or 3; Each R 10 and R 11 are independently C1-C6 alkyl, C1-C6 alkoxy, halogen, cyano, hydroxy, hydroxyC1-C6 alkyl, amino, mono- or di(C1-C6 alkyl)amino, C3-C6 cycloalkyl, phenyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with 1 to 3 halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, cyano, amino, or mono- or di(C1-C3)alkylamino. It is a group represented by the formula:

[0143] In certain embodiments of formula (I) described elsewhere herein, the compound has formula (III): [ka] [In the formula, R 1 is H, C1-C3 alkyl, or C3-C6 cycloalkyl; R 3is C1-C3 alkyl optionally substituted, polysubstituted, or fully substituted with fluoro, C3-C6 cycloalkyl, C2-C3 alkenyl, C2-C3 alkynyl, or C5-C6 cycloalkenyl; R 4 is H, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C2-C3 alkenyl, C2-C3 alkynyl, or C5-C6 cycloalkenyl, cyano, or halo, each of which C1-C3 alkyl and C3-C6 cycloalkyl is optionally substituted with 1 to 5 halo groups; a is 0, 1, 2, or 3; V is CR 14 or N; Each R 12 are independently C1-C4 alkyl, -OR A , -C(O)OR A , (C1-C3 alkyl)-OR A , -C(O)N(R B )2, cyano, or halogen; R 13 is (i) cyano, (ii) tetrazolyl, (iii) -C(O)OR A (In the formula, R A is H, C1-C6 alkyl, or C3-C6 cycloalkyl), or (iv) —C(O)N(R B )2(wherein, R B is H, —OH, C1-C6 alkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl; R 14 is hydrogen, cyano, halogen, hydroxy, C1-C4 alkoxy, C1-C4 alkyl, -C(O)OR A , (C1-C3 alkyl)-OR A , or -C(O)N(R B )2; Q represents a 4-8 membered saturated or unsaturated monocyclic, bicyclic, or polycyclic heterocyclyl group having 0, 1, or 2 additional ring heteroatoms selected from oxygen and nitrogen; b is 0, 1, 2, 3, or 4; Each R9 are independently C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, haloC1-C3 alkyl, hydroxyC1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino, or phenyl, phenyl(C1-C3 alkanoyl), 5- to 7-membered heterocyclyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxy, cyano, amino, or mono- or di-(C1-C3 alkyl)amino; and R 51 and R 52 independently represent hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogen, haloC1-C6 alkyl, cyano, hydroxy, hydroxyC1-C6 alkyl, amino, mono- or di(C1-C6 alkyl)amino, C3-C6 cycloalkyl, haloC3-C6 cycloalkyl, phenyl, or 5- to 6-membered heteroaryl, each alkyl and cycloalkyl optionally substituted with 1 to 3 hydroxy, C1-C3 alkyl, C1-C3 alkoxy, cyano, amino, or mono- or di(C1-C3)alkylamino, and each phenyl and heteroaryl optionally substituted with 1 to 3 halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, cyano, amino, or mono- or di(C1-C3)alkylamino. or a pharmaceutically acceptable salt thereof, or a deuterated version thereof.

[0144] In certain embodiments of Formula (III), R 1 is H or CH3 (embodiment 3-1).

[0145] In certain embodiments of Formula (III) or Embodiment 3-1, R 3 is C1-C3 alkyl, and the alkyl group is unsubstituted, substituted with 1 to 5 halo groups, or fully substituted (embodiment 3-2).

[0146] In certain embodiments of Formula (III) or Embodiment 3-1, R 3 is methyl (embodiment 3-3).

[0147] In certain embodiments of Formula (III) or Embodiments 3-1 through 3-3, R 4 is hydrogen (embodiment 3-4).

[0148] In certain embodiments of Formula (III) or Embodiments 3-1 through 3-3, R 4 is methyl (embodiments 3-5).

[0149] In certain embodiments of Formula (III) or Embodiments 3-1 through 3-3, R 4 is ethyl (Embodiments 3-5A).

[0150] In certain embodiments of Formula (III) or Embodiments 3-1 through 3-3, R 4 is cyclopropyl (Embodiments 3-5B).

[0151] In certain embodiments of Formula (III) or Embodiments 3-1 through 3-3, R 4 is methoxy (Embodiments 3-5C).

[0152] In certain embodiments of Formula (III) or Embodiments 3-1 through 3-3, R 4 is fluoro (embodiments 3-6).

[0153] In certain embodiments of Formula (III) or Embodiments 3-1 through 3-3, R 4 is chloro (embodiments 3-7).

[0154] In certain embodiments of Formula (III) or Embodiments 3-1 through 3-3, R 4 is bromo (embodiments 3-8).

[0155] In certain embodiments of Formula (III) or Embodiments 3-1 through 3-8, V is CR 12 (Embodiment 3-9).

[0156] In certain embodiments of Formula (III) or Embodiments 3-1 through 3-8, V is N (Embodiment 3-10).

[0157] In certain embodiments of Formula (III) or Embodiments 3-1 through 3-9, V is CH, a is 1, and R 12 is hydrogen, C1-C3 alkyl, or halogen (embodiments 3-11).

[0158] In certain embodiments of Formula (III) or Embodiments 3-1 through 3-9, V is CH, a is 1, and R 12 is hydrogen, methyl, chloro, bromo, or fluoro (embodiments 3-12).

[0159] In certain embodiments of Formula (III) or Embodiments 3-1 through 3-9, V is CH, a is 1, and R 12 is hydrogen (embodiment 3-13).

[0160] In certain embodiments of Formula (III) or Embodiments 3-1 through 3-9, V is CH, a is 1, and R 12 is chloro (embodiments 3-14).

[0161] In certain embodiments of Formula (III) or Embodiments 3-1 through 3-9, V is CH, a is 1, and R 12 is bromo (embodiments 3-15).

[0162] In certain embodiments of Formula (III) or Embodiments 3-1 through 3-9, V is CH, a is 1, and R 12 is methyl (embodiment 3-15.1).

[0163] In certain embodiments of Formula (III) or Embodiments 3-1 through 3-9, V is CH, a is 1, and R 12 is fluoro (embodiment 3-16).

[0164] In certain embodiments of Formula (III), or embodiments 3-1 through 3-8 or 3-10, V is N, a is 1, and R 12 is hydrogen, C1-C3 alkyl, or halogen (embodiments 3-17).

[0165] In certain embodiments of Formula (III), or embodiments 3-1 through 3-8 or 3-10, V is N, a is 1, and R 12 is hydrogen, methyl, chloro, bromo, or fluoro (embodiments 3-18).

[0166] In certain embodiments of Formula (III), or embodiments 3-1 through 3-8 or 3-10, V is N, a is 1, and R 12 is hydrogen (embodiment 3-19).

[0167] In certain embodiments of Formula (III), or embodiments 3-1 through 3-8 or 3-10, V is N, a is 1, and R 12 is chloro (embodiment 3-20).

[0168] In certain embodiments of Formula (III), or embodiments 3-1 through 3-8 or 3-10, V is N, a is 1, and R 12 is bromo (embodiment 3-21).

[0169] In certain embodiments of Formula (III), or embodiments 3-1 through 3-8 or 3-10, V is N, a is 1, and R 12 is methyl (embodiment 3-21.1).

[0170] In certain embodiments of Formula (III), or embodiments 3-1 through 3-8 or 3-10, V is N, a is 1, and R 12 is fluoro (embodiment 3-22).

[0171] In certain embodiments of Formula (III) or Embodiments 3-1 through 3-22, R 51 and R 52 independently represent hydrogen, C1-C3 alkyl, cyano, halogen, cyclopropyl, or halo(C1-C6)alkyl (embodiments 3-23).

[0172] In certain embodiments of Formula (III) or Embodiments 3-1 through 3-22, R 51 and R 52 is hydrogen and the other is methyl, ethyl, cyano, halogen, cyclopropyl, or halo(C1-C6)alkyl (embodiments 3-24).

[0173] In certain embodiments of Formula (III) or Embodiments 3-1 through 3-22, R 51 is hydrogen and R 52 is methyl, ethyl, cyano, halogen, cyclopropyl, or halo(C1-C6)alkyl (embodiments 3-25).

[0174] In certain embodiments of Formula (III) or Embodiments 3-1 through 3-22, R 51 is hydrogen and R 52 is methyl, ethyl, cyano, halogen, cyclopropyl, difluoromethyl, or trifluoromethyl (embodiments 3-26).

[0175] In certain embodiments of Formula (III) or Embodiments 3-1 through 3-22, R 52 is hydrogen and R 51 is methyl, ethyl, cyano, halogen, cyclopropyl, or halo(C1-C6)alkyl (embodiments 3-27).

[0176] In certain embodiments of Formula (III) or Embodiments 3-1 through 3-22, R 52 is hydrogen and R 51 is methyl, ethyl, cyano, halogen, cyclopropyl, difluoromethyl, or trifluoromethyl (embodiments 3-28).

[0177] In certain embodiments of Formula (III) or Embodiments 3-1 through 3-28, Q is selected from the formula: [ka] [In the formula, each b is 0, 1, or 2; D is C(R 29 )2, W, O, NR 19 , or C(R 29 )2, and R 19 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, haloC1-C3 alkyl, hydroxyC1-C6 alkyl, or amino- or mono- or di-(C1-C6 alkyl)amino(C1-C6 alkyl); and Each R 29 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, haloC1-C3 alkyl, hydroxyC1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino. (Embodiment 3-29).

[0178] In certain embodiments of embodiments 3-29, W is oxygen, b is 0 or 1, and R 9 is methyl or cyano (embodiments 3-30).

[0179] In certain embodiments of embodiment 3-29, W is oxygen and b is 0 (embodiment 3-31).

[0180] In certain embodiments of embodiments 3-29, D and W are C(R 29 )2, b is 0, and each R 29 are independently hydrogen, C1-C2 alkyl, C1-C2 alkoxy, cyclopropyl, cyano, hydroxy, halogen, haloC1-C2 alkyl, hydroxyC1-C2 alkyl, amino, mono- or di-(C1-C2 alkyl)amino (embodiments 3-32).

[0181] In certain embodiments of embodiments 3-29, D and W are C(R 29 )2, b is 0, and each R 29 is independently hydrogen, methyl, methoxy, cyano, hydroxy, chloro, fluoro, amino, methylamino, or dimethylamino (embodiments 3-33).

[0182] In certain embodiments of embodiments 3-29, D and W are C(R 29 )2, b is 0, and each R 29 is independently chloro or fluoro (embodiments 3-34).

[0183] In certain embodiments of embodiments 3-29, D and W are C(R 29 )2, b is 0, and each R 29 is fluoro (embodiment 3-35).

[0184] In certain embodiments of embodiments 3-29, D and W are C(R 29 )2, b is 0, and each R 29 is hydrogen (embodiment 3-36).

[0185] In certain embodiments of Formula (III) or Embodiments 3-1 through 3-28, Q is selected from the formula: [ka] [In the formula, each b is 0, 1, or 2; and W, O, NR 19, or C(R 29 )2, The R 19 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, haloC1-C3 alkyl, hydroxyC1-C6 alkyl, or amino- or mono- or di-(C1-C6 alkyl)amino(C1-C6 alkyl); and Each R 29 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, haloC1-C3 alkyl, hydroxyC1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino. (Embodiment 3-37).

[0186] In certain embodiments of embodiments 3-37, W is oxygen, b is 0 or 1, and R 9 is methyl or cyano (embodiments 3-38).

[0187] In certain embodiments of embodiments 3-37, W is oxygen and b is 0 (embodiments 3-39).

[0188] In certain embodiments of embodiments 3-37, W is C(R 29 ) 2, b is 0, and each R 29 are independently hydrogen, C1-C2 alkyl, C1-C2 alkoxy, cyclopropyl, cyano, hydroxy, halogen, haloC1-C2 alkyl, hydroxyC1-C2 alkyl, amino, mono- or di-(C1-C2 alkyl)amino (embodiments 3-40).

[0189] In certain embodiments of embodiments 3-37, W is C(R 29 ) 2, b is 0, and each R 29 is independently hydrogen, methyl, methoxy, cyano, hydroxy, chloro, fluoro, amino, methylamino, or dimethylamino (embodiments 3-41).

[0190] In certain embodiments of embodiments 3-37, W is C(R 29 ) 2, b is 0, and each R 29 is independently chloro or fluoro (embodiments 3-42).

[0191] In certain embodiments of embodiments 3-37, W is C(R 29 ) 2, b is 0, and each R 29 is fluoro (embodiment 3-43).

[0192] In certain embodiments of embodiments 3-37, W is C(R 29 ) 2, b is 0, and each R 29 is hydrogen (embodiment 3-44).

[0193] In certain embodiments of Formula (III) or Embodiments 3-1 through 3-28, Q is selected from the formula: TIFF2026504483000025.tif32160 [In the formula, each b is 0, 1, or 2; and W, O, NR 19 , or C(R 29 )2, The R 19 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, haloC1-C3 alkyl, hydroxyC1-C6 alkyl, or amino- or mono- or di-(C1-C6 alkyl)amino(C1-C6 alkyl); and Each R 29 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, haloC1-C3 alkyl, hydroxyC1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino. (Embodiment 3-45).

[0194] In certain embodiments of embodiments 3-45, W is oxygen, b is 0 or 1, and R 9is methyl, chloro, fluoro, or cyano (embodiments 3-46).

[0195] In certain embodiments of embodiments 3-45, W is oxygen and b is 0 (embodiment 3-47).

[0196] In certain embodiments of embodiments 3-45, W is C(R 29 ) 2, b is 0, and each R 29 are independently hydrogen, C1-C2 alkyl, C1-C2 alkoxy, cyclopropyl, cyano, hydroxy, halogen, haloC1-C2 alkyl, hydroxyC1-C2 alkyl, amino, mono- or di-(C1-C2 alkyl)amino (embodiments 3-48).

[0197] In certain embodiments of embodiments 3-45, W is C(R 29 ) 2, b is 0, and each R 29 is independently hydrogen, methyl, methoxy, cyano, hydroxy, chloro, fluoro, amino, methylamino, or dimethylamino (embodiments 3-49).

[0198] In certain embodiments of embodiments 3-45, W is C(R 29 ) 2, b is 0, and each R 29 is independently chloro or fluoro (embodiments 3-50).

[0199] In certain embodiments of embodiments 3-45, W is C(R 29 ) 2, b is 0, and each R 29 is fluoro (embodiment 3-51).

[0200] In certain embodiments of embodiments 3-45, W is C(R 29 ) 2, b is 0, and each R 29 is hydrogen (embodiment 3-52).

[0201] In certain embodiments of formula (I) described elsewhere herein, the compound has formula (IV): [ka] [In the formula, R 1 is H, C1-C3 alkyl, or C3-C6 cycloalkyl; R 3 is C1-C3 alkyl optionally substituted, polysubstituted, or fully substituted with fluoro, C3-C6 cycloalkyl, C2-C3 alkenyl, C2-C3 alkynyl, or C5-C6 cycloalkenyl; R 4 is H, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C2-C3 alkenyl, C2-C3 alkynyl, or C5-C6 cycloalkenyl, cyano, or halo, each of which C1-C3 alkyl and C3-C6 cycloalkyl is optionally substituted with 1 to 5 halo groups; a is 0, 1, 2, or 3; V is CR 14 or N; Each R 12 are independently C1-C4 alkyl, -OR A , -C(O)OR A , (C1-C3 alkyl)-OR A , -C(O)N(R A )2, cyano, or halogen; R 13 is (i) cyano, (ii) tetrazolyl, (iii) -C(O)OR A (In the formula, R A is H, C1-C6 alkyl, or C3-C6 cycloalkyl), or (iv) —C(O)N(R B )2(wherein, R B is H, —OH, C1-C6 alkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl; R 14 is hydrogen, cyano, halogen, hydroxy, C1-C4 alkoxy, C1-C4 alkyl, -C(O)OR A, (C1-C3 alkyl)-OR A , or -C(O)N(R B )2; Q represents a 4-8 membered saturated or unsaturated monocyclic, bicyclic, or polycyclic heterocyclyl group having 0, 1, or 2 additional ring heteroatoms selected from oxygen and nitrogen; b is 0, 1, 2, 3, or 4; Each R 9 are independently C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, haloC1-C3 alkyl, hydroxyC1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino, or phenyl, phenyl(C1-C3 alkanoyl), 5- to 7-membered heterocyclyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxy, cyano, amino, or mono- or di-(C1-C3 alkyl)amino; and R 52 represents hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogen, cyano, hydroxy, hydroxyC1-C6 alkyl, amino, mono- or di(C1-C6 alkyl)amino, C3-C6 cycloalkyl, phenyl, or 5- or 6-membered heteroaryl, each of which is optionally substituted with 1 to 3 halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, cyano, amino, or mono- or di(C1-C3)alkylamino. or a pharmaceutically acceptable salt thereof, or a deuterated version thereof.

[0202] In certain embodiments of Formula (IV), R 1 is H or CH3 (embodiment 4-1).

[0203] In certain embodiments of Formula (IV) or Embodiment 4-1, R3 is a C1-C3 alkyl group, which is unsubstituted, substituted with 1 to 5 halo groups, or fully substituted (embodiment 4-2).

[0204] In certain embodiments of Formula (IV) or Embodiment 4-1, R 3 is methyl (embodiment 4-3).

[0205] In certain embodiments of Formula (IV) or Embodiments 4-1 through 4-3, R 4 is hydrogen (embodiment 4-4).

[0206] In certain embodiments of Formula (IV) or Embodiments 4-1 through 4-3, R 4 is methyl (embodiments 4-5).

[0207] In certain embodiments of Formula (IV) or Embodiments 4-1 through 4-3, R 4 is ethyl (embodiments 4-6).

[0208] In certain embodiments of Formula (IV) or Embodiments 4-1 through 4-3, R 4 is cyclopropyl (embodiments 4-7).

[0209] In certain embodiments of Formula (IV) or Embodiments 4-1 through 4-3, R 4 is methoxy (embodiments 4-8).

[0210] In certain embodiments of Formula (IV) or Embodiments 4-1 through 4-3, R 4 is fluoro (embodiments 4-9).

[0211] In certain embodiments of Formula (IV) or Embodiments 4-1 through 4-3, R 4 is chloro (embodiments 4-10).

[0212] In certain embodiments of Formula (IV) or Embodiments 4-1 through 4-3, R 4 is bromo (embodiments 4-11).

[0213] In certain embodiments of Formula (IV) or Embodiments 4-1 through 4-8, V is CR 12 (Embodiment 4-12).

[0214] In certain embodiments of Formula (IV) or Embodiments 4-1 through 4-8, V is N (Embodiment 4-13).

[0215] In certain embodiments of Formula (IV) or Embodiments 4-1 through 4-12, V is CH, a is 1, and R 12 is hydrogen, C1-C3 alkyl, or halogen (embodiments 4-14).

[0216] In certain embodiments of Formula (IV) or Embodiments 4-1 through 4-12, V is CH, a is 1, and R 12 is hydrogen, methyl, chloro, bromo, or fluoro (embodiments 4-15).

[0217] In certain embodiments of Formula (IV) or Embodiments 4-1 through 4-12, V is CH, a is 1, and R 12 is hydrogen (embodiments 4-16).

[0218] In certain embodiments of Formula (IV) or Embodiments 4-1 through 4-12, V is CH, a is 1, and R 12 is chloro (embodiment 4-17).

[0219] In certain embodiments of Formula (IV) or Embodiments 4-1 through 4-12, V is CH, a is 1, and R 12 is bromo (embodiment 4-18).

[0220] In certain embodiments of Formula (IV) or Embodiments 4-1 through 4-12, V is CH, a is 1, and R 12 is methyl (embodiment 4-18.1).

[0221] In certain embodiments of Formula (IV) or Embodiments 4-1 through 4-12, V is CH, a is 1, and R 12 is fluoro (embodiment 4-19).

[0222] In certain embodiments of Formula (IV), or embodiments 4-1 through 4-11 or 4-13, V is N, a is 1, and R 12 is hydrogen, C1-C3 alkyl, or halogen (embodiments 4-20).

[0223] In certain embodiments of Formula (IV), or embodiments 4-1 through 4-11 or 4-13, V is N, a is 1, and R 12 is hydrogen, methyl, chloro, bromo, or fluoro (embodiments 4-21).

[0224] In certain embodiments of Formula (IV), or embodiments 4-1 through 4-11 or 4-13, V is N, a is 1, and R 12 is hydrogen (embodiment 4-22).

[0225] In certain embodiments of Formula (IV), or embodiments 4-1 through 4-11 or 4-13, V is N, a is 1, and R 12 is chloro (embodiment 4-23).

[0226] In certain embodiments of Formula (IV), or embodiments 4-1 through 4-11 or 4-13, V is N, a is 1, and R 12 is bromo (embodiment 4-24).

[0227] In certain embodiments of Formula (IV), or embodiments 4-1 through 4-11 or 4-13, V is N, a is 1, and R 12 is methyl (embodiment 4-24.1).

[0228] In certain embodiments of Formula (IV), or embodiments 4-1 through 4-11 or 4-13, V is N, a is 1, and R 12 is fluoro (embodiment 4-25).

[0229] In certain embodiments of Formula (IV) or Embodiments 4-1 through 4-25, R 52 represents hydrogen, C1-C3 alkyl, cyano, halogen, cyclopropyl, or halo(C1-C6)alkyl (embodiments 4-26).

[0230] In certain embodiments of Formula (IV) or Embodiments 4-1 through 4-25, R 52 is hydrogen, methyl, ethyl, cyano, halogen, cyclopropyl, or halo(C1-C6)alkyl (embodiments 4-27).

[0231] In certain embodiments of Formula (IV) or Embodiments 4-1 through 4-25, R 52 is methyl, ethyl, cyano, halogen, cyclopropyl, or halo(C1-C6)alkyl (embodiments 4-28).

[0232] In certain embodiments of Formula (IV) or Embodiments 4-1 through 4-25, R 52 is methyl, ethyl, cyano, halogen, cyclopropyl, difluoromethyl, or trifluoromethyl (embodiments 4-29).

[0233] In certain embodiments of Formula (IV) or Embodiments 4-1 through 4-25, R 52 is hydrogen (embodiment 4-30).

[0234] In certain embodiments of Formula (IV) or Embodiments 4-1 through 4-25, R 52 is difluoromethyl or trifluoromethyl (embodiment 4-31).

[0235] In certain embodiments of Formula (IV) or Embodiments 4-1 through 4-31, Q has the formula: [ka] [In the formula, each b is 0, 1, or 2; and D is C(R 29 )2, W, O, NR 19 , or C(R 29 )2, and R 19 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, haloC1-C3 alkyl, hydroxyC1-C6 alkyl, or amino-, mono-, or di-(C1-C6 alkyl)amino(C1-C6 alkyl); and Each R 29 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, haloC1-C3 alkyl, hydroxyC1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino. (Embodiment 4-32).

[0236] In certain embodiments of embodiments 4-32, W is oxygen, b is 0 or 1, and R 9 is methyl or cyano (embodiment 4-33).

[0237] In certain embodiments of embodiment 4-32, W is oxygen and b is 0 (embodiment 4-34).

[0238] In certain embodiments of embodiments 4-32, D and W are C(R 29 )2, b is 0, and each R 29 are independently hydrogen, C1-C2 alkyl, C1-C2 alkoxy, cyclopropyl, cyano, hydroxy, halogen, haloC1-C2 alkyl, hydroxyC1-C2 alkyl, amino, mono- or di-(C1-C2 alkyl)amino (embodiments 4-35).

[0239] In certain embodiments of embodiments 4-32, D and W are C(R 29 )2, b is 0, and each R 29 is independently hydrogen, methyl, methoxy, cyano, hydroxy, chloro, fluoro, amino, methylamino, or dimethylamino (embodiments 4-36).

[0240] In certain embodiments of embodiments 4-32, D and W are C(R 29 )2, b is 0, and each R 29 is independently chloro or fluoro (embodiment 4-).

[0241] In certain embodiments of embodiments 4-32, D and W are C(R 29 )2, b is 0, and each R 29 is fluoro (embodiment 4-37).

[0242] In certain embodiments of embodiments 4-32, D and W are C(R 29 )2, b is 0, and each R 29 is hydrogen (embodiment 4-38).

[0243] In certain embodiments of Formula (IV) or Embodiments 4-1 through 4-31, Q is selected from the formula: [ka] [In the formula, each b is 0, 1, or 2; and W, O, NR 19 , or C(R 29 )2, The R 19 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, haloC1-C3 alkyl, hydroxyC1-C6 alkyl, or amino- or mono- or di-(C1-C6 alkyl)amino(C1-C6 alkyl); and Each R 29are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, haloC1-C3 alkyl, hydroxyC1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino. (Embodiment 4-39).

[0244] In certain embodiments of embodiments 4-39, W is oxygen, b is 0 or 1, and R 9 is methyl or cyano (embodiments 4-40).

[0245] In certain embodiments of embodiment 4-39, W is oxygen and b is 0 (embodiment 4-41).

[0246] In certain embodiments of embodiments 4-39, W is C(R 29 ) 2, b is 0, and each R 29 are independently hydrogen, C1-C2 alkyl, C1-C2 alkoxy, cyclopropyl, cyano, hydroxy, halogen, haloC1-C2 alkyl, hydroxyC1-C2 alkyl, amino, mono- or di-(C1-C2 alkyl)amino (embodiments 4-42).

[0247] In certain embodiments of embodiments 4-39, W is C(R 29 ) 2, b is 0, and each R 29 is independently hydrogen, methyl, methoxy, cyano, hydroxy, chloro, fluoro, amino, methylamino, or dimethylamino (embodiments 4-43).

[0248] In certain embodiments of embodiments 4-39, W is C(R 29 ) 2, b is 0, and each R 29 is independently chloro or fluoro (embodiments 4-44).

[0249] In certain embodiments of embodiments 4-39, W is C(R 29) 2, b is 0, and each R 29 is fluoro (embodiments 4-45).

[0250] In certain embodiments of embodiments 4-39, W is C(R 29 ) 2, b is 0, and each R 29 is hydrogen (embodiment 4-46).

[0251] In certain embodiments of Formula (IV) or Embodiments 4-1 through 4-31, Q is selected from the formula: [ka] [In the formula, each b is 0, 1, or 2; and W, O, NR 19 , or C(R 29 )2, The R 19 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, haloC1-C3 alkyl, hydroxyC1-C6 alkyl, or amino- or mono- or di-(C1-C6 alkyl)amino(C1-C6 alkyl); and Each R 29 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, haloC1-C3 alkyl, hydroxyC1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino. (Embodiment 4-47).

[0252] In certain embodiments of embodiments 4-47, W is oxygen, b is 0 or 1, and R 9 is methyl, chloro, fluoro, or cyano (embodiments 4-48).

[0253] In certain embodiments of Embodiments 4-47, W is oxygen and b is 0 (Embodiments 4-49).

[0254] In certain embodiments of embodiments 4-47, W is C(R 29 ) 2, b is 0, and each R 29 are independently hydrogen, C1-C2 alkyl, C1-C2 alkoxy, cyclopropyl, cyano, hydroxy, halogen, haloC1-C2 alkyl, hydroxyC1-C2 alkyl, amino, mono- or di-(C1-C2 alkyl)amino (embodiments 4-50).

[0255] In certain embodiments of embodiments 4-47, W is C(R 29 ) 2, b is 0, and each R 29 is independently hydrogen, methyl, methoxy, cyano, hydroxy, chloro, fluoro, amino, methylamino, or dimethylamino (embodiments 4-51).

[0256] In certain embodiments of embodiments 4-47, W is C(R 29 ) 2, b is 0, and each R 29 is independently chloro or fluoro (embodiments 4-52).

[0257] In certain embodiments of embodiments 4-47, W is C(R 29 ) 2, b is 0, and each R 29 is fluoro (embodiment 4-53).

[0258] In certain embodiments of embodiments 4-47, W is C(R 29 ) 2, b is 0, and each R 29 is hydrogen (embodiment 4-54).

[0259] In certain embodiments of formula (I) described elsewhere herein, the compound has formula (III-A): [ka] [In the formula, R 1 is H, C1-C3 alkyl, or C3-C6 cycloalkyl; R 3 is C1-C3 alkyl optionally substituted, polysubstituted, or fully substituted with fluoro, C3-C6 cycloalkyl, C2-C3 alkenyl, C2-C3 alkynyl, or C5-C6 cycloalkenyl; R 4 is H, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C2-C3 alkenyl, C2-C3 alkynyl, or C5-C6 cycloalkenyl, cyano, or halo, each of which C1-C3 alkyl and C3-C6 cycloalkyl is optionally substituted with 1 to 5 halo groups; a is 0, 1, 2, or 3; V is CR 14 or N; Each R 12 are independently C1-C4 alkyl, -OR A , -C(O)OR A , (C1-C3 alkyl)-OR A , -C(O)N(R A )2, cyano, or halogen; R 13 is (i) cyano, (ii) tetrazolyl, (iii) -C(O)OR A (In the formula, R A is H, C1-C6 alkyl, or C3-C6 cycloalkyl), or (iv) —C(O)N(R B )2(wherein, R B is H, —OH, C1-C6 alkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl; R 14 is hydrogen, cyano, halogen, hydroxy, C1-C4 alkoxy, C1-C4 alkyl, -C(O)OR A , (C1-C3 alkyl)-OR A , or -C(O)N(R B )2; Q represents a 4-8 membered saturated or unsaturated monocyclic, bicyclic, or polycyclic heterocyclyl group having 0, 1, or 2 additional ring heteroatoms selected from oxygen and nitrogen; b is 0, 1, 2, 3, or 4; and Each R 9 are independently C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, haloC1-C3 alkyl, hydroxyC1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino, or phenyl, phenyl(C1-C3 alkanoyl), 5- to 7-membered heterocyclyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxy, cyano, amino, or mono- or di-(C1-C3 alkyl)amino. or a pharmaceutically acceptable salt thereof, or a deuterated version thereof.

[0260] In certain embodiments of Formula (III-A), R 1 is H or CH3 (embodiment 3A-1).

[0261] In certain embodiments of Formula (III-A) or Embodiment 3A-1, R 3 is C1-C3 alkyl, which is unsubstituted, substituted with 1 to 5 halo groups, or fully substituted (embodiment 3A-2).

[0262] In certain embodiments of Formula (III-A) or Embodiment 3A-1, R 3 is methyl (embodiment 3A-3).

[0263] In certain embodiments of Formula (III-A) or Embodiments 3A-1 through 3A-3, R 4 is hydrogen (embodiment 3A-4).

[0264] In certain embodiments of Formula (III-A) or Embodiments 3A-1 through 3A-3, R 4 is methyl (embodiment 3A-5).

[0265] In certain embodiments of Formula (III-A) or Embodiments 3A-1 through 3A-3, R 4 is fluoromethyl (embodiment 3A-5.1).

[0266] In certain embodiments of Formula (III-A) or Embodiments 3A-1 through 3A-3, R 4 is difluoromethyl (embodiment 3A-5.2).

[0267] In certain embodiments of Formula (III-A) or Embodiments 3A-1 through 3A-3, R 4 is trifluoromethyl (embodiment 3A-5.3).

[0268] In certain embodiments of Formula (III-A) or Embodiments 3A-1 through 3A-3, R 4 is ethyl (embodiment 3A-6).

[0269] In certain embodiments of Formula (III-A) or Embodiments 3A-1 through 3A-3, R 4 is cyclopropyl (embodiment 3A-7).

[0270] In certain embodiments of Formula (III-A) or Embodiments 3A-1 through 3A-3, R 4 is methoxy (embodiment 3A-8).

[0271] In certain embodiments of Formula (III-A) or Embodiments 3A-1 through 3A-3, R 4 is fluoro (embodiment 3A-9).

[0272] In certain embodiments of Formula (III-A) or Embodiments 3A-1 through 3A-3, R 4 is chloro (embodiment 3A-10).

[0273] In certain embodiments of Formula (III-A) or Embodiments 3A-1 through 3A-3, R 4 is bromo (embodiment 3A-11).

[0274] In certain embodiments of Formula (III-A) or Embodiments 3A-1 through 3A-8, V is CR 12 (Embodiment 3A-12).

[0275] In certain embodiments of Formula (III-A) or Embodiments 3A-1 through 3A-8, V is N (Embodiment 3A-13).

[0276] In certain embodiments of Formula (III-A) or Embodiments 3A-1 through 3A-12, V is CH, a is 1, and R 12 is hydrogen, C1-C3 alkyl, or halogen (embodiments 3A-14).

[0277] In certain embodiments of Formula (III-A) or Embodiments 3A-1 through 3A-12, V is CH, a is 1, and R 12 is hydrogen, methyl, chloro, bromo, or fluoro (embodiment 3A-15).

[0278] In certain embodiments of Formula (III-A) or Embodiments 3A-1 through 3A-12, V is CH, a is 1, and R 12 is hydrogen (embodiment 3A-16).

[0279] In certain embodiments of Formula (III-A) or Embodiments 3A-1 through 3A-12, V is CH, a is 1, and R 12 is chloro (embodiment 3A-17).

[0280] In certain embodiments of Formula (III-A) or Embodiments 3A-1 through 3A-12, V is CH, a is 1, and R 12 is bromo (embodiment 3A-18).

[0281] In certain embodiments of Formula (III-A) or Embodiments 3A-1 through 3A-12, V is CH, a is 1, and R 12 is methyl (Embodiment 3A-18.1).

[0282] In certain embodiments of Formula (III-A) or Embodiments 3A-1 through 3A-12, V is CH, a is 1, and R 12 is fluoro (Embodiment 3A-19).

[0283] In certain embodiments of Formula (III-A), or Embodiments 3A-1 through 3A-11, or 3A-13, V is N, a is 1, and R 12 is hydrogen, C1-C3 alkyl, or halogen (Embodiments 3A-20).

[0284] In certain embodiments of Formula (III-A), or Embodiments 3A-1 through 3A-11, or 3A-13, V is N, a is 1, and R 12 is hydrogen, methyl, chloro, bromo, or fluoro (embodiment 3A-21).

[0285] In certain embodiments of Formula (III-A), or Embodiments 3A-1 through 3A-11, or 3A-13, V is N, a is 1, and R 12 is hydrogen (Embodiment 3A-22).

[0286] In certain embodiments of Formula (III-A), or Embodiments 3A-1 through 3A-11, or 3A-13, V is N, a is 1, and R 12 is chloro (Embodiment 3A-23).

[0287] In certain embodiments of Formula (III-A), or Embodiments 3A-1 through 3A-11, or 3A-13, V is N, a is 1, and R 12 is bromo (embodiment 3A-24).

[0288] In certain embodiments of Formula (III-A), or Embodiments 3A-1 through 3A-11, or 3A-13, V is N, a is 1, and R 12 is methyl (Embodiment 3A-24.1).

[0289] In certain embodiments of Formula (III-A), or Embodiments 3A-1 through 3A-11, or 3A-13, V is N, a is 1, and R 12 is fluoro (Embodiment 3A-25).

[0290] In certain embodiments of Formula (III-A) or Embodiments 3A-1 through 3A-25, the group: [ka] teeth [ka] (Embodiment 3A-26).

[0291] In certain embodiments of Formula (III-A) or Embodiments 3A-1 through 3A-26, Q is of the formula: [ka] [In the formula, each b is 0, 1, or 2; D is C(R 29 )2, W, O, NR 19 , or C(R 29 )2, and R 19 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, haloC1-C3 alkyl, hydroxyC1-C6 alkyl, or amino- or mono- or di-(C1-C6 alkyl)amino(C1-C6 alkyl); and Each R 29 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, haloC1-C3 alkyl, hydroxyC1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino. (Embodiment 3A-27).

[0292] In certain embodiments of embodiments 3A-27, W is oxygen, b is 0 or 1, and R 9 is methyl or cyano (embodiment 3A-28).

[0293] In certain embodiments of Embodiment 3A-27, W is oxygen and b is 0 (Embodiment 3A-29).

[0294] In certain embodiments of embodiments 3A-27, D and W are C(R 29 )2, b is 0, and each R 29 are independently hydrogen, C1-C2 alkyl, C1-C2 alkoxy, cyclopropyl, cyano, hydroxy, halogen, haloC1-C2 alkyl, hydroxyC1-C2 alkyl, amino, mono- or di-(C1-C2 alkyl)amino (Embodiments 3A-30).

[0295] In certain embodiments of embodiments 3A-27, D and W are C(R 29 )2, b is 0, and each R 29 is independently hydrogen, methyl, methoxy, cyano, hydroxy, chloro, fluoro, amino, methylamino, or dimethylamino (Embodiments 3A-31).

[0296] In certain embodiments of embodiments 3A-27, D and W are C(R 29 )2, b is 0, and each R 29 is independently chloro or fluoro (embodiments 3A-31).

[0297] In certain embodiments of embodiments 3A-27, D and W are C(R 29 )2, b is 0, and each R 29 is fluoro (Embodiment 3A-33).

[0298] In certain embodiments of embodiments 3A-27, D and W are C(R 29 )2, b is 0, and each R 29 is hydrogen (Embodiment 3A-34).

[0299] In certain embodiments of Formula (III-A) or Embodiments 3A-1 through 3A-26, Q is of the formula: TIFF2026504483000034.tif27160 [In the formula, each b is 0, 1, or 2; and W, O, NR 19 , or C(R 29 )2, The R 19 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, haloC1-C3 alkyl, hydroxyC1-C6 alkyl, or amino- or mono- or di-(C1-C6 alkyl)amino(C1-C6 alkyl); and Each R 29 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, haloC1-C3 alkyl, hydroxyC1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino. (Embodiment 3A-35).

[0300] In certain embodiments of embodiments 3A-35, W is oxygen, b is 0 or 1, and R 9 is methyl or cyano (embodiments 3A-36).

[0301] In certain embodiments of Embodiment 3A-35, W is oxygen and b is 0 (Embodiment 3A-37).

[0302] In certain embodiments of embodiments 3A-35, W is C(R 29 ) 2, b is 0, and each R 29 are independently hydrogen, C1-C2 alkyl, C1-C2 alkoxy, cyclopropyl, cyano, hydroxy, halogen, haloC1-C2 alkyl, hydroxyC1-C2 alkyl, amino, mono- or di-(C1-C2 alkyl)amino (Embodiments 3A-38).

[0303] In certain embodiments of embodiments 3A-35, W is C(R 29 ) 2, b is 0, and each R 29 is independently hydrogen, methyl, methoxy, cyano, hydroxy, chloro, fluoro, amino, methylamino, or dimethylamino (Embodiments 3A-39).

[0304] In certain embodiments of embodiments 3A-35, W is C(R 29 ) 2, b is 0, and each R 29 is independently chloro or fluoro (Embodiments 3A-40).

[0305] In certain embodiments of embodiments 3A-35, W is C(R 29 ) 2, b is 0, and each R 29 is fluoro (Embodiment 3A-41).

[0306] In certain embodiments of embodiments 3A-35, W is C(R 29 ) 2, b is 0, and each R 29 is hydrogen (Embodiment 3A-42).

[0307] In certain embodiments of Formula (III-A) or Embodiments 3A-1 through 3A-26, Q is of the formula: [ka] [In the formula, each b is 0, 1, or 2; and W, O, NR 19 , or C(R 29 )2, The R 19 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, haloC1-C3 alkyl, hydroxyC1-C6 alkyl, or amino- or mono- or di-(C1-C6 alkyl)amino(C1-C6 alkyl); and Each R29 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, haloC1-C3 alkyl, hydroxyC1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino. (Embodiment 3A-43).

[0308] In certain embodiments of embodiments 3A-43, W is oxygen, b is 0 or 1, and R 9 is methyl, chloro, fluoro, or cyano (embodiments 3A-44).

[0309] In certain embodiments of Embodiment 3A-43, W is oxygen and b is 0 (Embodiment 3A-45).

[0310] In certain embodiments of embodiments 3A-43, W is C(R 29 ) 2, b is 0, and each R 29 are independently hydrogen, C1-C2 alkyl, C1-C2 alkoxy, cyclopropyl, cyano, hydroxy, halogen, haloC1-C2 alkyl, hydroxyC1-C2 alkyl, amino, mono- or di-(C1-C2 alkyl)amino (Embodiments 3A-46).

[0311] In certain embodiments of embodiments 3A-43, W is C(R 29 ) 2, b is 0, and each R 29 is independently hydrogen, methyl, methoxy, cyano, hydroxy, chloro, fluoro, amino, methylamino, or dimethylamino (Embodiments 3A-47).

[0312] In certain embodiments of embodiments 3A-43, W is C(R 29 ) 2, b is 0, and each R 29 is independently chloro or fluoro (Embodiments 3A-48).

[0313] In certain embodiments of embodiments 3A-43, W is C(R 29 ) 2, b is 0, and each R 29 is fluoro (Embodiment 3A-49).

[0314] In certain embodiments of embodiments 3A-43, W is C(R 29 ) 2, b is 0, and each R 29 is hydrogen (Embodiment 3A-50). In certain embodiments of Formula (I) described elsewhere herein, the compound has Formula (V): [ka] [In the formula, R 1 is H, C1-C3 alkyl, or C3-C6 cycloalkyl; R 3 is C1-C3 alkyl optionally substituted, polysubstituted, or fully substituted with fluoro, C3-C6 cycloalkyl, C2-C3 alkenyl, C2-C3 alkynyl, or C5-C6 cycloalkenyl; R 4 is H, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C2-C3 alkenyl, C2-C3 alkynyl, or C5-C6 cycloalkenyl, cyano, or halo, each of which C1-C3 alkyl and C3-C6 cycloalkyl is optionally substituted with 1 to 5 halo groups; a is 0, 1, 2, or 3; V is CR 14 or N; Each R 12 are independently C1-C4 alkyl, -OR A , -C(O)OR A , (C1-C3 alkyl)-OR A , -C(O)N(R A )2, cyano, or halogen; R 13 is (i) cyano, (ii) tetrazolyl, (iii) -C(O)OR A (In the formula, R Ais H, C1-C6 alkyl, or C3-C6 cycloalkyl), or (iv) —C(O)N(R B )2(wherein, R B is H, —OH, C1-C6 alkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl; and R 14 is hydrogen, cyano, halogen, hydroxy, C1-C4 alkoxy, C1-C4 alkyl, -C(O)OR A , (C1-C3 alkyl)-OR A , or -C(O)N(R B )2; and R 31 teeth, (i) a 5- to 7-membered heteroaryl, or (ii) A 3- to 8-membered monocyclic heterocyclyl group bonded to a tricyclic ring via a carbon atom, and the heterocyclyl group is saturated or unsaturated, optionally fused to an aromatic or non-aromatic ring containing 3 to 6 ring members (one or two of which are nitrogen, oxygen, or sulfur atoms, as appropriate, and the remainder are carbon atoms); or the carbon atoms of the monocyclic heterocyclyl group together with the additional carbon or nitrogen atoms form a spiro ring system having a total of up to 10 ring members, each of which is carbon or nitrogen; and The R 31 Each heteroaryl and heterocyclyl group in 39 group, and each R 39are independently C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, haloC1-C3 alkyl, hydroxyC1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino, or phenyl, phenyl(C1-C3 alkanoyl), 5- to 7-membered heterocyclyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxy, cyano, amino, or mono- or di-(C1-C3 alkyl)amino. or a pharmaceutically acceptable salt thereof, or a deuterated version thereof.

[0315] In certain embodiments of Formula (V), R 1 is H or CH3 (embodiment 5-1).

[0316] In certain embodiments of Formula (V) or Embodiment 5-1, R 3 is C1-C3 alkyl, and the alkyl group is unsubstituted, substituted with 1 to 5 halo groups, or fully substituted (embodiment 5-2).

[0317] In certain embodiments of Formula (V) or Embodiment 5-1, R 3 is methyl (embodiment 5-3).

[0318] In certain embodiments of Formula (V) or Embodiments 5-1 through 5-3, R 4 is hydrogen (embodiment 5-4).

[0319] In certain embodiments of Formula (V) or Embodiments 5-1 through 5-3, R 4 is methyl (embodiment 5-5).

[0320] In certain embodiments of Formula (V) or Embodiments 5-1 through 5-3, R 4 is fluoro (embodiments 5-6).

[0321] In certain embodiments of Formula (V) or Embodiments 5-1 through 5-3, R 4 is chloro (embodiments 5-7).

[0322] In certain embodiments of Formula (V) or Embodiments 5-1 through 5-3, R 4 is fluoromethyl (embodiments 5-8).

[0323] In certain embodiments of Formula (V) or Embodiments 5-1 through 5-3, R 4 is difluoromethyl (embodiments 5-9).

[0324] In certain embodiments of Formula (V) or Embodiments 5-1 through 5-3, R 4 is trifluoromethyl (embodiments 5-10).

[0325] In certain embodiments of Formula (V) or Embodiments 5-1 through 5-3, R 4 is bromo (embodiments 5-11).

[0326] In certain embodiments of Formula (V) or embodiments 5-1 through 5-11, V is CR 12 (Embodiments 5-12).

[0327] In certain embodiments of Formula (V) or Embodiments 5-1 through 5-11, V is N (Embodiment 5-13).

[0328] In certain embodiments of Formula (V) or embodiments 5-1 through 5-12, V is CH, a is 1, and R 12 is hydrogen, C1-C3 alkyl, or halogen (embodiments 5-14).

[0329] In certain embodiments of Formula (V) or embodiments 5-1 through 5-12, V is CH, a is 1, and R 12 is hydrogen, methyl, chloro, bromo, or fluoro (embodiments 5-15).

[0330] In certain embodiments of Formula (V) or embodiments 5-1 through 5-12, V is CH, a is 1, and R 12 is hydrogen (embodiments 5-16).

[0331] In certain embodiments of Formula (V) or embodiments 5-1 through 5-12, V is CH, a is 1, and R 12 is methyl (embodiments 5-17).

[0332] In certain embodiments of Formula (V) or embodiments 5-1 through 5-12, V is CH, a is 1, and R 12 is chloro (embodiments 5-18).

[0333] In certain embodiments of Formula (V) or embodiments 5-1 through 5-12, V is CH, a is 1, and R 12 is bromo (embodiments 5-19).

[0334] In certain embodiments of Formula (V) or embodiments 5-1 through 5-12, V is CH, a is 1, and R 12 is fluoro (embodiments 5-20).

[0335] In certain embodiments of Formula (V), or embodiments 5-1 through 5-11 or 5-13, V is N, a is 1, and R 12 is hydrogen, C1-C3 alkyl, or halogen (embodiments 5-21).

[0336] In certain embodiments of Formula (V), or embodiments 5-1 through 5-11 or 5-13, V is N, a is 1, and R 12 is hydrogen, methyl, chloro, bromo, or fluoro (embodiments 5-22).

[0337] In certain embodiments of Formula (V), or embodiments 5-1 through 5-11 or 5-13, V is N, a is 1, and R 12 is hydrogen (embodiment 5-23).

[0338] In certain embodiments of Formula (V), or embodiments 5-1 through 5-11 or 5-13, V is N, a is 1, and R 12 is chloro (embodiments 5-24).

[0339] In certain embodiments of Formula (V), or embodiments 5-1 through 5-11 or 5-13, V is N, a is 1, and R 12 is bromo (embodiments 5-25).

[0340] In certain embodiments of Formula (V), or embodiments 5-1 through 5-11 or 5-13, V is N, a is 1, and R 12 is methyl (embodiments 5-26).

[0341] In certain embodiments of Formula (V), or embodiments 5-1 through 5-11 or 5-13, V is N, a is 1, and R 12 is fluoro (embodiments 5-27).

[0342] In certain embodiments of Formula (V) or embodiments 5-1 through 5-27, the group: [ka] teeth [ka] (Embodiment 5-28).

[0343] In certain embodiments of Formula (V) or Embodiments 5-1 through 5-28, R 31 is a 4-, 5-, or 6-membered heterocyclyl group, and the heterocyclyl group is 39 group, and each R 39are independently C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, haloC1-C3 alkyl, hydroxyC1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino (embodiments 5-29).

[0344] In certain embodiments of Formula (V) or Embodiments 5-1 through 5-28, R 31 is independently one or two R 39 and tetrahydrofuranyl optionally substituted with a group (embodiments 5-30).

[0345] In certain embodiments of Formula (V) or Embodiments 5-1 through 5-28, R 31 is tetrahydrofuranyl optionally substituted independently with one or two methyl, cyano, or trifluoromethyl (embodiments 5-31).

[0346] In certain embodiments of Formula (V) or Embodiments 5-1 through 5-28, R 31 is independently one or two R 39 and tetrahydropyranyl optionally substituted with a group (embodiment 5-32).

[0347] In certain embodiments of Formula (V) or Embodiments 5-1 through 5-28, R 31 is tetrahydropyranyl optionally substituted independently with one or two methyl, cyano, or trifluoromethyl (embodiments 5-33).

[0348] In certain embodiments of Formula (V) or Embodiments 5-1 through 5-28, R 31 is one or two R 39 pyridyl optionally substituted with a group, 39 is independently C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, haloC1-C3 alkyl, hydroxyC1-C6 alkyl (embodiments 5-34).

[0349] In certain embodiments, the compound of Formula (I) is selected from the compounds disclosed in Table 1 below. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12] [Table 13] [Table 14] [Table 15] [Table 16] [Table 17] Table 18 Table 19 Table 20 Table 21 Table 22 Table 23 Table 24 Table 25 Table 26 Table 27 Table 28 Table 29 Table 30 Table 31 Table 32 Table 33 Table 34 [Table 35] [Table 36] [Table 37] [Table 38] [Table 39] [Table 40] [Table 41] [Table 42] [Table 43] [Table 44]

[0350] Pharmaceutical Composition The compounds of formula I may be formulated into pharmaceutical compositions.

[0351] In another aspect, the present invention provides pharmaceutical compositions comprising the PI3K alpha inhibitor of the present invention and pharmaceutically acceptable carriers, excipients or diluents.The compounds of the present invention can be formulated by any method known in the art and can be prepared for administration by any route (including but not limited to parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal or rectal).In certain embodiments, the compounds of the present invention are administered intravenously in hospitals.In other specific embodiments, oral administration is preferred.

[0352] The characteristics of the carrier will depend on the route of administration. As used herein, the term "pharmaceutically acceptable" refers to a non-toxic material that is compatible with a biological system (e.g., a cell, cell culture, tissue, or organism) and does not interfere with the effectiveness of the biological activity of the active ingredient. Thus, the compositions of the present invention may further contain inhibitors, diluents, fillers, salts, buffers, stabilizers, solubilizers, and other substances well known in the art. The preparation of pharmaceutically acceptable formulations is described, for example, in Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

[0353] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the compounds set forth above and exhibits minimal or no undesired toxicological effects. Examples of such salts include, but are not limited to, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.) and salts formed with organic acids (e.g., acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid). The compounds may also be prepared as pharmaceutically acceptable quaternary salts known to those skilled in the art, particularly salts of the formula -NR + They may be administered as quaternary ammonium salts designated Z-, where R is hydrogen, alkyl, or benzyl, and Z is a counterion comprising chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (e.g., benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamate, mandelate, benzyloate, and diphenylacetate).

[0354] The active compound is contained in a pharmaceutically acceptable carrier or diluent in an amount sufficient to administer a therapeutically effective amount to a patient without causing serious toxic effects to the patient being treated. The dosage of the active compound for all of the above conditions ranges from about 0.01 to 300 mg / kg, preferably 0.1 to 100 mg / kg daily, and more typically 0.5 to 15 mg / kg patient body weight daily. A typical topical dose would be in the range of 0.01 to 3% weight / weight in a suitable carrier. The effective dosage range of pharmaceutically acceptable derivatives can be calculated based on the weight of the parent compound from which they are derived. If the derivative is active in itself, the effective dosage can be estimated using the weight of the derivative as described above or by other methods known to those skilled in the art.

[0355] Pharmaceutical compositions containing the compounds of the invention may be used in the methods described herein.

[0356] How to use

[0357] In another aspect, the present disclosure generally relates to methods for treating cancer, comprising administering a therapeutically effective amount of a PI3K inhibitor (e.g., a PI3K alpha inhibitor or a PI3K alpha H1047R mutant inhibitor) to a patient in need thereof.

[0358] In some embodiments, the PI3K inhibitor (e.g., a PI3K alpha inhibitor or a PI3K alpha H1047R mutant inhibitor) is a compound represented by Formula (I), (lIa), (IIb), or (IIc), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof. In certain embodiments, the PI3K inhibitor comprises a compound selected from Table 1.

[0359] In another aspect, the disclosure provides compounds that can be obtained or may be obtained by the methods for preparing the compounds described herein (e.g., methods that include one or more of the steps described in the schemes).

[0360] In another aspect, the disclosure provides a pharmaceutical composition comprising a compound of Formula (I), (lIa), (IIb), (IIc), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, and a pharmaceutically acceptable diluent or carrier.

[0361] In another aspect, the disclosure provides an intermediate described herein, wherein the intermediate is suitable for use in the method of preparing a compound described herein (e.g., the intermediate is selected from the intermediates described in the Examples).

[0362] In another embodiment, the present disclosure provides a method (e.g., in vitro or in vivo) for modulating PI3K (e.g., PI3Kα) activity, comprising contacting a cell with a therapeutically effective amount of a compound represented by Formula (I), (lIa), (IIb), or (IIc), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof.

[0363] In certain embodiments, the PI3K associated with disease or disorder has H1047R mutation.For example, in certain embodiments described elsewhere herein, the compound has higher selectivity for inhibiting H1047R mutant PI3Kα compared to wild-type PI3Kα.This unexpected result suggests that certain compounds may be able to target and inhibit PI3Kα through a novel binding mechanism that is different from that of conventional wild-type PI3Kα inhibitors.Without wishing to be bound by theory, H1047R mutant PI3Kα has a modification at a position away from the wild-type PI3Kα active site.Therefore, it is believed that compounds that have selectivity for H1047R mutant PI3Kα rather than wild-type PI3Kα do not bind strongly to the PI3Kα active site, but rather favorably target other binding pockets.Since the active site of PI3K proteins is thought to be more conserved among different mutants, compounds that effectively bind to a position other than the active site may provide higher selectivity for inhibiting PI3Kα than other PI3K proteins (such as PI3Kβ).

[0364] In another aspect, a method for treating cancer is provided, comprising administering to a patient with cancer a therapeutically effective amount of a compound of Formula I, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound or a pharmaceutically acceptable salt thereof.

[0365] The compositions and methods provided herein may be used for the treatment of a wide variety of cancers, including tumors such as prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, testicular cancer, etc. More particularly, cancers that may be treated by the compositions and methods of the present invention include, but are not limited to, tumor types (e.g., astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, testicular, and thyroid carcinomas and sarcomas). More specifically, these compounds are effective against the following: heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung: bronchial carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchial) carcinoma, bronchial adenocarcinoma, sarcoma, lymphoma, chondroitin hamartoma, mesothelioma; digestive system: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor), , Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colon (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary system: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma); liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary system: gallbladder carcinoma, ampullary carcinoma, cholangiocarcinoma; bone: osteosarcoma (osteogenic sarcoma) (osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, osteochondroma (cartilaginous exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor; nervous system: skull (osteoma, hemangioma, granuloma, xanthomatosis, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma);Gynecological system: uterus (endometrial cancer), cervix (cervical cancer, preneoplastic cervical dysplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiable carcinoma), granulosa cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (cancer); blood system: blood (myeloid leukemia (acute and chronic), It can be used to treat acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma. In certain embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL).

[0366] In some embodiments, the cancer is selected from hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, and head and neck cancer.

[0367] In another embodiment, the cancer is selected from breast cancer, uterine carcinosarcoma, endometrial carcinoma, colorectal adenocarcinoma, gastric adenocarcinoma, head and neck squamous cell carcinoma, bile duct carcinoma, esophageal adenocarcinoma, bladder carcinoma, lung squamous cell carcinoma, brain glioma, adrenocortical carcinoma, hepatocellular carcinoma, sarcoma, prostate adenocarcinoma, renal cell carcinoma, lung adenocarcinoma, ovarian cystadenocarcinoma, glioblastoma multiforme, and melanoma.

[0368] In another embodiment, the cancer is gastric cancer, breast cancer, colon cancer, or endometrial cancer.

[0369] In another embodiment, the cancer is gastric cancer.

[0370] In another embodiment, the cancer is breast cancer.

[0371] In another embodiment, the cancer is colon cancer.

[0372] In another embodiment, the cancer is endometrial cancer.

[0373] Thus, in certain embodiments, the present disclosure provides a method of treating cancer, comprising administering a compound of Formula (I) or a pharmaceutical composition thereof and a KRAS inhibitor to a patient in need thereof, wherein the cancer is breast cancer, uterine carcinosarcoma, endometrial carcinoma, colorectal adenocarcinoma, gastric adenocarcinoma, head and neck squamous cell carcinoma, bile duct carcinoma, esophageal adenocarcinoma, bladder carcinoma, lung squamous cell carcinoma, brain glioma, adrenocortical carcinoma, hepatocellular carcinoma, sarcoma, prostate adenocarcinoma, renal cell carcinoma, lung adenocarcinoma, ovarian cystadenocarcinoma, glioblastoma multiforme, or melanoma.

[0374] In another embodiment, the present disclosure provides a method of treating cancer, comprising administering a compound of Formula (I) or a pharmaceutical composition thereof and a mutant-selective KRAS inhibitor to a patient in need thereof, wherein the cancer is breast cancer, uterine carcinosarcoma, endometrial carcinoma, colorectal adenocarcinoma, gastric adenocarcinoma, head and neck squamous cell carcinoma, cholangiocarcinoma, esophageal adenocarcinoma, bladder carcinoma, lung squamous cell carcinoma, brain glioma, adrenocortical carcinoma, hepatocellular carcinoma, sarcoma, prostate adenocarcinoma, renal cell carcinoma, lung adenocarcinoma, ovarian cystadenocarcinoma, glioblastoma multiforme, or melanoma.

[0375] In another embodiment, the disclosure provides compounds of Formula (I) and pharmaceutical compositions thereof for use in combination with a KRAS inhibitor in the treatment of cancer, wherein the cancer is breast cancer, uterine carcinosarcoma, endometrial carcinoma, colorectal adenocarcinoma, gastric adenocarcinoma, head and neck squamous cell carcinoma, bile duct carcinoma, esophageal adenocarcinoma, bladder carcinoma, lung squamous cell carcinoma, brain glioma, adrenocortical carcinoma, hepatocellular carcinoma, sarcoma, prostate adenocarcinoma, renal cell carcinoma, lung adenocarcinoma, ovarian cystadenocarcinoma, glioblastoma multiforme, or melanoma.

[0376] The concentration and route of administration to a patient will vary depending on the cancer being treated. The compounds, their pharmaceutically acceptable salts, and pharmaceutical compositions containing such compounds and salts may also be administered together with other anti-tumor compounds (e.g., chemotherapy), or used in combination with other treatments (e.g., radiation or surgical intervention) as either pre- or post-operative adjuvants.

[0377] The present disclosure provides methods for treating, preventing, or alleviating a disease or disorder in which PI3K functions by administering a therapeutically effective amount of a PI3K inhibitor to a patient in need thereof. The methods of the disclosure can be used to treat a variety of PI3K-dependent diseases and disorders.

[0378] In some embodiments, the disorder or disease is cancer (e.g., breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colon cancer, lung cancer, ovarian cancer, skin cancer, and head and neck cancer). In some embodiments, PI3K-associated diseases or disorders include, but are not limited to, CLOVES syndrome (congenital fatty overgrowth, vascular malformations, epidermal nevus, scoliosis / skeletal spine syndrome), PIK3CA-associated overgrowth syndrome (PROS), endometrial cancer, breast cancer, esophageal squamous cell carcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, bladder urothelial carcinoma, glioblastoma, ovarian cancer, non-small cell lung cancer, esophagogastric cancer, nerve sheath tumor, head and neck squamous cell carcinoma, melanoma, esophagogastric adenocarcinoma, soft tissue sarcoma, prostate cancer, fibrolamellar hepatocellular carcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, cholangiocarcinoma, B-cell lymphoma, mesothelioma, adrenocortical cell carcinoma, renal non-clear cell carcinoma, renal clear cell carcinoma, germ cell carcinoma, thymic tumor, pheochromocytoma, mixed neuroepithelial tumor, thyroid cancer, leukemia, and encapsulating glioma.

[0379] Details of the present disclosure are set forth in the description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are described here. Other features, objects, and advantages of the present disclosure will be apparent from the description and claims. In the specification and the appended claims, the singular forms include the plural forms unless the context clearly dictates otherwise. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and literature cited herein are incorporated herein by reference in their entirety.

[0380] General Reaction Schemes, Intermediates, and Examples The compounds of the invention may be prepared in the synthetic methods and reaction schemes described herein using commercially available reagents and intermediates, or may be prepared using other reagents and conventional methods well known to those skilled in the art.

[0381] When reference is made to a "first eluting enantiomer" or a "second eluting enantiomer," unless specifically stated otherwise, the specific stereochemistry of such enantiomer has not yet been determined and has been arbitrarily assigned to any stereochemistry depicted in the corresponding compound structure.

[0382] For example, intermediates for the preparation of compounds of the present invention and compounds of formula (I) can be prepared according to general reaction schemes I, II, III, and IV:

[0383] General Reaction Scheme I [ka] In General Reaction Scheme I, compound 10 is an example of formula (I). In this General Reaction Scheme I, compound 1 is reacted with ethyl chloroformate at elevated temperature to give compound 2. Compound 2 can be reacted with an appropriate hydrazide at elevated temperature to give compound 3. Compound 3 can then be activated, for example, with phosphorus oxychloride to give an aryl chloride capable of reacting with an amine, or activated in situ with a coupling reagent (e.g., benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate) and the desired amine added to give compound 4. Compound 4 undergoes a Heck or Stille coupling with an enol ether coupling partner, followed by acidic workup to give the ketone product 5. Compound 5 can then be cross-coupled (e.g., Suzuki reaction) with an alkylboronic acid to give compound 6. Condensation with a chiral sulfinamide, such as Ellman's reagent, followed by a Lewis acid (e.g., titanium(IV) ethoxide) can give the imine 7. Compound 7 can be reduced using a reducing agent (e.g., diisobutylaluminum hydride, sodium borohydride, or zirconocene chloride hydride) to give sulfinamide 8. After acidic deprotection of 8, for example, using hydrochloric acid / dioxane, amine 9 can be displaced via nucleophilic substitution or metal-catalyzed reaction in the presence of a suitable base to prepare compound 10.

[0384] General Reaction Scheme II [ka] In General Reaction Scheme II, compound 19 is an example of Formula (I). In this General Reaction Scheme II, compound 11 is reacted with ammonia in methanol to prepare compound 12. Compound 12 can be condensed with an appropriate α-haloaldehyde or ketone at elevated temperature to prepare compound 13. Compound 13 can then be reacted with a substituted amine in the presence of a suitable base (e.g., diisopropylethylamine) at elevated temperature to give compound 14. An aryl bromide can undergo Heck or Stille coupling with an enol ether coupling partner to give vinyl ether 15, which can be exposed to a suitable acid (e.g., hydrochloric acid or trifluoroacetic acid) to give compound 16. Reduction of ketone 16 can be carried out using a common reducing agent (e.g., sodium borohydride) to give compound 17. Conversion of alcohol 17 to alcohol 18 can be carried out using a chlorinating agent (e.g., thionyl chloride). Compound 19 can be obtained via nucleophilic displacement of an alkyl chloride with the desired aniline in the presence of a base such as potassium iodide and a suitable base such as diisopropylethylamine.

[0385] General Reaction Scheme III [ka] In General Reaction Scheme III, compound 29 is an example of Formula (I). In this General Reaction Scheme III, the preparation of compound 12 is the same as in General Reaction Scheme II. Compound 12 is then reacted with a substituted amine in the presence of a suitable base, such as diisopropylethylamine, at elevated temperature. Compound 20 can be condensed with a 3-halo-2-oxopropanoate to give ester 21. Ester aminolysis can be carried out using a reagent such as ammonia / methanol to give amide 22. 22 can be reacted with a suitable dehydrating reagent (e.g., trifluoroacetic anhydride) to give 23. Aryl bromide 23 can be subjected to Heck or Stille coupling with an enol ether coupling partner to give a vinyl ether, which can then be exposed to a suitable acid (e.g., hydrochloric acid or trifluoroacetic acid) to give 25. Condensation with a chiral sulfinamide, such as Ellman's reagent, followed by the use of a Lewis acid (e.g., titanium(IV) ethoxide) can give imine 26. Compound 26 can be reduced using a reducing agent (e.g., diisobutylaluminum hydride, sodium borohydride, or zirconocene chloride hydride) to give sulfinamide 27. After acidic deprotection of 27, for example with molecular iodine, the resulting amine 28 can be displaced via nucleophilic substitution or metal-catalyzed reaction in the presence of a suitable base to prepare compound 29.

[0386] General Reaction Scheme IV [ka] In General Reaction Scheme IV, compound 37 is an example of Formula (I). In this General Reaction Scheme IV, compound 30 can undergo nucleophilic aromatic ring substitution in the presence of a suitable base (e.g., diisopropylethylamine) and a suitable dehydrating reagent (e.g., phosphorus oxychloride) and condensation with a suitable hydrazide to give compound 31. A substituted amine can be used in the nucleophilic aromatic ring substitution of compound 31 in the presence of a suitable base (e.g., diisopropylethylamine) to give compound 32. Aryl bromide 32 can undergo Heck or Stille coupling with an enol ether coupling partner to give the ketone product 33 after acidic workup. After condensation with a chiral sulfinamide, such as Ellman's reagent, imine 34 can be obtained using a Lewis acid (e.g., titanium(IV) ethoxide). Compound 34 can be reduced to form sulfinamide 35 using a reducing agent (e.g., diisobutylaluminum hydride, sodium borohydride, or zirconocene chloride hydride). After acidic deprotection of 35, for example using hydrochloric acid / dioxane, the amine salt 36 can be substituted via nucleophilic substitution or metal-catalyzed reaction in the presence of a suitable base to prepare compound 37.

[0387] The substituents shown in Schemes I, II, III, and IV have the same definitions as for formula (I) above.

[0388] Intermediate A Ethyl (4-bromo-2-cyano-6-iodophenyl)carbamate [ka] Step A: To a flask fitted with a reflux condenser was added 2-amino-5-bromo-3-iodobenzonitrile (5.4 g, 1.0 eq., 17 mmol), ethyl chloroformate (36 g, 32 mL, 20 eq., 0.33 mol), and a stir bar. The flask was heated to 100° C. for 3 days and then cooled to room temperature. Upon cooling, the reaction was concentrated by rotary evaporation. The residue was then suspended in diethyl ether and heptane was added slowly to induce crystallization. The suspension was filtered and rinsed with heptane to give ethyl (4-bromo-2-cyano-6-iodophenyl)carbamate (5.64 g, 14.3 mmol, 85% yield) as a tan solid. LCMS [M+1] + =394.8.

[0389] 1 H NMR(500MHz, CDCl3)δ ppm=8.19(d, J=2.19Hz, 1H), 7.79(d, J=2.19Hz, 1H), 6.45(br s, 1H), 4.30(q, J=7.12Hz, 2H), 1.34(t, J=7.12Hz, 3H).

[0390] Intermediate B [ka] Step A: A mixture of ethyl (4-bromo-2-cyano-6-iodophenyl)carbamate (204 mg, 1.0 eq., 516 μmol) and formylhydrazine (31 mg, 1.0 eq., 520 μmol) in N-methyl-2-pyrrolidinone (2.6 mL) was heated at 160° C. for 3 hours. The reaction mixture was cooled to room temperature, water (2 mL) was added, and the mixture was then poured onto ice. The resulting precipitate was collected, washed with diethyl ether, and dried to give 9-bromo-7-iodo-[1,2,4]triazolo[1,5-c]quinazolin-5(6H)-one (181 mg, 462 μmol, 89% yield) as a yellow solid, which was used without further purification. LCMS [M+1] + =390.8.

[0391] 1H NMR(400MHz, CDCl3)δ ppm=8.56(br s, 1H), 8.48(d, J=2.00Hz, 1H), 8.42(s, 1H), 8.21(d, J=1.88Hz, 1H).

[0392] Step B: To a solution of 9-bromo-7-iodo-[1,2,4]triazolo[1,5-c]quinazolin-5(6H)-one (90 mg, 1.0 eq., 0.23 mmol) and benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (0.16 g, 1.3 eq., 0.30 mmol) in dimethyl sulfoxide (0.80 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (53 mg, 52 μL, 1.5 eq., 0.35 mmol) at room temperature. The resulting mixture was stirred for 1 h, and upon completion, piperidine (22 mg, 25 μL, 1.1 eq., 0.25 mmol) was added dropwise, and the reaction was stirred for 12 h. The reaction was quenched with 10% sodium carbonate and extracted with ethyl acetate. The combined organic layers were washed successively with water and brine, then dried over magnesium sulfate, filtered, and concentrated to give a residue that was purified by silica gel chromatography (0% to 70% ethyl acetate / heptane) to give 9-bromo-7-iodo-5-(piperidin-1-yl)-[1,2,4]triazolo[1,5-c]quinazoline (40 mg, 87 μmol, 38% yield). LCMS [M+3] + =460.0.

[0393] Step C: Palladium(II) acetate (7.11 mg, 0.05 eq., 31.7 μmol), 1,3-bis(diphenylphosphino)propane (26.1 mg, 0.10 eq., 63.3 μmol), and 9-bromo-7-iodo-5-(piperidin-1-yl)-[1,2,4]triazolo[1,5-c]quinazoline (290 mg, 1.0 eq., 633 μmol) were added to a vial and a stir bar. The flask was evacuated and backfilled with nitrogen three times. Next, ethylene glycol (2.53 mL), N,N-dicyclohexylmethylamine (371 mg, 405 μL, 3.0 eq., 1.90 mmol), and n-butyl vinyl ether (317 mg, 410 μL, 5.0 eq., 3.17 mmol) were added, and the solution was sparged with nitrogen. The vial was placed on a heating block, and the mixture was stirred and heated at 115° C. After complete conversion, the reaction was cooled to room temperature, and 1N HCl (8 mL) was added to the reaction. The reaction was stirred until ketone deprotection was complete (approximately 1 h). The aqueous layer was extracted three times with ethyl acetate, and the organic layers were combined, washed successively with water and brine, dried over magnesium sulfate, filtered, and concentrated to give a residue. This residue was purified by silica gel chromatography to give 1-(9-bromo-5-(piperidin-1-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethan-1-one (118 mg, 315 μmol, 50% yield) as a yellow solid. LCMS [M+1] + =374.3.

[0394] 1 H NMR(500MHz, CDCl3)δ ppm=8.64(d, J=2.46Hz, 1H), 8.34(s, 1H), 8.07(d, J=2.19Hz, 1H), 4.05-4.11(m, 4H), 2.91(s, 3H), 1.81(br m, 6H).

[0395] Step D: To a vial was added methylboronic acid (44.4 mg, 2.5 eq., 742 μmol), 1-(9-bromo-5-(piperidin-1-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethan-1-one (111 mg, 1.0 eq., 297 μmol), potassium carbonate (102 mg, 2.5 eq., 742 μmol), and tetrakis(triphenylphosphine)palladium(0) (34.3 mg, 0.1 eq., 29.7 μmol). The flask was evacuated and backfilled with nitrogen three times. Next, a solution of deoxygenated 1,4-dioxane (1.19 mL) and water (297 μL) was added, and the reaction was heated to 100 °C and stirred overnight. The reaction was cooled to room temperature, quenched with saturated sodium bicarbonate, and extracted three times with dichloromethane. The combined organic layers were washed successively with water, then brine, and dried over magnesium sulfate. After filtration, the mixture was concentrated under reduced pressure and purified by silica gel chromatography to give 1-(9-methyl-5-(piperidin-1-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethan-1-one (56 mg, 0.18 mmol, 61% yield) as a yellow solid. LCMS [M+1] + =310.2.

[0396] 1 H NMR(400MHz, CDCl3)δ ppm=8.36(d, J=1.25Hz, 1H), 8.34(s, 1H), 7.86(d, J=2.00Hz, 1H), 3.99-4.07(m, 4H), 2.93(s, 3H), 2.53(s, 3H), 1.75-1.88(m, 6H).

[0397] Step E: To a solution of 1-(9-methyl-5-(piperidin-1-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethan-1-one (56 mg, 1.0 eq., 0.18 mmol) and (R)-2-methylpropane-2-sulfinamide (26 mg, 1.2 eq., 0.22 mmol) in tetrahydrofuran (0.72 mL) was added titanium ethoxide (0.21 g, 0.19 mL, 5.0 eq., 0.91 mmol). The mixture was stirred for 4 hours at 80° C. and then cooled to room temperature. Once at room temperature, a minimal amount of brine was added to form a suspension. The resulting suspension was diluted with ethyl acetate and filtered through Celite, washing the filter cake several times with ethyl acetate. The filtrate was concentrated by rotary evaporation to give (R)-2-methyl-N-(1-(9-methyl-5-(piperidin-1-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethylidene)propane-2-sulfinamide (crude weight 92 mg) as a crude yellow solid, which was carried forward without further purification.

[0398] Step F: To a room temperature solution of (R)-2-methyl-N-(1-(9-methyl-5-(piperidin-1-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethylidene)propane-2-sulfinamide (92 mg, 1.0 eq., 0.22 mmol) in anhydrous dichloromethane (1.5 mL) was added the solid Schwartz reagent (63 mg, 1.1 eq., 0.25 mmol) in several portions. The reaction was stirred at room temperature for 15 minutes and then quenched with ammonium chloride. The aqueous layer was extracted with dichloromethane, and the combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a residue. The solid was purified by silica gel chromatography (0% to 10% methanol / dichloromethane) to give (R)-2-methyl-N-((R)-1-(9-methyl-5-(piperidin-1-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethyl)propane-2-sulfinamide (47 mg, 0.11 mmol, 51% yield) as a white solid. LCMS [M+1] + =415.2.

[0399] Step G: To a room temperature solution of (R)-2-methyl-N-((R)-1-(9-methyl-5-(piperidin-1-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethyl)propane-2-sulfinamide (47 mg, 1.0 eq., 0.11 mmol) in methanol (0.45 mL) was added 71 μL of HCl (4 M / 1,4-dioxane). The reaction conversion was determined by LCMS, and once complete, trituration with diethyl ether afforded (R)-1-(9-methyl-5-(piperidin-1-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethan-1-amine hydrochloride as a salt, which was used without further purification. LCMS [M+1] + =311.1.

[0400] Intermediate C [ka] Step A: A mixture of ethyl (4-bromo-2-cyano-6-iodophenyl)carbamate (500 mg, 1.0 eq., 1.27 mmol) and benzohydrazide (181 mg, 1.05 eq., 1.33 mmol) in N-methyl-2-pyrrolidinone (6.33 mL) was heated at 160° C. for 3 h. The reaction mixture was cooled to room temperature, water (10 mL) was added, and the mixture was poured onto ice. The resulting precipitate was collected and washed with diethyl ether to give 9-bromo-7-iodo-2-phenyl-[1,2,4]triazolo[1,5-c]quinazolin-5(6H)-one (548 mg, 1.17 mmol, 93% yield) as a yellow solid, which was used without further purification. LCMS [M+1] + =466.9.

[0401] 1 H NMR(500MHz, DMSO-d6)δ ppm=10.93(br s, 1H), 8.39(d, J=2.19Hz, 1H), 8.34(d, J=2.19Hz, 1H), 8.19-8.26(m, 2H), 7.55-7.61(m, 3H).

[0402] Step B: To a vial containing 9-bromo-7-iodo-2-phenyl-[1,2,4]triazolo[1,5-c]quinazolin-5(6H)-one (291 mg, 1.0 eq., 623 μmol) and a stir bar, phosphorus oxychloride (955 mg, 581 μL, 10 eq., 6.23 mmol) and N,N-diisopropylethylamine (322 mg, 434 μL, 4.0 eq., 2.49 mmol) were added sequentially. The vial was sealed and heated to 100° C. for 12 hours. The reaction was then cooled to room temperature, and the contents were concentrated in vacuo to give a black residue. Ice was added to the residue, and the contents were mixed. After thawing, the aqueous suspension was filtered, and the solid was rinsed three times with water and dried to give a brown solid, which was purified by silica gel chromatography (0% to 70% ethyl acetate / heptane) to give 9-bromo-5-chloro-7-iodo-2-phenyl-[1,2,4]triazolo[1,5-c]quinazoline (273 mg, 562 μmol, 90% yield) as a white solid.

[0403] 1 H NMR(500MHz, DMSO-d6)δ ppm=8.69(d, J=2.19Hz, 1H), 8.65(d, J=2.19Hz, 1H), 8.28-8.33(m, 2H), 7.58-7.66(m, 3H).

[0404] Step C: To a vial and stir bar was added 9-bromo-5-chloro-7-iodo-2-phenyl-[1,2,4]triazolo[1,5-c]quinazoline (273 mg, 1.0 eq., 562 μmol) as a solid dissolved in anhydrous 1,2-dichloroethane (2.25 mL). Next, diisopropylethylamine (145 mg, 196 μL, 2.0 eq., 1.12 mmol) and piperidine (52.7 mg, 61.1 μL, 1.1 eq., 619 μmol) were added sequentially, and the reaction was sealed and stirred at room temperature overnight. Saturated sodium bicarbonate was added to the reaction, and the solution was diluted with dichloromethane. The aqueous layer was separated and extracted three times. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated to give a solid that was purified by silica gel chromatography (0% to 70% ethyl acetate / heptane) to give 9-bromo-7-iodo-2-phenyl-5-(piperidin-1-yl)-[1,2,4]triazolo[1,5-c]quinazoline (278 mg, 520 μmol, 93% yield) as a white solid.

[0405] 1 H NMR(500MHz, DMSO-d6)δ ppm=8.40(s, 2H), 8.24-8.28(m, 2H), 7.55-7.64(m, 3H), 4.20(br m, 4H), 1.72-1.81(m, 6H).

[0406] Step D: To a vial and stir bar was added palladium(II) acetate (5.84 mg, 0.05 eq., 26.0 μmol), 1,3-bis(diphenylphosphino)propane (21.5 mg, 0.10 eq., 52.0 μmol), and 9-bromo-7-iodo-2-phenyl-5-(piperidin-1-yl)-[1,2,4]triazolo[1,5-c]quinazoline (278 mg, 1.0 eq., 520 μmol). The flask was evacuated and backfilled with nitrogen three times. Next, ethylene glycol (1.30 mL), N,N-dicyclohexylmethylamine (305 mg, 333 μL, 3.0 eq., 1.56 mmol), and n-butyl vinyl ether (261 mg, 337 μL, 5.0 eq., 2.60 mmol) were charged, and the solution was sparged with nitrogen. The vial was placed on a heating block, and the mixture was stirred and heated to 115 °C. After complete conversion, the reaction was cooled to room temperature, and 1 N HCl (5 mL) was added to the reaction. The reaction was stirred until ketone deprotection was complete (approximately 1 h). The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed successively with water and brine, dried over magnesium sulfate, filtered, and concentrated to give a residue. The residue was purified by silica gel chromatography to give 1-(9-bromo-2-phenyl-5-(piperidin-1-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethan-1-one (202 mg, 449 μmol, 86% yield) as a yellow solid. LCMS [M+1] + =452.1.

[0407] 1 H NMR(400MHz, CDCl3)δ ppm 8.75(d, J=2.38Hz, 1H), 8.30-8.38(m, 2H), 8.08(d, J=2.50Hz, 1H), 7.52(br d, J=1.88Hz, 3H), 4.12-4.21(m, 4H), 2.92(s, 3H), 1.78-1.92(m, 6H).

[0408] Step E: To a vial was added methylboronic acid (67.1 mg, 2.5 eq., 1.12 mmol), 1-(9-bromo-2-phenyl-5-(piperidin-1-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethan-1-one (202 mg, 1.0 eq., 449 μmol), potassium carbonate (155 mg, 2.5 eq., 1.12 mmol), and tetrakis(triphenylphosphine)palladium(0) (51.8 mg, 0.1 eq., 44.9 μmol). The flask was evacuated and backfilled with nitrogen three times. Next, a solution of deoxygenated 1,4-dioxane (1.79 mL) and water (449 μL) was added, and the reaction was heated to 100 °C and stirred overnight. The reaction was cooled to room temperature, quenched with saturated sodium bicarbonate, and extracted three times with dichloromethane. The combined organic layers were washed successively with water, then brine, and dried over magnesium sulfate. After filtration, the mixture was concentrated under reduced pressure and purified by silica gel chromatography to give 1-(9-methyl-2-phenyl-5-(piperidin-1-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethan-1-one as a yellow solid. LCMS [M+1] + =386.2.

[0409] 1 H NMR(400MHz, CDCl3)δ ppm=8.48(s, 1H), 8.37(dd, J=7.63, 1.88Hz, 2H), 7.87(d, J=2.13Hz, 1H), 7.49-7.56(m, 3H), 4.06-4.14(m, 4H), 2.95(s, 3H), 2.55(s, 3H), 1.85(br m, 4H), 1.75-1.82(m, 2H).

[0410] Step F: To a solution of 1-(9-methyl-2-phenyl-5-(piperidin-1-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethan-1-one (36 mg, 1.0 eq., 93 μmol) and (R)-2-methylpropane-2-sulfinamide (14 mg, 1.2 eq., 0.11 mmol) in tetrahydrofuran (0.37 mL) was added titanium(IV) ethoxide (0.11 g, 97 μL, 5.0 eq., 0.47 mmol). The mixture was stirred for 4 hours at 80° C. and then cooled to room temperature. Once at room temperature, a minimal amount of brine was added to form a suspension. The resulting suspension was diluted with ethyl acetate and filtered through Celite, washing the filter cake several times with ethyl acetate. The filtrate was concentrated by rotary evaporation to give (R)-2-methyl-N-(1-(9-methyl-2-phenyl-5-(piperidin-1-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethylidene)propane-2-sulfinamide (52 mg crude weight) as a crude yellow solid. The product was carried forward without further purification.

[0411] Step G: To a room temperature solution of (R)-2-methyl-N-(1-(9-methyl-2-phenyl-5-(piperidin-1-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethylidene)propane-2-sulfinamide (52 mg, 1.0 eq., 0.11 mmol) in anhydrous dichloromethane (0.71 mL) was added the solid Schwartz reagent (30 mg, 1.1 eq., 0.12 mmol) in several portions. The reaction was stirred at room temperature for 15 minutes and quenched with ammonium chloride. The aqueous layer was extracted with dichloromethane, and the combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a residue. The solid was purified by silica gel chromatography (0% to 10% methanol / dichloromethane) to give (R)-2-methyl-N-((R)-1-(9-methyl-2-phenyl-5-(piperidin-1-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethyl)propane-2-sulfinamide (17 mg, 35 μmol, 33% yield) as a white solid. LCMS [M+1] +=491.3.

[0412] Step H: To a room temperature solution of (R)-2-methyl-N-((R)-1-(9-methyl-2-phenyl-5-(piperidin-1-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethyl)propane-2-sulfinamide (17 mg, 1.0 eq., 35 μmol) in methanol (0.35 mL) was added 22 μL of HCl (4 M in dioxane). The reaction was measured and upon completion, triturated with diethyl ether and dried under vacuum to give (R)-1-(9-methyl-2-phenyl-5-(piperidin-1-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethan-1-amine hydrochloride as a salt, which was used without further purification. LCMS [M+1] + =387.1.

[0413] Intermediate D [ka] Step A: A mixture of ethyl (4-bromo-2-cyano-6-iodophenyl)carbamate (500 mg, 1.00 eq., 1.27 mmol) and pyrazine-2-carbohydrazide (184 mg, 1.05 eq., 1.33 mmol) in N-methyl-2-pyrrolidinone (6.33 mL) was heated at 160° C. for 3 hours. The reaction mixture was cooled to room temperature, water (10 mL) was added, and the mixture was then poured onto ice. The resulting precipitate was collected and washed with diethyl ether to give 9-bromo-7-iodo-2-(pyrazin-2-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5(6H)-one (581 mg, 1.24 mmol, 98% yield), which was used without further purification. LCMS: [M+1] + =468.9.

[0414] 1H NMR(500MHz, DMSO-d6)δ ppm=11.05(br s, 1H), 9.46(d, J=1.37Hz, 1H), 8.87(dd, J=2.33, 1.51Hz, 1H), 8.84(d, J=2.46Hz, 1H), 8.42(d, J=2.19Hz, 1H), 8.37(d, J=2.19Hz, 1H).

[0415] Step B: To a vial containing 9-bromo-7-iodo-2-(pyrazin-2-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5(6H)-one (330 mg, 1 eq., 704 μmol) and a stir bar, phosphorus oxychloride (1.08 g, 656 μL, 10 eq., 7.04 mmol) and diisopropylethylamine (364 mg, 490 μL, 4 eq., 2.81 mmol) were added sequentially. The vial was sealed and heated at 100° C. for 12 hours. The reaction was then cooled to room temperature, and the contents were concentrated in vacuo to give a black residue. To the residue, ice was added, and the contents were mixed. After thawing, the aqueous suspension was filtered, and the solid was rinsed three times with water and dried to give a brown solid that was purified by silica gel chromatography (0% to 70% ethyl acetate / heptane) to give 9-bromo-5-chloro-7-iodo-2-(pyrazin-2-yl)-[1,2,4]triazolo[1,5-c]quinazoline (312 mg, 640 μmol, 91% yield) as a white solid. LCMS: [M+1] + =486.7.

[0416] 1 H NMR(500MHz, DMSO-d6)δ ppm=9.53(d, J=1.10Hz, 1H), 8.90-8.94(m, 1H), 8.88(d, J=2.19Hz, 1H), 8.71(d, J=1.92Hz, 1H), 8.67(d, J=1.92Hz, 1H).

[0417] Step C: To a vial and stir bar was added 9-bromo-5-chloro-7-iodo-2-(pyrazin-2-yl)-[1,2,4]triazolo[1,5-c]quinazoline (312 mg, 1.0 eq., 640 μmol) as a solid, dissolved in anhydrous 1,2-dichloroethane (2.56 mL). Next, diisopropylethylamine (165 mg, 223 μL, 2.0 eq., 1.28 mmol) and piperidine (59.9 mg, 69.5 μL, 1.1 eq., 704 μmol) were added sequentially, and the reaction was sealed and stirred at room temperature overnight. Saturated sodium bicarbonate was added to the reaction, and the solution was diluted with dichloromethane. The aqueous layer was separated and extracted three times. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by silica gel chromatography (0% to 70% ethyl acetate / heptane) to afford 9-bromo-7-iodo-5-(piperidin-1-yl)-2-(pyrazin-2-yl)-[1,2,4]triazolo[1,5-c]quinazoline (295 mg, 550 μmol, 86% yield) as a white solid. LCMS: [M+1] + =536.3.

[0418] 1 H NMR(500MHz, DMSO-d6)δ ppm=9.52(d, J=1.64Hz, 1H), 8.87-8.90(m, 1H), 8.85(d, J=2.46Hz, 1H), 8.42-8.45(m, 2H), 4.21(br m, 4H), 1.77(br m, 6H).

[0419] Step D: To a vial and stir bar was added palladium(II) acetate (6 mg, 0.05 eq., 27.5 μmol), 1,3-bis(diphenylphosphino)propane (23 mg, 0.10 eq., 55.0 μmol), and 9-bromo-7-iodo-5-(piperidin-1-yl)-2-(pyrazin-2-yl)-[1,2,4]triazolo[1,5-c]quinazoline (295 mg, 1.0 eq., 550 μmol). The flask was evacuated and backfilled with nitrogen three times. Next, ethylene glycol (1.4 mL), N,N-dicyclohexylmethylamine (322 mg, 352 μL, 3.0 eq., 1.65 mmol), and n-butyl vinyl ether (276 mg, 356 μL, 5.0 eq., 2.75 mmol) were charged, and the solution was sparged with nitrogen. The vial was placed on a heating block, and the mixture was stirred and heated to 115 °C. After complete conversion, the reaction was cooled to room temperature, and 1 N HCl (5 mL) was added to the reaction. The reaction was stirred until ketone deprotection was complete (approximately 1 h). The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed successively with water and brine, dried over magnesium sulfate, filtered, and concentrated to give a residue. The residue was purified by silica gel chromatography to give 1-(9-bromo-5-(piperidin-1-yl)-2-(pyrazin-2-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethan-1-one (118 mg, 261 μmol, 47% yield) as a yellow solid. LCMS: [M+1] + =452.0.

[0420] Step E: To a vial was added methylboronic acid (39.0 mg, 2.5 eq., 652 μmol), 1-(9-bromo-5-(piperidin-1-yl)-2-(pyrazin-2-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethan-1-one (118 mg, 1.0 eq., 261 μmol), potassium carbonate (90.1 mg, 2.5 eq., 652 μmol), and tetrakis(triphenylphosphine)palladium(0) (30.1 mg, 0.1 eq., 26.1 μmol). The flask was evacuated and backfilled with nitrogen three times. Next, a solution of deoxygenated 1,4-dioxane (1.0 mL) and water (260 μL) was added, and the reaction was heated to 100 °C and stirred overnight. The reaction was cooled to room temperature, quenched with saturated sodium bicarbonate, and extracted three times with dichloromethane. The combined organic layers were washed successively with water, then brine, and dried over magnesium sulfate. After filtration, the mixture was concentrated under reduced pressure and purified by silica gel chromatography to give 1-(9-methyl-5-(piperidin-1-yl)-2-(pyrazin-2-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethan-1-one (44 mg, 0.11 mmol, 44% yield) as a yellow solid. LCMS: [M+1] + =388.1.

[0421] 1 H NMR(400MHz, CDCl3)δ ppm=9.62(d, J=1.38Hz, 1H), 8.82(dd, J=2.38, 1.50Hz, 1H), 8.72(d, J=2.50Hz, 1H), 8.55(d, J=1.25Hz, 1H), 7.89(d, J=2.00Hz, 1H), 4.07-4.14(m, 4H), 2.95(s, 3H), 2.54(s, 3H), 1.77-1.92(m, 6H).

[0422] Step F: To a solution of 1-(9-methyl-5-(piperidin-1-yl)-2-(pyrazin-2-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethan-1-one (44 mg, 1.0 eq., 0.11 mmol) and (R)-2-methylpropane-2-sulfinamide (17 mg, 1.2 eq., 0.14 mmol) in tetrahydrofuran (0.45 mL) was added titanium(IV) ethoxide (0.13 g, 0.12 mL, 5.0 eq., 0.57 mmol). The mixture was stirred at 80° C. for 4 hours and then cooled to room temperature. Once at room temperature, a minimal amount of brine was added to form a suspension. The resulting suspension was diluted with ethyl acetate and filtered through Celite, washing the filter cake several times with ethyl acetate. The filtrate was concentrated by rotary evaporation to give (R)-2-methyl-N-(1-(9-methyl-5-(piperidin-1-yl)-2-(pyrazin-2-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethylidene)propane-2-sulfinamide (crude weight 55 mg) as a crude yellow solid. The product was carried forward without further purification.

[0423] Step G: To a room temperature solution of (R)-2-methyl-N-(1-(9-methyl-5-(piperidin-1-yl)-2-(pyrazin-2-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethylidene)propane-2-sulfinamide (55 mg, 1.0 eq., 0.11 mmol) in anhydrous dichloromethane (0.75 mL) was added Schwartz's reagent (32 mg, 1.1 eq., 0.12 mmol) as a solid in several portions. The reaction was stirred at room temperature for 15 minutes and then quenched with ammonium chloride. The aqueous layer was extracted with dichloromethane, and the combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a residue. The solid was purified by silica gel chromatography (0% to 10% methanol / dichloromethane) to give (R)-2-methyl-N-((R)-1-(9-methyl-5-(piperidin-1-yl)-2-(pyrazin-2-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethyl)propane-2-sulfinamide (23 mg, 47 μmol, 42% yield) as a white solid. LCMS [M+1] + =493.3.

[0424] Step H: To a room temperature solution of (R)-2-methyl-N-((R)-1-(9-methyl-5-(piperidin-1-yl)-2-(pyrazin-2-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethyl)propane-2-sulfinamide (23 mg, 1.0 eq., 47 μmol) in methanol (0.23 mL) was added 29 μL of HCl (4 M in dioxane). The reaction was measured and upon completion, triturated with diethyl ether and dried under vacuum to give (R)-1-(9-methyl-5-(piperidin-1-yl)-2-(pyrazin-2-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethan-1-amine hydrochloride as a salt, which was used without further purification. LCMS [M+1] + =389.2.

[0425] Intermediate E [ka] Step A: A mixture of ethyl (4-bromo-2-cyano-6-iodophenyl)carbamate (500 mg, 1.00 eq., 1.27 mmol) and thiazole-4-carbohydrazide (190 mg, 1.05 eq., 1.33 mmol) in N-methyl-2-pyrrolidinone (6.33 mL) was heated at 160° C. for 3 h. The reaction mixture was cooled to room temperature, water (10 mL) was added, and the mixture was then poured onto ice. The resulting precipitate was collected and washed with diethyl ether to give 9-bromo-7-iodo-2-(thiazol-4-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5(6H)-one (568 mg, 1.20 mmol, 95% yield), which was used without further purification. LCMS: [M+1] + =473.9.

[0426] 1 H NMR(500MHz, DMSO-d6)δ ppm=9.31(d, J=1.92Hz, 1H), 8.53(d, J=1.92Hz, 1H), 8.40(d, J=2.19Hz, 1H), 8.32(d, J=2.19Hz, 1H).

[0427] Step B: To a vial containing 9-bromo-7-iodo-2-(thiazol-4-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5(6H)-one (319 mg, 1.0 eq., 673 μmol) and a stir bar was added, successively, phosphorus oxychloride (1.03 g, 627 μL, 10.0 eq., 6.73 mmol) and diisopropylethylamine (348 mg, 469 μL, 4.0 eq., 2.69 mmol). The vial was sealed and heated to 100 °C for 12 hours. The reaction was then cooled to room temperature, and the contents were concentrated in vacuo to give a black residue. Ice was added to the residue, and the contents were mixed. After thawing, the aqueous suspension was filtered, and the solid was rinsed three times with water and dried to give a brown solid that was purified by silica gel chromatography (0% to 70% ethyl acetate / heptane) to give 4-(9-bromo-5-chloro-7-iodo-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)thiazole (302 mg, 613 μmol, 91% yield) as a white solid. LCMS: [M+1] + =491.6.

[0428] 1 H NMR(500MHz, DMSO-d6)δ ppm=9.34(d, J=1.92Hz, 1H), 8.69(d, J=2.19Hz, 1H), 8.65(d, J=1.92Hz, 1H), 8.62(d, J=2.19Hz, 1H).

[0429] Step C: To a vial and stir bar was added 4-(9-bromo-5-chloro-7-iodo-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)thiazole (302 mg, 1.0 eq., 613 μmol) as a solid dissolved in anhydrous 1,2-dichloroethane (2.45 mL). Next, diisopropylethylamine (159 mg, 214 μL, 2.0 eq., 1.23 mmol) and piperidine (57.4 mg, 66.6 μL, 1.1 eq., 674 μmol) were added sequentially, and the reaction was sealed and stirred at room temperature overnight. Saturated sodium bicarbonate was added to the reaction, and the solution was diluted with dichloromethane. The aqueous layer was separated and extracted three times. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by silica gel chromatography (0% to 70% ethyl acetate / heptane) to afford 4-(9-bromo-7-iodo-5-(piperidin-1-yl)-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)thiazole (304 mg, 562 μmol, 92% yield) as a white solid. LCMS: [M+1] + =541.2.

[0430] 1 H NMR(500MHz, DMSO-d6)δ ppm=9.31(d, J=1.92Hz, 1H), 8.56(d, J=1.92Hz, 1H), 8.41(d, J=2.19Hz, 1H), 8.38(d, J=2.19Hz, 1H), 4.20(br m, 4H), 1.75(br m, 6H).

[0431] Step D: To a vial and stir bar was added palladium(II) acetate (6.31 mg, 0.05 eq., 28.1 μmol), 1,3-bis(diphenylphosphino)propane (23.2 mg, 0.10 eq., 56.2 μmol), and 4-(9-bromo-7-iodo-5-(piperidin-1-yl)-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)thiazole (304 mg, 1.0 eq., 562 μmol). The flask was evacuated and backfilled with nitrogen three times. Next, ethylene glycol (1.40 mL), N,N-dicyclohexylmethylamine (329 mg, 359 μL, 3.0 eq., 1.69 mmol), and n-butyl vinyl ether (281 mg, 363 μL, 5.0 eq., 2.81 mmol) were charged, and the solution was sparged with nitrogen. The vial was placed on a heating block, and the mixture was stirred and heated at 115 °C. After complete conversion, the reaction was cooled to room temperature, and 1 N HCl (5 mL) was added to the reaction. The reaction was stirred until ketone deprotection was complete (approximately 1 h). The aqueous layer was diluted three times with ethyl acetate, and the combined organic layers were washed successively with water and brine, dried over magnesium sulfate, filtered, and concentrated to give a residue. The residue was purified by silica gel chromatography to give 1-(9-bromo-5-(piperidin-1-yl)-2-(thiazol-4-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethan-1-one (149 mg, 326 μmol, 58% yield) as a yellow solid. LCMS: [M+1] + =457.0.

[0432] 1 H NMR(400MHz, CDCl3)δ ppm=9.05(d, J=2.00Hz, 1H), 8.81(d, J=2.38Hz, 1H), 8.36(d, J=2.13Hz, 1H), 8.12(d, J=2.38Hz, 1H), 4.19(br m, 4H), 2.95(s, 3H), 1.85(br m, 6H).

[0433] Step E: To a vial was added methylboronic acid (48.8 mg, 2.5 eq., 814 μmol), 1-(9-bromo-5-(piperidin-1-yl)-2-(thiazol-4-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethan-1-one (149 mg, 1.0 eq., 326 μmol), potassium carbonate (113 mg, 2.5 eq., 814 μmol), and tetrakis(triphenylphosphine)palladium(0) (37.6 mg, 0.1 eq., 32.6 μmol). The flask was evacuated and backfilled with nitrogen three times. Next, a solution of deoxygenated 1,4-dioxane (1.3 mL) and water (326 μL) was added, and the reaction was heated to 100 °C and stirred overnight. The reaction was cooled to room temperature, quenched with saturated sodium bicarbonate, and extracted three times with dichloromethane. The combined organic layers were washed successively with water, then brine, and dried over magnesium sulfate. After filtration, the mixture was concentrated under reduced pressure and purified by silica gel chromatography to give 1-(9-methyl-5-(piperidin-1-yl)-2-(thiazol-4-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethan-1-one (60 mg, 0.15 mmol, 47% yield) as a yellow solid. LCMS [M+1] + =393.1.

[0434] 1 H NMR(400MHz, CDCl3)δ ppm=9.01(d, J=2.00Hz, 1H), 8.51(d, J=1.00Hz, 1H), 8.37(d, J=2.00Hz, 1H), 7.88(d, J=2.13Hz, 1H), 4.08-4.12(m, 4H), 2.95(s, 3H), 2.54(s, 3H), 1.84(br m, 6H).

[0435] Step F: To a solution of 1-(9-methyl-5-(piperidin-1-yl)-2-(thiazol-4-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethan-1-one (60 mg, 1.0 eq., 0.15 mmol) and (R)-2-methylpropane-2-sulfinamide (22 mg, 1.2 eq., 0.18 mmol) in tetrahydrofuran (0.6 mL) was added titanium(IV) ethoxide (0.17 g, 0.16 mL, 5.0 eq., 0.76 mmol). The mixture was stirred at 80° C. for 4 hours and then cooled to room temperature. Once at room temperature, a minimal amount of brine was added to form a suspension. The resulting suspension was diluted with ethyl acetate. The mixture was filtered through Celite, and the filter cake was washed several times with ethyl acetate. The filtrate was dried, evaporated and concentrated to give (R)-2-methyl-N-(1-(9-methyl-5-(piperidin-1-yl)-2-(thiazol-4-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethylidene)propane-2-sulfinamide (crude weight 93 mg) as a crude yellow solid. The product was carried forward without further purification.

[0436] Step G: To a room temperature solution of (R)-2-methyl-N-(1-(9-methyl-5-(piperidin-1-yl)-2-(thiazol-4-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethylidene)propane-2-sulfinamide (93 mg, 1.0 eq., 0.19 mmol) in anhydrous dichloromethane (1.3 mL) was added Schwartz's reagent (53 mg, 1.1 eq., 0.21 mmol) as a solid in several portions. The reaction was stirred at room temperature for 15 minutes and then quenched with ammonium chloride. The aqueous layer was extracted with dichloromethane, and the combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a residue. The solid was purified by silica gel chromatography (0% to 10% methanol / dichloromethane) to give (R)-2-methyl-N-((R)-1-(9-methyl-5-(piperidin-1-yl)-2-(thiazol-4-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethyl)propane-2-sulfinamide (38 mg, 76 μmol, 41% yield) as a white solid. LCMS [M+1] + =498.2.

[0437] Step H: To a room temperature solution of (R)-2-methyl-N-((R)-1-(9-methyl-5-(piperidin-1-yl)-2-(thiazol-4-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethyl)propane-2-sulfinamide (38 mg, 1.0 eq., 76 μmol) in methanol (0.31 mL) was added 48 μL of HCl (4.0 M in dioxane). The reaction was measured and upon completion, triturated with diethyl ether, dried under vacuum, and (R)-1-(9-methyl-5-(piperidin-1-yl)-2-(thiazol-4-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethan-1-amine hydrochloride was used as a salt without further purification. LCMS [M+1] + =394.2.

[0438] Intermediate F 8-Bromo-2,4-dichloro-6-methylquinazoline [ka] Step A: To a solution of 2-amino-3-bromo-5-methyl-benzoic acid (30.0 g, 130 mmol, 1.00 eq.) in water (1000 mL) was added acetic acid (23.5 g, 391 mmol, 22.4 mL, 3.00 eq.). The mixture was stirred at 35° C. for 0.2 hours. Sodium cyanate (25.4 g, 391 mmol, 3.00 eq.) in water (400 mL) was then added. The mixture was stirred at 35° C. for 12 hours. Sodium hydroxide (235 g, 5.87 mol, 45.0 eq.) was then added to the mixture. The mixture was stirred at 35° C. for 0.2 hours. After completion of the reaction, the reaction mixture was adjusted to pH 4 with hydrochloric acid at 0° C., the mixture was filtered and rinsed with water (1 L), and the crude product was then purified by recrystallization from ethyl acetate (30 mL) at 25° C. for 10 min to give 8-bromo-6-methyl-1H-quinazoline-2,4-dione (30 g) as a white solid. LCMS [M+2] + =257.0.

[0439] Step B: A solution of 8-bromo-6-methyl-1H-quinazoline-2,4-dione (9.50 g, 37.2 mmol, 1.00 eq.) in phosphorus oxychloride (70 mL) was stirred at 120 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove excess phosphorus oxychloride. The reaction mixture was quenched by adding water (100 mL) at 0 °C and then extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (50.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to give 8-bromo-2,4-dichloro-6-methyl-quinazoline (4.3 g) as a yellow solid. LCMS [M+2] + =293.0.

[0440] 7-Bromo-5-chloro-9-methyl-[1,2,4]triazolo[4,3-c]quinazoline [ka] Step A: To a solution of 8-bromo-2,4-dichloro-6-methyl-quinazoline (4.3 g, 14.7 mmol, 1.00 eq.) in tetrahydrofuran (40.0 mL) was added diisopropylethylamine (1.90 g, 14.7 mmol, 2.57 mL, 1.00 eq.) at 0 °C for 0.2 h, followed by the addition of formylhydrazine (884 mg, 14.7 mmol, 1.00 eq.), and the mixture was stirred at 0 °C. Upon complete conversion to the intermediate aryl hydrazide, phosphorus oxychloride (3.39 g, 22.1 mmol, 2.06 mL, 1.50 eq.) was added to the mixture at 25 °C, and the reaction was heated to 60 °C for 6 h. After completion of the reaction, the reaction mixture was carefully poured onto ice, and the resulting aqueous suspension was neutralized to pH 7 with sodium hydroxide. The product was filtered and rinsed with water, and the mixture was suspended in water (100 mL) and extracted with ethyl acetate (100 mL x 2). The aqueous layer was then adjusted to pH = 10 with aqueous sodium hydroxide and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (0% to 100% ethyl acetate / petroleum ether) to give 7-bromo-5-chloro-9-methyl-[1,2,4]triazolo[4,3-c]quinazoline (6 g, crude) as a yellow solid. LCMS [M+2] + =299.0. [Example]

[0441] Example 1-1 (R)-2-((1-(9-methyl-5-(piperidin-1-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethyl)amino)benzoic acid [ka] To a vial and stir bar were added (R)-1-(9-methyl-5-(piperidin-1-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethan-1-amine hydrochloride (39 mg, 1.0 eq., 0.11 mmol), 2-carboxyphenylboronic acid (56 mg, 3.0 eq., 0.34 mmol), and copper(II) acetate (31 mg, 1.5 eq., 0.17 mmol) as solids. The vial was then sealed with a septum cap, and dimethylformamide (1.1 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (86 mg, 85 μL, 5.0 eq., 0.56 mmol) were added sequentially. A vent needle was pierced through the septum, and the reaction was allowed to warm to ambient temperature. The reaction was stirred at room temperature for 12 h. The reaction was quenched with aqueous ammonium chloride and diluted with ethyl acetate. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed successively with saturated ammonium chloride and brine, then dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The reaction residue was purified by silica gel chromatography (0% to 100% ethyl acetate / heptane) to afford (R)-2-((1-(9-methyl-5-(piperidin-1-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethyl)amino)benzoic acid (16 mg, 37 μmol, 33% yield) as a white solid. LCMS [M+1] + =431.2.

[0442] 1 H NMR(400MHz, CDCl3)δ ppm=8.35(s, 1H), 8.15(br s, 1H), 7.97(d, J=7.88Hz, 1H), 7.56-7.71(m, 1H), 7.13-7.21(m, 1H), 6.59-6.73(m, 1H), 6.44-6.57(m, 1H), 5.69(br m, J=1.63Hz, 1H), 3.99(br m, 4H), 2.47(s, 3H), 1.73-1.89(m, 9H).

[0443] The compounds in Table 2 are prepared essentially according to the procedures described in the schemes and examples above. [Table 45] [Table 46]

[0444] Example 2-1 2-((1-(9-methyl-5-(piperidin-1-yl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzoic acid [ka] Step A: To a solution of 8-bromo-2,4-dichloro-6-methyl-quinazoline (3.17 g, 10.7 mmol, 1.00 eq.) in dichloromethane (5 mL) was added 16 mL of ammonia (7 M / methanol). The mixture was stirred at 25° C. for 16 hours. Upon completion, the reaction mixture was concentrated in vacuo to give the crude product. The crude product was triturated with petroleum ether (50.0 mL) at 25° C. for 1 hour and then dried under reduced pressure to give 8-bromo-2-chloro-6-methyl-quinazolin-4-amine (3.06 g, 10.7 mmol, 98% yield) as a white solid. LCMS [M+3] + =273.8.

[0445] Step B: To a solution of 8-bromo-2-chloro-6-methyl-quinazolin-4-amine (3.00 g, 11.0 mmol, 1.0 eq.) in dioxane (50 mL), 2-chloroacetaldehyde (19.4 g, 99.1 mmol, 15.9 mL, 40% purity, 9.00 eq.) was added, and the mixture was stirred at 100 °C for 16 hours. Upon completion, the mixture was cooled to 25 °C and concentrated under reduced pressure to give a residue. The residue was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with brine (50 mL x 3), dried over sodium sulfate, and concentrated in vacuo to give compound 7-bromo-5-chloro-9-methyl-imidazo[1,2-c]quinazoline (2.95 g, 7.96 mmol, 72% yield) as a white solid. LCMS [M+3] + =297.8.

[0446] 1 H NMR(400MHz, CDCl3)8.35(s, 1H), 7.86(d, J=1.2Hz, 1H), 7.81(d, J=1.2Hz, 1H), 7.70(d, J=1.2Hz, 1H), 2.57(s, 3H)

[0447] Step C: To a solution of 7-bromo-5-chloro-9-methyl-imidazo[1,2-c]quinazoline (2.95 g, 9.95 mmol, 1.00 eq.) in acetonitrile (5 mL) was added piperidine (847 mg, 9.95 mmol, 982 μL, 1.00 eq.), and the mixture was stirred at 60 °C for 16 h. Upon completion, the mixture was cooled to 25 °C and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel (0% to 40% ethyl acetate / petroleum ether) to give 7-bromo-9-methyl-5-(1-piperidyl)imidazo[1,2-c]quinazoline (2.16 g, 4.38 mmol, 44% yield) as a yellow solid. LCMS [M+3] + =346.8.

[0448] 1 H NMR(400MHz, CDCl3)δ ppm=8.96(s, 1H), 8.18(br s, 1H), 8.06-7.92(m, 1H), 7.74-7.62(m, 1H), 3.56(br d, J=5.2Hz, 3H), 2.64-2.50(m, 3H), 1.72-1.68(m, 6H).

[0449] Step D: A mixture of 7-bromo-9-methyl-5-(1-piperidyl)imidazo[1,2-c]quinazoline (400 mg, 1.16 mmol, 1.00 eq.), butyl vinyl ether (116 mg, 1.16 mmol, 149 μL, 1.00 eq.), N,N-dicyclohexylmethylamine (231 mg, 1.27 mmol, 254 μL, 1.10 eq.), and chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (89.1 mg, 174 μmol, 0.15 eq.) in dioxane (5.0 mL) was degassed and purged with nitrogen for 3 minutes, then stirred at 100° C. for 12 hours under a nitrogen atmosphere. Upon completion, the mixture was cooled to 25° C., filtered and concentrated under reduced pressure to give the crude product which was used directly in the next step without purification. LCMS [M+1] + =365.1.

[0450] Step E: To a solution of 7-(1-butoxyvinyl)-9-methyl-5-(1-piperidyl)imidazo[1,2-c]quinazoline (325 mg, 892 μmol, 1.00 eq.) in tetrahydrofuran (2.00 mL) was added 2.00 mL of hydrochloric acid (3 M / water), and the mixture was stirred at 25° C. for 3 hours. Upon completion, the mixture was adjusted to pH=8 with saturated aqueous sodium bicarbonate solution, and then extracted with ethyl acetate (20 mL×3). The combined organic layer was washed with brine (30 mL×3), dried over sodium sulfate, and concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (0% to 50% ethyl acetate / petroleum ether) to give 1-(9-methyl-5-(piperidin-1-yl)imidazo[1,2-c]quinazolin-7-yl)ethan-1-one (65.0 mg, 179 μmol, 20% yield) as a yellow solid. LCMS [M+1] + =309.0.

[0451] Step F: To a solution of 1-(9-methyl-5-(piperidin-1-yl)imidazo[1,2-c]quinazolin-7-yl)ethan-1-one (60.0 mg, 195 μmol, 1.0 eq.) in methanol (1.0 mL) was added sodium borohydride (8 mg, 200 μmol, 1.1 eq.) at 0° C. After the addition, the reaction mixture was stirred at 0° C. for 1 hour. The mixture was quenched by adding water (5 mL) and then extracted with ethyl acetate (5 mL×3). The combined organic layer was washed with brine (5 mL×3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 1-(9-methyl-5-(piperidin-1-yl)imidazo[1,2-c]quinazolin-7-yl)ethan-1-ol (40.0 mg, 129 μmol, 66% yield) as a yellow solid. LCMS[M+1] + =310.9.

[0452] Step G: A mixture of 1-(9-methyl-5-(piperidin-1-yl)imidazo[1,2-c]quinazolin-7-yl)ethan-1-ol (50 mg, 160 μmol, 1.0 eq.) in thionyl chloride (1.64 g, 14 mmol, 1.0 mL, 86 eq.) was stirred at 50° C. for 30 min. Upon completion, the mixture was cooled to 25° C. and concentrated under reduced pressure to give 7-(1-chloroethyl)-9-methyl-5-(piperidin-1-yl)imidazo[1,2-c]quinazoline (55 mg, crude) as a pale brown gum.

[0453] Step H: A mixture of 7-(1-chloroethyl)-9-methyl-5-(piperidin-1-yl)imidazo[1,2-c]quinazoline (40 mg, 120 μmol, 1.0 eq.), tert-butyl 2-aminobenzoate (47 mg, 240 μmol, 44 μL, 2.0 eq.), potassium iodide (20 mg, 120 μmol, 1.0 eq.), and diisopropylethylamine (63 mg, 490 μmol, 85 μL, 4.0 eq.) in dimethylformamide (2.0 mL) was stirred at 80° C. for 4 hours under a nitrogen atmosphere. Upon completion, the mixture was cooled to 25° C. and diluted with ethyl acetate (20 mL). The resulting mixture was washed with brine (10 mL×3). The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (0% to 20% ethyl acetate / petroleum ether) to afford tert-butyl 2-((1-(9-methyl-5-(piperidin-1-yl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzoate (15 mg, 24 μmol, 20% yield) as a pale yellow solid. LCMS [M+1] + =486.2.

[0454] Step I: A mixture of tert-butyl 2-((1-(9-methyl-5-(piperidin-1-yl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzoate (15 mg, 31 μmol, 1.0 eq.) and trifluoroacetic acid (1.5 mL) in dichloroethane (2.0 mL) was stirred at 50° C. for 2 hours. Upon completion, the reaction mixture was concentrated in vacuo to provide a residue. The residue was purified by preparative HPLC (Phenomenex C18x80x40mm 3µm column, mobile phase A: water (NH3H2O ​​+ NH4HCO3), mobile phase B: acetonitrile, flow rate: 25mL / min, gradient conditions: 30%B to 60%B) to give 2-((1-(9-methyl-5-(piperidin-1-yl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzoic acid (5mg, 11µmol, 36% yield) as a white solid. LCMS [M+1] + =430.1.

[0455] 1 H NMR(400MHz, CD3OD)δ ppm=8.06(s, 1H), 7.93-7.86(m, 1H), 7.83-7.78(m, 1H), 7.63-7.55(m, 1H), 7.51-7.44(m, 1H), 7.14-7.05(m, 1H), 6.53-6.43(m, 2H), 5.68(q, J=6.8Hz, 1H), 3.60-3.50(m, 4H), 2.45(s, 3H), 1.96-1.75(m, 6H), 1.68(d, J=6.8Hz, 3H).

[0456] Example 2-2 (R)-2-((1-(2-cyano-9-methyl-5-(piperidin-1-yl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzoic acid [ka] Step A: 8-Bromo-2-chloro-6-methyl-quinazolin-4-amine (3.70 g, 13.6 mmol, 1.00 eq.) was added as a solid to piperidine (5.78 g, 67.9 mmol, 6.70 mL, 5.00 eq.). The mixture was heated and stirred at 130 °C for 1 h. Upon completion of the reaction, the mixture was cooled to 25 °C and the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (0% to 50% ethyl acetate / petroleum ether) to give 8-bromo-6-methyl-2-(piperidin-1-yl)quinazolin-4-amine (4.00 g, 12.3 mmol, 90% yield) as a yellow solid. LCMS [M+1] + =321.2.

[0457] 1 H NMR(400MHz, DMSO-d6)δ ppm=7.79(s, 1H), 7.70(d, J=1.6Hz, 1H), 7.38(br s, 2H), 3.82-3.75(m, 4H), 2.31(s, 3H), 1.60(br d, J=4.4Hz, 2H), 1.51(br d, J=4.0Hz, 4H)

[0458] Step B: To a solution of 8-bromo-6-methyl-2-(piperidin-1-yl)quinazolin-4-amine (3.00 g, 9.34 mmol, 1.00 eq.) in toluene (360 mL) was added ethyl 3-bromo-2-oxopropanoate (9.11 g, 46.7 mmol, 5.84 mL, 5.00 eq.) and 4A molecular sieves (40.0 g). The mixture was sealed and stirred at 140 °C for 15 h. Upon completion of the reaction, the mixture was cooled to 25 °C and the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (0% to 100% ethyl acetate / petroleum ether) to give ethyl 7-bromo-9-methyl-5-(piperidin-1-yl)imidazo[1,2-c]quinazoline-2-carboxylate (3.50 g, 8.39 mmol) as a yellow solid. LCMS[M+3] + =419.1.

[0459] 1 H NMR(400MHz, DMSO-d6)δ ppm=8.24(s, 1H), 8.13(s, 1H), 7.84(d, J=1.6Hz, 1H), 4.36(q, J=7.2Hz, 2H), 3.52-3.45(m, 4H), 2.47(s, 3H), 1.77(br d, J=3.6Hz, 4H), 1.69(br d, J=4.4Hz, 2H), 1.35(t, J=7.2Hz, 3H).

[0460] Step C: To a solution of ethyl 7-bromo-9-methyl-5-(piperidin-1-yl)imidazo[1,2-c]quinazoline-2-carboxylate (900 mg, 2.16 mmol, 1.00 eq.) in methanol (2.00 mL) was added 9.00 mL of ammonia (7.00 M in methanol). The mixture was stirred at 35 °C for 48 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (0% to 100% ethyl acetate / petroleum ether) to give 7-bromo-9-methyl-5-(piperidin-1-yl)imidazo[1,2-c]quinazoline-2-carboxamide (500 mg, 1.29 mmol, 60% yield) as a yellow solid. LCMS [M+3] + =390.1.

[0461] 1 H NMR(400MHz, DMSO-d6)δ ppm=8.11(s, 2H), 7.83(s, 2H), 7.57(br s, 1H), 3.47(br d, J=4.8Hz, 4H), 2.47(s, 3H), 1.77(br d, J=2.8Hz, 4H), 1.69(br d, J=4.0Hz, 2H).

[0462] Step D: To a solution of 7-bromo-9-methyl-5-(piperidin-1-yl)imidazo[1,2-c]quinazoline-2-carboxamide (480 mg, 1.24 mmol, 1.00 eq.) and triethylamine (188 mg, 1.85 mmol, 258 μL, 1.50 eq.) in dichloromethane (50.0 mL) was added trifluoroacetic anhydride (389 mg, 1.85 mmol, 258 μL, 1.50 eq.) dropwise at 0° C. The mixture was stirred at 0° C. for 30 minutes. The reaction mixture was quenched at 25° C. by the addition of water (20 mL) and then extracted with ethyl acetate (20 mL×3). The combined organic layer was washed with 30 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (0% to 30% ethyl acetate / petroleum ether) to give 7-bromo-9-methyl-5-(piperidin-1-yl)imidazo[1,2-c]quinazoline-2-carbonitrile (301 mg, 813 μmol) as a yellow solid. LCMS [M+1] + =370.2.

[0463] Step E: A mixture of 7-bromo-9-methyl-5-(piperidin-1-yl)imidazo[1,2-c]quinazoline-2-carbonitrile (270 mg, 729 μmol, 1.00 eq.), n-butyl vinyl ether (365 mg, 3.65 mmol, 469 μL, 5.00 eq.), N,N-dicyclohexylmethylamine (397 mg, 2.19 mmol, 436 μL, 3.00 eq.), and chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (37.4 mg, 72.9 μmol, 0.10 eq.) was evacuated and backfilled with nitrogen three times, and deoxygenated dioxane (6.00 mL) was added. The mixture was then stirred at 100° C. for 10 hours under a nitrogen atmosphere. After the reaction was completed, the mixture was cooled to 25° C., and the reaction mixture was filtered and concentrated under reduced pressure to give the crude product 7-(1-butoxyvinyl)-9-methyl-5-(piperidin-1-yl)imidazo[1,2-c]quinazoline-2-carbonitrile (280 mg, 719 μmol, 99% yield) as a yellow solid. LCMS [M+1] + =390.3.

[0464] Step F: To a solution of 7-(1-butoxyvinyl)-9-methyl-5-(piperidin-1-yl)imidazo[1,2-c]quinazoline-2-carbonitrile (249 mg, 639 μmol, 1.00 eq.) in dichloromethane (2.50 mL) was added trifluoroacetic acid (729 mg, 6.39 mmol, 475 μL, 10.0 eq.). The mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (10% to 20% ethyl acetate / petroleum ether) to give 7-acetyl-9-methyl-5-(piperidin-1-yl)imidazo[1,2-c]quinazoline-2-carbonitrile (201 mg, 603 μmol, 94% yield) as a yellow solid.

[0465] 1 H NMR(400MHz, CDCl3)δ ppm=8.38(s, 1H), 8.00(s, 1H), 7.80(d, J=1.6Hz, 1H), 3.49-3.40(m, 4H), 2.90(s, 3H), 2.55-2.51(m, 3H), 2.02-1.85(m, 6H).

[0466] Step G: To a solution of 7-acetyl-9-methyl-5-(piperidin-1-yl)imidazo[1,2-c]quinazoline-2-carbonitrile (190 mg, 570 μmol, 1.00 eq.) in 2-methyltetrahydrofuran (10.0 mL), (R)-2-methylpropane-2-sulfinamide (345.37 mg, 2.85 mmol, 5.00 eq.), titanium(IV) ethoxide (650 mg, 2.85 mmol, 591 μL, 5.00 eq.), and 1,2-dimethoxyethane (51.4 mg, 570 μmol, 59.2 μL, 1.00 eq.) were added. The mixture was stirred at 95 °C for 12 h. After completion of the reaction, the mixture was cooled to 25 °C, and water (15 mL) was added to the reaction mixture and stirred for 30 min. The reaction mixture was filtered. The filtrate was extracted with 60.0 mL of ethyl acetate (20 mL x 3). The combined organic layers were washed with 60 mL of brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (0% to 100% ethyl acetate / petroleum ether) to give (R)-N-(1-(2-cyano-9-methyl-5-(piperidin-1-yl)imidazo[1,2-c]quinazolin-7-yl)ethylidene)-2-methylpropane-2-sulfinamide (160 mg, 360 μmol, 63% yield, 98% purity) as a yellow solid. LCMS [M+1] + =437.4.

[0467] Step H: To a solution of (R)—N-(1-(2-cyano-9-methyl-5-(piperidin-1-yl)imidazo[1,2-c]quinazolin-7-yl)ethylidene)-2-methylpropane-2-sulfinamide (130 mg, 298 μmol, 1.00 eq.) in dichloromethane (1.50 mL) was added Schwartz's reagent (95.4 mg, 357 μmol, 1.20 eq.) in portions. The mixture was stirred at 25° C. for 1 hour. The reaction mixture was partitioned between 30 mL of ethyl acetate and 30 mL of water. The organic layer was separated, washed with 90 mL of brine (30 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide a residue. The residue was purified by flash silica gel chromatography (0% to 100% ethyl acetate / petroleum ether) to afford (R)-N-((R)-1-(2-cyano-9-methyl-5-(piperidin-1-yl)imidazo[1,2-c]quinazolin-7-yl)ethyl)-2-methylpropane-2-sulfinamide (80 mg, 170 μmol, 57% yield) as a yellow solid. LCMS [M+1] + =439.2.

[0468] 1 H NMR(400MHz, CDCl3)δ ppm=8.18(s, 1H), 7.98(s, 1H), 7.46(d, J=1.2Hz, 1H), 5.09(t, J=6.8Hz, 1H), 3.44-3.39(m, 4H), 2.52(s, 3H), 1.86(br s, 4H), 1.77(br d, J=4.4Hz, 2H), 1.66(d, J=6.8Hz, 3H), 1.24(s, 8H).

[0469] Step I: To a solution of (R)-N-((R)-1-(2-cyano-9-methyl-5-(piperidin-1-yl)imidazo[1,2-c]quinazolin-7-yl)ethyl)-2-methylpropane-2-sulfinamide (70 mg, 160 μmol, 1.0 eq.) in dioxane (1.00 mL) was added 300 μL of HCl (4 M in dioxane). The mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give the crude product (R)-7-(1-aminoethyl)-9-methyl-5-(piperidin-1-yl)imidazo[1,2-c]quinazoline-2-carbonitrile hydrochloride (50 mg, 150 μmol, 84% yield) as a yellow solid. LCMS [M+1] + =335.3.

[0470] Step J: To a solution of (R)-7-(1-aminoethyl)-9-methyl-5-(piperidin-1-yl)imidazo[1,2-c]quinazoline-2-carbonitrile hydrochloride (50 mg, 150 μmol, 1.0 eq.) in dimethylformamide (0.50 mL) was added 2-carboxyphenylboronic acid (74 mg, 450 μmol, 3.0 eq.), diazabicyclo[5.4.0]undec-7-ene (114 mg, 748 μmol, 113 μL, 5.0 eq.), copper(II) acetate (41 mg, 220 μmol, 1.5 eq.), and 4A molecular sieves (40.0 mg). The mixture was stirred at 25 °C for 12 h. 20 mL of saturated aqueous ammonium chloride solution was added to the reaction mixture at 25 °C, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (33% ethyl acetate / petroleum ether) to give a residue. The residue was purified by preparative HPLC (FA conditions; column: Phenomenex Luna C18 150 x 25 mm x 10 μm; mobile phase: [water (FA)-ACN]; gradient: 62% to 92% B over 9 min) to give (R)-2-((1-(2-cyano-9-methyl-5-(piperidin-1-yl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzoic acid (24 mg, 53 μmol, 35% yield) as a white solid. LCMS [M+1]+ =455.2.

[0471] 1 H NMR(400MHz, CDCl3)δ ppm=11.81-10.40(m, 1H), 8.46-8.09(m, 2H), 8.05-7.98(m, 2H), 7.53(s, 1H), 7.18(br t, J=7.6Hz, 1H), 6.58(t, J=7.6Hz, 1H), 6.45(d, J=8.8Hz, 1H), 5.63(q, J=6.4Hz, 1H), 3.48(br s, 4H), 2.47(s, 3H), 1.88(br s, 4H), 1.80(br d, J=4.4Hz, 2H), 1.70(brd, J=6.8Hz, 3H).

[0472] Example 3-1 (R)-2-((1-(5-(piperidin-1-yl)-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid [ka] Step A: To a reaction vial containing tetrahydrofuran (36.0 mL) and a stir bar was added 8-bromo-2,4-dichloroquinazoline (3.00 g, 1.0 eq., 10.8 mmol) as a solid and diisopropylethylamine (1.40 g, 1.88 mL, 1.0 eq., 10.8 mmol). After dissolution, the vial was cooled to 0 °C, and formylhydrazine (648 mg, 1.0 eq., 10.8 mmol) was added portionwise. Upon completion of the addition, the cooling bath was removed, and the reaction was stirred at room temperature for 12 h. Upon complete conversion to the intermediate aryl hydrazide (as observed by LCMS), phosphorus oxychloride (2.48 g, 1.51 mL, 1.5 eq., 16.2 mmol) was added, and the reaction was heated to 60 °C until complete conversion to the tricyclic product was observed. The reaction was carefully poured onto ice, and the resulting aqueous suspension was neutralized to pH 7 with sodium hydroxide. The product was filtered, rinsed with water, dried, and purified by silica gel chromatography (0% to 100% ethyl acetate / heptane) to give 7-bromo-5-chloro-[1,2,4]triazolo[4,3-c]quinazoline (1.0 g, 3.5 mmol, 33% yield) as an orange solid. LCMS [M+1] + =284.9.

[0473] 1 H NMR(500MHz, CDCl3)δ ppm=8.98(s, 1H), 8.60(dd, J=7.94, 1.37Hz, 1H), 8.10(dd, J=7.80, 1.23Hz, 1H), 7.61(t, J=7.94Hz, 1H).

[0474] Step B: To a vial and stir bar was added 7-bromo-5-chloro-[1,2,4]triazolo[4,3-c]quinazoline (500 mg, 1 eq., 1.76 mmol) as a solid dissolved in anhydrous 1,2-dichloroethane (7.05 mL). Next, diisopropylethylamine (456 mg, 614 μL, 2.0 eq., 3.53 mmol) and piperidine (165 mg, 192 μL, 1.1 eq., 1.94 mmol) were added sequentially, and the reaction was sealed and heated to 80 °C overnight. Saturated sodium bicarbonate was added to the reaction, and the solution was diluted with dichloromethane. The aqueous layer was separated and extracted three times. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by silica gel chromatography (0% to 70% ethyl acetate / heptane) to afford 7-bromo-5-(piperidin-1-yl)-[1,2,4]triazolo[4,3-c]quinazoline (270 mg, 813 μmol, 46% yield) as a white solid. LCMS [M+1] + =332.0.

[0475] 1 H NMR(500MHz, CDCl3)δ ppm=8.77(s, 1H), 8.50(dd, J=7.80, 1.23Hz, 1H), 7.96(dd, J=7.67, 1.37Hz, 1H), 7.34(t, J=7.94Hz, 1H), 3.59-3.66(m, 4H), 1.83-1.91(m, 4H), 1.76-1.83(m, 2H).

[0476] Step C: Palladium(II) acetate (9.12 mg, 0.05 eq., 40.6 μmol), 1,3-bis(diphenylphosphino)propane (33.5 mg, 0.10 eq., 81.3 μmol), and 7-bromo-5-(piperidin-1-yl)-[1,2,4]triazolo[4,3-c]quinazoline (270 mg, 1.0 eq., 813 μmol) were added to a vibratory flask and stirred. The flask was evacuated and backfilled with nitrogen three times. Next, ethylene glycol (4.1 mL), N,N-dicyclohexylmethylamine (476 mg, 519 μL, 3.0 eq., 2.44 mmol), and n-butyl vinyl ether (407 mg, 526 μL, 5.0 eq., 4.06 mmol) were added, and the solution was sparged with nitrogen. The vial was placed on a heating block, and the mixture was stirred and heated at 115°C. After complete conversion, the reaction was cooled to room temperature, and 1N HCl (15 mL) was added to the reaction. The reaction was stirred until ketone deprotection was complete (approximately 1 hour). The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed successively with water and brine, dried over magnesium sulfate, filtered, and concentrated to give a residue. This residue was purified by silica gel chromatography to give 1-(5-(piperidin-1-yl)-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethan-1-one (107 mg, 362 µmol, 45% yield) as a yellow solid. LCMS [M+H] + =296.1.

[0477] 1 H NMR(400MHz, CDCl3)δ ppm=8.86(br m, 1H), 8.83(s, 1H), 8.05(d, J=7.50Hz, 1H), 7.61(t, J=7.75Hz, 1H), 3.58-3.65(m, 4H), 2.92(s, 3H), 1.89(br m, 4H), 1.78-1.85(m, 2H).

[0478] Step D: To a solution of 1-(5-(piperidin-1-yl)-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethan-1-one (156 mg, 1.0 eq., 528 μmol) and (R)-2-methylpropane-2-sulfinamide (76.8 mg, 1.2 eq., 634 μmol) in tetrahydrofuran (2.1 mL) was added titanium(IV) ethoxide (602 mg, 550 μL, 5.0 eq., 2.64 mmol). The mixture was stirred at 80° C. for 4 hours and then cooled to room temperature. Once at room temperature, a minimal amount of brine was added to form a suspension. The resulting suspension was diluted with ethyl acetate and filtered through Celite, washing the filter cake several times with ethyl acetate. The filtrate was concentrated by evaporation under reduced pressure, and the yellow residue was quickly purified by silica gel chromatography (30% to 100% ethyl acetate / heptane) to give (R)-2-methyl-N-(1-(5-(piperidin-1-yl)-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethylidene)propane-2-sulfinamide (145 mg, 364 μmol, 69% yield) as a yellow solid.

[0479] Step E: To a room temperature solution of (R)-2-methyl-N-(1-(5-(piperidin-1-yl)-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethylidene)propane-2-sulfinamide (145 mg, 1.0 eq., 364 μmol) in anhydrous dichloromethane (2.4 mL) was added Schwartz's reagent (103 mg, 1.1 eq., 400 μmol) as a solid in several portions. The reaction was stirred at room temperature for 15 minutes and then quenched with ammonium chloride. The aqueous layer was extracted with dichloromethane, and the combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a residue. The solid was purified by silica gel chromatography (0% to 10% methanol / dichloromethane) to give (R)-2-methyl-N-((R)-1-(5-(piperidin-1-yl)-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)propane-2-sulfinamide (8.8 mg, 22 μmol, 6% yield) as a white solid. LCMS [M+1] + =401.1.

[0480] Step F: To a room temperature solution of (R)-2-methyl-N-((R)-1-(5-(piperidin-1-yl)-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)propane-2-sulfinamide (8.8 mg, 1.0 eq., 22 μmol) in methanol (0.22 mL) was added 14 μL of HCl (4.0 M in dioxane). The reaction was measured and, upon completion, triturated with diethyl ether and dried under vacuum to give (R)-1-(5-(piperidin-1-yl)-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethan-1-amine hydrochloride as a salt, which was used without further purification. LCMS [M+1] + =297.2.

[0481] Step G: (R)-1-(5-(piperidin-1-yl)-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethan-1-amine, HCl (7.3 mg, 1.0 eq., 22 μmol), 2-carboxyphenylboronic acid (11 mg, 3.0 eq., 66 μmol), and copper(II) acetate (6.0 mg, 1.5 eq., 33 μmol) were added as solids to a vial and stir bar. The vial was then sealed with a septum cap, and dimethylformamide (0.22 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (17 mg, 17 μL, 5.0 eq., 0.11 mmol) were added sequentially. A vent needle was pierced through the septum, and the reaction was allowed to warm to ambient temperature. The reaction was stirred at room temperature for 12 h. The reaction was quenched with aqueous ammonium chloride and diluted with ethyl acetate. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed successively with saturated ammonium chloride and brine, then dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The reaction residue was purified by preparative thin-layer chromatography to give (R)-2-((1-(5-(piperidin-1-yl)-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid (2.0 mg, 4.8 μmol, 22% yield) as a white solid. [M+1] + =417.2.

[0482] 1 H NMR(400MHz, CDCl3)δ ppm=8.81(s, 1H), 8.41-8.51(m, 1H), 8.00(dd, J=8.00, 1.38Hz, 1H), 7.72(d, J=7.50Hz, 1H), 7.44(t, J=7.75Hz, 1H), 7.10-7.20(m, 1H), 6.57(t, J=7.50Hz, 1H), 6.42(d, J=8.63Hz, 1H), 5.63(q, J=6.67Hz, 1H), 3.53-3.63(m, 4H), 1.88(br m, 4H), 1.80(br m, 2H), 1.70(d, J=6.63Hz, 3H).

[0483] Example 4-1 (R)-2-((1-(9-methyl-5-(piperidin-1-yl)-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid [ka] Step A: To a solution of 7-bromo-5-chloro-9-methyl-[1,2,4]triazolo[4,3-c]quinazoline (6.00 g, 20.2 mmol, 1.00 eq.) in acetonitrile (50 mL) was added piperidine (1.89 g, 22.2 mmol, 1.10 eq.). The reaction was stirred at 60 °C for 16 h. Upon completion, the mixture was cooled to 25 °C, filtered, and the filter cake was washed with acetonitrile (30 mL) to give a residue that was triturated with water (150 mL) at 20 °C for 30 min, filtered, and dried under reduced pressure to give 7-bromo-9-methyl-5-(piperidin-1-yl)-[1,2,4]triazolo[4,3-c]quinazoline (4.20 g, 12.1 mmol, 60% yield) as a yellow solid. LCMS [M+1] + =346.1.

[0484] 1H NMR(400MHz, DMSO-d6)δ ppm=9.38(s, 1H), 8.15(d, J=0.8Hz, 1H), 7.88(d, J=1.6Hz, 1H), 3.60-3.51(m, 4H), 2.47(s, 3H), 1.81-1.62(m, 6H).

[0485] Step B: A mixture of 7-bromo-9-methyl-5-(piperidin-1-yl)-[1,2,4]triazolo[4,3-c]quinazoline (2.00 g, 5.78 mmol, 1.00 eq.), butyl vinyl ether (868 mg, 8.66 mmol, 1.11 mL, 1.5 eq.), chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (148 mg, 289 μmol, 0.05 eq.), and N,N-dicyclohexylmethylamine (2.09 g, 11.5 mmol, 2.30 mL, 2.00 eq.) was evacuated and backfilled with nitrogen three times, and deoxygenated dioxane (50 mL) was added. The reaction was stirred at 100 °C for 2 h under a nitrogen atmosphere. Upon completion, the mixture was cooled to 25 °C. The mixture was diluted with water (20.0 mL) and used in the next step without further purification. LCMS [M+1] + =366.2.

[0486] Step C: To a solution of 7-(1-butoxyvinyl)-9-methyl-5-(piperidin-1-yl)-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethan-1-one (1.50 g, 4.85 mmol, 84% yield) as a yellow solid was added 5.75 mL of HCl (3M / water). The reaction was stirred at 20° C. for 4 hours. The mixture was then diluted with water (150 mL) and filtered to give a residue, which was triturated with ethyl acetate (50 mL) at 20° C. for 30 minutes, filtered, and dried under reduced pressure. LCMS [M+1] + =310.3.

[0487] Step D: To a solution of 1-(9-methyl-5-(piperidin-1-yl)-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethan-1-one (1.00 g, 3.23 mmol, 1.00 eq.), (R)-2-methylpropane-2-sulfinamide (509 mg, 4.20 mmol, 1.30 eq.) in tetrahydrofuran (30 mL) was added titanium(IV) ethoxide (1.47 g, 6.46 mmol, 1.34 mL, 2.00 eq.). The reaction was stirred at 70° C. for 12 hours. The mixture was concentrated under reduced pressure to give a residue that was used in the next step without further purification. LCMS [M+1] + =413.3.

[0488] Step E: To a solution of (R)-2-methyl-N-(1-(9-methyl-5-(piperidin-1-yl)-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethylidene)propane-2-sulfinamide (1.20 g, 2.91 mmol, 1.00 eq.) in dichloromethane (30 mL) was added Schwartz's reagent (1.55 g, 5.82 mmol, 2.00 eq.) in portions. The reaction was stirred at 25° C. for 3 hours. The mixture was concentrated under reduced pressure to give a residue that was used in the next step without further purification. LCMS [M+1] + =415.3.

[0489] Step F: To a solution of (R)-2-methyl-N-((R)-1-(9-methyl-5-(piperidin-1-yl)-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)propane-2-sulfinamide (1.10 g, 2.65 mmol, 1.00 eq.) in tetrahydrofuran (30 mL) was added iodine (878 mg, 3.45 mmol, 1.30 eq.) and water (6 mL). The reaction was stirred at 50° C. for 2 hours. Upon completion, the mixture was cooled to 25° C. The mixture was then concentrated under reduced pressure, purified by reverse-phase flash (0% to 40% acetonitrile / water (0.3% FA)), and lyophilized to give (R)-1-(9-methyl-5-(piperidin-1-yl)-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethan-1-amine (500 mg, 1.61 mmol, 61% yield) as a yellow solid. LCMS [M+1] + =311.2.

[0490] Step G: A mixture of (R)-1-(9-methyl-5-(piperidin-1-yl)-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethan-1-amine (200 mg, 644 μmol, 1.00 eq.), 2-carboxyphenylboronic acid (214 mg, 1.29 mmol, 2.00 eq.), copper(II) acetate (234 mg, 1.29 mmol, 2.00 eq.), and diazabicyclo[5.4.0]undec-7-ene (294 mg, 1.93 mmol, 291 μL, 3.00 eq.) in dimethylformamide (3 mL) was purged with oxygen three times. The reaction was stirred under an oxygen atmosphere for 12 h at 25 °C. The mixture was filtered and then purified by preparative HPLC (column: Phenomenex luna C18 150x25mmx10μm; mobile phase: [water (FA)-ACN]; gradient: 52% to 82% B over 9 min) and lyophilized to give (R)-2-((1-(9-methyl-5-(piperidin-1-yl)-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid (8 mg, 18μmol, 3% yield) as a yellow solid. LCMS [M+1] + =431.3.

[0491] 1 H NMR(400MHz, CD3OD)δ ppm=9.22(br s, 1H), 8.10(s, 1H), 7.86(br d, J=7.6Hz, 1H), 7.55(s, 1H), 7.07(t, J=7.6Hz, 1H), 6.55-6.37(m, 2H), 5.60(q, J=6.4Hz, 1H), 3.58(s, 4H), 2.43(s, 3H), 1.88(s, 4H), 1.79(d, J=5.2Hz, 2H), 1.65(d, J=6.4Hz, 3H). Examples 5-1 to 5-50 The following compounds are prepared essentially according to the procedures described above in Schemes I-IV and Examples 1-1, 2-1, 2-2, 3-1, and 4-1. [Table 47] [Table 48] [Table 49] [Table 50] [Table 51] [Table 52] [Table 53] [Table 54] [Table 55] [Table 56] [Table 57] [Table 58] [Table 59] [Table 60] [Table 61] [Table 62] [Table 63]

[0492] Intermediate H [ka] Step A: To a suspension of 2-amino-3-bromo-5-methyl-benzoic acid (5.21 g, 22.7 mmol, 1.00 eq.) in water (35.0 mL) was added acetic acid (2.72 g, 45.3 mmol, 2.59 mL, 2.00 eq.), the mixture was heated to 45 °C, and then a solution of potassium cyanate (5.79 g, 67.9 mmol, 3.00 eq.) in water (10.0 mL) was added dropwise over 5 min. Stirring was continued at 45 °C for 1 h after addition. Upon completion, the reaction solution was cooled to 25 °C and adjusted to approximately pH 6 with 10% aqueous sodium hydroxide. The precipitate was collected by filtration and then dried under vacuum to give 8-bromo-6-methylquinazoline-2,4(1H,3H)-dione (3.00 g, 9.41 mmol, 42% yield) as a white solid.

[0493] Step B: A solution of 8-bromo-6-methylquinazoline-2,4(1H,3H)-dione (3.00 g, 11.8 mmol, 1.00 eq.) in phosphorus oxychloride (30.0 mL) was stirred at 100° C. for 16 hours. Upon completion, the reaction solution was cooled to 25° C. and then slowly poured into ice-water (300 mL). The solution was then diluted, extracted with ethyl acetate (100 mL×3), washed with brine (50 mL×2), dried over sodium sulfate, filtered, and concentrated in vacuo to give 8-bromo-2,4-dichloro-6-methylquinazoline (3.17 g, 10.6 mmol, 91% yield) as a white solid. LCMS [M+2] + =292.6.

[0494] Step C: To a solution of 8-bromo-2,4-dichloro-6-methylquinazoline (3.17 g, 10.7 mmol, 1.00 eq.) in dichloromethane (5.00 mL) was added ammonia / methanol solution (7 M, 15.5 mL, 10.0 eq.). The mixture was stirred at 25 °C for 16 h. Upon completion, the reaction mixture was concentrated in vacuo to give the crude product. The crude product was triturated with petroleum ether (50.0 mL) at 25 °C for 1 h and then dried under reduced pressure to give 8-bromo-2-chloro-6-methylquinazolin-4-amine (3.06 g, 10.7 mmol, 98% yield) as a white solid. LCMS [M+3] + =273.8.

[0495] Step D: A solution of 8-bromo-2-chloro-6-methylquinazolin-4-amine (1.30 g, 4.77 mmol, 1.00 eq.) and 3-bromo-1,1,1-trifluoropropan-2-one (1.82 g, 9.54 mmol, 991 μL, 2.00 eq.) in dioxane (8.00 mL) was stirred at 100 °C for 12 h. After completion of the reaction, the reaction mixture was cooled to 25 °C and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 10:1 to 8:1) to give 7-bromo-5-chloro-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazoline (1.00 g, 2.58 mmol, 54% yield) as a yellow solid. LCMS [M+3]+ =365.8.

[0496] Example 6-1 (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid [ka] Step A: A solution of 7-bromo-5-chloro-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazoline (1.00 g, 2.74 mmol, 1.00 eq.) and 4,4-difluoropiperidine (498 mg, 4.11 mmol, 1.50 eq.) in acetonitrile (10.0 mL) was prepared. The mixture was stirred at 80 °C for 1 hour. After completion of the reaction, the reaction mixture was cooled to 25 °C, diluted with water (100 mL), and extracted with ethyl acetate (100 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 7-bromo-5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazoline (1.25 g, 2.41 mmol, 88% yield) as a white solid. LCMS[M+1] + =449.0.

[0497] Step B: A mixture of 7-bromo-5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazoline (1.25 g, 2.78 mmol, 1.00 eq.), tributyl(1-ethoxyvinyl)stannane (1.51 g, 4.17 mmol, 1.41 mL, 1.50 eq.), and bis(triphenylphosphine)palladium(II) dichloride (195 mg, 278 μmol, 0.10 eq.) in dioxane (10 mL) was evacuated and backfilled with nitrogen three times, and then the mixture was stirred under a nitrogen atmosphere at 100° C. for 2 hours. After completion of the reaction, the mixture was poured into saturated aqueous potassium fluoride solution (100 mL) at 25° C. and stirred for 1 hour. The aqueous layer was extracted with dichloromethane (50.0 mL x 3), and the combined organic layers were washed with brine (50.0 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 5-(4,4-difluoropiperidin-1-yl)-7-(1-ethoxyvinyl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazoline (1.22 g, crude) as a yellow solid. LCMS [M+1] + =441.3.

[0498] Step C: To a solution of 5-(4,4-difluoropiperidin-1-yl)-7-(1-ethoxyvinyl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazoline (1.22 g, 2.77 mmol, 1.00 eq.) in tetrahydrofuran (10.0 mL) was added p-toluenesulfonic acid (527 mg, 2.77 mmol, 1.00 eq.). The mixture was stirred for 1 hour at 25 °C. After completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 8:1 to 6:1) to give 1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethan-1-one (1.08 g, 2.54 mmol, 92% yield) as a yellow solid. LCMS [M+1] + =413.1.

[0499] 1 H NMR(400MHz, CDCl3)δ ppm=8.49(s, 1H), 7.96(s, 1H), 7.90(s, 1H), 3.83(br s, 4H), 2.86(s, 3H), 2.59-2.52(m, 3H), 2.43-2.33(m, 4H).

[0500] Step D: To a solution of 1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethan-1-one (1.08 g, 2.62 mmol, 1.00 eq.) and (R)-2-methylpropane-2-sulfinamide (476 mg, 3.93 mmol, 1.50 eq.) in 2-methyltetrahydrofuran (15.0 mL) was added titanium(IV) ethoxide (1.79 g, 7.86 mmol, 1.63 mL, 3.00 eq.). The mixture was stirred at 90 °C for 12 hours. After completion of the reaction, the reaction mixture was diluted with water (4.00 mL) and ethyl acetate (20.0 mL) at 25 °C, and the resulting suspension was filtered to obtain a filtrate. The filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate = 6:1 to 4:1) to give (R)-N-(1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethylidene)-2-methylpropane-2-sulfinamide (810 mg, 1.49 mmol, 57% yield) as a yellow solid. LCMS [M+1] + =516.2.

[0501] Step E: To a solution of (R)—N-(1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethylidene)-2-methylpropane-2-sulfinamide (810 mg, 1.57 mmol, 1.00 eq.) in methanol (8.00 mL) and dichloromethane (8.00 mL) was added sodium cyanoborohydride (296 mg, 4.71 mmol, 3.00 eq.) and acetic acid (9.44 mg, 157 μmol, 8.99 μL, 0.10 eq.). The mixture was stirred for 1.5 hours at 25° C. After completion of the reaction, the pH of the mixture was adjusted to approximately pH=8 with saturated aqueous sodium bicarbonate solution. The resulting solution was then extracted with dichloromethane (30.0 mL × 3), and the combined organic layers were washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, dichloromethane:methanol = 15:1 to 10:1) to give (R)-N-((R)-1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)-2-methylpropane-2-sulfinamide (600 mg, 1.05 mmol, 67% yield) as a white solid. Then, (R)-N-((R)-1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)-2-methylpropane-2-sulfinamide was purified by SFC (column: (S,S)WHELK-O1 (250 mm x 30 mm, 10 μm); mobile phase: [CO2-EtOH]; B%: 25%, isocratic elution mode) to obtain (R)-N-((R)-1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)-2-methylpropane-2-sulfinamide as a white solid. LCMS [M+1] + =518.1.

[0502] 1H NMR(400MHz, DMSO-d6)δ ppm=8.59(s, 1H), 8.08(s, 1H), 7.69(d, J=1.2Hz, 1H), 5.74(d, J=8.0Hz, 1H), 5.44-5.19(m, 1H), 3.60(t, J=5.2Hz, 4H), 2.50(s, 3H), 2.42-2.23(m, 4H), 1.50(d, J=6.8Hz, 3H), 1.11(s, 9H).

[0503] Step F: To a solution of (R)—N—((R)-1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)-2-methylpropane-2-sulfinamide (540 mg, 1.04 mmol, 1.00 eq.) in ethyl acetate, hydrochloric acid / ethyl acetate (10.0 mL, 2 M) was added and stirred for 1.5 hours at 25° C. After completion of the reaction, the pH of the mixture was adjusted to approximately pH=8 with saturated aqueous sodium bicarbonate. The solution was then extracted with dichloromethane (30.0 mL x 3), and the combined organic layers were washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (R)-1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethan-1-amine (420 mg, 782 μmol, 75% yield) as a white solid. LCMS [M+1] + =414.1.

[0504] Step G: To a solution of (R)-1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethan-1-amine (420 mg, 1.02 mmol, 1.00 eq.), methyl 6-chloro-3-fluoropicolinate (289 mg, 1.52 mmol, 1.50 eq.) in dimethylformamide (10.0 mL) was added diisopropylethylamine (394 mg, 3.05 mmol, 531 μL, 3.00 eq.). The mixture was stirred at 90° C. for 12 hours. After completion of the reaction, the reaction mixture was diluted with water (100 mL) at 25° C. and extracted with ethyl acetate (100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 7:1 to 5:1) to give (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)methyl picolinate (450 mg, 687 μmol, 68% yield) as a white solid. LCMS [M+1] + =583.1.

[0505] Step H: To a solution of (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)methyl picolinate (50.0 mg, 85.8 μmol, 1.00 eq.) in tetrahydrofuran (1.00 mL) and methanol (1.00 mL) was added lithium hydroxide (2 M, 428 μL, 10.0 eq.). The mixture was stirred for 1 hour at 40° C. After completion of the reaction, the pH of the mixture was adjusted to approximately pH=5 with aqueous citric acid. The solution was then extracted with dichloromethane (30.0 mL×3), and the combined organic layers were washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150x25mmx10μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 60% to 90% acetonitrile over 9 min) to give (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid (11.0 mg, 19.2 μmol, 22% yield) as an off-white solid. LCMS [M+1] + =569.1.

[0506] 1 H NMR(400MHz, CD3OD)δ=8.34(s, 1H), 8.16(s, 1H), 7.54(d, J=1.6Hz, 1H), 7.16(d, J=8.8Hz, 1H), 7.03(d, J=9.2Hz, 1H), 5.57(d, J=6.4Hz, 1H), 3.72(t, J=5.2Hz, 4H), 2.46(s, 3H), 2.39-2.21(m, 4H), 1.72(d, J=6.8Hz, 3H).

[0507] 19 F NMR(377MHz, CD3OD)δ ppm=-64.0, -64.2.

[0508] Example 6-2 (R)-6-chloro-3-((1-(9-methyl-5-morpholino-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid [ka] Step A: To a mixture of 7-bromo-5-chloro-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-5-yl (50.0 g, 137 mmol, 1.00 eq) in acetonitrile (300 mL) was added morpholine (23.9 g, 274 mmol, 24.1 mL, 2.00 eq), and the mixture was heated to 60 °C for 0.5 h. Upon completion, the mixture was poured into water (1000 mL), extracted with ethyl acetate (1500 mL), and the organic layer was concentrated in vacuo to give the crude product. The crude product was purified by silica gel chromatography (SiO, petroleum ether:ethyl acetate = 10 / 1 to 2 / 1) to give 4-(7-bromo-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-5-yl)morpholine (43.0 g, 104 mmol, 76% yield) as a yellow solid.

[0509] 1 H NMR(400MHz, CDCl3)δ ppm=8.25(s, 1H), 7.83(s, 1H), 7.78(s, 1H), 4.00-3.97(m, 4H), 3.61-3.59(m, 4H), 2.50(s, 3H).

[0510] Step B: To a solution of 4-(7-bromo-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-5-yl)morpholine (40.0 g, 96.3 mmol, 1.00 eq) and tributyl(1-ethoxyvinyl)stannane (52.2 g, 145 mmol, 48.8 mL, 1.50 eq) in dioxane (400 mL) was added bis(triphenylphosphine)palladium(II) dichloride (6.76 g, 9.63 mmol, 0.10 eq), the mixture was evacuated and backfilled with nitrogen, and then heated to 100 °C under a nitrogen atmosphere for 16 h. Upon completion, the mixture was quenched with saturated aqueous potassium fluoride (1000 mL) and extracted with ethyl acetate (500 mL). The organic layer was concentrated in vacuo to give 4-(7-(1-ethoxyvinyl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-5-yl)morpholine (39.2 g, crude) as a yellow solid which was used in the next reaction without further purification.

[0511] Step C: To a mixture of 4-(7-(1-ethoxyvinyl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-5-yl)morpholine (39.2 g, 96.3 mmol, 1.00 eq) in tetrahydrofuran (400 mL) was added hydrochloric acid (4 M, 24.1 mL, 1.00 eq) and the mixture was stirred at 25 °C for 1 h. Upon completion, the mixture was diluted with water (1000 mL) to give a suspension, and the solid was collected by filtration and dried under vacuum to give 1-(9-methyl-5-morpholino-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethan-1-one (32.0 g, 84.6 mmol, 88% yield) as a yellow solid.

[0512] Step D: To a mixture of 1-(9-methyl-5-morpholino-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethan-1-one (32.0 g, 84.6 mmol, 1.00 eq) in 2-methyltetrahydrofuran (500 mL) was added (R)-2-methylpropane-2-sulfinamide (61.5 g, 507 mmol, 6.00 eq) followed by titanium(IV) ethoxide (116 g, 507 mmol, 105 mL, 6.00 eq) and the mixture was heated to 90° C. for 16 h. After completion of the reaction, the mixture was diluted with water (1500 mL), extracted with ethyl acetate (1000 mL), the solid was filtered, and the organic layer was concentrated in vacuo to give (R)-2-methyl-N-(1-(9-methyl-5-morpholino-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethylidene)propane-2-sulfinamide (40.7 g, crude) as a yellow oil, which was carried forward without further purification.

[0513] Step E: To a mixture of (R)-2-methyl-N-(1-(9-methyl-5-morpholino-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethylidene)propane-2-sulfinamide (40.7 g, 84.6 mmol, 1.00 eq) in dichloromethane (200 mL) and methanol (200 mL) was added acetic acid (25.4 g, 423 mmol, 24.2 mL, 5.00 eq), and then sodium cyanoborohydride (21.3 g, 338 mmol, 4.00 eq) was added portionwise to the mixture at 25° C. The mixture was stirred for 2 hours at 25° C. Upon completion, the mixture was diluted with water (1000 mL), extracted with dichloromethane (500 mL), and the organic layer was concentrated in vacuo to give a crude solid. The crude solid was purified by silica gel chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give (R)-2-methyl-N-((R)-1-(9-methyl-5-morpholino-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)propane-2-sulfinamide (27.0 g, 51.4 mmol, 61% yield) as a yellow solid. LCMS [M+1] + =484.3.

[0514] 1 H NMR(400MHz, CDCl3)δ ppm=8.27-8.26(m, 1H), 7.83(s, 1H), 7.48(s, 1H), 5.21 -5.19(m, 1H), 4.00-3.98(m, 4H), 3.52-3.49(m, 4H), 2.52(s, 3H), 1.66(d, J=7.2Hz, 3H), 1.25(s, 9H).

[0515] Step F: To a mixture of (R)-2-methyl-N-((R)-1-(9-methyl-5-morpholino-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)propane-2-sulfinamide (8.00 g, 16.5 mmol, 1.00 eq) in acetonitrile (50 mL) was added a solution of hydrochloric acid in ethyl acetate (2 M, 24.8 mL, 3.00 eq) and the mixture was stirred for 1 h at 25 °C. Upon completion, the mixture was concentrated in vacuo to give a yellow solid. The solid was triturated with ethyl acetate (50 mL), filtered, and dried in vacuo to give (R)-1-(9-methyl-5-morpholino-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethan-1-amine (5.70 g, 13.6 mmol, 82%) as a white hydrochloride salt. LCMS[M+1] + =380.1.

[0516] Step G: To a solution of (R)-1-(9-methyl-5-morpholino-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethan-1-amine hydrochloride (5.40 g, 14.2 mmol, 1.00 eq) and methyl 6-chloro-3-fluoropicolinate (4.05 g, 21.4 mmol, 1.50 eq) in dimethylformamide (30 mL) was added diisopropylethylamine (9.20 g, 71.2 mmol, 12.4 mL, 5.00 eq) and the mixture was heated to 90 °C for 16 h. Upon completion, the mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL), the organic layers were combined, washed with brine (50 mL) and concentrated in vacuo to give (R)-6-chloro-3-((1-(9-methyl-5-morpholino-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)methyl picolinate (7.10 g, crude) as a pale yellow solid which was carried forward without further purification. LCMS [M+1] + =549.1.

[0517] Step H: To a mixture of (R)-6-chloro-3-((1-(9-methyl-5-morpholino-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)methyl picolinate (7.10 g, 12.9 mmol, 1.00 eq) in dimethyl sulfoxide (70 mL) was added lithium chloride (5.48 g, 129 mmol, 10.0 eq) and the mixture was heated to 130 °C for 16 h. Upon completion, the mixture was cooled to 25 °C and poured into water (200 mL) to give a suspension. The solid was collected by filtration and then dissolved in ethyl acetate (100 mL). The organic layer was washed with brine (50 mL x 2) and concentrated in vacuo to give a crude solid. The solid was purified by silica gel chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1, then dichloromethane / methanol = 10 / 1) and then by preparative HPLC (column: Phenomenex luna C18 250 * 50mm *Purification on a 10 μm column (mobile phase: [water (0.1% formic acid)-acetonitrile]; gradient: 50% to 80% acetonitrile over 20 min) gave (R)-6-chloro-3-((1-(9-methyl-5-morpholino-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid (3.90 g, 7.28 mmol, 56% yield) as a yellow solid. LCMS [M+23] + =557.1.

[0518] 1 H NMR(400MHz, DMSO-d6)δ ppm=13.00(s, 1H), 8.63(s, 1H), 8.57(d, J=6.8Hz, 1H), 8.09(s, 1H), 7.55(s, 1H), 7.30(d, J=8.8Hz, 1H), 7.13(d, J=9.2Hz, 1H), 5.50(t, J=6.4Hz, 1H), 3.97-3.80(m, 4H), 3.65-3.45(m, 4H), 2.44(s, 3H), 1.68(d, J=6.4Hz, 3H).

[0519] 19 F NMR(377MHz, DMSO-d6)δ ppm=-61.15.

[0520] Example 6-3 (R)-6-chloro-3-((1-(9-methyl-5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid [ka] Step A: To a mixture of 7-bromo-5-chloro-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazoline (20.0 g, 54.8 mmol, 1.00 eq) in acetonitrile (400 mL) was added triethylamine (16.6 g, 164 mmol, 22.9 mL, 3.00 eq) and 2-oxa-6-azaspiro[3.3]heptane (11.8 g, 82.3 mmol, 1.50 eq, 0.5% oxalic acid). The mixture was stirred at 60 °C for 2 h. After completion, the mixture was poured into water and extracted with ethyl acetate (400 mL x 4). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 6-(7-bromo-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-5-yl)-2-oxa-6-azaspiro[3.3]heptane (14.2 g, 69%) as a yellow solid.

[0521] 1 H NMR(400MHz, CDCl3)δ ppm=8.18(d, J=2.0Hz, 1H), 7.74(dd, J=1.6, 5.2Hz, 1H), 4.92(s, 4H), 4.66(s, 4H), 2.47(s, 3H).

[0522] Step B: To a mixture of 6-(7-bromo-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-5-yl)-2-oxa-6-azaspiro[3.3]heptane (14.2 g, 33.2 mmol, 1.00 eq) in dioxane (500 mL) was added tributyl(1-ethoxyvinyl)stannane (18.0 g, 49.8 mmol, 16.8 mL, 1.50 eq) and bis(triphenylphosphine)palladium(II) dichloride (2.33 g, 3.32 mmol, 0.10 eq) under nitrogen. The mixture was stirred at 100 °C for 10 h under nitrogen. Upon completion, the mixture was cooled to 20 °C and quenched with aqueous potassium fluoride (10%, 1.5 L). Ethyl acetate (2 L) was then added to the mixture and stirred for 10 min. The mixture was filtered, and the filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 6-(7-(1-ethoxyvinyl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-5-yl)-2-oxa-6-azaspiro[3.3]heptane (10.7 g, crude) as a yellow solid, which was used in the next step without further purification.

[0523] Step C: To a mixture of 6-(7-(1-ethoxyvinyl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-5-yl)-2-oxa-6-azaspiro[3.3]heptane (10.7 g, 25.5 mmol, 1.00 eq) in tetrahydrofuran (120 mL) was added hydrochloric acid (1 M, 25.5 mL, 1.00 eq). The mixture was stirred for 1 h at 20 °C. Upon completion, the mixture was poured into water (400 mL) and filtered. The filter cake was dried under vacuum to give 1-(9-methyl-5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethan-1-one (9.00 g, 23.0 mmol, 90% yield) as a yellow solid which was used without further purification. LCMS [M+1] + =391.2.

[0524] Step D: To a mixture of 1-(9-methyl-5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethan-1-one (7.70 g, 19.7 mmol, 1.00 eq) and (R)-2-methylpropane-2-sulfinamide (14.3 g, 118 mmol, 6.00 eq) in 2-methyltetrahydrofuran (100 mL) was added titanium(IV) ethoxide (27.0 g, 118 mmol, 24 mL, 6.00 eq). The mixture was stirred at 90 °C for 10 h. Upon completion, the mixture was cooled to 20 °C and poured into water (300 mL) and ethyl acetate (300 mL), and the mixture was stirred for 10 min. The mixture was filtered, and the filtrate was separated, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give (R)-2-methyl-N-(1-(9-methyl-5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethylidene)propane-2-sulfinamide (10 g, crude) as a yellow oil, which was used without further purification.

[0525] Step E: To a mixture of (R)-2-methyl-N-(1-(9-methyl-5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethylidene)propane-2-sulfinamide (10.0 g, 20.3 mmol, 1.00 eq) in dichloromethane (250 mL) and methanol (250 mL) was added acetic acid (6.08 g, 101 mmol, 5.80 mL, 5.00 eq) and sodium cyanoborohydride (5.09 g, 81.0 mmol, 4.00 eq). The mixture was stirred for 2 hours at 20 °C. Upon completion, the mixture was poured into water (500 mL) and extracted with dichloromethane (200 mL × 2). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (SiO2, petroleum ether / ethyl acetate = 15 / 1 to 5 / 1) to give (R)-2-methyl-N-((R)-1-(9-methyl-5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)propane-2-sulfinamide (8.00 g, 15.3 mmol, 76% yield) as a yellow solid. LCMS [M+1] + =496.1.

[0526] Step F: To a mixture of (R)-2-methyl-N-((R)-1-(9-methyl-5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)propane-2-sulfinamide (14.0 g, 28.2 mmol, 1.00 eq) in acetonitrile (100 mL) was added a solution of hydrochloric acid in ethyl acetate (1 M, 28.2 mL, 1.00 eq). The mixture was stirred at 20 °C for 30 min. Upon completion, the mixture was filtered, the filter cake washed with ethyl acetate (50 mL) and dried under vacuum to give (R)-1-(9-methyl-5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethan-1-amine (8.00 g, crude) as a yellow hydrochloride salt. LCMS [M+1] + =392.0.

[0527] Step G: To a mixture of (R)-1-(9-methyl-5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethan-1-amine hydrochloride (8.00 g, 18.7 mmol, 1.00 eq) and methyl 6-chloro-3-fluoropicolinate (3.54 g, 18.7 mmol, 1.00 eq), diisopropylethylamine (12.1 g, 93.5 mmol, 16.3 mL, 5.00 eq) was added. The mixture was stirred at 90 °C for 10 h. Upon completion, the mixture was cooled to 25 °C, poured into water (500 mL), and stirred for 10 min. The suspension was filtered, and the filter cake was washed with water (100 mL×2) and dried in vacuo to give (R)-6-chloro-3-((1-(9-methyl-5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)methyl picolinate (8.00 g, crude) as a yellow solid.

[0528] Step H: To a mixture of (R)-6-chloro-3-((1-(9-methyl-5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)methyl picolinate (8.00 g, 14.3 mmol, 1.00 eq) in tetrahydrofuran (80 mL) and water (20 mL) was added lithium hydroxide monohydrate (1.20 g, 28.5 mmol, 2.00 eq). The mixture was stirred at 40 °C for 1 hour. Upon completion, the mixture was poured into water (300 mL) and the mixture was adjusted to approximately pH = 6 with hydrochloric acid (0.5 M). The aqueous solution was extracted with ethyl acetate (200 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250 * 70mm *Further purification with 10 μm column chromatography (mobile phase: [water (0.1% trifluoroacetic acid)-acetonitrile]; gradient: 52% to 82% acetonitrile over 20 min) gave (R)-6-chloro-3-((1-(9-methyl-5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid (2.09 g, 26% yield, 97% purity) as a yellow solid. LCMS [M+1] + =547.1

[0529] 1 H NMR(400MHz, CDCl3)δ ppm=8.48(d, J=6.4Hz, 1H), 8.17(s, 1H), 7.78(s, 1H), 7.38(d, J=1.2Hz, 1H), 7.11(d, J=9.2Hz, 1H), 6.91(d, J=8.8Hz, 1H), 5.39-5.34(m, 1H), 4.98-4.93(m, 4H), 4.75(d, J=9.2Hz, 2H), 4.63(d, J=8.8Hz, 2H), 2.43(s, 3H), 1.74(d, J=6.8Hz, 3H).

[0530] Example 6-4 (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methylimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid [ka] Step A: To a solution of 7-bromo-5-chloro-9-methylimidazo[1,2-c]quinazoline (3.00 g, 10.1 mmol, 1.00 eq.) in acetonitrile (35.0 mL) was added 4,4-difluoropiperidine (2.45 g, 20.2 mmol, 2.00 eq.) and diisopropylethylamine (3.92 g, 30.4 mmol, 5.29 mL, 3.00 eq.). The mixture was stirred at 60 °C for 1 h. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica column, eluent: 0 to 100% ethyl acetate / petroleum ether gradient, 60 mL / min) to give 7-bromo-5-(4,4-difluoropiperidin-1-yl)-9-methylimidazo[1,2-c]quinazoline (1.60 g, 2.81 mmol, 28% yield) as a yellow solid. LCMS [M+3] + =383.0.

[0531] Step B: A mixture of 7-bromo-5-(4,4-difluoropiperidin-1-yl)-9-methylimidazo[1,2-c]quinazoline (1.60 g, 2.81 mmol, 1.00 eq.), tributyl(1-ethoxyvinyl)stannane (1.29 g, 3.56 mmol, 1.20 mL, 1.27 eq.), and bis(triphenylphosphine)palladium(II) chloride (197 mg, 281 μmol, 0.10 eq.) in dioxane (16 mL) was evacuated and backfilled with nitrogen three times, and then the mixture was stirred under a nitrogen atmosphere for 6 h at 100° C. After completion of the reaction, the mixture was cooled to 25° C., poured into saturated potassium fluoride solution (80 mL), and stirred for 1 h. The aqueous layer was extracted with dichloromethane (80.0 mL x 3), and the combined organic layers were washed with brine (80.0 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 5-(4,4-difluoropiperidin-1-yl)-7-(1-ethoxyvinyl)-9-methylimidazo[1,2-c]quinazoline (1.00 g, 2.69 mmol, crude) as a yellow oil. LCMS [M+1] + =373.1.

[0532] Step C: To a solution of 5-(4,4-difluoropiperidin-1-yl)-7-(1-ethoxyvinyl)-9-methylimidazo[1,2-c]quinazoline (1.00 g, 2.69 mmol, 1.00 eq.) in acetone (15.0 mL) was added p-toluenesulfonic acid hydrate (511 mg, 2.69 mmol, 1.00 eq.). The mixture was stirred at 25 °C for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in dichloromethane (80.0 mL), washed with saturated aqueous sodium bicarbonate solution (80.0 mL x 3) and brine (80.0 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent: 0-60% ethyl acetate / petroleum ether gradient, 36 mL / min) to give 1-(5-(4,4-difluoropiperidin-1-yl)-9-methylimidazo[1,2-c]quinazolin-7-yl)ethan-1-one (800 mg, 2.32 mmol, 87% yield) as a yellow solid. LCMS [M+1] + =345.3.

[0533] 1 H NMR(400MHz, CDCl3)δ ppm=8.43(d, J=1.2Hz, 1H), 7.75(d, J=2.0Hz, 1H), 7.63(d, J=1.2Hz, 1H), 7.53(d, J=1.6Hz, 1H), 3.70-3.63(m, 4H), 2.90(s, 3H), 2.55(s, 3H), 2.36-2.19(m, 4H).

[0534] Step D: To a solution of 1-(5-(4,4-difluoropiperidin-1-yl)-9-methylimidazo[1,2-c]quinazolin-7-yl)ethan-1-one (800 mg, 2.32 mmol, 1.00 eq.) in 2-methyltetrahydrofuran (10.0 mL), (R)-2-methylpropane-2-sulfinamide (563 mg, 4.65 mmol, 2.00 eq.) and titanium(IV) ethoxide (1.80 g, 7.88 mmol, 1.63 mL, 3.39 eq.) were added. The mixture was stirred at 80° C. for 12 hours. After the reaction was completed, the mixture was cooled to 25° C., and water (0.60 mL) and dichloromethane (30.0 mL) were added. The mixture was stirred for 30 minutes. The resulting mixture was filtered, and the filter cake was washed with dichloromethane (50.0 mL x 3). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent: 0-100% ethyl acetate / petroleum ether gradient, 36 mL / min) to give (R)—N-(1-(5-(4,4-difluoropiperidin-1-yl)-9-methylimidazo[1,2-c]quinazolin-7-yl)ethylidene)-2-methylpropane-2-sulfinamide (900 mg, 2.01 mmol, 87% yield) as a yellow oil. LCMS [M+1] + =448.1.

[0535] Step E: To a solution of (R)—N-(1-(5-(4,4-difluoropiperidin-1-yl)-9-methylimidazo[1,2-c]quinazolin-7-yl)ethylidene)-2-methylpropane-2-sulfinamide (800 mg, 1.79 mmol, 1.00 eq.) in dichloromethane (4.00 mL) and methanol (4.00 mL) were added acetic acid (1.07 g, 17.9 mmol, 1.02 mL, 10.0 eq.) and sodium cyanoborohydride (337 mg, 5.36 mmol, 3.00 eq.) at 0° C. The mixture was stirred at 0° C. for 2 hours. After completion of the reaction, the mixture was warmed to 25° C. and adjusted to approximately pH=7 with saturated aqueous sodium bicarbonate solution (15.0 mL). The resulting mixture was concentrated under reduced pressure to remove methanol and dichloromethane, then diluted with dichloromethane (20.0 mL). The organic layer was separated, washed with brine (20.0 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 x 40 mm x 15 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 35% to 65% acetonitrile over 15 min) to give (R)-N-((R)-1-(5-(4,4-difluoropiperidin-1-yl)-9-methylimidazo[1,2-c]quinazolin-7-yl)ethyl)-2-methylpropane-2-sulfinamide (500 mg, 1.10 mmol, 62% yield, 99% purity) as a yellow solid. LCMS [M+1] + =450.2.

[0536] 1 H NMR(400MHz, CDCl3)δ ppm=8.22(d, J=0.8Hz, 1H), 7.60(d, J=1.2Hz, 1H), 7.50(d, J=1.2Hz, 1H), 7.43(d, J=1.6Hz, 1H), 5.21(quin, J=6.8Hz, 1H), 3.71-3.58(m, 4H), 2.53(s, 3H), 2.36-2.21(m, 4H), 1.66(d, J=6.8Hz, 3H), 1.23(s, 9H).

[0537] Step F: To a solution of (R)—N—((R)-1-(5-(4,4-difluoropiperidin-1-yl)-9-methylimidazo[1,2-c]quinazolin-7-yl)ethyl)-2-methylpropane-2-sulfinamide (121 mg, 267 μmol, 1.00 eq.) in acetonitrile (1.00 mL) was added a solution of hydrochloric acid / ethyl acetate (2.00 M, 1.33 mL, 10.0 eq.). The mixture was stirred for 1 hour at 25° C. Upon completion, the reaction mixture was concentrated under reduced pressure to provide a residue. The residue was triturated with ethyl acetate (10.0 mL) at 25° C. for 10 minutes, filtered, and the filter cake was dried under vacuum to give (R)-1-(5-(4,4-difluoropiperidin-1-yl)-9-methylimidazo[1,2-c]quinazolin-7-yl)ethan-1-amine (100 mg, 262 μmol, 98% yield) as a yellow hydrochloride salt. LCMS [M+1] + =346.2.

[0538] Step G: To a solution of (R)-1-(5-(4,4-difluoropiperidin-1-yl)-9-methylimidazo[1,2-c]quinazolin-7-yl)ethan-1-amine hydrochloride (100 mg, 262 μmol, 1.00 eq.) in dimethylformamide (1.00 mL) was added methyl 6-chloro-3-fluoropicolinate (124 mg, 655 μmol, 2.50 eq.) and diisopropylethylamine (101 mg, 786 μmol, 137 μL, 3.00 eq.). The mixture was stirred at 90° C. for 12 hours. After completion of the reaction, the mixture was cooled to 25° C. and partitioned with ethyl acetate (30.0 mL) and water (30.0 mL). The organic layer was separated, washed with brine (30.0 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, eluent: 0-100% ethyl acetate / petroleum ether gradient, 36 mL / min) to afford (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methylimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)methyl picolinate (100 mg, 194 μmol, 74% yield) as a yellow solid. LCMS [M+1] + =515.1.

[0539] Step H: To a solution of (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methylimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)methyl picolinate (90.0 mg, 175 μmol, 1.00 eq.) in dimethyl sulfoxide (1.00 mL) was added lithium chloride (74.1 mg, 1.75 mmol, 35.8 μL, 10.0 eq.). The mixture was stirred at 120° C. for 4 hours. After completion of the reaction, the mixture was cooled to 25° C. and filtered. The filtrate was purified by preparative HPLC (column: Welch Xtimate C18 150x25mmx5μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 45% to 75% acetonitrile over 40 min) to give (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methylimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid (34.8 mg, 69.0 μmol, 40% yield) as an off-white solid. LCMS [M+1] + =501.2.

[0540] 1 H NMR(400MHz, CDCl3)δ ppm=8.39(br d, J=6.4Hz, 1H), 8.20(d, J=0.8Hz, 1H), 7.63(d, J=1.6Hz, 1H), 7.54(d, J=1.6Hz, 1H), 7.40(d, J=2.0Hz, 1H), 7.09(d, J=8.8Hz, 1H), 6.87(d, J=8.8Hz, 1H), 5.53(quin, J=6.8Hz, 1H), 3.79-3.59(m, 4H), 2.46(s, 3H), 2.37-2.23(m, 4H), 1.72(d, J=6.4Hz, 3H).

[0541] 19 F NMR(377MHz, CDCl3)δ ppm=-97.4.

[0542] Examples 6-5 (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-2,9-dimethylimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid [ka] Step A: To a solution of 8-bromo-2-chloro-6-methylquinazolin-4-amine (2.20 g, 8.07 mmol, 1.00 eq.) in dioxane (25.0 mL) was added 1-bromo-2,2-dimethoxypropane (7.39 g, 40.4 mmol, 5.45 mL, 5.00 eq.). The mixture was stirred at 100 °C for 16 h. After completion of the reaction, the reaction mixture was cooled to 25 °C to obtain a suspension. The suspension was filtered, and the filter cake was triturated with petroleum ether / ethyl acetate = 1 / 1 (25.0 mL) at 25 °C for 5 min, filtered, and dried under vacuum to give 7-bromo-5-chloro-2,9-dimethylimidazo[1,2-c]quinazoline (2.50 g, 8.05 mmol, 99% yield) as a gray solid. LCMS [M+3] + =311.9.

[0543] Step B: To a solution of 7-bromo-5-chloro-2,9-dimethylimidazo[1,2-c]quinazoline (2.50 g, 8.05 mmol, 1.00 eq.) and 4,4-difluoropiperidine (1.27 g, 10.5 mmol, 1.30 eq.) in acetonitrile (15.0 mL) was added diisopropylethylamine (5.20 g, 40.3 mmol, 7.01 mL, 5.00 eq.). The mixture was stirred at 60 °C for 2 h. After completion of the reaction, the mixture was cooled to 25 °C and concentrated under reduced pressure to give a solid. The solid was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to give 7-bromo-5-(4,4-difluoropiperidin-1-yl)-2,9-dimethylimidazo[1,2-c]quinazoline (2.40 g, 6.07 mmol, 75% yield) as a yellow solid. LCMS [M+1] + =395.1.

[0544] 1H NMR(400MHz, CDCl3)δ ppm=8.20(d, J=0.8Hz, 1H), 7.72(d, J=1.6Hz, 1H), 7.24(d, J=0.8Hz, 1H), 3.77-3.68(m, 4H), 2.50(d, J=0.4Hz, 3H), 2.49(s, 3H), 2.36-2.21(m, 4H).

[0545] Step C: To a solution of 7-bromo-5-(4,4-difluoropiperidin-1-yl)-2,9-dimethylimidazo[1,2-c]quinazoline (3.10 g, 7.84 mmol, 1.00 eq.) in dioxane (40.0 mL) was added bis(triphenylphosphine)palladium(II) chloride (551 mg, 784 μmol, 0.10 eq.) and tributyl(1-ethoxyvinyl)stannane (4.14 g, 11.5 mmol, 3.87 mL, 1.46 eq.). The mixture was stirred at 100 °C for 3.5 h under a nitrogen atmosphere. After completion of the reaction, the mixture was cooled to 25 °C and quenched by the addition of saturated aqueous potassium fluoride (100 mL) and diluted with dichloromethane (100 mL) at 25 °C. The reaction was stirred for 1 hour, filtered, and the filter cake was washed three times with dichloromethane (60.0 mL x 3). The combined organic layers were washed with brine (20.0 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 5-(4,4-difluoropiperidin-1-yl)-7-(1-ethoxyvinyl)-2,9-dimethylimidazo[1,2-c]quinazoline (2.70 g, crude) as a yellow solid, which was used without further purification. LCMS [M+1] + =387.1.

[0546] Step D: To a solution of 5-(4,4-difluoropiperidin-1-yl)-7-(1-ethoxyvinyl)-2,9-dimethylimidazo[1,2-c]quinazoline (2.70 g, 6.99 mmol, 1.00 eq.) in acetone (25.0 mL) was added p-toluenesulfonic acid hydrate (1.33 g, 6.99 mmol, 1.00 eq.). The mixture was stirred for 1 hour at 25 °C. After the reaction was completed, the mixture was adjusted to approximately pH = 7 with saturated aqueous sodium bicarbonate solution, then diluted with water (20.0 mL) and extracted with dichloromethane (60.0 mL × 3). The combined organic layer was washed with brine (20.0 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a solid. The solid was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1 to dichloromethane / methanol = 10 / 1) to give 1-(5-(4,4-difluoropiperidin-1-yl)-2,9-dimethylimidazo[1,2-c]quinazolin-7-yl)ethan-1-one (2.13 g, 5.94 mmol, 85% yield) as a yellow solid. LCMS [M+1] + =359.1.

[0547] 1 H NMR(400MHz, CDCl3)δ ppm=8.39(d, J=0.8Hz, 1H), 7.72(d, J=1.6Hz, 1H), 7.24(d, J=0.8Hz, 1H), 3.73-3.52(m, 4H), 2.89(s, 3H), 2.52(s, 3H), 2.51(d, J=0.8Hz, 3H), 2.36-2.16(m, 4H).

[0548] Step E: To a solution of 1-(5-(4,4-difluoropiperidin-1-yl)-2,9-dimethylimidazo[1,2-c]quinazolin-7-yl)ethan-1-one (1.00 g, 2.79 mmol, 1.00 eq.) and (R)-2-methylpropane-2-sulfinamide (846 mg, 6.98 mmol, 2.50 eq.) in toluene (10.0 mL) was added titanium(IV) ethoxide (1.91 g, 8.37 mmol, 1.74 mL, 3.00 eq.). The mixture was stirred at 100 °C for 16 h. After completion of the reaction, the mixture was cooled to 25 °C and quenched by the addition of water (4.00 mL) at 25 °C, during which time a yellow precipitate formed. The suspension was filtered, the filtrate was removed, and the filter cake was collected and triturated with dichloromethane / methanol = 10 / 1 (70.0 mL x 3), filtered, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1 to dichloromethane / methanol = 10 / 1) to give (R)-N-(1-(5-(4,4-difluoropiperidin-1-yl)-2,9-dimethylimidazo[1,2-c]quinazolin-7-yl)ethylidene)-2-methylpropane-2-sulfinamide (1.10 g, 2.38 mmol, 85% yield) as a yellow solid. LCMS [M+1] + =462.2.

[0549] Step F: To a solution of (R)—N-(1-(5-(4,4-difluoropiperidin-1-yl)-2,9-dimethylimidazo[1,2-c]quinazolin-7-yl)ethylidene)-2-methylpropane-2-sulfinamide (1.10 g, 2.38 mmol, 1.00 eq.) in dichloromethane (10 mL) and methanol (10 mL), glacial acetic acid (1.43 g, 23.8 mmol, 1.36 mL, 10.0 eq.) and sodium cyanoborohydride (450 mg, 7.15 mmol, 3.00 eq.) were added. The mixture was stirred for 2 hours at 25° C. After completion of the reaction, the mixture was quenched with aqueous sodium bicarbonate solution and the pH was adjusted to approximately pH=7 at 25° C. The resulting solution was extracted with dichloromethane / methanol=10 / 1 (90 mL×3). The combined organic layers were washed with brine (30.0 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 x 40 mm x 15 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 30% to 60% acetonitrile over 15 min) to give (R)-N-((R)-1-(5-(4,4-difluoropiperidin-1-yl)-2,9-dimethylimidazo[1,2-c]quinazolin-7-yl)ethyl)-2-methylpropane-2-sulfinamide (750 mg, 1.62 mmol, 68% yield) as a yellow solid. LCMS [M+1] + =464.3.

[0550] 1 H NMR(400MHz, CDCl3)δ ppm=8.18(s, 1H), 7.40(d, J=1.6Hz, 1H), 7.22(s, 1H), 5.19(quin, J=6.4Hz, 1H), 4.60(br d, J=6.4Hz, 1H), 3.67-3.57(m, 4H), 2.50(s, 3H), 2.50(s, 3H), 2.35-2.18(m, 4H), 1.65(d, J=6.8Hz, 3H), 1.23(s, 9H).

[0551] Step G: To a solution of (R)-N-((R)-1-(5-(4,4-difluoropiperidin-1-yl)-2,9-dimethylimidazo[1,2-c]quinazolin-7-yl)ethyl)-2-methylpropane-2-sulfinamide (200 mg, 431 μmol, 1.00 eq.) in ethyl acetate (2.00 mL) was added a solution of hydrochloric acid in ethyl acetate (2 M, 1.29 mL, 6.00 eq.). The mixture was stirred for 1 hour at 0° C. After completion of the reaction, the mixture was concentrated in vacuo to give a residue. The residue was triturated with ethyl acetate (3.00 mL) for 5 minutes at 25° C. and filtered. The filter cake was dried under vacuum to give (R)-1-(5-(4,4-difluoropiperidin-1-yl)-2,9-dimethylimidazo[1,2-c]quinazolin-7-yl)ethan-1-amine (150 mg, 379 μmol, 88% yield) as a yellow hydrochloride salt. LCMS [M-16] + =343.2.

[0552] Step H: To a solution of (R)-1-(5-(4,4-difluoropiperidin-1-yl)-2,9-dimethylimidazo[1,2-c]quinazolin-7-yl)ethan-1-amine hydrochloride (150 mg, 379 μmol, 1.00 eq.) in dimethylformamide (3.00 mL) was added diisopropylethylamine (245 mg, 1.89 mmol, 330 μL, 5.00 eq.) and methyl 6-chloro-3-fluoropicolinate (180 mg, 947 μmol, 2.50 eq.). The mixture was stirred at 90° C. for 16 hours. After completion of the reaction, the mixture was cooled to 25° C., diluted with water (10.0 mL), and extracted with dichloromethane (30 mL×3). The combined organic layer was washed with brine (10 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to give (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-2,9-dimethylimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)methyl picolinate (150 mg, 284 μmol, 75% yield) as a yellow solid. LCMS [M+1] + =529.3.

[0553] Step I: To a solution of (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-2,9-dimethylimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)methyl picolinate (130 mg, 246 μmol, 1.00 eq.) in dimethyl sulfoxide (1.50 mL) was added anhydrous lithium chloride (125 mg, 2.95 mmol, 60.5 μL, 12.0 eq.). The mixture was stirred at 120° C. for 7 hours. After the reaction was completed, the reaction mixture was directly filtered to obtain the filtrate. The filtrate was purified by preparative HPLC (column: Welch Xtimate C18 150x25mmx5μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 35% to 65% acetonitrile over 15 min) to give (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-2,9-dimethylimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid (22.8 mg, 43.6 μmol, 18% yield) as an off-white solid. LCMS [M+1] + =515.2.

[0554] 1 H NMR(400MHz, CD3OD)δ ppm=8.06(d, J=0.8Hz, 1H), 7.61(s, 1H), 7.46(d, J=1.6Hz, 1H), 7.15(d, J=8.8Hz, 1H), 7.02(d, J=9.2Hz, 1H), 5.58(q, J=6.8Hz, 1H), 3.68(br t, J=5.2Hz, 4H), 2.47(s, 3H), 2.44(s, 3H), 2.38-2.22(m, 4H), 1.71(d, J=6.8Hz, 3H).

[0555] 19 F NMR(377MHz, CD3OD)δ ppm=-98.7.

[0556] Example 6-6 (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-3,9-dimethylimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid [ka] Step A: To a solution of 8-bromo-2-chloro-6-methylquinazolin-4-amine (3.50 g, 12.8 mmol, 1.00 eq.) in dioxane (40.0 mL) was added 2-bromo-1,1-dimethoxypropane (4.70 g, 25.6 mmol, 2.00 eq.). The mixture was stirred at 100°C for 12 hours. After the reaction was complete, the reaction mixture was cooled to 25°C to obtain a suspension, which was then filtered. The filter cake was triturated with petroleum ether / ethyl acetate = 1 / 1 (50.0 mL) at 25°C for 5 minutes, filtered, and the filter cake was collected and dried under vacuum to give 7-bromo-5-chloro-3,9-dimethylimidazo[1,2-c]quinazoline (3.50 g, 11.2 mmol, 88% yield) as a yellow solid. LCMS [M+1] + =311.9.

[0557] Step B: To a solution of 7-bromo-5-chloro-3,9-dimethylimidazo[1,2-c]quinazoline (3.40 g, 10.9 mmol, 1.00 eq.) and 4,4-difluoropiperidine (2.65 g, 21.9 mmol, 2.00 eq.) in acetonitrile (30.0 mL) was added diisopropylethylamine (4.24 g, 32.8 mmol, 5.72 mL, 3.00 eq.), and the mixture was stirred at 60 °C for 12 h. After the reaction was complete, the mixture was cooled to 25° C., water (100 mL) was added to obtain a suspension, which was then filtered and the filter cake was dried under vacuum to give 7-bromo-5-(4,4-difluoropiperidin-1-yl)-3,9-dimethylimidazo[1,2-c]quinazoline (3.00 g, 7.59 mmol, 69% yield) as a yellow solid. LCMS [M+3] + =396.9.

[0558] 1H NMR(400MHz, DMSO-d6)δ ppm=8.06(d, J=0.8Hz, 1H), 7.77(d, J=1.6Hz, 1H), 7.37(d, J=0.8Hz, 1H), 3.46(s, 4H), 2.70(s, 3H), 2.46(s, 3H), 2.33-2.24(m, 4H).

[0559] Step C: To a solution of 7-bromo-5-(4,4-difluoropiperidin-1-yl)-3,9-dimethylimidazo[1,2-c]quinazoline (2.50 g, 6.33 mmol, 1.00 eq.) and 1-trimethylsilylethanone (1.47 g, 12.6 mmol, 2.00 eq.) in 1,2-dichloroethane (10.0 mL) was added tetrakis(triphenylphosphine)palladium(0) (730 mg, 632 μmol, 0.10 eq.) and cesium fluoride (2.88 g, 18.9 mmol, 3.00 eq.). The mixture was stirred at 80 °C under a nitrogen atmosphere for 2 hours. After completion of the reaction, the mixture was cooled to 25 °C, filtered, and concentrated under reduced pressure to give a solid. The solid was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent: 0 to 50% ethyl acetate / petroleum ether gradient at 40 mL / min) to give 1-(5-(4,4-difluoropiperidin-1-yl)-3,9-dimethylimidazo[1,2-c]quinazolin-7-yl)ethan-1-one (2.20 g, 6.14 mmol, 97% yield) as a yellow solid. LCMS [M+1] + =359.2.

[0560] Step D: To a solution of 1-(5-(4,4-difluoropiperidin-1-yl)-3,9-dimethylimidazo[1,2-c]quinazolin-7-yl)ethan-1-one (2.20 g, 6.14 mmol, 1.00 eq.) and (R)-2-methylpropane-2-sulfinamide (1.49 g, 12.2 mmol, 2.00 eq.) in tetrahydrofuran (20.0 mL), titanium(IV) ethoxide (4.20 g, 18.4 mmol, 3.82 mL, 3.00 eq.) and 1,2-dimethoxyethane (774.5 mg, 8.59 mmol, 893 μL, 1.40 eq.) were added. The mixture was stirred at 70 °C for 2 h under a nitrogen atmosphere. After completion of the reaction, the mixture was cooled to 25 °C, and water (2.00 mL) was added to obtain a suspension. The suspension was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent: 0-50% ethyl acetate / petroleum ether gradient, 40 mL / min) to give (R)—N-(1-(5-(4,4-difluoropiperidin-1-yl)-3,9-dimethylimidazo[1,2-c]quinazolin-7-yl)ethylidene)-2-methylpropane-2-sulfinamide (2.00 g, 4.33 mmol, 71% yield) as a yellow solid. LCMS [M+1] + =462.1.

[0561] Step E: To a solution of (R)—N-(1-(5-(4,4-difluoropiperidin-1-yl)-3,9-dimethylimidazo[1,2-c]quinazolin-7-yl)ethylidene)-2-methylpropane-2-sulfinamide (2.00 g, 4.33 mmol, 1.00 eq.) in dichloromethane (20.0 mL) was added sodium cyanoborohydride (1.09 g, 17.3 mmol, 4.00 eq.) and acetic acid (260 mg, 4.33 mmol, 248 μL, 1.00 eq.). The mixture was stirred for 1 h at 0° C. After completion of the reaction, the reaction mixture was quenched at 25° C. with water (2 mL), filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent: 0-80% ethyl acetate / petroleum ether gradient, 40 mL / min) to give (R)-N-((R)-1-(5-(4,4-difluoropiperidin-1-yl)-3,9-dimethylimidazo[1,2-c]quinazolin-7-yl)ethyl)-2-methylpropane-2-sulfinamide (2.00 g, 4.31 mmol, 99% yield) as a white solid. LCMS [M+1] + =464.2.

[0562] 1 H NMR(400MHz, CDCl3)δ ppm=8.07(s, 1H), 7.29(d, J=1.6Hz, 1H), 5.06(t, J=6.8Hz, 1H), 4.51(d, J=6.8Hz, 1H), 3.68-3.18(m, 4H), 2.66(s, 3H), 2.42(s, 3H), 2.33-2.05(m, 4H), 1.57(d, J=6.8Hz, 3H), 1.17-1.15(m, 9H).

[0563] Step F: A solution of (R)-N-((R)-1-(5-(4,4-difluoropiperidin-1-yl)-3,9-dimethylimidazo[1,2-c]quinazolin-7-yl)ethyl)-2-methylpropane-2-sulfinamide (800 mg, 1.73 mmol, 1.00 eq.) in 4.0 M hydrochloric acid in dioxane (5.00 mL) was stirred for 2 hours at 25° C. After completion of the reaction, the reaction mixture was concentrated in vacuo to give (R)-1-(5-(4,4-difluoropiperidin-1-yl)-3,9-dimethylimidazo[1,2-c]quinazolin-7-yl)ethan-1-amine (600 mg, 1.67 mmol, 97% yield) as a white hydrochloride salt. LCMS [M+1] + =360.1.

[0564] Step G: To a solution of (R)-1-(5-(4,4-difluoropiperidin-1-yl)-3,9-dimethylimidazo[1,2-c]quinazolin-7-yl)ethan-1-amine hydrochloride (500 mg, 1.39 mmol, 1.00 eq.) and methyl 6-chloro-3-fluoropicolinate (527 mg, 2.78 mmol, 2.00 eq.) in dimethylformamide (10.0 mL) was added diisopropylethylamine (539 mg, 4.17 mmol, 726 μL, 3.00 eq.). The mixture was stirred at 100 °C for 2 h. After completion of the reaction, the mixture was cooled to 25 °C, diluted with water (10.0 mL), and extracted with dichloromethane (30.0 mL x 3). The combined organic layers were washed with brine (10.0 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO™; 12 g SepaFlash™ silica flash column, eluent: 0-50% ethyl acetate / petroleum ether gradient, 40 mL / min) to give (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-3,9-dimethylimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)methyl picolinate (400 mg, 756 μmol, 54% yield) as a white solid. LCMS [M+1] + =529.1.

[0565] Step H: To a solution of (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-3,9-dimethylimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)methyl picolinate (300 mg, 567 μmol, 1.00 eq.) in dimethyl sulfoxide (1.00 mL) was added lithium chloride (240 mg, 5.67 mmol, 116 μL, 10.0 eq.). The mixture was stirred at 130° C. for 2 hours. After the reaction was completed, the mixture was cooled to 25° C., diluted with water (10.0 mL), and extracted with dichloromethane (30.0 mL×3). The combined organic layer was washed with brine (10.0 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150x40mmx15μm; mobile phase: [water (0.1% formic acid)-acetonitrile]; gradient: 38% to 68% acetonitrile over 15 min) to give (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-3,9-dimethylimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid (58.7 mg, 112μmol, 19% yield) as a yellow solid. LCMS [M+1] + =515.2.

[0566] 1 H NMR(400MHz, CD3OD)δ ppm=8.04(s, 1H), 7.44(d, J=1.6Hz, 1H), 7.30(d, J=0.8Hz, 1H), 7.17(d, J=9.2Hz, 1H), 7.04(d, J=9.2Hz, 1H), 5.56(q, J=6.8Hz, 1H), 3.81-3.36(m, 4H), 2.80(s, 3H), 2.44(s, 3H), 2.29(br d, J=7.6Hz, 4H), 1.71(d, J=6.8Hz, 3H).

[0567] Examples 6-7 to 6-130 The following compounds are prepared essentially according to the procedures of Schemes I-IV and Examples 2-2, 3-1, 6-1, 6-2, 6-3, 6-4, 6-5, and 6-6 above. Table 64 Table 65 Table 66 Table 67 Table 68 Table 69 Table 70 Table 71 Table 72 Table 73 Table 74 Table 75 Table 76 Table 77 Table 78 Table 79 Table 80 Table 81 Table 82 Table 83 Table 84 Table 85 Table 86 Table 87 Table 88 Table 89 Table 90 Table 91 Table 92 Table 93 Table 94 Table 95 Table 96 Table 97 Table 98 [Table 99] [Table 100] [Table 101] [Table 102] [Table 103] [Table 104] [Table 105]

[0568] Example A This example illustrates that representative compounds of the present invention inhibit the formation of phospho-AKT (pAKT) in cells.

[0569] The potency of compounds of Formula (I) to inhibit the formation of pAKT was measured using the alphaLISA Surefire Ultra AKT 1 / 2 / 3 (pS473) Assay Kit (#ALSU-PAKT-B50K) purchased from Perkin Elmer (Waltham, MA).

[0570] To prepare assay plates for the pAKT alphaLISA assay, cells were trypsinized and resuspended in fresh medium, and viable cells were counted using trypan blue exclusion. Prior to plating, cells were washed with PBS and resuspended in HBSS (Gibco, #14025092). T47D (12,000 / w), SKBR3 (12,000 / w), or MKN1 (24,000 / w) cells were seeded at 12 μl per well into solid white flat-bottom 384 cell culture plates (Perkin Elmer #6007680).

[0571] Immediately after seeding, compounds were serially diluted (1:4) at a starting concentration of 10.4 μM using an Echo liquid handler (Beckman Coulter) for a total of 10 concentrations. Fourteen vehicle (DMSO) and fourteen positive control (alpelisib, 3.125 μM) wells were included in each assay plate. Cells were incubated with compounds (dissolved in DMSO) for approximately 1 hour or 24 hours at 37°C. After 1 hour or 24 hours of treatment, cells were lysed with 3 μl of 5x lysis buffer (provided and incubated for 15 minutes at room temperature on a microtiter plate shaker). Once cells were fully lysed, 7.5 μl of acceptor bead mix (made at the manufacturer's recommended dilution) was added to each well and placed on a microtiter plate shaker for 1 minute. The plate was then incubated at room temperature for 1 hour, protected from light. After 1 hour of incubation with the acceptor bead mix, 7.5 μl of the donor bead mix (made at the manufacturer's recommended dilution) was added to each well and placed on a microtiter plate shaker for 1 minute. The plates were then incubated overnight at room temperature in the dark and measured the next day using a CLARIOstar microplate reader (BMG Labtech, Germany).

[0572] Percentage of control values ​​was calculated by subtracting the mean signal of the positive control (alpelisib)-treated wells from all treated wells (including DMSO control wells) and then dividing by the mean signal of the vehicle DMSO-treated control wells. Percentage of vehicle control values ​​was plotted as log(inhibitor) vs. response and curve-fitted with a variable slope (4 parameters) to obtain IC values. 50 Values ​​were determined using XLfit.

[0573] The results are shown in the table below. [Table 106] [Table 107] [Table 108]

[0574] Example B This example illustrates that exemplary compounds of the present invention decrease cell viability.

[0575] The potency of compounds of Formula (I) to reduce cell viability was measured using the CellTiter-Glo 2.0 (CTG) Luminescent Cell Viability Assay (#G9241) purchased from Promega (Madison, WI).

[0576] To prepare assay plates for viability assays, cells were trypsinized and resuspended in fresh medium, and viable cells were counted using trypan blue exclusion. T47D, SKBR3, or MKN1 cells were seeded at 1000 cells / 30 μl per well into solid white flat-bottom 384 cell culture plates (Perkin Elmer #6007680) and incubated overnight at 37°C.

[0577] On assay day 1, compounds were serially diluted (1:4) starting at 10 μM and added to the cells using an Echo liquid handler (Beckman Coulter) for a total of 10 concentrations. Cells were incubated with compounds (dissolved in DMSO) at 37°C for approximately 72 hours. After 72 hours of treatment, the cell plates were allowed to come to room temperature, after which 15 μl of CTG was added to each well. The plates were then covered with aluminum foil, protected from light, and incubated on a microtiter plate shaker at room temperature for 30 minutes. Luminescence measurements were collected using a CLARIOstar microplate reader (BMG Labtech, Germany). Percentages of vehicle control values ​​were plotted as log(inhibitor) vs. response, and curve fitting with a variable slope (4 parameters) was performed to determine IC values. 50 Values ​​were determined using XLfit. [Table 109] [Table 110]

[0578] It should be understood that the examples and embodiments described herein are merely illustrative examples, and that those skilled in the art will devise various changes or modifications based thereon, which changes or modifications are to be incorporated within the spirit and scope of this application and the scope of the appended claims. All documents, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

1. Formula (I): 【Chemistry 1】 [In the formula, R １ is H, C １ -C ３ Alkyl, or C ３ -C ６ is cycloalkyl; R ２ is a phenyl or a 5- or 6-membered heteroaryl group, and each of the phenyl and heteroaryl groups is １２ may be substituted with; Each R １２ are independently １ -C ４ Alkyl, -OR Ａ , -C(O)OR Ａ , (C １ -C ３ alkyl)-OR Ａ , -C(O)N(R Ｂ ) ２ , cyano, tetrazolyl, or halogen; Each R Ａ are independently H, C １ -C ６ Alkyl, or C ３ -C ６ is cycloalkyl; Each R Ｂ are independently H, —OH, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, or C ３ -C ６ is cycloalkyl; and R ３ Fluoro, C ３ -C ６ Cycloalkyl, C ２ -C ３ Alkenyl, C ２ -C ３ Alkynyl, or C ５ -C ６ C optionally substituted, polysubstituted, or fully substituted with cycloalkenyl １ -C ３ is alkyl; R ４ is H, C １ -C ３ Alkyl, C １ -C ３ Alkoxy, C ３ -C ６ Cycloalkyl, C ３ -C ６ Cycloalkyloxy, C ２ -C ３ Alkenyl, C ２ -C ３ Alkynyl, or C ５ -C ６ cycloalkenyl, cyano, or halo, １ -C ３ Alkyl and C ３ -C ６ The cycloalkyl may be optionally substituted with 1 to 5 halo groups; T is N or CR ６ and The R ６ is H or C １ -C ６ is alkyl; Formula (Z): 【Chemistry 2】 is represented by formula (E), (G), (J), (K), (L), or (M): 【Transformation 3】 represents each d is a point of attachment to a bridgehead carbon bonded to T; In formula (E), both X and Y are CR ５ , or one of X and Y is CR ５ and the other is N; In formula (J), both X and Y are N; Each R ５ are independently hydrogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkoxy, halogen, haloC １ -C ６ Alkyl, cyano, hydroxy, hydroxy C １ -C ６ Alkyl, amino, mono- or di(C １ -C ６ alkyl)amino, C ３ -C ６ Cycloalkyl, haloC ３ -C ６ cycloalkyl, phenyl, or 5- or 6-membered heteroaryl, each of which alkyl and cycloalkyl is selected from the group consisting of 1 to 3 hydroxy, C １ -C ３ Alkyl, C １ -C ３ Alkoxy, cyano, amino, or mono- or di(C １ -C ３ ) alkylamino, each of said phenyl and heteroaryl being optionally substituted with 1 to 3 halogen, hydroxy, C １ -C ３ Alkyl, C １ -C ３ Alkoxy, cyano, amino, or mono- or di(C １ -C ３ ) optionally substituted with alkylamino; R ３０ is -NR ７ NR ８ or R ３１ represents R ３１ teeth, (i) a 5- to 7-membered heteroaryl, or (ii) a 3- to 8-membered monocyclic heterocyclyl group linked to a tricyclic ring via a carbon atom, the heterocyclyl group being may be fused to an aromatic or non-aromatic ring that is saturated or unsaturated and contains 3 to 6 ring members (one or two of which may be nitrogen, oxygen, or sulfur atoms, and the remainder are carbon atoms); or the carbon atoms of the monocyclic heterocyclyl group together with the additional carbon or nitrogen atom form a spiro ring system having a total of up to 10 ring members, each of which is carbon or nitrogen; and R ３１ Each such heteroaryl and heterocyclyl group in ３９ may be substituted with a group, and each R ３９ are independently １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C ６ Cycloalkyl, cyano, hydroxy, oxo, halogen, haloC １ -C ３ Alkyl, hydroxy C １ -C ６ Alkyl, amino, mono- or di-(C １ -C ６ alkyl)amino, or phenyl, phenyl (C １ -C ３ alkanoyl), 5- to 7-membered heterocyclyl, or 5- to 6-membered heteroaryl, and each of the phenyl, 5- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl is C １ -C ３ Alkyl, C １ -C ３ Alkoxy, halogen, hydroxy, cyano, amino, or mono- or di(C １ -C ３ optionally substituted with alkyl)amino; R ７ is H or C １ -C ３ represents alkyl; R ８ is H or a 5- to 8-membered heterocyclyl, C ３ -C ６ cycloalkyl, or C ３ -C ６ Cycloalkyl (C １ -C ３ C optionally substituted with alkyl １ -C ６ represents alkyl; or R ７ and R ８ together with the nitrogen to which it is attached form a ring Q, which is a 3- to 8-membered monocyclic heterocyclyl group containing one or two ring nitrogens, the heterocyclyl group being may be fused to an aromatic or non-aromatic ring containing from 3 to 6 ring members (one or two of which may be nitrogen, oxygen, or sulfur atoms, as appropriate, and the remainder being carbon atoms); or the carbon atoms of the monocyclic heterocyclyl group together with the additional carbon or nitrogen atom form a spiro ring system having a total of up to 10 ring members, each of which is carbon or nitrogen; and Each ring Q may contain 1 to 4 R ９ may be substituted with a group, and each R ９ are independently １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C ６ Cycloalkyl, cyano, hydroxy, oxo, halogen, haloC １ -C ３ Alkyl, hydroxy C １ -C ６ Alkyl, amino, mono- or di-(C １ -C ６ alkyl)amino, or phenyl, phenyl (C １ -C ３ alkanoyl), 5- to 7-membered heterocyclyl, or 5- to 6-membered heteroaryl, and each of the phenyl, 5- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl is C １ -C ３ Alkyl, C １ -C ３ Alkoxy, halogen, hydroxy, cyano, amino, or mono- or di(C １ -C ３ may be substituted with alkyl)amino] or a pharmaceutically acceptable salt thereof, or a deuterated version thereof.

2. Formula (III): 【Chemistry 4】 [In the formula, a is 0, 1, 2, or 3; V is CR １４ or N; Each R １２ are independently １ -C ４ Alkyl, -OR Ａ , -C(O)OR Ａ , (C １ -C ３ alkyl)-OR Ａ , -C(O)N(R Ａ ) ２ , cyano, or halogen; R １３ is (i) cyano, (ii) tetrazolyl, (iii) —C(O)OR Ａ (In the formula, R Ａ is H, C １ -C ６ Alkyl, or C ３ -C ６ cycloalkyl), or (iv) —C(O)N(R Ｂ ) ２ (In the formula, R Ｂ is H, -OH, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, or C ３ -C ６ cycloalkyl); R １４ is hydrogen, cyano, halogen, hydroxy, C １ -C ４ Alkoxy, C １ -C ４ Alkyl, —C(O)OR Ａ , (C １ -C ３ alkyl)-OR Ａ , or C(O)N(R Ｂ ) ２ and Q represents a 4-8 membered saturated or unsaturated monocyclic, bicyclic, or polycyclic heterocyclyl group having 0, 1, or 2 additional ring heteroatoms selected from oxygen and nitrogen; b is 0, 1, 2, 3, or 4; Each R ９ are independently １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C ６ Cycloalkyl, cyano, hydroxy, oxo, halogen, haloC １ -C ３ Alkyl, hydroxy C １ -C ６ Alkyl, amino, mono- or di-(C １ -C ６ alkyl)amino, or phenyl, phenyl (C １ -C ３ alkanoyl), 5- to 7-membered heterocyclyl, or 5- to 6-membered heteroaryl, and each of the phenyl, 5- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl is C １ -C ３ Alkyl, C １ -C ３ Alkoxy, halogen, hydroxy, cyano, amino, or mono- or di(C １ -C ３ optionally substituted with alkyl)amino; and R ５１ and R ５２ are independently hydrogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkoxy, halogen, haloC １ -C ６ Alkyl, cyano, hydroxy, hydroxy C １ -C ６ Alkyl, amino, mono- or di(C １ -C ６ alkyl)amino, C ３ -C ６ Cycloalkyl, haloC ３ -C ６ cycloalkyl, phenyl, or 5- or 6-membered heteroaryl, each of which may be substituted with 1 to 3 hydroxyl, C １ -C ３ Alkyl, C １ -C ３ Alkoxy, cyano, amino, or mono- or di(C １ -C ３ ) alkylamino, each of said phenyl and heteroaryl being optionally substituted with 1 to 3 halogen, hydroxy, C １ -C ３ Alkyl, C １ -C ３ Alkoxy, cyano, amino, or mono- or di(C １ -C ３ ) optionally substituted with alkylamino] having 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a deuterated version thereof.

3. R １ is H or CH ３ That is, The compound of claim 2.

4. R ３ But C １ -C ３ alkyl, wherein the alkyl group is unsubstituted, substituted with 1 to 5 halo groups, or fully substituted with fluorine atoms; A compound according to claim 2 or claim 3.

5. R ３ is methyl, A compound according to claim 2 or claim 3.

6. R ４ is hydrogen, The compound according to any one of claims 2 to 5.

7. R ４ is methyl, The compound according to any one of claims 2 to 5.

8. R ４ is fluoro, The compound according to any one of claims 2 to 5.

9. R ４ is chloro, The compound according to any one of claims 2 to 5.

10. R ４ is trifluoromethyl; The compound according to any one of claims 2 to 5.

11. R ４ is difluoromethyl; The compound according to any one of claims 2 to 5.

12. R ４ is fluoromethyl; The compound according to any one of claims 2 to 5.

13. R ４ is bromo, The compound according to any one of claims 2 to 5.

14. V is CR １２ That is, The compound according to any one of claims 2 to 13.

15. V is N; The compound according to any one of claims 2 to 13.

16. V is CH, a is 1, and R １２ is hydrogen or halogen; The compound according to any one of claims 2 to 13.

17. V is CH, a is 1, and R １２ is hydrogen, or chloro, bromo, or fluoro; The compound according to any one of claims 2 to 13.

18. V is CH, a is 1, and R １２ is hydrogen, The compound according to any one of claims 2 to 13.

19. V is CH, a is 1, and R １２ is chloro, The compound according to any one of claims 2 to 13.

20. V is CH, a is 1, and R １２ is bromo, The compound according to any one of claims 2 to 13.

21. V is CH, a is 1, and R １２ is fluoro, The compound according to any one of claims 2 to 13.

22. V is CH, a is 1, and R １２ is methyl, The compound according to any one of claims 2 to 13.

23. V is N, a is 1, and R １２ is hydrogen or halogen; The compound according to any one of claims 2 to 13.

24. V is N, a is 1, and R １２ is hydrogen, or chloro, bromo, or fluoro; The compound according to any one of claims 2 to 13.

25. V is N, a is 1, and R １２ is hydrogen, The compound according to any one of claims 2 to 13.

26. V is N, a is 1, and R １２ is chloro, The compound according to any one of claims 2 to 13.

27. V is N, a is 1, and R １２ is bromo, The compound according to any one of claims 2 to 13.

28. V is N, a is 1, and R １２ is methyl, The compound according to any one of claims 2 to 13.

29. V is N, a is 1, and R １２ is fluoro, The compound according to any one of claims 2 to 13.

30. R ５１ and R ５２ are independently hydrogen, C １ -C ３ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, cyano, halogen, cyclopropyl, haloC ３ -C ６ cycloalkyl, or halo (C １ -C ６ ) represents alkyl, The compound according to any one of claims 2 to 29.

31. R ５１ and R ５２ One of the groups is hydrogen, and the other is methyl, ethyl, C ２ Alkenyl, C ２ Alkynyl, cyano, halogen, cyclopropyl, haloC ３ -C ６ cycloalkyl, or halo (C １ -C ６ ) alkyl; The compound according to any one of claims 2 to 29.

32. R ５１ is hydrogen, and R ５２ However, methyl, ethyl, C ２ Alkenyl, C ２ Alkynyl, cyano, halogen, cyclopropyl, haloC ３ -C ６ cycloalkyl, or halo (C １ -C ６ ) alkyl; The compound according to any one of claims 2 to 29.

33. R ５１ is hydrogen, and R ５２ However, methyl, ethyl, C ２ Alkenyl, C ２ alkynyl, cyano, halogen, cyclopropyl, difluoromethyl, trifluoromethyl, trifluoroethyl, pentafluoroethyl, tetrafluorocyclopropyl, or perfluorocyclopropyl; The compound according to any one of claims 2 to 29.

34. R ５２ is hydrogen, and R ５１ However, methyl, ethyl, C ２ Alkenyl, C ２ Alkynyl, cyano, halogen, cyclopropyl, haloC ３ -C ６ cycloalkyl, or halo (C １ -C ６ ) alkyl; The compound according to any one of claims 2 to 29.

35. R ５２ is hydrogen, and R ５１ However, methyl, ethyl, C ２ Alkenyl, C ２ alkynyl, cyano, halogen, cyclopropyl, difluoromethyl, trifluoromethyl, trifluoroethyl, pentafluoroethyl, tetrafluorocyclopropyl, or perfluorocyclopropyl; The compound according to any one of claims 2 to 29.

36. Q is a group of the formula: 【Transformation 5】 [In the formula, each b is 0, 1, or 2; D is C(R ２９ ) ２ represents W is O, NR １９ , or C(R ２９ ) ２ represents, and R １９ is hydrogen, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, haloC １ -C ３ Alkyl, hydroxy C １ -C ６ Alkyl, or amino-, or mono-, or di-(C １ -C ６ alkyl)amino(C １ -C ６ alkyl); and Each R ２９ are independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C ６ Cycloalkyl, cyano, hydroxy, oxo, halogen, haloC １ -C ３ Alkyl, hydroxy C １ -C ６ Alkyl, amino, mono- or di-(C １ -C ６ alkyl)amino] represents a group represented by The compound according to any one of claims 2 to 35.

37. W is oxygen, b is 0 or 1, and R ９ is methyl or cyano; 37. The compound of claim 36.

38. W is oxygen and b is 0; The compound according to any one of claims 36 to 37.

39. D and W are C(R ２９ ) ２ b is 0, and each R ２９ are independently hydrogen, C １ -C ２ Alkyl, C １ -C ２ Alkoxy, cyclopropyl, cyano, hydroxy, halogen, haloC １ -C ２ Alkyl, hydroxy C １ -C ２ Alkyl, amino, mono- or di-(C １ -C ２ alkyl)amino; 37. The compound of claim 36.

40. D and W are C(R ２９ ) ２ b is 0, and each R ２９ is independently hydrogen, methyl, methoxy, cyano, hydroxy, chloro, fluoro, amino, methylamino, or dimethylamino; 37. The compound of claim 36.

41. D and W are C(R ２９ ) ２ b is 0, and each R ２９ is independently chloro or fluoro; 37. The compound of claim 36.

42. D and W are C(R ２９ ) ２ b is 0, and each R ２９ is fluoro, 37. The compound of claim 36.

43. D and W are C(R ２９ ) ２ b is 0, and each R ２９ is hydrogen, 37. The compound of claim 36.

44. Q is a group of the formula: 【Transformation 6】 [In the formula, each b is 0, 1, or 2; and W is O, NR １９ , or C(R ２９ ) ２ represents The R １９ is hydrogen, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, haloC １ -C ３ Alkyl, hydroxy C １ -C ６ Alkyl, or amino-, or mono-, or di-(C １ -C ６ alkyl)amino(C １ -C ６ alkyl); and Each R ２９ are independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C ６ Cycloalkyl, cyano, hydroxy, oxo, halogen, haloC １ -C ３ Alkyl, hydroxy C １ -C ６ Alkyl, amino, mono- or di-(C １ -C ６ alkyl)amino] represents a group represented by The compound according to any one of claims 2 to 35.

45. W is oxygen, b is 0 or 1, and R ９ is methyl or cyano; 45. The compound of claim 44.

46. W is oxygen and b is 0; 45. The compound of claim 44.

47. W is C (R ２９ ) ２ b is 0, and each R ２９ are independently hydrogen, C １ -C ２ Alkyl, C １ -C ２ Alkoxy, cyclopropyl, cyano, hydroxy, halogen, haloC １ -C ２ Alkyl, hydroxy C １ -C ２ Alkyl, amino, mono- or di-(C １ -C ２ alkyl)amino; 45. The compound of claim 44.

48. W is C (R ２９ ) ２ b is 0, and each R ２９ is independently hydrogen, methyl, methoxy, cyano, hydroxy, chloro, fluoro, amino, methylamino, or dimethylamino; 45. The compound of claim 44.

49. W is C (R ２９ ) ２ b is 0, and each R ２９ is independently chloro or fluoro; 45. The compound of claim 44.

50. W is C (R ２９ ) ２ b is 0, and each R ２９ is fluoro, 45. The compound of claim 44.

51. W is C (R ２９ ) ２ b is 0, and each R ２９ is hydrogen, 45. The compound of claim 44.

52. Q is a group of the formula: 【Transformation 7】 [In the formula, each b is 0, 1, or 2; and W is O, NR １９ , or C(R ２９ ) ２ represents The R １９ is hydrogen, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, haloC １ -C ３ Alkyl, hydroxy C １ -C ６ Alkyl, or amino-, or mono-, or di-(C １ -C ６ alkyl)amino(C １ -C ６ alkyl); and Each R ２９ are independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C ６ Cycloalkyl, cyano, hydroxy, oxo, halogen, haloC １ -C ３ Alkyl, hydroxy C １ -C ６ Alkyl, amino, mono- or di-(C １ -C ６ alkyl)amino] represents a group represented by The compound according to any one of claims 2 to 35.

53. W is oxygen, b is 0 or 1, and R ９ is methyl, chloro, fluoro, or cyano; 53. The compound of claim 52.

54. W is oxygen and b is 0; 53. The compound of claim 52.

55. W is C (R ２９ ) ２ b is 0, and each R ２９ are independently hydrogen, C １ -C ２ Alkyl, C １ -C ２ Alkoxy, cyclopropyl, cyano, hydroxy, halogen, haloC １ -C ２ Alkyl, hydroxy C １ -C ２ Alkyl, amino, mono- or di-(C １ -C ２ alkyl)amino; 53. The compound of claim 52.

56. W is C (R ２９ ) ２ b is 0, and each R ２９ is independently hydrogen, methyl, methoxy, cyano, hydroxy, chloro, fluoro, amino, methylamino, or dimethylamino; 53. The compound of claim 52.

57. W is C (R ２９ ) ２ b is 0, and each R ２９ is independently chloro or fluoro; 53. The compound of claim 52.

58. W is C (R ２９ ) ２ b is 0, and each R ２９ is fluoro, 53. The compound of claim 52.

59. W is C (R ２９ ) ２ b is 0, and each R ２９ is hydrogen, 53. The compound of claim 52.

60. Formula (IV): 【Transformation 8】 [In the formula, a is 0, 1, 2, or 3; V is CR １４ or N; Each R １２ are independently １ -C ４ Alkyl, -OR Ａ , -C(O)OR Ａ , (C １ -C ３ alkyl)-OR Ａ , -C(O)N(R Ｂ ) ２ , cyano, or halogen; R １３ is (i) cyano, (ii) tetrazolyl, (iii) —C(O)OR Ａ (In the formula, R Ａ is H, C １ -C ６ Alkyl, or C ３ -C ６ cycloalkyl), or (iv) —C(O)N(R Ｂ ) ２ (In the formula, R Ｂ is H, -OH, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, or C ３ -C ６ cycloalkyl); R １４ is hydrogen, cyano, halogen, hydroxy, C １ -C ４ Alkoxy, C １ -C ４ Alkyl, —C(O)OR Ａ , (C １ -C ３ alkyl)-OR Ａ , or —C(O)N(R Ｂ ) ２ and Q represents a 4-8 membered saturated or unsaturated monocyclic, bicyclic, or polycyclic heterocyclyl group having 0, 1, or 2 additional ring heteroatoms selected from oxygen and nitrogen; b is 0, 1, 2, 3, or 4; Each R ９ are independently １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C ６ Cycloalkyl, cyano, hydroxy, oxo, halogen, haloC １ -C ３ Alkyl, hydroxy C １ -C ６ Alkyl, amino, mono-, or di-(C １ -C ６ alkyl)amino, or phenyl, phenyl (C １ -C ３ alkanoyl), 5- to 7-membered heterocyclyl, or 5- to 6-membered heteroaryl, and each of the phenyl, 5- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl is C １ -C ３ Alkyl, C １ -C ３ Alkoxy, halogen, hydroxy, cyano, amino, or mono- or di(C １ -C ３ optionally substituted with alkyl)amino; and R ５２ is hydrogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkoxy, halogen, cyano, hydroxy, hydroxy C １ -C ６ Alkyl, amino, mono- or di(C １ -C ６ alkyl)amino, C ３ -C ６ cycloalkyl, phenyl, or 5- or 6-membered heteroaryl, each of which may contain 1 to 3 halogen atoms, hydroxyl, C １ -C ３ Alkyl, C １ -C ３ Alkoxy, cyano, amino, or mono- or di(C １ -C ３ ) optionally substituted with alkylamino] having 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a deuterated version thereof.

61. R １ is H or CH ３ That is, 61. The compound of claim 60.

62. R ３ is C １ -C ３ alkyl, wherein the alkyl group is unsubstituted, substituted with 1 to 5 halo groups, or fully substituted with fluorine; 62. A compound according to claim 60 or claim 61.

63. R ３ is methyl, 62. A compound according to claim 60 or claim 61.

64. R ４ is hydrogen, The compound according to any one of claims 60 to 63.

65. R ４ is methyl, The compound according to any one of claims 60 to 63.

66. R ４ is ethyl, The compound according to any one of claims 60 to 63.

67. R ４ is cyclopropyl; The compound according to any one of claims 60 to 63.

68. R ４ is methoxy, The compound according to any one of claims 60 to 63.

69. R ４ is fluoro, The compound according to any one of claims 60 to 63.

70. R ４ is chloro, The compound according to any one of claims 60 to 63.

71. R ４ is trifluoromethyl; The compound according to any one of claims 60 to 63.

72. R ４ is difluoromethyl; The compound according to any one of claims 60 to 63.

73. R ４ is fluoromethyl; The compound according to any one of claims 60 to 63.

74. R ４ is bromo, The compound according to any one of claims 60 to 63.

75. V is CR １２ That is, The compound according to any one of claims 60 to 74.

76. V is N; The compound according to any one of claims 60 to 74.

77. V is CH, a is 1, and R １２ is hydrogen or halogen; The compound according to any one of claims 60 to 74.

78. V is CH, a is 1, and R １２ is hydrogen, or chloro, bromo, or fluoro; The compound according to any one of claims 60 to 74.

79. V is CH, a is 1, and R １２ is hydrogen, The compound according to any one of claims 60 to 74.

80. V is CH, a is 1, and R １２ is methyl, The compound according to any one of claims 60 to 74.

81. V is CH, a is 1, and R １２ is chloro, The compound according to any one of claims 60 to 74.

82. V is CH, a is 1, and R １２ is bromo, The compound according to any one of claims 60 to 74.

83. V is CH, a is 1, and R １２ is fluoro, The compound according to any one of claims 60 to 74.

84. V is N, a is 1, and R １２ is hydrogen or halogen; The compound according to any one of claims 60 to 74.

85. V is N, a is 1, and R １２ is hydrogen, or chloro, bromo, or fluoro; The compound according to any one of claims 60 to 74.

86. V is N, a is 1, and R １２ is hydrogen, The compound according to any one of claims 60 to 74.

87. V is N, a is 1, and R １２ is chloro, The compound according to any one of claims 60 to 74.

88. V is N, a is 1, and R １２ is bromo, The compound according to any one of claims 60 to 74.

89. V is N, a is 1, and R １２ is methyl, The compound according to any one of claims 60 to 74.

90. V is N, a is 1, and R １２ is fluoro, The compound according to any one of claims 60 to 74.

91. R ５２ But hydrogen, C １ -C ３ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, cyano, halogen, cyclopropyl, or halo(C １ -C ６ ) represents alkyl, The compound according to any one of claims 60 to 90.

92. R ５２ is hydrogen, methyl, ethyl, C ２ Alkenyl, C ２ Alkynyl, cyano, halogen, cyclopropyl, or halo(C １ -C ６ ) alkyl; The compound according to any one of claims 60 to 90.

93. R ５２ However, methyl, ethyl, C ２ Alkenyl, C ２ Alkynyl, cyano, halogen, cyclopropyl, or halo(C １ -C ６ ) alkyl; The compound according to any one of claims 60 to 90.

94. R ５２ is methyl, ethyl, cyano, halogen, cyclopropyl, fluoromethyl, difluoromethyl, or trifluoromethyl; The compound according to any one of claims 60 to 90.

95. R ５２ But C ２ alkenyl or C ２ is alkynyl, The compound according to any one of claims 60 to 90.

96. R ５２ is hydrogen, The compound according to any one of claims 60 to 90.

97. R ５２ is fluoromethyl, difluoromethyl, or trifluoromethyl; The compound according to any one of claims 60 to 90.

98. Q is a group of the formula: 【Chemistry 9】 [In the formula, each b is 0, 1, or 2; and D is C (R ２９ ) ２ represents W is O, NR １９ , or C(R ２９ ) ２ represents, and R １９ is hydrogen, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, haloC １ -C ３ Alkyl, hydroxy C １ -C ６ Alkyl, or amino-, or mono-, or di-(C １ -C ６ alkyl)amino(C １ -C ６ alkyl); and Each R ２９ are independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C ６ Cycloalkyl, cyano, hydroxy, oxo, halogen, haloC １ -C ３ Alkyl, hydroxy C １ -C ６ Alkyl, amino, mono- or di-(C １ -C ６ alkyl)amino] represents a group represented by The compound according to any one of claims 60 to 97.

99. W is oxygen, b is 0 or 1, and R ９ is methyl or cyano; 99. The compound of claim 98.

100. W is oxygen and b is 0; 99. The compound of claim 98.

101. D and W are C(R ２９ ) ２ b is 0, and each R ２９ are independently hydrogen, C １ -C ２ Alkyl, C １ -C ２ Alkoxy, cyclopropyl, cyano, hydroxy, halogen, haloC １ -C ２ Alkyl, hydroxy C １ -C ２ Alkyl, amino, mono- or di-(C １ -C ２ alkyl)amino; 99. The compound of claim 98.

102. D and W are C(R ２９ ) ２ b is 0, and each R ２９ is independently hydrogen, methyl, methoxy, cyano, hydroxy, chloro, fluoro, amino, methylamino, or dimethylamino; 99. The compound of claim 98.

103. D and W are C(R ２９ ) ２ b is 0, and each R ２９ is independently chloro or fluoro; 99. The compound of claim 98.

104. D and W are C(R ２９ ) ２ b is 0, and each R ２９ is fluoro, 99. The compound of claim 98.

105. D and W are C(R ２９ ) ２ b is 0, and each R ２９ is hydrogen, 99. The compound of claim 98.

106. Q is a group of the formula: 【Chemistry 10】 [In the formula, each b is 0, 1, or 2; and W is O, NR １９ , or C(R ２９ ) ２ and The R １９ is hydrogen, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, haloC １ -C ３ Alkyl, hydroxy C １ -C ６ Alkyl, or amino-, or mono-, or di-(C １ -C ６ alkyl)amino(C １ -C ６ alkyl); and Each R ２９ are independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C ６ Cycloalkyl, cyano, hydroxy, oxo, halogen, haloC １ -C ３ Alkyl, hydroxy C １ -C ６ Alkyl, amino, mono- or di-(C １ -C ６ alkyl)amino] represents a group represented by The compound according to any one of claims 60 to 97.

107. W is oxygen, b is 0 or 1, and R ９ is methyl or cyano; The compound of claim 106.

108. W is oxygen and b is 0; The compound of claim 106.

109. W is C (R ２９ ) ２ b is 0, and each R ２９ are independently hydrogen, C １ -C ２ Alkyl, C １ -C ２ Alkoxy, cyclopropyl, cyano, hydroxy, halogen, haloC １ -C ２ Alkyl, hydroxy C １ -C ２ Alkyl, amino, mono- or di-(C １ -C ２ alkyl)amino; The compound of claim 106.

110. W is C (R ２９ ) ２ b is 0, and each R ２９ is independently hydrogen, methyl, methoxy, cyano, hydroxy, chloro, fluoro, amino, methylamino, or dimethylamino; The compound of claim 106.

111. W is C (R ２９ ) ２ b is 0, and each R ２９ is independently chloro or fluoro; The compound of claim 106.

112. W is C (R ２９ ) ２ b is 0, and each R ２９ is fluoro, The compound of claim 106.

113. W is C (R ２９ ) ２ b is 0, and each R ２９ is hydrogen, The compound of claim 106.

114. Q is a group of the formula: 【Chemistry 11】 [In the formula, each b is 0, 1, or 2; and W is O, NR １９ , or C(R ２９ ) ２ and The R １９ is hydrogen, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, haloC １ -C ３ Alkyl, hydroxy C １ -C ６ Alkyl, or amino-, or mono-, or di-(C １ -C ６ alkyl)amino(C １ -C ６ alkyl); and Each R ２９ are independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C ６ Cycloalkyl, cyano, hydroxy, oxo, halogen, haloC １ -C ３ Alkyl, hydroxy C １ -C ６ Alkyl, amino, mono- or di-(C １ -C ６ alkyl)amino] represents a group represented by The compound according to any one of claims 60 to 97.

115. W is oxygen, b is 0 or 1, and R ９ is methyl, chloro, fluoro, or cyano; The compound of claim 114.

116. W is oxygen and b is 0; The compound of claim 114.

117. W is C (R ２９ ) ２ b is 0, and each R ２９ are independently hydrogen, C １ -C ２ Alkyl, C １ -C ２ Alkoxy, cyclopropyl, cyano, hydroxy, halogen, haloC １ -C ２ Alkyl, hydroxy C １ -C ２ Alkyl, amino, mono- or di-(C １ -C ２ alkyl)amino; The compound of claim 114.

118. W is C (R ２９ ) ２ b is 0, and each R ２９ is independently hydrogen, methyl, methoxy, cyano, hydroxy, chloro, fluoro, amino, methylamino, or dimethylamino; The compound of claim 114.

119. W is C (R ２９ ) ２ b is 0, and each R ２９ is independently chloro or fluoro; The compound of claim 114.

120. W is C (R ２９ ) ２ b is 0, and each R ２９ is fluoro, The compound of claim 114.

121. W is C (R ２９ ) ２ b is 0, and each R ２９ is hydrogen, The compound of claim 114.

122. Formula (III-A): 【Chemistry 12】 [In the formula, a is 0, 1, 2, or 3; V is CR １４ or N; Each R １２ are independently １ -C ４ Alkyl, -OR Ａ , -C(O)OR Ａ , (C １ -C ３ alkyl)-OR Ａ , -C(O)N(R Ａ ) ２ , cyano, or halogen; R １３ is (i) cyano, (ii) tetrazolyl, (iii) —C(O)OR Ａ (In the formula, R Ａ is H, C １ -C ６ Alkyl, or C ３ -C ６ cycloalkyl), or (iv) —C(O)N(R Ｂ ) ２ (In the formula, R Ｂ is H, -OH, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, or C ３ -C ６ cycloalkyl); R １４ is hydrogen, cyano, halogen, hydroxy, C １ -C ４ Alkoxy, C １ -C ４ Alkyl, —C(O)OR Ａ , (C １ -C ３ alkyl)-OR Ａ , or —C(O)N(R Ｂ ) ２ and Q represents a 4-8 membered saturated or unsaturated monocyclic, bicyclic, or polycyclic heterocyclyl group having 0, 1, or 2 additional ring heteroatoms selected from oxygen and nitrogen; b is 0, 1, 2, 3, or 4; and Each R ９ are independently １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C ６ Cycloalkyl, cyano, hydroxy, oxo, halogen, haloC １ -C ３ Alkyl, hydroxy C １ -C ６ Alkyl, amino, mono- or di-(C １ -C ６ alkyl)amino, or phenyl, phenyl (C １ -C ３ alkanoyl), 5- to 7-membered heterocyclyl, or 5- to 6-membered heteroaryl, and each of the phenyl, 5- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl is C １ -C ３ Alkyl, C １ -C ３ Alkoxy, halogen, hydroxy, cyano, amino, or mono- or di(C １ -C ３ may be substituted with alkyl)amino] having 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a deuterated version thereof.

123. R １ is H or CH ３ That is, The compound of claim 122.

124. R ３ is C １ -C ３ alkyl, wherein the alkyl group is unsubstituted, substituted with 1 to 5 halo groups, or fully substituted with fluorine; 124. A compound according to claim 122 or claim 123.

125. R ３ is methyl, 124. A compound according to claim 122 or claim 123.

126. R ４ is hydrogen, The compound according to any one of claims 122 to 125.

127. R ４ is methyl, The compound according to any one of claims 122 to 125.

128. R ４ is fluoro, The compound according to any one of claims 122 to 125.

129. R ４ is chloro, The compound according to any one of claims 122 to 125.

130. R ４ is fluoromethyl; The compound according to any one of claims 122 to 125.

131. R ４ is difluoromethyl; The compound according to any one of claims 122 to 125.

132. R ４ is trifluoromethyl; The compound according to any one of claims 122 to 125.

133. R ４ is bromo, The compound according to any one of claims 122 to 125.

134. V is CR １２ That is, The compound according to any one of claims 122 to 133.

135. V is N; The compound according to any one of claims 122 to 133.

136. V is CH, a is 1, and R １２ is hydrogen or halogen; The compound according to any one of claims 122 to 133.

137. V is CH, a is 1, and R １２ is hydrogen, or chloro, bromo, or fluoro; The compound according to any one of claims 122 to 133.

138. V is CH, a is 1, and R １２ is hydrogen, The compound according to any one of claims 122 to 133.

139. V is CH, a is 1, and R １２ is methyl, The compound according to any one of claims 122 to 133.

140. V is CH, a is 1, and R １２ is chloro, The compound according to any one of claims 122 to 133.

141. V is CH, a is 1, and R １２ is bromo, The compound according to any one of claims 122 to 133.

142. V is CH, a is 1, and R １２ is fluoro, The compound according to any one of claims 122 to 133.

143. V is N, a is 1, and R １２ is hydrogen or halogen; The compound according to any one of claims 122 to 133.

144. V is N, a is 1, and R １２ is hydrogen, or chloro, bromo, or fluoro; The compound according to any one of claims 122 to 133.

145. V is N, a is 1, and R １２ is hydrogen, The compound according to any one of claims 122 to 133.

146. V is N, a is 1, and R １２ is chloro, The compound according to any one of claims 122 to 133.

147. V is N, a is 1, and R １２ is bromo, The compound according to any one of claims 122 to 133.

148. V is N, a is 1, and R １２ is methyl, The compound according to any one of claims 122 to 133.

149. V is N, a is 1, and R １２ is fluoro, The compound according to any one of claims 122 to 133.

150. Base: 【Chemistry 13】 but, 【Chemistry 14】 Represents, The compound according to any one of claims 122 to 149.

151. Q is a group of the formula: 【Chemistry 15】 [In the formula, each b is 0, 1, or 2; D is C (R ２９ ) ２ represents W is O, NR １９ , or C(R ２９ ) ２ represents, and R １９ is hydrogen, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, haloC １ -C ３ Alkyl, hydroxy C １ -C ６ Alkyl, or amino-, or mono-, or di-(C １ -C ６ alkyl)amino(C １ -C ６ alkyl); and Each R ２９ are independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C ６ Cycloalkyl, cyano, hydroxy, oxo, halogen, haloC １ -C ３ Alkyl, hydroxy C １ -C ６ Alkyl, amino, mono- or di-(C １ -C ６ alkyl)amino] represents a group represented by The compound according to any one of claims 122 to 150.

152. W is oxygen, b is 0 or 1, and R ９ is methyl or cyano; The compound of claim 151.

153. W is oxygen and b is 0; The compound of claim 151.

154. D and W are C(R ２９ ) ２ b is 0, and each R ２９ are independently hydrogen, C １ -C ２ Alkyl, C １ -C ２ Alkoxy, cyclopropyl, cyano, hydroxy, halogen, haloC １ -C ２ Alkyl, hydroxy C １ -C ２ Alkyl, amino, mono- or di-(C １ -C ２ alkyl)amino; The compound of claim 151.

155. D and W are C(R ２９ ) ２ b is 0, and each R ２９ is independently hydrogen, methyl, methoxy, cyano, hydroxy, chloro, fluoro, amino, methylamino, or dimethylamino; The compound of claim 151.

156. D and W are C(R ２９ ) ２ b is 0, and each R ２９ is independently chloro or fluoro; The compound of claim 151.

157. D and W are C(R ２９ ) ２ b is 0, and each R ２９ is fluoro, The compound of claim 151.

158. D and W are C(R ２９ ) ２ b is 0, and each R ２９ is hydrogen, The compound of claim 151.

159. Q is a group of the formula: 【Chemistry 16】 [In the formula, each b is 0, 1, or 2; and W is O, NR １９ , or C(R ２９ ) ２ represents The R １９ is hydrogen, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, haloC １ -C ３ Alkyl, hydroxy C １ -C ６ Alkyl, or amino-, or mono-, or di-(C １ -C ６ alkyl)amino(C １ -C ６ alkyl); and Each R ２９ are independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C ６ Cycloalkyl, cyano, hydroxy, oxo, halogen, haloC １ -C ３ Alkyl, hydroxy C １ -C ６ Alkyl, amino, mono- or di-(C １ -C ６ alkyl)amino] represents a group represented by The compound according to any one of claims 122 to 150.

160. W is oxygen, b is 0 or 1, and R ９ is methyl or cyano; The compound of claim 159.

161. W is oxygen and b is 0; The compound of claim 159.

162. W is C (R ２９ ) ２ b is 0, and each R ２９ are independently hydrogen, C １ -C ２ Alkyl, C １ -C ２ Alkoxy, cyclopropyl, cyano, hydroxy, halogen, haloC １ -C ２ Alkyl, hydroxy C １ -C ２ Alkyl, amino, mono- or di-(C １ -C ２ alkyl)amino; The compound of claim 159.

163. W is C (R ２９ ) ２ b is 0, and each R ２９ is independently hydrogen, methyl, methoxy, cyano, hydroxy, chloro, fluoro, amino, methylamino, or dimethylamino; The compound of claim 159.

164. W is C (R ２９ ) ２ b is 0, and each R ２９ is independently chloro or fluoro; The compound of claim 159.

165. W is C (R ２９ ) ２ b is 0, and each R ２９ is fluoro, The compound of claim 159.

166. W is C (R ２９ ) ２ b is 0, and each R ２９ is hydrogen, The compound of claim 159.

167. Q is a group of the formula: 【Chemistry 17】 [In the formula, each b is 0, 1, or 2; and W is O, NR １９ , or C(R ２９ ) ２ represents The R １９ is hydrogen, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, haloC １ -C ３ Alkyl, hydroxy C １ -C ６ Alkyl, or amino-, or mono-, or di-(C １ -C ６ alkyl)amino(C １ -C ６ alkyl); and Each R ２９ are independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C ６ Cycloalkyl, cyano, hydroxy, oxo, halogen, haloC １ -C ３ Alkyl, hydroxy C １ -C ６ Alkyl, amino, mono- or di-(C １ -C ６ alkyl)amino] represents a group represented by The compound according to any one of claims 122 to 150.

168. W is oxygen, b is 0 or 1, and R ９ is methyl, chloro, fluoro, or cyano; The compound of claim 167.

169. W is oxygen and b is 0; The compound of claim 167.

170. W is C (R ２９ ) ２ b is 0, and each R ２９ are independently hydrogen, C １ -C ２ Alkyl, C １ -C ２ Alkoxy, cyclopropyl, cyano, hydroxy, halogen, haloC １ -C ２ Alkyl, hydroxy C １ -C ２ Alkyl, amino, mono- or di-(C １ -C ２ alkyl)amino; The compound of claim 167.

171. W is C (R ２９ ) ２ b is 0, and each R ２９ is independently hydrogen, methyl, methoxy, cyano, hydroxy, chloro, fluoro, amino, methylamino, or dimethylamino; The compound of claim 167.

172. W is C (R ２９ ) ２ b is 0, and each R ２９ is independently chloro or fluoro; The compound of claim 167.

173. W is C (R ２９ ) ２ b is 0, and each R ２９ is fluoro, The compound of claim 167.

174. W is C (R ２９ ) ２ b is 0, and each R ２９ is hydrogen, The compound of claim 167.

175. Formula (V): [Chemistry 18] [In the formula, a is 0, 1, 2, or 3; V is CR １４ or N; Each R １２ are independently １ -C ４ Alkyl, -OR Ａ , -C(O)OR Ａ , (C １ -C ３ alkyl)-OR Ａ , -C(O)N(R Ａ ) ２ , cyano, or halogen; R １３ is (i) cyano, (ii) tetrazolyl, (iii) —C(O)OR Ａ (In the formula, R Ａ is H, C １ -C ６ Alkyl, or C ３ -C ６ cycloalkyl), or (iv) —C(O)N(R Ｂ ) ２ (In the formula, R Ｂ is H, -OH, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, or C ３ -C ６ cycloalkyl); R １４ is hydrogen, cyano, halogen, hydroxy, C １ -C ４ Alkoxy, C １ -C ４ Alkyl, —C(O)OR Ａ , (C １ -C ３ alkyl)-OR Ａ , or —C(O)N(R Ｂ ) ２ is] having 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a deuterated version thereof.

176. R １ is H or CH ３ That is, The compound of claim 175.

177. R ３ is C １ -C ３ alkyl, wherein the alkyl group is unsubstituted, substituted with 1 to 5 halo groups, or fully substituted with fluorine; A compound according to claim 175 or claim 176.

178. R ３ is methyl, A compound according to claim 175 or claim 176.

179. R ４ is hydrogen, The compound according to any one of claims 175 to 178.

180. R ４ is methyl, The compound according to any one of claims 175 to 178.

181. R ４ is fluoro, The compound according to any one of claims 175 to 178.

182. R ４ is chloro, The compound according to any one of claims 175 to 178.

183. R ４ is fluoromethyl; The compound according to any one of claims 175 to 178.

184. R ４ is difluoromethyl; The compound according to any one of claims 175 to 178.

185. R ４ is trifluoromethyl; The compound according to any one of claims 175 to 178.

186. R ４ is bromo, The compound according to any one of claims 175 to 178.

187. V is CR １２ That is, The compound according to any one of claims 175 to 186.

188. V is N; The compound according to any one of claims 175 to 186.

189. V is CH, a is 1, and R １２ is hydrogen or halogen; The compound according to any one of claims 175 to 186.

190. V is CH, a is 1, and R １２ is hydrogen, or chloro, bromo, or fluoro; The compound according to any one of claims 175 to 186.

191. V is CH, a is 1, and R １２ is hydrogen, The compound according to any one of claims 175 to 186.

192. V is CH, a is 1, and R １２ is methyl, The compound according to any one of claims 175 to 186.

193. V is CH, a is 1, and R １２ is chloro, The compound according to any one of claims 175 to 186.

194. V is CH, a is 1, and R １２ is bromo, The compound according to any one of claims 175 to 186.

195. V is CH, a is 1, and R １２ is fluoro, The compound according to any one of claims 175 to 186.

196. V is N, a is 1, and R １２ is hydrogen or halogen; The compound according to any one of claims 175 to 186.

197. V is N, a is 1, and R １２ is hydrogen, or chloro, bromo, or fluoro; The compound according to any one of claims 175 to 186.

198. V is N, a is 1, and R １２ is hydrogen, The compound according to any one of claims 175 to 186.

199. V is N, a is 1, and R １２ is chloro, The compound according to any one of claims 175 to 186.

200. V is N, a is 1, and R １２ is bromo, The compound according to any one of claims 175 to 186.

201. V is N, a is 1, and R １２ is methyl, The compound according to any one of claims 175 to 186.

202. V is N, a is 1, and R １２ is fluoro, The compound according to any one of claims 175 to 186.

203. Base: 【Chemistry 19】 but, 【Chemistry 20】 Represents, The compound according to any one of claims 175 to 202.

204. R ３１ But one or two R ３９ a 4-, 5-, or 6-membered heterocyclyl group optionally substituted with a group, ３９ But independently, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C ６ Cycloalkyl, cyano, hydroxy, oxo, halogen, haloC １ -C ３ Alkyl, hydroxy C １ -C ６ Alkyl, amino, mono- or di-(C １ -C ６ alkyl)amino; The compound according to any one of claims 175 to 203.

205. R ３１ independently, one or two R ３９ is tetrahydrofuranyl optionally substituted by The compound of claim 204.

206. R ３１ is tetrahydrofuranyl optionally substituted by one or two methyl, cyano, or trifluoromethyl, The compound of claim 204.

207. R ３１ independently, one or two R ３９ is tetrahydropyranyl optionally substituted by The compound of claim 204.

208. R ３１ is tetrahydropyranyl optionally substituted by one or two methyl, cyano, or trifluoromethyl, The compound of claim 204.

209. R ３１ But one or two R ３９ and pyridyl optionally substituted with each of the R ３９ But independently, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C ６ Cycloalkyl, cyano, hydroxy, oxo, halogen, haloC １ -C ３ Alkyl, hydroxy C １ -C ６ is alkyl, The compound according to any one of claims 175 to 203.

210. below: (R)-2-((1-(9-methyl-5-(piperidin-1-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-2-((1-(9-methyl-2-phenyl-5-(piperidin-1-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-2-((1-(9-methyl-5-(piperidin-1-yl)-2-(pyrazin-2-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-2-((1-(9-methyl-5-(piperidin-1-yl)-2-(thiazol-4-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethyl)amino)benzoic acid; 2-((1-(9-methyl-5-(piperidin-1-yl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-cyano-9-methyl-5-(piperidin-1-yl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-2-((1-(5-(piperidin-1-yl)-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-2-((1-(9-methyl-5-(piperidin-1-yl)-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-2-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-2-((1-(5-(4,4-difluoropiperidin-1-yl)-2,9-dimethyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-2-((1-(4-(4,4-difluoropiperidin-1-yl)-8-methylthieno[3,2-c]quinolin-6-yl)ethyl)amino)benzoic acid; (R)-2-((1-(4-(4,4-difluoropiperidin-1-yl)-8-methyl-[1,2,4]triazolo[4,3-a]quinoxalin-6-yl)ethyl)amino)benzoic acid; (R)-2-((1-(4-(4,4-difluoropiperidin-1-yl)-1,8-dimethyl-[1,2,4]triazolo[4,3-a]quinoxalin-6-yl)ethyl)amino)benzoic acid; (R)-2-((1-(4-(4,4-difluoropiperidin-1-yl)-8-methyl-[1,2,3]triazolo[1,5-a]quinoxalin-6-yl)ethyl)amino)benzoic acid; (R)-2-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-2-((1-(5-(3,3-difluoropiperidin-1-yl)-9-methyl-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-2-((1-(9-methyl-5-(6-azaspiro[2.5]octan-6-yl)-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-2-((1-(5-(4,4-difluoro-6-azaspiro[2.5]octan-6-yl)-9-methyl-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-2-((1-(5-(4,4-dimethylpiperidin-1-yl)-9-methyl-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-2-((1-(9-methyl-5-(4-phenylpiperazin-1-yl)-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-2-((1-(5-(4-(2-cyanophenyl)piperazin-1-yl)-9-methyl-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-2-((1-(5-(4-(4-cyanophenyl)piperazin-1-yl)-9-methyl-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-2-((1-(5-(5,6-difluoroisoindolin-2-yl)-9-methyl-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-2-((1-(5-(5-fluoroisoindolin-2-yl)-9-methyl-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-2-((1-(5-(1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-9-methyl-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(5-(3-azabicyclo[4.1.0]heptan-3-yl)-9-methyl-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(5-(6,6-difluoro-3-azabicyclo[3.1.1]heptan-3-yl)-9-methyl-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-2-((1-(9-methyl-5-(2-azaspiro[3.3]heptan-2-yl)-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-2-((1-(5-(2-azabicyclo[2.2.2]octan-2-yl)-9-methyl-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(5-(3-azabicyclo[3.1.0]hexan-3-yl)-9-methyl-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(5-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-9-methyl-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-2-((1-(5-(1,1-difluoro-6-azaspiro[2.5]octan-6-yl)-9-methyl-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-2-((1-(9-methyl-5-(1,1,2,2-tetrafluoro-6-azaspiro[2.5]octan-6-yl)-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(9-methyl-5-((S)-3-(trifluoromethyl)piperidin-1-yl)-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(9-methyl-5-((R)-3-(trifluoromethyl)piperidin-1-yl)-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(5-((1S,4S)-5,5-difluoro-2-azabicyclo[2.2.1]heptan-2-yl)-9-methyl-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(5-((1R,4R)-5,5-difluoro-2-azabicyclo[2.2.1]heptan-2-yl)-9-methyl-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(5-((1S,4R)-6,6-difluoro-2-azabicyclo[2.2.1]heptan-2-yl)-9-methyl-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(5-((1R,4S)-6,6-difluoro-2-azabicyclo[2.2.1]heptan-2-yl)-9-methyl-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(9-methyl-5-(3,4,4-trifluoropiperidin-1-yl)-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-2-((1-(9-methyl-5-(piperazin-1-yl)-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-2-((1-(9-methyl-5-(4-methylpiperazin-1-yl)-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-2-((1-(5-(4-methylpiperazin-1-yl)-9-vinyl-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-2-((1-(5-(4-ethylpiperazin-1-yl)-9-methyl-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-2-((1-(9-methyl-5-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-2-((1-(5-(4-cyclopropylpiperazin-1-yl)-9-methyl-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(5-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-9-methyl-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(9-methyl-5-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(9-methyl-5-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-2-((1-(5-(4-benzoylpiperazin-1-yl)-9-methyl-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-2-((1-(9-methyl-5-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-2-((1-(9-methyl-5-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-2-((1-(5-(isobutylamino)-9-methyl-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-2-((1-(5-((cyclopropylmethyl)amino)-9-methyl-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-2-((1-(9-methyl-5-(pyrrolidin-1-yl)-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-2-((1-(5-(isoindolin-2-yl)-9-methyl-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-2-((1-(5-(isoindolin-2-yl)-3,9-dimethyl-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(5-(5,5-difluoro-2-azabicyclo[2.2.1]heptan-2-yl)-9-methyl-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(9-methyl-5-morpholino-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(9-methyl-5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methylimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-2,9-dimethylimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-3,9-dimethylimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-2-((1-(9-methyl-5-morpholino-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-2-((1-(9-methyl-5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-2-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-6-chloro-3-((1-(5-(3,3-difluoroazetidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-2-((1-(5-(3,3-difluoroazetidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-6-chloro-3-((1-(5-(3,3-difluoropyrrolidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-2-((1-(5-(3,3-difluoropyrrolidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-6-chloro-3-((1-(2-(difluoromethyl)-5-(4,4-difluoropiperidin-1-yl)-9-methylimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-2-((1-(2-(difluoromethyl)-5-(4,4-difluoropiperidin-1-yl)-9-methylimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-2-(fluoromethyl)-9-methylimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-2-((1-(5-(4,4-difluoropiperidin-1-yl)-2-(fluoromethyl)-9-methylimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzoic acid; 6-chloro-3-(((1R)-1-(9-methyl-5-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; 2-(((1R)-1-(9-methyl-5-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-6-chloro-3-((1-(2-cyano-5-(4,4-difluoropiperidin-1-yl)-9-methylimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(2-cyano-9-methyl-5-morpholinoimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-2-fluoro-6-((1-(9-methyl-5-morpholino-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-5-fluoro-2-((1-(9-methyl-5-morpholino-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-4-fluoro-2-((1-(9-methyl-5-morpholino-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-3-fluoro-2-((1-(9-methyl-5-morpholino-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzoic acid; 6-chloro-3-(((1R)-1-(9-methyl-5-(tetrahydrofuran-3-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; 2-(((1R)-1-(9-methyl-5-(tetrahydrofuran-3-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-4-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)thiophene-3-carboxylic acid; (R)-4-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)isothiazole-3-carboxylic acid; (R)-6-chloro-3-((1-(9-chloro-5-morpholino-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(9-fluoro-5-morpholino-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(5-morpholino-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(9-chloro-5-(4,4-difluoropiperidin-1-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-9-fluoro-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-2-ethyl-9-methylimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(9-chloro-5-(4,4-difluoropiperidin-1-yl)-2-ethylimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-2-methoxy-9-methylimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(9-chloro-5-(4,4-difluoropiperidin-1-yl)-2-methoxyimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-9-fluoro-2-methoxyimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-2-methoxyimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-2-ethyl-9-fluoroimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-2-ethylimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(2-chloro-5-(4,4-difluoropiperidin-1-yl)-9-methylimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(2,9-dichloro-5-(4,4-difluoropiperidin-1-yl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(2-chloro-5-(4,4-difluoropiperidin-1-yl)-9-fluoroimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(2-chloro-5-(4,4-difluoropiperidin-1-yl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(2-cyclopropyl-5-(4,4-difluoropiperidin-1-yl)-9-methylimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(9-chloro-2-cyclopropyl-5-(4,4-difluoropiperidin-1-yl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(2-chloro-9-methyl-5-morpholinoimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(2-cyano-9-methyl-5-morpholinoimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(2-(difluoromethyl)-9-methyl-5-morpholinoimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(2-(fluoromethyl)-9-methyl-5-morpholinoimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((1R)-1-(5-(3-fluoropyrrolidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((1R)-1-(5-(3,4-difluoropyrrolidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((1R)-1-(9-methyl-5-(2-methylmorpholino)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((1R)-1-(5-(2-ethylmorpholino)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(9-methyl-5-(6-oxa-2-azaspiro[3.4]octan-2-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(9-methyl-5-(2-oxa-6-azaspiro[3.4]octan-6-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(9-methyl-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((1R)-1-(5-(1-fluoro-3-azabicyclo[3.2.0]heptan-3-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; 3-(((1R)-1-(5-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)-6-chloropicolinic acid; 6-chloro-3-(((1R)-1-(5-(3-cyanopyrrolidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; 3-(((1R)-1-(5-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)-6-chloropicolinic acid; (R)-6-chloro-3-((1-(9-methyl-5-(tetrahydro-2H-pyran-4-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; 3-(((1R)-1-(5-(3-oxabicyclo[4.1.0]heptan-6-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)-6-chloropicolinic acid; 6-chloro-3-(((1R)-1-(5-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((1R)-1-(5-(6-fluoro-3-azabicyclo[3.1.0]hexan-3-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((1R)-1-(5-(1-fluoro-3-azabicyclo[3.1.0]hexan-3-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(9-methyl-5-(pyridin-3-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(9-methyl-5-(pyridin-4-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(9-methyl-5-((oxetan-3-ylmethyl)amino)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(9-methyl-5-(methyl(oxetan-3-ylmethyl)amino)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((1R)-1-(5-(3,3-difluoro-4-methylpyrrolidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((1R)-1-(5-(4,4-difluoro-3-methylpiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((1R)-1-(5-(6,6-difluoro-3-azabicyclo[3.1.1]heptan-3-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((1R)-1-(5-(5,5-difluoro-2-azabicyclo[2.2.1]heptan-2-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(5-(3,3-difluoropiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((1R)-1-(5-(6,6-difluoro-2-azabicyclo[2.2.1]heptan-2-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(9-methyl-2-(trifluoromethyl)-5-(3-(trifluoromethyl)azetidin-1-yl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-N-(1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)-2-(1H-tetrazol-5-yl)pyridin-3-amine; (R)-6-chloro-N-(1-(9-methyl-5-morpholino-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)-2-(1H-tetrazol-5-yl)pyridin-3-amine; (R)—N-(1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)-2-(1H-tetrazol-5-yl)aniline; (R)—N-(1-(9-methyl-5-morpholino-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)-2-(1H-tetrazol-5-yl)aniline; (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)ethyl picolinate; (R)-6-chloro-3-((1-(9-methyl-5-morpholino-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)ethyl picolinate; (R)-2-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzoate; (R)-2-((1-(9-methyl-5-morpholino-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzoate; (R)-2-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzonitrile; (R)-2-((1-(9-methyl-5-morpholino-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzonitrile; (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinonitrile; (R)-6-chloro-3-((1-(9-methyl-5-morpholino-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinonitrile; (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinamide; (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)-N-methylpicolinamide; (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)-N-hydroxypicolinamide; (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)-N-hydroxy-N-methylpicolinamide; (R)-6-chloro-3-((1-(9-methyl-5-morpholino-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinamide; (R)-6-chloro-N-methyl-3-((1-(9-methyl-5-morpholino-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinamide; (R)-6-chloro-N-hydroxy-3-((1-(9-methyl-5-morpholino-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinamide; (R)-6-chloro-N-hydroxy-N-methyl-3-((1-(9-methyl-5-morpholino-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinamide; (R)-2-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzamide; (R)-2-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)-N-methylbenzamide; (R)-2-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)-N-hydroxybenzamide; (R)-2-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)-N-hydroxy-N-methylbenzamide; (R)-2-((1-(9-methyl-5-morpholino-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzamide; (R)-N-methyl-2-((1-(9-methyl-5-morpholino-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzamide; (R)-N-hydroxy-2-((1-(9-methyl-5-morpholino-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzamide; (R)-N-hydroxy-N-methyl-2-((1-(9-methyl-5-morpholino-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzamide; (R)-N-hydroxy-N-methyl-2-((1-(9-methyl-5-morpholino-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzamide; (R)-2-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(2,2,2-trifluoroethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(2,2,2-trifluoroethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-2-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(perfluoroethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(perfluoroethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-2-((1-(9-methyl-5-morpholino-2-(2,2,2-trifluoroethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-6-chloro-3-((1-(9-methyl-5-morpholino-2-(2,2,2-trifluoroethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-2-((1-(9-methyl-5-morpholino-2-(perfluoroethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-6-chloro-3-((1-(9-methyl-5-morpholino-2-(perfluoroethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-2-((1-(5-(4,4-difluoropiperidin-1-yl)-2,9-bis(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-2,9-bis(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-2-((1-(5-morpholino-2,9-bis(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-6-chloro-3-((1-(5-morpholino-2,9-bis(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(9-(difluoromethyl)-5-(4,4-difluoropiperidin-1-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(9-(difluoromethyl)-5-morpholino-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-9-(fluoromethyl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(9-(fluoromethyl)-5-morpholino-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-3-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)-6-methylpicolinic acid; (R)-2-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)-5-methylbenzoic acid; (R)-6-methyl-3-((1-(9-methyl-5-morpholino-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-5-methyl-2-((1-(9-methyl-5-morpholino-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(2,2,3,3-tetrafluorocyclopropyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(9-methyl-5-morpholino-2-(2,2,3,3-tetrafluorocyclopropyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; or and pharmaceutically acceptable salts thereof. The compound of claim 1.

211. A pharmaceutical composition comprising a compound or salt according to any one of claims 1 to 210 together with a pharmaceutically acceptable carrier, excipient or diluent.

212. 212. A method for treating a disease or disorder associated with the regulation of phosphoinositide 3 kinase (PI3K), comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 210, or a pharmaceutical composition according to claim 211.

213. the PI3K is PI3Kα; The method of claim 212.

214. the PI3K associated with the disease or disorder has the H1047R mutation; The method of claim 212 or claim 213.

215. the disease or disorder is cancer, 215. The method of any one of claims 212 to 214.

216. The cancer is endometrial cancer, stomach cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain tumor, or prostate cancer, The method of claim 215.

217. the disease or disorder is CLOVES syndrome (congenital lipomatous overgrowth-vascular malformation-epidermal nevus-scoliosis / skeletal spine syndrome) or PIK3Cα-associated overgrowth syndrome (PROS); 215. The method of any one of claims 212 to 214.

218. 212. A method for inhibiting phosphoinositide 3-kinase (PI3K), comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 210, or a pharmaceutical composition according to claim 211.

219. 212. A method for treating cancer or a disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 210, or a pharmaceutical composition according to claim 211.

220. The cancer is endometrial cancer, stomach cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain tumor, or prostate cancer; The method of claim 219.

221. the disorder is CLOVES syndrome (congenital lipomatous overgrowth-vascular malformation-epidermal nevus-scoliosis / skeletal spine syndrome) or PIK3Cα-related overgrowth syndrome (PROS); The method of claim 219.

222. 212. A method for treating cancer, comprising administering to a patient in need thereof a compound according to any one of claims 1 to 210, or a pharmaceutical composition according to claim 211, and a KRAS inhibitor, wherein the cancer is breast cancer, uterine carcinosarcoma, endometrial carcinoma, colorectal adenocarcinoma, gastric adenocarcinoma, head and neck squamous cell carcinoma, bile duct carcinoma, esophageal adenocarcinoma, bladder carcinoma, lung squamous cell carcinoma, brain glioma, adrenocortical carcinoma, hepatocellular carcinoma, sarcoma, prostate adenocarcinoma, renal cell carcinoma, lung adenocarcinoma, ovarian cystadenocarcinoma, glioblastoma multiforme, or melanoma.

223. A method for treating cancer, comprising administering a compound according to any one of claims 1 to 210, or a pharmaceutical composition according to claim 211, and a mutant-selective KRAS inhibitor to a patient in need thereof, wherein the cancer is breast cancer, uterine carcinosarcoma, endometrial carcinoma, colorectal adenocarcinoma, gastric adenocarcinoma, head and neck squamous cell carcinoma, bile duct carcinoma, esophageal adenocarcinoma, bladder carcinoma, lung squamous cell carcinoma, brain glioma, adrenocortical carcinoma, hepatocellular carcinoma, sarcoma, prostate adenocarcinoma, renal cell carcinoma, lung adenocarcinoma, ovarian cystadenocarcinoma, glioblastoma multiforme, or melanoma.

224. 212. A compound according to any one of claims 1 to 210, or a pharmaceutical composition according to claim 211, for use in combination with a KRAS inhibitor in the treatment of cancer, wherein the cancer is breast cancer, uterine carcinosarcoma, endometrial carcinoma, colorectal adenocarcinoma, gastric adenocarcinoma, head and neck squamous cell carcinoma, bile duct carcinoma, esophageal adenocarcinoma, bladder carcinoma, lung squamous cell carcinoma, brain glioma, adrenocortical carcinoma, hepatocellular carcinoma, sarcoma, prostate adenocarcinoma, renal cell carcinoma, lung adenocarcinoma, ovarian cystadenocarcinoma, glioblastoma multiforme, or melanoma.

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