Substituted tricyclic compounds

Abstract

Disclosed herein are substituted tricyclic compounds, comprising an imidazo quinazoline compound, an imidazo pyridopyrimidine compound, a triazolo quinazoline compound, a pyridino triazolo pyrimidine compound, a triazolo quinoxaline compound, a pyridino triazolo pyrazine compound, a thieno naphthyridine compound and a thieno quinoline compound, as well as a preparation method and application of the imidazo quinazoline compound, the imidazo pyridopyrimidine compound, the triazolo quinazoline compound, the pyridino triazolo pyrimidine compound, the triazolo quinoxaline compound, the pyridino triazolo pyrazine compound and the thieno quinoline compound.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 483,070, filed February 3, 2023, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0003] The present disclosure relates to substituted tricyclic compounds, including imidazoquinazolines, imidazopyridopyrimidines, triazoloquinazolines, pyridotriazolopyrimidines, triazoloquinoxalines, pyridotriazolopyrazines, thienonaphthyridines, and thienoquinolines, and thus such compounds are useful in treating diseases or disorders associated with PI3K regulation.

[0004] background

[0005] Cellular activity can be regulated by external signals that stimulate or inhibit intracellular events. The process by which stimulatory or inhibitory signals are transmitted into cells to elicit intracellular responses is known as signal transduction. Over the past few decades, the cascade of signal transduction events has been elucidated and found to play a central role in a wide variety of biological responses. Defects in various components of signal transduction pathways have been implicated in numerous diseases, including various forms of cancer, inflammatory disorders, metabolic disorders, and vascular and neurological diseases.

[0006] Kinases represent an important class of signaling molecules. Kinases can be generally divided into protein kinases and lipid kinases, and some kinases show dual specificity. Protein kinases are enzymes that can phosphorylate other proteins and / or themselves (i.e., autophosphorylation). Based on their substrate utilization, protein kinases can be generally divided into three major categories: tyrosine kinases (e.g., erb2, PDGF receptor, EGF receptor, VEGF receptor, src, abl) that mainly phosphorylate the tyrosine residues of the substrate, serine / threonine kinases (e.g., mTORC1, mTORC2, ATM, ATR, DNA-PK, Akt) that mainly phosphorylate the serine and / or threonine residues of the substrate, and dual specificity kinases that phosphorylate the tyrosine, serine and / or threonine residues of the substrate.

[0007] Lipid kinases are enzymes that catalyze the phosphorylation of lipids within cells. These enzymes, as well as the phosphorylated lipids and lipid-derived bioactive organic molecules produced thereby, play a role in many different 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 within or associated with cell membranes. Examples of such enzymes include phosphoinositide kinases (e.g., PI3-kinase, PI4-kinase), diacylglycerol kinase, and sphingosine kinase.

[0008] The phosphoinositide 3-kinase (PI3K) signaling pathway is one of the most highly mutated systems in human cancer. PI3K signaling is involved in many other disease states, including allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, psoriasis, multiple sclerosis, asthma, diseases associated with diabetic complications, and inflammatory complications of the cardiovascular system (such as acute coronary syndrome).

[0009] PI3K is a member of a unique and conserved family of intracellular lipid kinases that phosphorylates 3'-OH groups on phosphatidylinositol or phosphoinositide. The PI3K family comprises 15 kinases with different substrate specificities, expression patterns, and regulatory pathways. Class I PI3Ks (PI10a, PI10b, PI106, and PI10g) are typically activated by tyrosine kinases or G protein-coupled receptors to generate PIP3, which binds to downstream effectors such as Akt / PDK1, mTOR, Tec family kinases, and Rho family GTPases pathways. Class II and Class III PI3-Ks play a key role in intracellular trafficking through the synthesis of PI(3)P and PI(3,4)P2.

[0010] PI3K isoforms are associated with a variety of human cancers and disorders. Mutations in genes encoding PI3K isoforms or leading to their upregulation are thought to occur in a variety of human cancers. Mutations in genes encoding PI3K isoforms are concentrated as point mutations within several hotspots within the helical and kinase domains. Given the high mutation rate of PI3K, targeting this pathway offers valuable therapeutic opportunities.

[0011] Genetic alterations in genes involved in PI3K signaling are believed to be associated with a variety 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 cancer, schwannoma, head and neck squamous cell carcinoma, melanoma, esophagogastric adenocarcinoma, soft tissue sarcoma, prostate cancer, fibrolamellar carcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, bile duct cancer, B-cell lymphoma, mesothelioma, adrenocortical carcinoma, non-clear cell renal carcinoma, clear cell renal carcinoma, germ cell carcinoma, thymoma, pheochromocytoma, other neuroepithelial tumors, thyroid cancer, leukemia, and encapsulated glioma.

[0012] The α isoform of PI3K is associated with, for example, a variety of human cancers. Angiogenesis has been shown to require the selective utilization of the α isoform of PI3K to control endothelial cell migration. Mutations in the gene encoding PI3Kα or mutations that lead to PI3Kα upregulation are believed to occur in a variety of human cancers, such as lung, gastric, endometrial, ovarian, bladder, breast, colon, brain, prostate, and skin cancers. Mutations in the gene encoding PI3Kα are point mutations clustered in several hotspots within the helical and kinase domains, such as E542K, E545K, and H1047R. Many of these mutations have been shown to be oncogenic gain-of-function mutations. Due to the high mutation rate of PI3Kα, targeting this pathway may offer valuable therapeutic opportunities. While other PI3K isoforms, such as PI3Kδ and PI3Kγ, are primarily expressed in hematopoietic cells, both PI3Kα and PI3Kβ are constitutively expressed.

[0013] Due to the central role of PI3Kα in regulating glucose homeostasis, PI3K inhibition often causes hyperglycemia and / or hyperinsulinemia in patients. High levels of circulating insulin may have potential effects on cancer cell mitosis and / or anti-apoptosis, thereby negating the anti-proliferative effects of PI3K inhibitors.

[0014] In cancers with mutant PI3Kα, one approach to overcoming the compensatory insulin and / or glucose production problems caused by systemic PI3Kα inhibition is to develop inhibitors with enhanced selectivity for mutant PI3Kα relative to wild-type PI3Kα. This would create an increased drug dosing window to selectively inhibit the pathological signaling of mutant PI3Kα in cancer cells without affecting wild-type PI3Kα in host tissues that control systemic metabolism, thereby limiting toxicity and allowing the use of higher doses and more complete inhibition of the drug target.

[0015] Existing PI3Kα inhibitors are nearly equally effective against wild-type and mutant PI3Kα. Because the PI3Kα mutation site is distant from the active site, mutation-selective inhibitors have been elusive. Therefore, inhibitors targeting a second peripheral binding pocket near known mutations (such as H1047R) may provide a pathway for selective PI3Kα inhibition. Therefore, targeting the peripheral binding pocket of mutant PI3Kα may in turn provide valuable therapeutic targets for drug development.

[0016] Therefore, kinases, for example lipid kinases such as PI3K, are major targets for drug development.

[0017] Overview

[0018] In one aspect, the present disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, as well as prodrugs, solvates, hydrates, isomers, deuterated forms, and tautomers thereof:

[0019]

[0020] in:

[0021] R 1 is H, C1-C3 alkyl or C3-C6 cycloalkyl;

[0022] R 2 is phenyl or 5-6 membered heteroaryl, wherein each phenyl and heteroaryl is optionally substituted by 1-5 R 12 replace;

[0023] 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;

[0024] Each R A are independently H, C1-C6 alkyl or C3-C6 cycloalkyl;

[0025] Each R B are independently H, -OH, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl; and

[0026] R 3 is a C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 alkenyl, C2-C3 alkynyl or C5-C6 cycloalkenyl group which is optionally substituted, multi-substituted or fully substituted by fluorine;

[0027] 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 halogen, wherein each C1-C3 alkyl and C3-C6 cycloalkyl is optionally substituted with 1-5 halogen groups;

[0028] T is N or CR 6 ,in,

[0029] R 6 is H or C1-C6 alkyl;

[0030] Expression (E), (G), (J), (K), (L), or (M)

[0031]

[0032] in,

[0033] Each d represents the point of attachment of a bridgehead carbon bonded to T;

[0034] In formula (E), both X and Y are CR 5 , or one of X and Y is CR 5 , and the other is N;

[0035] In formula (J), X and Y are both N;

[0036] Each ring A is a 4-8 membered carbocyclic ring or a 3-7 membered heterocyclic ring,

[0037] Each R 5 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogen, halo-substituted C1-C6 alkyl, cyano, hydroxy, hydroxyC1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino, C3-C6 cycloalkyl, halo-substituted C3-C6 cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein each 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 groups, and each phenyl and heteroaryl is optionally substituted with 1-3 halo, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, cyano, amino, or mono- or di-(C1-C3)alkylamino groups;

[0038] R 30 express

[0039] -NR 7 NR 8 or R 31 ,

[0040] R 31 express

[0041] (i) 5-7 membered heteroaryl or

[0042] (ii) a 3-8 membered monocyclic heterocyclic group linked to the tricyclic ring system via a carbon atom, wherein the heterocyclic group

[0043] is saturated or unsaturated and is optionally fused to an aromatic or non-aromatic ring containing 3 to 6 ring members, wherein 1 or 2 of the ring members are optionally nitrogen atoms, oxygen atoms or sulfur atoms and the remaining ring members are carbon, or

[0044] forms a spirocyclic ring system with a carbon atom from a monocyclic heterocyclyl and an additional carbon or nitrogen atom having up to 10 total ring members, wherein the ring members are carbon or nitrogen, and

[0045] where R 31 Each heteroaryl and heterocyclic group in the aromatic or non-aromatic part is optionally replaced by 1-4 R 39 group substituted, where each R 39 is 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), 5-7 membered heterocyclyl, or 5-6 membered heteroaryl, wherein each phenyl, 5-7 membered heterocyclyl, and 5-6 membered heteroaryl is optionally substituted with C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxy, cyano, amino, or mono- or di-(C1-C3 alkyl)amino;

[0046] R 7 represents H or C1-C3 alkyl;

[0047] R 8 represents (i) H, (ii) C1-C6 alkyl optionally substituted by 5-8 membered heterocyclyl, (iii) C3-C6 cycloalkyl, or (iv) C3-C6 cycloalkyl(C1-C3 alkyl); or

[0048] R 7 and R 8 Together with the nitrogen to which they are attached, they form Ring Q, wherein Ring Q is

[0049] A 3-8 membered monocyclic heterocyclic group containing one or two ring nitrogen atoms, wherein the heterocyclic group

[0050] optionally fused to an aromatic or non-aromatic ring containing 3 to 6 ring members, wherein 1 or 2 of the ring members are optionally nitrogen atoms, oxygen atoms or sulfur atoms and the remaining ring members are carbon, or

[0051] forms with a carbon atom from a monocyclic heterocyclyl and an additional carbon or nitrogen atom a spirocyclic ring system having up to 10 total ring members, wherein the ring members are carbon or nitrogen (the spiro center in the spirocyclic ring system is a carbon atom in a 3-7 membered monocyclic heterocyclyl), and

[0052] wherein each ring Q is optionally substituted with 1 to 4 R 9 group substituted, where each R 9independently 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), 5-7 membered heterocyclyl or 5-6 membered heteroaryl, wherein each phenyl, 5-7 membered heterocyclyl and 5-6 membered heteroaryl is optionally substituted with C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxy, cyano, amino or mono- or di-(C1-C3 alkyl)amino.

[0053] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound or salt as otherwise described herein and a pharmaceutically acceptable carrier, excipient, or diluent.

[0054] In another aspect, the present disclosure provides a method of treating a disease or disorder associated with modulation of phosphoinositide 3-kinase (PI3K), comprising administering to a patient in need thereof a therapeutically effective amount of any compound as otherwise described herein or a pharmaceutical composition as otherwise described herein.

[0055] In another aspect, the present disclosure provides a method of inhibiting phosphoinositide 3-kinase (PI3K), comprising administering to a patient in need thereof a therapeutically effective amount of a compound as otherwise described herein or a pharmaceutical composition as otherwise described herein.

[0056] In another aspect, the present disclosure provides a method of treating cancer or a disorder comprising administering to a patient in need thereof a therapeutically effective amount of a compound as otherwise described herein or a pharmaceutical composition as otherwise described herein.

[0057] The compounds disclosed herein selectively bind to H1047R-mutated PI3Kα and do not bind to wild-type PI3Kα.

[0058] In other aspects, the present disclosure provides intermediates and synthetic methods that are useful in preparing compounds of formula (I).

[0059] Other aspects and embodiments of the disclosure will be apparent in view of the detailed description provided herein. Detailed Description of the Invention

[0061] The present invention relates to inhibitors of PI3Kα. In particular, the present invention relates to compounds that inhibit PI3Kα activity, pharmaceutical compositions comprising therapeutically effective amounts of the compounds, and methods of use thereof.

[0062] definition

[0063] 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 the present invention belongs. All patents, patent applications and publications mentioned herein are incorporated herein by reference to the extent they are consistent with the present disclosure. Terms and scopes have their commonly defined definitions unless otherwise explicitly defined.

[0064] For simplicity, chemical moiety is mainly defined and referred to as monovalent chemical moiety (such as alkyl, aryl etc.) in the whole text. However, in the case of appropriate structures clearly known to those skilled in the art, such terms can also be used to represent corresponding multivalent moieties. For example, although " alkyl " part generally refers to monovalent groups (such as, CH3-CH2-), in some cases divalent linking moieties can be " alkyl", in which case, those skilled in the art will understand that alkyl is a divalent group (such as, -CH2-CH2-), which is equivalent to the term "alkylidene". (Similarly, in the case where a divalent moiety is needed and is expressed as "aryl", those skilled in the art will understand that the term "aryl" refers to the corresponding divalent moiety, arylene). All atoms are understood to have the quantity (that is, carbon is 4, N is 3, O is 2, and S is 2, 4 or 6, depending on the oxidation state of S) of their normal valence for bond formation.

[0065] The term "amino" refers to -NH2.

[0066] The term "acetyl" refers to -C(O)CH3.

[0067] As used herein, the term "acyl" refers to an alkylcarbonyl or arylcarbonyl substituent, wherein the alkyl and aryl portions are as defined herein.

[0068] As used herein, the term "alkyl" refers to saturated straight and branched chain aliphatic groups having 1 to 12 carbon atoms. Thus, "alkyl" encompasses C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 and C 12 The alkyl group may be branched or straight-chain. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0069] As used herein, the term "alkenyl" refers to an unsaturated straight or branched chain aliphatic group having one or more carbon-carbon double bonds and having 2 to 12 carbon atoms. Thus, "alkenyl" encompasses C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 and C 12 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

[0070] As used herein, the term "alkynyl" refers to an unsaturated straight or branched chain aliphatic group having one or more carbon-carbon triple bonds and having 2 to 12 carbon atoms. Thus, "alkynyl" encompasses C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 and C 12 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0071] An "alkylene," "alkenylene," or "alkynylene" group refers to an alkyl, alkenyl, or alkynyl group, as defined above, positioned between and serving to link 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, vinylene, propenylene, and butenylene. Representative alkynylene groups include, but are not limited to, ethynylene, propynylene, and butynylene.

[0072] The term "alkoxy" refers to -O(C1-C6 alkyl).

[0073] As used herein, the term "cycloalkyl" is a saturated and partially unsaturated cyclic hydrocarbon group having 3 to 12 carbon atoms. Thus, "cycloalkyl" encompasses C1, C2, C3, C4, C5, C6, C7, C8, C9, C 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.

[0074] The term "heteroalkyl" refers to an alkyl group as defined above wherein one or more carbon atoms in the chain are independently replaced by O, S or NR x Substitute, where R x is hydrogen or C1-C3 alkyl. Examples of heteroalkyl groups include methoxymethyl, methoxyethyl and methoxypropyl.

[0075] An "aryl" group refers to a C6-C8 group containing one to three aromatic rings. 14 Aromatic moieties. Thus, "aryl" includes C6, C 10 、C 13 and C 14 Representative aryl groups are C6-C 10 Aryl. Specific aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and fluorenyl. "Aryl" groups also include fused polycyclic (e.g., bicyclic) ring systems in which one or more of the fused rings is non-aromatic, provided that at least one ring is aromatic, such as indenyl.

[0076] "Aralkyl" or "arylalkyl" groups include an aryl group covalently linked to an alkyl group, wherein the moiety is linked to another group through the alkyl moiety. Representative aralkyl groups are -(C1-C6)alkyl (C6-C 10 ) aryl groups, including but not limited to benzyl, phenethyl and naphthylmethyl. For example, aryl C1-C3 alkyl is an aryl group covalently linked to a C1-C3 alkyl group.

[0077] A "heterocyclyl" or "heterocyclic" 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), for example 4 to 8 atoms, in which one or more ring atoms are independently -C(O)-, N, NR 4 , O or S, and the remaining ring atoms are quaternary carbon or carbonyl carbon.The example of heterocyclic radical includes but is not limited to epoxy, oxirane, oxetane, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, thietanyl, dithiolanyl, trithiolanyl, azathiolanyl, oxathiolanyl, dioxolanyl, oxazolidinyl, oxazolidinone, decahydroquinolinyl, piperidone, 4-piperidone, thiomorpholinyl, dimethylmorpholinyl and morpholinyl. As the example of the heterocyclic radical of spiro ring system, be azaspiro [2.5] octyl-6-base, 5-azaspiro [2.4] heptyl-5-base, 6-azaspiro [3.4] octyl-6-base, 5-oxa-7-azaspiro [3.4] octyl-7-base, 5,5-dimethyl-4-oxa-7-azaspiro [2.5] octyl-7-base and 7,7-dimethyl-5-azaspiro [2.5] octyl-5-base. Particularly excluded from the scope of this term are compounds with adjacent ring O and / or S atoms. Heterocyclic radical can be connected to the parent group by any ring atom in the heterocyclic radical, including one of heteroatoms or one of carbon atoms (i.e., point of attachment). According to chemical needs, heterocycle can be connected to one or more other groups, for example, as a bridging group. The term "heterocyclyl" also includes fused polycyclic (e.g., bicyclic) ring systems in which one or more of the fused rings is aromatic or non-aromatic, provided that at least one ring is non-aromatic and contains N, O, or S ring atoms. Examples of such fused polycyclic ring systems are 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 9-membered heterocyclyl.

[0078] 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; having 6, 10 or 14 π electrons shared in a cyclic array; and having 1 to 3 heteroatoms other than carbon atoms, each of which is independently N, O or S. "Heteroaryl" also includes fused polycyclic (e.g., bicyclic) ring systems in which one or more fused rings are non-aromatic, provided that at least one ring is aromatic and at least one ring contains N, O or S ring atoms. The heteroaryl group can be attached to the parent group through any ring atom in the heteroaryl ring group, including one of the heteroatoms or one of the carbon atoms (i.e., the point of attachment). Depending on chemical requirements, the heteroaryl group can be attached to one or more other groups, for example as a bridging group.

[0079] 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, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, yl, furanyl, furazanyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolene, 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, oxazolyl, oxadiazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiyl, phenoxazinyl, phthalazinyl, piperitinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl , quinuclidine, 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, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl.

[0080] "Arylene," "heteroarylene," or "heterocyclylene" is a divalent aryl, heteroaryl, or heterocyclyl group, respectively, positioned between two other chemical groups and serving to link the two chemical groups as defined above.

[0081] As used herein, when a moiety (e.g., cycloalkyl, aryl, heteroaryl, heterocyclyl, urea, etc.) is described as "optionally substituted" without specifying the substituents, it means that the group optionally has multiple non-hydrogen substituents, e.g., one to five, or one to four, or one to three, or one or two non-hydrogen substituents.

[0082] As used herein, the term "halogen" or "halo" refers to chlorine, bromine, fluorine, or iodine.

[0083] The term "haloalkyl", for example halo C1-C6 alkyl, refers to an alkyl chain in which one or more hydrogens are replaced by halogen. Representative haloalkyls are trifluoromethyl, difluoromethyl, fluorochloromethyl, chloromethyl, fluoromethyl, trifluoroethyl, pentafluoroethyl (perfluoroethyl), heptafluoropropyl (perfluoropropyl), tetrafluorocyclopropyl and pentafluorocyclopropyl (perfluorocyclopropyl).

[0084] The term "halocycloalkyl", such as halo C3-C6 cycloalkyl, refers to a cycloalkyl group in which one or more hydrogen atoms are replaced by halogen. Representative halocycloalkyl groups are 2,2-difluorocyclopropyl, 2,2,3,3-tetrafluorocyclopropyl, 2,3,4-trifluorocyclobutyl, and 2,4-difluorocyclopentyl.

[0085] The term "hydroxyalkyl" refers to an -alkylene-OH group.

[0086] In embodiments of formula (I), wherein the group (eg, -C(O)OR A or -C(O)N(R B )2) In R 2 Relative to R 2 The α or ortho position of the connection point of the nitrogen atom is connected to R 2 The connection, as will be understood, is intended to adopt a structure such as

[0087]

[0088] It should be understood that each individual atom present in Formula (I) and the compounds within Formula (I) may exist in the form of any of its naturally occurring isotopes, preferably the most abundant isotope. Thus, for example, each individual hydrogen atom present in Formula (I) or the structural formulas described below may exist as a 1H, 2H (deuterium; D) or 3H (tritium; T) atom, preferably 1H. Similarly, for example, each individual carbon atom present in Formula (I) or the structural formulas described below may exist as a 12C, 13C or 14C atom, preferably 12C.

[0089] As used herein, an "effective amount" of a compound is an amount sufficient to negatively regulate or inhibit PI3K alpha activity.

[0090] As used herein, a "therapeutically effective amount" of a compound is an amount sufficient to improve or alleviate symptoms in some way or to stop or reverse the progression of a disease, or to negatively regulate or inhibit PI3Kα activity. This amount can be administered as a single dose or according to an effective regimen.

[0091] As used herein, "treat" or "treating" refers to any manner in which the symptoms or pathology of a condition, disorder, or disease in a patient are ameliorated or otherwise beneficially altered.

[0092] As used herein, "amelioration of the symptoms of a specified disorder by administration of a specified compound or pharmaceutical composition" refers to any relief, whether permanent or temporary, long-lasting or transient, attributable to or associated with administration of the composition.

[0093] Compound

[0094] In one aspect, the present disclosure provides compounds of formula (I):

[0095]

[0096] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, deuterated forms and tautomers thereof, wherein:

[0097] R 1 is H, C1-C3 alkyl or C3-C6 cycloalkyl;

[0098] R 2 is phenyl or 5-6 membered heteroaryl, wherein each phenyl and heteroaryl is optionally substituted by 1-5 R 12 replace;

[0099] 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;

[0100] Each R A are independently H, C1-C6 alkyl or C3-C6 cycloalkyl;

[0101] Each R B are independently H, -OH, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl; and

[0102] R 3 is a C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkenyl, C2-C3 alkynyl or C5-C6 cycloalkenyl group which is optionally substituted, multi-substituted or fully substituted by fluorine;

[0103] R 4 is H, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkenyl, C2-C3 alkynyl or C5-C6 cycloalkenyl, cyano or halogen, wherein each C1-C3 alkyl and C3-C6 cycloalkyl is optionally substituted with 1-5 halogen groups;

[0104] T is N or CR 6 ,in,

[0105] R 6 is H or C1-C6 alkyl;

[0106] Expression (E), (G), (J), (K), (L), or (M)

[0107]

[0108] in,

[0109] Each d represents the point of attachment of a bridgehead carbon bonded to T;

[0110] In formula (E), both X and Y are CR 5 , or one of X and Y is CR 5 , and the other is N;

[0111] In formula (J), X and Y are both N;

[0112] Each ring A is a 4-8 membered carbocyclic ring or a 3-7 membered heterocyclic ring,

[0113] Each R 5 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogen, halo-substituted C1-C6 alkyl, cyano, hydroxy, hydroxyC1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino, C3-C6 cycloalkyl, halo-substituted C3-C6 cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein each 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 groups, and each phenyl and heteroaryl is optionally substituted with 1-3 halo, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, cyano, amino, or mono- or di-(C1-C3)alkylamino groups;

[0114] R 30 express

[0115] -NR 7 NR 8 or R 31 ,

[0116] R 31 express

[0117] (i) 5-7 membered heteroaryl or

[0118] (ii) a 3-8 membered monocyclic heterocyclic group linked to the tricyclic ring system via a carbon atom, wherein the heterocyclic group

[0119] is saturated or unsaturated and is optionally fused to an aromatic or non-aromatic ring containing 3 to 6 ring members, wherein 1 or 2 of the ring members are optionally nitrogen atoms, oxygen atoms or sulfur atoms and the remaining ring members are carbon, or

[0120] forms with the carbon atom from the monocyclic heterocyclyl and an additional carbon or nitrogen atom a spirocyclic ring system having up to 10 total ring members, wherein the ring members are carbon or nitrogen, and

[0121] where R 31 Each heteroaryl and heterocyclic group in the aromatic or non-aromatic part is optionally replaced by 1-4 R 39 group substituted, where each R 39 is 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), 5-7 membered heterocyclyl, or 5-6 membered heteroaryl, wherein each phenyl, 5-7 membered heterocyclyl, and 5-6 membered heteroaryl is optionally substituted with C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxy, cyano, amino, or mono- or di-(C1-C3 alkyl)amino;

[0122] R 7 represents H or C1-C3 alkyl;

[0123] R 8 represents H, C1-C6 alkyl, C3-C6 cycloalkyl or C3-C6 cycloalkyl(C1-C3 alkyl) optionally substituted by 5-8 membered heterocyclyl; or

[0124] R 7 and R 8 Together with the nitrogen to which they are attached, they form Ring Q, wherein Ring Q is

[0125] A 3-8 membered monocyclic heterocyclic group containing one or two ring nitrogen atoms and only nitrogen heteroatoms, wherein the heterocyclic group

[0126] optionally fused to an aromatic or non-aromatic ring containing 3 to 6 ring members, wherein 1 or 2 of the ring members are optionally nitrogen atoms, oxygen atoms or sulfur atoms and the remaining ring members are carbon, or

[0127] forms with a carbon atom from a monocyclic heterocyclyl and an additional carbon or nitrogen atom a spirocyclic ring system having up to 10 total ring members, wherein the ring members are carbon or nitrogen (the spiro center in the spirocyclic ring system is a carbon atom in a 3-7 membered monocyclic heterocyclyl), and

[0128] wherein each ring Q is optionally substituted with 1 to 4 R 9 group substituted, where each R 9 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), 5-7 membered heterocyclyl or 5-6 membered heteroaryl, wherein each phenyl, 5-7 membered heterocyclyl and 5-6 membered heteroaryl is optionally substituted with C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxy, cyano, amino or mono- or di-(C1-C3 alkyl)amino.

[0129] In certain embodiments of Formula (I) as otherwise described herein, Formula (Z) represents Formula (E).

[0130] In certain embodiments of Formula (I) as otherwise described herein, Formula (Z) represents Formula (G).

[0131] In certain embodiments of Formula (I) as otherwise described herein, Formula (Z) represents Formula (J).

[0132] In certain embodiments of Formula (I) as otherwise described herein, Formula (Z) represents Formula (K).

[0133] In certain embodiments of Formula (I) as otherwise described herein, Formula (Z) represents Formula (L).

[0134] In certain embodiments of Formula (I) as otherwise described herein, Formula (Z) represents Formula (M).

[0135] In certain embodiments of Formula (I) as otherwise described herein, T represents CR 6 .

[0136] In certain embodiments of Formula (I) as otherwise described herein, R 1 It is H or CH3.

[0137] In certain embodiments of Formula (I) as otherwise described herein, R 2is phenyl, pyridyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, pyrazinyl, pyridazinyl or pyrimidinyl, each of which is optionally substituted by 1-5 R 12 replace.

[0138] In certain embodiments of Formula (I) as otherwise described herein, R 2 is phenyl or pyridyl, each of which is optionally replaced by 1-5 R 12 replace.

[0139] In certain embodiments of Formula (I) as otherwise described herein, R 2 is phenyl or a 5-7 membered heteroaryl group, each of which is surrounded by 1, 2, 3 or 4 R 12 Group substitution.

[0140] In certain embodiments of Formula (I) as otherwise described herein, R 2 Is it 1, 2 or 3 R 12 substituted phenyl or 5-7 membered heteroaryl.

[0141] In certain embodiments of Formula (I) as otherwise described herein, R 2 is phenyl or a 5-7 membered heteroaryl group, each of which is surrounded by 1, 2, 3 or 4 R 12 group substituted, and at least one R 12 The group is -C(O)OR A .

[0142] In certain embodiments of Formula (I) as otherwise described herein, R 2 Is it 1, 2 or 3 R 12 phenyl or 5-7 membered heteroaryl substituted by a group, and at least one R 12 The group is -C(O)OR A .

[0143] In certain embodiments of Formula (I) as otherwise described herein, R 2 By a -C(O)OR A Substituted, wherein -C(O)OR A In R 2 Relative to R 2 The α position of the connection point of the nitrogen atom connected to R 2 connect.

[0144] In certain embodiments of Formula (I) as otherwise described herein, R 2 is phenyl or a 5-7 membered heteroaryl group, each of which is surrounded by 1, 2, 3 or 4 R 12 group substituted, and at least one R 12 The group is -C(O)ORA , among which, -C(O)OR A In R 2 Relative to R 2 The α position of the connection point of the nitrogen atom is connected to R 2 connect.

[0145] In certain embodiments of Formula (I) as otherwise described herein, R 2 Is it 1, 2 or 3 R 12 phenyl or 5-7 membered heteroaryl substituted by a group, and at least one R 12 The group is -C(O)OR A , among which, -C(O)OR A In R 2 Relative to R 2 The α position of the connection point of the nitrogen atom is connected to R 2 connect.

[0146] In certain embodiments of Formula (I) as otherwise described herein, R 3 is C1-C3 alkyl, wherein the alkyl group is unsubstituted, substituted with 1 to 5 halogen groups or perfluorinated.

[0147] In certain embodiments of Formula (I) as otherwise described herein, R 2 is optionally replaced by 1, 2, 3 or 4 R 12 substituted phenyl groups.

[0148] In certain embodiments of Formula (I) as otherwise described herein, R 2 is optionally replaced by 1, 2, 3 or 4 R 12 A pyridyl group substituted with a group.

[0149] In certain embodiments of Formula (I) as otherwise described herein, R 2 is optionally replaced by 1, 2, 3 or 4 R 12 A thienyl group substituted with a group.

[0150] In certain embodiments of Formula (I) as otherwise described herein, R 2 is optionally replaced by 1, 2, 3 or 4 R 12 Thiazolyl substituted with a group.

[0151] In certain embodiments of Formula (I) as otherwise described herein, R 2 is optionally replaced by 1, 2, 3 or 4 R 12 Oxazolyl substituted with a group.

[0152] In certain embodiments of Formula (I) as otherwise described herein, R 2 is optionally replaced by 1, 2, 3 or 4 R12 isoxazolyl substituted with a group.

[0153] In certain embodiments of Formula (I) as otherwise described herein, R 2 is optionally replaced by 1, 2, 3 or 4 R 12 imidazolyl substituted with a group.

[0154] In certain embodiments of Formula (I) as otherwise described herein, R 2 is optionally replaced by 1, 2, 3 or 4 R 12 A pyrazolyl group substituted with a group.

[0155] In certain embodiments of Formula (I) as otherwise described herein, R 2 is optionally replaced by 1, 2, 3 or 4 R 12 A pyrazinyl group substituted with a group.

[0156] In certain embodiments of Formula (I) as otherwise described herein, R 2 is optionally replaced by 1, 2, 3 or 4 R 12 A pyridazinyl group substituted with a group.

[0157] In certain embodiments of Formula (I) as otherwise described herein, R 2 is optionally replaced by 1, 2, 3 or 4 R 12 A pyrimidinyl group substituted with a group.

[0158] In certain embodiments of Formula (I) as otherwise described herein, R 2 Optionally replaced by a -C(O)OR A replace.

[0159] In certain embodiments of Formula (I) as otherwise described herein, R 4 is hydrogen, fluorine, chlorine, bromine, methyl, methoxy, ethyl, ethoxy, cyclopropyl, trifluoromethyl or cyano.

[0160] In certain embodiments of Formula (I) as otherwise described herein, R 4 is hydrogen, methyl, ethyl or cyano.

[0161] In certain embodiments of Formula (I) as otherwise described herein, R 4 It's a methoxy group.

[0162] In certain embodiments of Formula (I) as otherwise described herein, R 4 It is fluorine, chlorine or bromine.

[0163] In certain embodiments of Formula (I) as otherwise described herein, R 4 It's hydrogen.

[0164] In certain embodiments of Formula (I) as otherwise described herein, R 4 It's fluorine.

[0165] In certain embodiments of Formula (I) as otherwise described herein, R 4 It's chlorine.

[0166] In certain embodiments of Formula (I) as otherwise described herein, R 4 It's bromine.

[0167] In certain embodiments of Formula (I) as otherwise described herein, R 4 It's methyl.

[0168] In certain embodiments of Formula (I) as otherwise described herein, R 4 It's ethyl.

[0169] In certain embodiments of Formula (I) as otherwise described herein, R 4 It's cyano.

[0170] In certain embodiments of Formula (I) as otherwise described herein, R 4 It is cyclopropyl.

[0171] In certain embodiments of Formula (I) as otherwise described herein, R 4 It is trifluoromethyl.

[0172] In certain embodiments of Formula (I) as otherwise described herein, if more than one R 5 When an R 5 is hydrogen, and the other R 5 is hydrogen, halogen, C3-C6 cycloalkyl, phenyl or 5-6 membered heteroaryl, wherein each cycloalkyl, 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 groups.

[0173] In certain embodiments of Formula (I) as otherwise described herein, if more than one R 5 When an R 5 is hydrogen, and the other R 5 is hydrogen, halogen, C3-C6 cycloalkyl, phenyl or 5-6 membered heteroaryl, wherein each cycloalkyl, phenyl and heteroaryl is optionally substituted with 1 or 2 halogen, hydroxy, C1-C2 alkyl, C1-C2 alkoxy, cyano, amino or mono- or di-(C1-C2)alkylamino groups.

[0174] In certain embodiments of Formula (I) as otherwise described herein, when one R 5 When R 5is hydrogen, halogen, C3-C6 cycloalkyl, phenyl or 5-6 membered heteroaryl, wherein each cycloalkyl, 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 groups.

[0175] In certain embodiments of Formula (I) as otherwise described herein, when one R 5 When R 5 is hydrogen, and the other R 5 is halogen, C3-C6 cycloalkyl, phenyl or 5-6 membered heteroaryl, wherein each cycloalkyl, phenyl and heteroaryl is optionally substituted with 1 or 2 halogen, hydroxy, C1-C2 alkyl, C1-C2 alkoxy, cyano, amino or mono- or di-(C1-C2)alkylamino groups.

[0176] In certain embodiments of Formula (I) as otherwise described herein, when one R 5 When R 5 is hydrogen, halogen, hydroxy, cyano or amino.

[0177] In certain embodiments of Formula (I) as otherwise described herein, if more than one R 5 When an R 5 is hydrogen, and the other R 5 is hydrogen, halogen, hydroxy, cyano or amino.

[0178] In certain embodiments of Formula (I) as otherwise described herein, R 2 is optionally substituted phenyl.

[0179] In certain embodiments of Formula (I) as otherwise described herein, R 2 is optionally substituted pyridinyl.

[0180] In certain embodiments of Formula (I) as otherwise described herein, R 7 is hydrogen, and R 8 represents hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl or C3-C6 cycloalkyl(C1-C3 alkyl).

[0181] In certain embodiments of Formula (I) as otherwise described herein, R 7 and R 8 Together with the nitrogen to which they are attached, they form Ring Q, wherein Ring Q is

[0182] a 3-7 membered monocyclic heterocyclyl containing one or two ring nitrogen atoms (and, in certain embodiments, only nitrogen heteroatoms), and

[0183] The heterocyclic group is optionally substituted by 1-4 R 9group substituted, where each R 9 is 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), wherein each phenyl group is optionally substituted with C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxy, cyano, amino or mono- or di-(C1-C3 alkyl)amino.

[0184] In certain embodiments of Formula (I) as otherwise described herein, the group express

[0185] in,

[0186] a is 0, 1, 2, or 3;

[0187] V is CR 14 or N;

[0188] 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;

[0189] R 13 is (i) cyano, (ii) tetrazolyl, (iii) -C(O)OR A , where R A is H, C1-C6 alkyl or C3-C6 cycloalkyl, or (iv) -C(O)N(R B )2, where R B is H, -OH, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl; and

[0190] 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.

[0191] In certain other embodiments of Formula (I) as otherwise described herein, the group express

[0192] in,

[0193] V is CR14 or N;

[0194] 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;

[0195] R 13 is (i) cyano, (ii) tetrazolyl, (iii) -C(O)OR A , where R A is H, C1-C6 alkyl or C3-C6 cycloalkyl, or (iv) -C(O)N(R B )2, where R B is H, -OH, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl; and

[0196] 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.

[0197] In certain embodiments of Formula (I) as otherwise described herein, R 7 and R 8 Together with the nitrogen to which they are attached, they form Ring Q, wherein Ring Q represents a nitrogen-containing ring selected from:

[0198]

[0199] where each v represents 0, 1, 2, 3, or 4.

[0200] In certain embodiments of Formula (I) as otherwise described herein, the nitrogen-containing ring Q contains only nitrogen atoms.

[0201] In certain embodiments of formula (I) as otherwise described herein, the nitrogen-containing ring Q contains one nitrogen atom and one other heteroatom selected from oxygen and sulfur. Examples of such groups include

[0202]

[0203] Each R 39 As defined for formula (I), and each v represents 0, 1, 2, 3 or 4.

[0204] 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.

[0205] In certain embodiments, the nitrogen-containing ring is substituted with phenyl or phenyl(C1-C3 alkanoyl), wherein each phenyl is optionally substituted with C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxy, cyano, amino, or mono- or di(C1-C3 alkyl)amino.

[0206] In certain embodiments of Formula (I) as otherwise described herein, R 7 and R 8 Together with the nitrogen to which they are attached, they form Ring Q, wherein Ring Q is

[0207] a 3-7 membered monocyclic heterocyclyl containing one or two ring nitrogen atoms, said monocyclic heterocyclyl optionally containing one or two additional heteroatoms selected from oxygen and sulfur, and

[0208] A heterocyclyl group is fused to an aromatic or non-aromatic ring containing 3 to 6 ring members, 1 or 2 of which are optionally nitrogen atoms, and the remainder are carbon, wherein

[0209] The fused heterocyclic group is optionally substituted by 1 to 4 R 9 group substituted, where each R 9 is 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), wherein each phenyl group is optionally substituted with C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxy, cyano, amino or mono- or di-(C1-C3 alkyl)amino.

[0210] In certain embodiments of Formula (I) as otherwise described herein, R 7 and R 8 Together with the nitrogen to which they are attached, they form Ring Q, wherein Ring Q represents a fused bicyclic ring selected from:

[0211]

[0212] where each v represents 0, 1, 2, 3, or 4, and R 9 The group may be on either ring.

[0213] 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.

[0214] In certain embodiments, the fused bicyclic group is independently substituted with 1, 2, 3, or 4 halogens. In certain embodiments, the halogens are independently fluorine or chlorine atoms. In other embodiments, the halogens are fluorine atoms.

[0215] In other embodiments, the fused bicyclic group is substituted with phenyl or phenyl(C1-C3 alkanoyl), wherein each phenyl group is optionally substituted with C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxy, cyano, amino, or mono- or di(C1-C3 alkyl)amino.

[0216] In certain embodiments of Formula (I) as otherwise described herein, R 7 and R 8 Together with the nitrogen to which they are attached, they form a 3-7 membered monocyclic heterocyclyl containing one or two ring nitrogen atoms, and in certain embodiments, the monocyclic heterocyclyl contains only nitrogen heteroatoms, and

[0217] The heterocyclyl group forms with the carbon atom from the monocyclic heterocyclyl group and an additional carbon or nitrogen atom a spirocyclic ring system containing up to 10 total ring members, wherein

[0218] The spirocyclic ring system is optionally substituted with 1-4 R 9 group substituted, where each R 9 is 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), wherein each phenyl group is optionally substituted with C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxy, cyano, amino or mono- or di-(C1-C3 alkyl)amino.

[0219] In certain embodiments of Formula (I) as otherwise described herein, R 7 and R 8 Together with the nitrogen to which they are attached, they represent a spirocyclic ring system containing one or two nitrogen atoms and up to 10 total ring members. The spirocyclic ring system is optionally substituted with up to 4 R 9 Examples of such optionally substituted spirocyclic ring systems are

[0220]

[0221] where each v represents 0, 1, 2, 3, or 4, and R 9 The group may be on either ring.

[0222] In certain embodiments, the spirocyclic ring system is independently substituted with 1, 2, 3, or 4 C1-C4 alkyl, C3-C6 cycloalkyl, C1-C3 haloalkyl, or halogen.

[0223] In certain embodiments, the spirocyclic ring system is independently substituted with 1, 2, 3, or 4 halogens. In certain embodiments, the halogens are independently fluorine or chlorine atoms. In certain embodiments, the halogens are fluorine atoms.

[0224] In certain embodiments, the spirocyclic ring system is substituted with phenyl or phenyl(C1-C3 alkanoyl), wherein each phenyl is optionally substituted with C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxy, cyano, amino, or mono- or di(C1-C3 alkyl)amino.

[0225] In certain embodiments of Formula (I) as otherwise described herein, T is N.

[0226] In certain embodiments of Formula (I) as otherwise described herein, T is CR 6 , and R 6 is H or C1-C2 alkyl, especially methyl.

[0227] In certain embodiments of Formula (I) as otherwise described herein, T is CR 6 , and R 6 It’s H.

[0228] In certain embodiments of Formula (I) as otherwise described herein, the compound is of Formula (II-e), (II-g), (II-j), (II-k), (II-1), or (II-m):

[0229]

[0230] or a pharmaceutically acceptable salt thereof.

[0231] In certain embodiments of Formula (II-e), (II-g), (II-j), (II-k), (II-1), and (II-m) as otherwise described herein,

[0232] R 1 is H, C1-C3 alkyl or C3-C6 cycloalkyl;

[0233] R 2 is phenyl or pyridinyl, wherein each phenyl and pyridinyl is optionally substituted by 1-5 R 12 replace;

[0234] 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;

[0235] Each R A are independently H, C1-C6 alkyl or C3-C6 cycloalkyl;

[0236] Each R B are independently H, -OH, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl; and

[0237] R 3 is C1-C3 alkyl or C3-C6 cycloalkyl; and

[0238] R 4 is H, C1-C3 alkyl, C3-C6 cycloalkyl, cyano or halogen, wherein each C1-C3 alkyl group is optionally substituted with 1 to 5 halogen groups.

[0239] In certain embodiments of Formulas (II-e), (II-g), (II-j), (II-k), (II-1), and (II-m) as otherwise described herein, T is N.

[0240] In certain embodiments of Formulas (II-e), (II-g), (II-j), (II-k), (II-1), and (II-m) as otherwise described herein, T is CR 6 , and R 6 is H or C1-C2 alkyl, especially methyl.

[0241] In certain embodiments of Formulas (II-e), (II-g), (II-j), (II-k), (II-1), and (II-m) as otherwise described herein, T is CR 6 , and R 6 It’s H.

[0242] In certain embodiments of Formulas (II-e), (II-g), (II-j), (II-k), (II-1), and (II-m) as otherwise described herein, R 3 It is a C1-C3 alkyl group.

[0243] In certain embodiments of Formulas (II-e), (II-g), (II-j), (II-k), (II-1), and (II-m) as otherwise described herein, R 3 It's methyl.

[0244] In certain embodiments of Formulas (II-e), (II-g), (II-j), (II-k), (II-1), and (II-m) as otherwise described herein, R 4 It is H, C1-C3 alkyl, C3-C4 cycloalkyl or cyano.

[0245] In certain embodiments of Formulas (II-e), (II-g), (II-j), (II-k), (II-1), and (II-m) as otherwise described herein, R 2 Optionally replaced by a -C(O)OR A replace.

[0246] In certain embodiments of Formulas (II-e), (II-g), (II-j), (II-k), (II-1), and (II-m) as otherwise described herein, the group express

[0247] in,

[0248] a is 0, 1, 2, or 3;

[0249] V is CR 14 or N;

[0250] 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;

[0251] R 13 is (i) cyano, (ii) tetrazolyl, (iii) -C(O)OR A , where R A is H, C1-C6 alkyl or C3-C6 cycloalkyl, or (iv) -C(O)N(R B )2, where R B is H, -OH, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl; and

[0252] 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.

[0253] In certain embodiments of Formulas (II-e), (II-g), (II-j), (II-k), (II-1), and (II-m) as otherwise described herein, the group express

[0254] in,

[0255] V is CR 14or N;

[0256] 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;

[0257] R 13 is (i) cyano, (ii) tetrazolyl, (iii) -C(O)OR A , where R A is H, C1-C6 alkyl or C3-C6 cycloalkyl, or (iv) -C(O)N(R B )2, where R B is H, -OH, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl; and

[0258] 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.

[0259] In certain embodiments of Formulas (II-e), (II-g), (II-j), (II-k), (II-1), and (II-m) as otherwise described herein, R 7 is hydrogen, and R 8 represents hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl or C3-C6 cycloalkyl (C1-. In certain embodiments of formulas (II-e), (II-g), (II-j), (II-k), (II-l) and (II-m) as otherwise described herein, R 7 and R 8 Together with the nitrogen to which they are attached, they form ring Q, and ring Q is a C1-C6 heterocyclic group.

[0260] In certain embodiments of Formulas (II-e), (II-g), (II-j), (II-k), (II-1), and (II-m) as otherwise described herein, R 7 and R 8 Together with the nitrogen to which they are attached, they form Ring Q, and Ring Q is aziridine, azetidinyl, pyrrolidinyl, piperidinyl or azepanyl, each of which is optionally substituted by 1-2 R 9 group substituted, where 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, 5-7 membered heterocyclyl or 5-6 membered heteroaryl, wherein each phenyl, 5-7 membered heterocyclyl and 5-6 membered heteroaryl is optionally substituted with C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxy, cyano, amino or mono- or di-(C1-C3 alkyl)amino.

[0261] In certain embodiments of Formulas (II-e), (II-g), (II-j), (II-k), (II-1), and (II-m) as otherwise described herein, R 7 and R 8 Together with the nitrogen to which they are attached they form Ring Q, and Ring Q is aziridine, azetidinyl, pyrrolidinyl, piperidinyl or azepanyl, each of which is optionally substituted with 1, 2, 3 or 4 halogens.

[0262] In certain embodiments of Formulas (II-e), (II-g), (II-j), (II-k), (II-1), and (II-m) as otherwise described herein, R 7 and R 8 Together with the nitrogen to which they are attached, they form Ring Q, and Ring Q is a 5-6 membered monocyclic heterocyclyl containing one or two ring nitrogens, and in certain embodiments, the monocyclic heterocyclyl contains only nitrogen heteroatoms, and the heterocyclyl group is fused to an aromatic or non-aromatic ring containing 3-6 ring members, 1 or 2 of which are optionally nitrogen atoms, and the remainder are carbon, and the fused ring system is optionally substituted on any ring by 1-4 R 9 group substituted, where 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.

[0263] In certain embodiments of Formulas (II-e), (II-g), (II-j), (II-k), (II-1), and (II-m) as otherwise described herein, R 7 and R 8 Together with the nitrogen to which they are attached, they form Ring Q, wherein Ring Q is a group having the formula:

[0264]

[0265] in,

[0266] Each ring A is a 3-6 membered carbocyclic ring or a 3-6 membered heterocyclic ring,

[0267] m is 0, 1, 2, 3, or 4;

[0268] n is 0, 1, or 2;

[0269] p and r are independently 1 or 2, provided that the sum of p and r is 2 or 3;

[0270] Each R 10 and R 11 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 5-6 membered heteroaryl, wherein each cycloalkyl, 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 groups.

[0271] In certain embodiments of Formula (I) as otherwise described herein, the compound is of Formula (III):

[0272]

[0273] or a pharmaceutically acceptable salt or deuterated form thereof, wherein:

[0274] R 1 is H, C1-C3 alkyl or C3-C6 cycloalkyl;

[0275] R 3 is a C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 alkenyl, C2-C3 alkynyl or C5-C6 cycloalkenyl group which is optionally substituted, multi-substituted or fully substituted by fluorine;

[0276] 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 halogen, wherein each C1-C3 alkyl and C3-C6 cycloalkyl is optionally substituted with 1-5 halogen groups;

[0277] a is 0, 1, 2, or 3;

[0278] V is CR 14 or N;

[0279] 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;

[0280] R 13 is (i) cyano, (ii) tetrazolyl, (iii) -C(O)OR A , where R A is H, C1-C6 alkyl or C3-C6 cycloalkyl, or (iv) -C(O)N(R B )2, where R B is H, -OH, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl;

[0281] 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;

[0282] Q represents a 4-8 membered saturated or unsaturated monocyclic, bicyclic or polycyclic heterocyclic group having 0, 1 or 2 additional ring heteroatoms selected from oxygen and nitrogen;

[0283] b is 0, 1, 2, 3, or 4;

[0284] Each R 9 is 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), 5-7 membered heterocyclyl, or 5-6 membered heteroaryl, wherein each phenyl, 5-7 membered heterocyclyl, and 5-6 membered heteroaryl is optionally substituted with C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxy, cyano, amino, or mono- or di-(C1-C3 alkyl)amino; and

[0285] R 51 and R 52 independently represents hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogen, halo-substituted C1-C6 alkyl, cyano, hydroxy, hydroxyC1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino, C3-C6 cycloalkyl, halo-substituted C3-C6 cycloalkyl, phenyl or 5-6 membered heteroaryl, wherein each 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 groups, and each 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 groups.

[0286] In certain embodiments of Formula (III), R 1 is H or CH3 (Implementation Option 3-1).

[0287] In certain embodiments of Formula (III) or Embodiment 3-1, R 3 is C1-C3 alkyl, wherein the alkyl group is unsubstituted, substituted with 1-5 halogen groups or perfluorinated (Embodiment 3-2).

[0288] In certain embodiments of Formula (III) or Embodiment 3-1, R 3 It is methyl (Embodiment 3-3).

[0289] In certain embodiments of Formula (III) or Embodiments 3-1 to 3-3, R 4 is hydrogen (Implementation Options 3-4).

[0290] In certain embodiments of Formula (III) or Embodiments 3-1 to 3-3, R 4 is methyl (Embodiment 3-5).

[0291] In certain embodiments of Formula (III) or Embodiments 3-1 to 3-3, R 4 is ethyl (Embodiment 3-5A).

[0292] In certain embodiments of Formula (III) or Embodiments 3-1 to 3-3, R 4 is cyclopropyl (Embodiment 3-5B).

[0293] In certain embodiments of Formula (III) or Embodiments 3-1 to 3-3, R 4 is methoxy (Embodiment 3-5C).

[0294] In certain embodiments of Formula (III) or Embodiments 3-1 to 3-3, R 4 is fluorine (Embodiment 3-6).

[0295] In certain embodiments of Formula (III) or Embodiments 3-1 to 3-3, R 4 is chlorine (Embodiment 3-7).

[0296] In certain embodiments of Formula (III) or Embodiments 3-1 to 3-3, R 4 is bromine (Embodiment 3-8).

[0297] In certain embodiments of Formula (III) or Embodiments 3-1 to 3-8, V is CR 12 (Implementation Plan 3-9).

[0298] In certain embodiments of formula (III) or Embodiments 3-1 through 3-8, V is N (Embodiment 3-10).

[0299] In certain embodiments of Formula (III) or Embodiments 3-1 to 3-9, V is CH, a is 1, and R 12 is hydrogen, C1-C3 alkyl or halogen (Embodiment 3-11).

[0300] In certain embodiments of Formula (III) or Embodiments 3-1 to 3-9, V is CH, a is 1, and R 12 is hydrogen, methyl, chlorine, bromine or fluorine (Embodiments 3-12).

[0301] In certain embodiments of Formula (III) or Embodiments 3-1 to 3-9, V is CH, a is 1, and R 12 It is hydrogen (Implementation Option 3-13).

[0302] In certain embodiments of Formula (III) or Embodiments 3-1 to 3-9, V is CH, a is 1, and R 12 is chlorine (Embodiment 3-14).

[0303] In certain embodiments of Formula (III) or Embodiments 3-1 to 3-9, V is CH, a is 1, and R 12 is bromine (Embodiment 3-15).

[0304] In certain embodiments of Formula (III) or Embodiments 3-1 to 3-9, V is CH, a is 1, and R 12 is methyl (Embodiment 3-15.1).

[0305] In certain embodiments of Formula (III) or Embodiments 3-1 to 3-9, V is CH, a is 1, and R 12 is fluorine (Implementation Option 3-16).

[0306] In certain embodiments of Formula (III) or Embodiments 3-1 to 3-8 or 3-10, V is N, a is 1, and R 12 is hydrogen, C1-C3 alkyl or halogen (Embodiment 3-17).

[0307] In certain embodiments of Formula (III) or Embodiments 3-1 to 3-8 or 3-10, V is N, a is 1, and R 12 is hydrogen, methyl, chlorine, bromine or fluorine (Embodiments 3-18).

[0308] In certain embodiments of Formula (III) or Embodiments 3-1 to 3-8 or 3-10, V is N, a is 1, and R 12 It is hydrogen (Implementation Option 3-19).

[0309] In certain embodiments of Formula (III) or Embodiments 3-1 to 3-8 or 3-10, V is N, a is 1, and R 12 is chlorine (Embodiment 3-20).

[0310] In certain embodiments of Formula (III) or Embodiments 3-1 to 3-8 or 3-10, V is N, a is 1, and R 12 is bromine (Embodiment 3-21).

[0311] In certain embodiments of Formula (III) or Embodiments 3-1 to 3-8 or 3-10, V is N, a is 1, and R 12 is methyl (Embodiment 3-21.1).

[0312] In certain embodiments of Formula (III) or Embodiments 3-1 to 3-8 or 3-10, V is N, a is 1, and R 12 is fluorine (Embodiment 3-22).

[0313] In certain embodiments of Formula (III) or Embodiments 3-1 to 3-22, R 51 and R 52 independently represents hydrogen, C1-C3 alkyl, cyano, halogen, cyclopropyl or halo(C1-C6)alkyl (embodiments 3-23).

[0314] In certain embodiments of Formula (III) or Embodiments 3-1 to 3-22, R 51 and R 52 One is hydrogen and the other is methyl, ethyl, cyano, halogen, cyclopropyl or halo(C1-C6)alkyl (Embodiments 3-24).

[0315] In certain embodiments of Formula (III) or Embodiments 3-1 to 3-22, R 51 is hydrogen, and R 52 is methyl, ethyl, cyano, halogen, cyclopropyl or halo(C1-C6)alkyl (embodiments 3-25).

[0316] In certain embodiments of Formula (III) or Embodiments 3-1 to 3-22, R 51 is hydrogen, and R 52 is methyl, ethyl, cyano, halogen, cyclopropyl, difluoromethyl or trifluoromethyl (Embodiment 3-26).

[0317] In certain embodiments of Formula (III) or Embodiments 3-1 to 3-22, R 52 is hydrogen, and R 51 is methyl, ethyl, cyano, halogen, cyclopropyl or halo(C1-C6)alkyl (Embodiment 3-27).

[0318] In certain embodiments of Formula (III) or Embodiments 3-1 to 3-22, R 52 is hydrogen, and R 51 is methyl, ethyl, cyano, halogen, cyclopropyl, difluoromethyl or trifluoromethyl (Embodiment 3-28).

[0319] In certain embodiments of formula (III) or embodiments 3-1 to 3-28, Q represents a group having the formula

[0320]

[0321] in,

[0322] Each b is 0, 1, or 2;

[0323] D means C(R 29 )2,

[0324] W represents O, NR 19 or C(R 29 )2, and

[0325] 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

[0326] Each R 29 Independently, it is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, halo-C1-C3 alkyl, hydroxy C1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino (embodiments 3-29).

[0327] In certain embodiments of embodiments 3-29, W is oxygen, b is 0 or 1, and R 9 is methyl or cyano (Embodiment 3-30).

[0328] In certain embodiments of Embodiment 3-29, W is oxygen, and b is O (Embodiment 3-31).

[0329] In certain embodiments of embodiments 3-29, D and W are C(R 29 )2, b is 0, and each R 29Independently, it is 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).

[0330] 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).

[0331] 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).

[0332] In certain embodiments of embodiments 3-29, D and W are C(R 29 )2, b is 0, and each R 29 is fluorine (Embodiment 3-35).

[0333] In certain embodiments of embodiments 3-29, D and W are C(R 29 )2, b is 0, and each R 29 is hydrogen (Implementation Options 3-36).

[0334] In certain embodiments of formula (III) or embodiments 3-1 to 3-28, Q represents a group having the formula

[0335]

[0336] in,

[0337] Each b is 0, 1, or 2; and

[0338] W represents O, NR 19 or C(R 29 )2, where

[0339] 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

[0340] Each R 29Independently, it is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, halo-C1-C3 alkyl, hydroxyC1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino (embodiments 3-37).

[0341] In certain embodiments of embodiments 3-37, W is oxygen, b is 0 or 1, and R 9 is methyl or cyano (Embodiment 3-38).

[0342] In certain embodiments of Embodiments 3-37, W is oxygen, and b is O (Embodiment 3-39).

[0343] In certain embodiments of embodiments 3-37, W is C(R 29 )2, b is 0, and each R 29 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).

[0344] 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).

[0345] 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).

[0346] In certain embodiments of embodiments 3-37, W is C(R 29 )2, b is 0, and each R 29 is fluorine (Embodiment 3-43).

[0347] 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).

[0348] In certain embodiments of formula (III) or embodiments 3-1 to 3-28, Q represents a group having the formula

[0349]

[0350] in,

[0351] Each b is 0, 1, or 2; and

[0352] W represents O, NR 19 or C(R 29 )2, where

[0353] 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

[0354] Each R 29 Independently, it is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, halo-C1-C3 alkyl, hydroxy C1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino (embodiments 3-45).

[0355] In certain embodiments of embodiments 3-45, W is oxygen, b is 0 or 1, and R 9 is methyl, chloro, fluoro or cyano (Embodiment 3-46).

[0356] In certain embodiments of Embodiments 3-45, W is oxygen, and b is O (Embodiment 3-47).

[0357] In certain embodiments of embodiments 3-45, W is C(R 29 )2, b is 0, and each R 29 Independently, it is 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).

[0358] 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).

[0359] 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).

[0360] In certain embodiments of embodiments 3-45, W is C(R 29 )2, b is 0, and each R 29is fluorine (Embodiment 3-51).

[0361] In certain embodiments of embodiments 3-45, W is C(R 29 )2, b is 0, and each R 29 It is hydrogen (Implementation Option 3-52).

[0362] In certain embodiments of Formula (I) as otherwise described herein, the compound is of Formula (IV):

[0363]

[0364] or a pharmaceutically acceptable salt or deuterated form thereof, wherein:

[0365] R 1 is H, C1-C3 alkyl or C3-C6 cycloalkyl;

[0366] R 3 is a C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 alkenyl, C2-C3 alkynyl or C5-C6 cycloalkenyl group which is optionally substituted, multi-substituted or fully substituted by fluorine;

[0367] 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 halogen, wherein each C1-C3 alkyl and C3-C6 cycloalkyl is optionally substituted with 1-5 halogen groups;

[0368] a is 0, 1, 2, or 3;

[0369] V is CR 14 or N;

[0370] 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;

[0371] R 13 is (i) cyano, (ii) tetrazolyl, (iii) -C(O)OR A , where R A is H, C1-C6 alkyl or C3-C6 cycloalkyl, or (iv) -C(O)N(R B )2, where R B is H, -OH, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl;

[0372] 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;

[0373] Q represents a 4-8 membered saturated or unsaturated monocyclic, bicyclic or polycyclic heterocyclic group having 0, 1 or 2 additional ring heteroatoms selected from oxygen and nitrogen;

[0374] b is 0, 1, 2, 3, or 4;

[0375] Each R 9 is 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), 5-7 membered heterocyclyl, or 5-6 membered heteroaryl, wherein each phenyl, 5-7 membered heterocyclyl, and 5-6 membered heteroaryl is optionally substituted with C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxy, cyano, amino, or mono- or di-(C1-C3 alkyl)amino; and

[0376] 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 5-6 membered heteroaryl, wherein each alkyl, cycloalkyl, phenyl and heteroaryl is optionally substituted by 1-3 halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, cyano, amino or mono- or di(C1-C3)alkylamino groups.

[0377] In certain embodiments of Formula (IV), R 1 is H or CH3 (Implementation Option 4-1).

[0378] In certain embodiments of Formula (IV) or Embodiment 4-1, R 3 is C1-C3 alkyl, wherein the alkyl group is unsubstituted, substituted with 1-5 halogen groups or perfluorinated (embodiment 4-2).

[0379] In certain embodiments of Formula (IV) or Embodiment 4-1, R 3 is methyl (Embodiment 4-3).

[0380] In certain embodiments of Formula (IV) or Embodiments 4-1 to 4-3, R 4It is hydrogen (Implementation Option 4-4).

[0381] In certain embodiments of Formula (IV) or Embodiments 4-1 to 4-3, R 4 is methyl (Embodiment 4-5).

[0382] In certain embodiments of Formula (IV) or Embodiments 4-1 to 4-3, R 4 is ethyl (Embodiment 4-6).

[0383] In certain embodiments of Formula (IV) or Embodiments 4-1 to 4-3, R 4 is cyclopropyl (Embodiment 4-7).

[0384] In certain embodiments of Formula (IV) or Embodiments 4-1 to 4-3, R 4 is methoxy (Embodiment 4-8).

[0385] In certain embodiments of Formula (IV) or Embodiments 4-1 to 4-3, R 4 is fluorine (Embodiment 4-9).

[0386] In certain embodiments of Formula (IV) or Embodiments 4-1 to 4-3, R 4 is chlorine (Embodiment 4-10).

[0387] In certain embodiments of Formula (IV) or Embodiments 4-1 to 4-3, R 4 is bromine (Embodiment 4-11).

[0388] In certain embodiments of Formula (IV) or Embodiments 4-1 to 4-8, V is CR 12 (Implementation Plan 4-12).

[0389] In certain embodiments of formula (IV) or embodiments 4-1 through 4-8, V is N (embodiment 4-13).

[0390] In certain embodiments of Formula (IV) or Embodiments 4-1 to 4-12, V is CH, a is 1, and R 12 is hydrogen, C1-C3 alkyl or halogen (Embodiment 4-14).

[0391] In certain embodiments of Formula (IV) or Embodiments 4-1 to 4-12, V is CH, a is 1, and R 12 is hydrogen, methyl, chlorine, bromine or fluorine (Embodiments 4-15).

[0392] In certain embodiments of Formula (IV) or Embodiments 4-1 to 4-12, V is CH, a is 1, and R12 is hydrogen (Implementation Option 4-16).

[0393] In certain embodiments of Formula (IV) or Embodiments 4-1 to 4-12, V is CH, a is 1, and R 12 is chlorine (Embodiment 4-17).

[0394] In certain embodiments of Formula (IV) or Embodiments 4-1 to 4-12, V is CH, a is 1, and R 12 is bromine (Embodiment 4-18).

[0395] In certain embodiments of Formula (IV) or Embodiments 4-1 to 4-12, V is CH, a is 1, and R 12 is methyl (Embodiment 4-18.1).

[0396] In certain embodiments of Formula (IV) or Embodiments 4-1 to 4-12, V is CH, a is 1, and R 12 is fluorine (Embodiment 4-19).

[0397] In certain embodiments of Formula (IV) or Embodiments 4-1 to 4-11 or 4-13, V is N, a is 1, and R 12 is hydrogen, C1-C3 alkyl or halogen (Embodiment 4-20).

[0398] In certain embodiments of Formula (IV) or Embodiments 4-1 to 4-11 or 4-13, V is N, a is 1, and R 12 is hydrogen, methyl, chlorine, bromine or fluorine (Embodiment 4-21).

[0399] In certain embodiments of Formula (IV) or Embodiments 4-1 to 4-11 or 4-13, V is N, a is 1, and R 12 is hydrogen (Implementation Option 4-22).

[0400] In certain embodiments of Formula (IV) or Embodiments 4-1 to 4-11 or 4-13, V is N, a is 1, and R 12 is chlorine (Embodiment 4-23).

[0401] In certain embodiments of Formula (IV) or Embodiments 4-1 to 4-11 or 4-13, V is N, a is 1, and R 12 is bromine (Embodiment 4-24).

[0402] In certain embodiments of Formula (IV) or Embodiments 4-1 to 4-11 or 4-13, V is N, a is 1, and R 12 is methyl (Embodiment 4-24.1).

[0403] In certain embodiments of Formula (IV) or Embodiments 4-1 to 4-11 or 4-13, V is N, a is 1, and R 12 is fluorine (Embodiment 4-25).

[0404] In certain embodiments of Formula (IV) or Embodiments 4-1 to 4-25, R 52 represents hydrogen, C1-C3 alkyl, cyano, halogen, cyclopropyl or halo(C1-C6)alkyl (embodiment 4-26).

[0405] In certain embodiments of Formula (IV) or Embodiments 4-1 to 4-25, R 52 is hydrogen, methyl, ethyl, cyano, halogen, cyclopropyl or halo(C1-C6)alkyl (embodiment 4-27).

[0406] In certain embodiments of Formula (IV) or Embodiments 4-1 to 4-25, R 52 is methyl, ethyl, cyano, halogen, cyclopropyl or halo(C1-C6)alkyl (embodiment 4-28).

[0407] In certain embodiments of Formula (IV) or Embodiments 4-1 to 4-25, R 52 is methyl, ethyl, cyano, halogen, cyclopropyl, difluoromethyl or trifluoromethyl (Embodiment 4-29).

[0408] In certain embodiments of Formula (IV) or Embodiments 4-1 to 4-25, R 52 is hydrogen (Implementation Option 4-30).

[0409] In certain embodiments of Formula (IV) or Embodiments 4-1 to 4-25, R 52 is difluoromethyl or trifluoromethyl (Embodiment 4-31).

[0410] In certain embodiments of formula (IV) or embodiments 4-1 to 4-31, Q represents a group having the formula

[0411]

[0412] in,

[0413] Each b is 0, 1, or 2; and

[0414] D means C(R 29 )2,

[0415] W represents O, NR 19 or C(R 29 )2, and

[0416] 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

[0417] Each R 29 Independently, it is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, halo-C1-C3 alkyl, hydroxyC1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino (embodiments 4-32).

[0418] 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).

[0419] In certain embodiments of Embodiment 4-32, W is oxygen, and b is O (Embodiment 4-34).

[0420] In certain embodiments of embodiments 4-32, D and W are C(R 29 )2, b is 0, and each R 29 Independently, it is 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).

[0421] 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).

[0422] 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-).

[0423] In certain embodiments of embodiments 4-32, D and W are C(R 29 )2, b is 0, and each R 29 is fluorine (Embodiment 4-37).

[0424] In certain embodiments of embodiments 4-32, D and W are C(R 29 )2, b is 0, and each R 29is hydrogen (Implementation Option 4-38).

[0425] In certain embodiments of formula (IV) or embodiments 4-1 to 4-31, Q represents a group having the formula

[0426]

[0427] in,

[0428] Each b is 0, 1, or 2; and

[0429] W represents O, NR 19 or C(R 29 )2, where

[0430] 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

[0431] Each R 29 Independently, it is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, halo-C1-C3 alkyl, hydroxyC1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino (embodiments 4-39).

[0432] In certain embodiments of embodiments 4-39, W is oxygen, b is 0 or 1, and R 9 is methyl or cyano (Embodiment 4-40).

[0433] In certain embodiments of Embodiment 4-39, W is oxygen, and b is O (Embodiment 4-41).

[0434] In certain embodiments of embodiments 4-39, W is C(R 29 )2, b is 0, and each R 29 Independently, it is 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).

[0435] 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).

[0436] 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).

[0437] In certain embodiments of embodiments 4-39, W is C(R 29 )2, b is 0, and each R 29 is fluorine (Embodiment 4-45).

[0438] 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).

[0439] In certain embodiments of formula (IV) or embodiments 4-1 to 4-31, Q represents a group having the formula

[0440]

[0441] in,

[0442] Each b is 0, 1, or 2; and

[0443] W represents O, NR 19 or C(R 29 )2, where

[0444] 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

[0445] Each R 29 Independently, it is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, halo-C1-C3 alkyl, hydroxyC1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino (embodiments 4-47).

[0446] In certain embodiments of embodiments 4-47, W is oxygen, b is 0 or 1, and R 9 is methyl, chloro, fluoro or cyano (Embodiment 4-48).

[0447] In certain embodiments of Embodiments 4-47, W is oxygen, and b is O (Embodiment 4-49).

[0448] In certain embodiments of embodiments 4-47, W is C(R 29 )2, b is 0, and each R29 Independently, it is 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).

[0449] 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).

[0450] 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).

[0451] In certain embodiments of embodiments 4-47, W is C(R 29 )2, b is 0, and each R 29 is fluorine (Embodiment 4-53).

[0452] 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).

[0453] In certain embodiments of Formula (I) as otherwise described herein, the compound is of Formula (III-A):

[0454]

[0455] or a pharmaceutically acceptable salt or deuterated form thereof, wherein:

[0456] R 1 is H, C1-C3 alkyl or C3-C6 cycloalkyl;

[0457] R 3 is a C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 alkenyl, C2-C3 alkynyl or C5-C6 cycloalkenyl group which is optionally substituted, multi-substituted or fully substituted by fluorine;

[0458] 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 halogen, wherein each C1-C3 alkyl and C3-C6 cycloalkyl is optionally substituted with 1-5 halogen groups;

[0459] a is 0, 1, 2, or 3;

[0460] V is CR 14 or N;

[0461] 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;

[0462] R 13 is (i) cyano, (ii) tetrazolyl, (iii) -C(O)OR A , where R A is H, C1-C6 alkyl or C3-C6 cycloalkyl, or (iv) -C(O)N(R B )2, where R B is H, -OH, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl;

[0463] 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;

[0464] Q represents a 4-8 membered saturated or unsaturated monocyclic, bicyclic or polycyclic heterocyclic group having 0, 1 or 2 additional ring heteroatoms selected from oxygen and nitrogen;

[0465] b is 0, 1, 2, 3, or 4; and

[0466] Each R 9 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), 5-7 membered heterocyclyl or 5-6 membered heteroaryl, wherein each phenyl, 5-7 membered heterocyclyl and 5-6 membered heteroaryl is optionally substituted with C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxy, cyano, amino or mono- or di-(C1-C3 alkyl)amino.

[0467] In certain embodiments of Formula (III-A), R 1 is H or CH3 (Embodiment 3A-1).

[0468] In certain embodiments of Formula (III-A) or Embodiment 3A-1, R 3 is C1-C3 alkyl, wherein the alkyl group is unsubstituted, substituted with 1-5 halogen groups, or perfluorinated (Embodiment 3A-2).

[0469] In certain embodiments of Formula (III-A) or Embodiment 3A-1, R 3 is methyl (Embodiment 3A-3).

[0470] In certain embodiments of Formula (III-A) or Embodiments 3A-1 to 3A-3, R 4 is hydrogen (Embodiment 3A-4).

[0471] In certain embodiments of Formula (III-A) or Embodiments 3A-1 to 3A-3, R 4 is methyl (Embodiment 3A-5).

[0472] In certain embodiments of Formula (III-A) or Embodiments 3A-1 to 3A-3, R 4 is fluoromethyl (Embodiment 3A-5.1).

[0473] In certain embodiments of Formula (III-A) or Embodiments 3A-1 to 3A-3, R 4 is difluoromethyl (Embodiment 3A-5.2).

[0474] In certain embodiments of Formula (III-A) or Embodiments 3A-1 to 3A-3, R 4 is trifluoromethyl (Embodiment 3A-5.3).

[0475] In certain embodiments of Formula (III-A) or Embodiments 3A-1 to 3A-3, R 4 is ethyl (Embodiment 3A-6).

[0476] In certain embodiments of Formula (III-A) or Embodiments 3A-1 to 3A-3, R 4 is cyclopropyl (Embodiment 3A-7).

[0477] In certain embodiments of Formula (III-A) or Embodiments 3A-1 to 3A-3, R 4 is methoxy (Embodiment 3A-8).

[0478] In certain embodiments of Formula (III-A) or Embodiments 3A-1 to 3A-3, R 4 is fluorine (Embodiment 3A-9).

[0479] In certain embodiments of Formula (III-A) or Embodiments 3A-1 to 3A-3, R 4 is chlorine (Embodiment 3A-10).

[0480] In certain embodiments of Formula (III-A) or Embodiments 3A-1 to 3A-3, R 4 is bromine (Embodiment 3A-11).

[0481] In certain embodiments of Formula (III-A) or Embodiments 3A-1 to 3A-8, V is CR 12 (Implementation Plan 3A-12).

[0482] In certain embodiments of Formula (III-A) or Embodiments 3A-1 through 3A-8, V is N (Embodiment 3A-13).

[0483] In certain embodiments of Formula (III-A) or Embodiments 3A-1 to 3A-12, V is CH, a is 1, and R 12 is hydrogen, C1-C3 alkyl or halogen (Embodiment 3A-14).

[0484] In certain embodiments of Formula (III-A) or Embodiments 3A-1 to 3A-12, V is CH, a is 1, and R 12 is hydrogen, methyl, chlorine, bromine or fluorine (Embodiment 3A-15).

[0485] In certain embodiments of Formula (III-A) or Embodiments 3A-1 to 3A-12, V is CH, a is 1, and R 12 is hydrogen (Embodiment 3A-16).

[0486] In certain embodiments of Formula (III-A) or Embodiments 3A-1 to 3A-12, V is CH, a is 1, and R 12 is chlorine (Embodiment 3A-17).

[0487] In certain embodiments of Formula (III-A) or Embodiments 3A-1 to 3A-12, V is CH, a is 1, and R 12 is bromine (Embodiment 3A-18).

[0488] In certain embodiments of Formula (III-A) or Embodiments 3A-1 to 3A-12, V is CH, a is 1, and R 12 is methyl (Embodiment 3A-18.1).

[0489] In certain embodiments of Formula (III-A) or Embodiments 3A-1 to 3A-12, V is CH, a is 1, and R 12is fluorine (Embodiment 3A-19).

[0490] In certain embodiments of Formula (III-A) or Embodiments 3A-1 to 3A-11 or 3A-13, V is N, a is 1, and R 12 is hydrogen, C1-C3 alkyl or halogen (Embodiment 3A-20).

[0491] In certain embodiments of Formula (III-A) or Embodiments 3A-1 to 3A-11 or 3A-13, V is N, a is 1, and R 12 is hydrogen, methyl, chlorine, bromine or fluorine (Embodiment 3A-21).

[0492] In certain embodiments of Formula (III-A) or Embodiments 3A-1 to 3A-11 or 3A-13, V is N, a is 1, and R 12 is hydrogen (Embodiment 3A-22).

[0493] In certain embodiments of Formula (III-A) or Embodiments 3A-1 to 3A-11 or 3A-13, V is N, a is 1, and R 12 is chlorine (Embodiment 3A-23).

[0494] In certain embodiments of Formula (III-A) or Embodiments 3A-1 to 3A-11 or 3A-13, V is N, a is 1, and R 12 is bromine (Embodiment 3A-24).

[0495] In certain embodiments of Formula (III-A) or Embodiments 3A-1 to 3A-11 or 3A-13, V is N, a is 1, and R 12 is methyl (Embodiment 3A-24.1).

[0496] In certain embodiments of Formula (III-A) or Embodiments 3A-1 to 3A-11 or 3A-13, V is N, a is 1, and R 12 is fluorine (Embodiment 3A-25).

[0497] In certain embodiments of Formula (III-A) or Embodiments 3A-1 to 3A-25, the group express (Implementation Plan 3A-26).

[0498] In certain embodiments of formula (III-A) or embodiments 3A-1 to 3A-26, Q represents a group having the formula

[0499]

[0500] in,

[0501] Each b is 0, 1, or 2;

[0502] D means C(R 29 )2,

[0503] W represents O, NR 19 or C(R 29 )2, and

[0504] 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

[0505] 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 (Embodiments 3A-27).

[0506] 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).

[0507] In certain embodiments of Embodiments 3A-27, W is oxygen, and b is O (Embodiment 3A-29).

[0508] 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).

[0509] 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).

[0510] 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).

[0511] In certain embodiments of embodiments 3A-27, D and W are C(R 29 )2, b is 0, and each R 29 is fluorine (Embodiments 3A-33).

[0512] In certain embodiments of embodiments 3A-27, D and W are C(R 29 )2, b is 0, and each R 29 is hydrogen (Embodiments 3A-34).

[0513] In certain embodiments of formula (III-A) or embodiments 3A-1 to 3A-26, Q represents a group having the formula

[0514]

[0515] in,

[0516] Each b is 0, 1, or 2; and

[0517] W represents O, NR 19 or C(R 29 )2, where

[0518] 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

[0519] 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 (Embodiments 3A-35).

[0520] 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).

[0521] In certain embodiments of Embodiments 3A-35, W is oxygen, and b is O (Embodiment 3A-37).

[0522] In certain embodiments of embodiments 3A-35, W is C(R 29 )2, b is 0, and each R 29are 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).

[0523] 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).

[0524] 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).

[0525] In certain embodiments of embodiments 3A-35, W is C(R 29 )2, b is 0, and each R 29 is fluorine (Embodiment 3A-41).

[0526] 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).

[0527] In certain embodiments of formula (III-A) or embodiments 3A-1 to 3A-26, Q represents a group having the formula

[0528]

[0529] in,

[0530] Each b is 0, 1, or 2; and

[0531] W represents O, NR 19 or C(R 29 )2, where

[0532] 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

[0533] 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 (Embodiments 3A-43).

[0534] 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).

[0535] In certain embodiments of Embodiments 3A-43, W is oxygen, and b is O (Embodiment 3A-45).

[0536] 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).

[0537] 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).

[0538] 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).

[0539] In certain embodiments of embodiments 3A-43, W is C(R 29 )2, b is 0, and each R 29 is fluorine (Embodiment 3A-49).

[0540] 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).

[0541] In certain embodiments of Formula (I) as otherwise described herein, the compound is of Formula (V):

[0542]

[0543] or a pharmaceutically acceptable salt or deuterated form thereof, wherein:

[0544] R 1 is H, C1-C3 alkyl or C3-C6 cycloalkyl;

[0545] R 3 is a C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 alkenyl, C2-C3 alkynyl or C5-C6 cycloalkenyl group which is optionally substituted, multi-substituted or fully substituted by fluorine;

[0546] 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 halogen, wherein each C1-C3 alkyl and C3-C6 cycloalkyl is optionally substituted with 1-5 halogen groups;

[0547] a is 0, 1, 2, or 3;

[0548] V is CR 14 or N;

[0549] 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;

[0550] R 13 is (i) cyano, (ii) tetrazolyl, (iii) -C(O)OR A , where R A is H, C1-C6 alkyl or C3-C6 cycloalkyl, or (iv) -C(O)N(R B )2, where R B is H, -OH, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl;

[0551] 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

[0552] R 31 express

[0553] (i) 5-7 membered heteroaryl, or

[0554] (ii) a 3-8 membered monocyclic heterocyclic group linked to the tricyclic ring system via a carbon atom, wherein the heterocyclic group

[0555] is saturated or unsaturated and is optionally fused to an aromatic or non-aromatic ring containing 3 to 6 ring members, wherein 1 or 2 of the ring members are optionally nitrogen, oxygen or sulfur atoms and the remaining ring members are carbon, or

[0556] forms with the carbon atom from the monocyclic heterocyclyl and an additional carbon or nitrogen atom a spirocyclic ring system having up to 10 total ring members, wherein the ring members are carbon or nitrogen, and

[0557] where R 31 Each heteroaryl and heterocyclic group in the aromatic or non-aromatic part is optionally replaced by 1-4 R 39 group substituted, where each R 39 is 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), 5-7 membered heterocyclyl, or 5-6 membered heteroaryl, wherein each phenyl, 5-7 membered heterocyclyl, and 5-6 membered heteroaryl is optionally substituted with C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxy, cyano, amino, or mono- or di-(C1-C3 alkyl)amino;

[0558] In certain embodiments of Formula (V), R 1 is H or CH3 (Implementation Option 5-1).

[0559] In certain embodiments of Formula (V) or Embodiment 5-1, R 3 is C1-C3 alkyl, wherein the alkyl group is unsubstituted, substituted with 1-5 halogen groups or perfluorinated (Embodiment 5-2).

[0560] In certain embodiments of Formula (V) or Embodiment 5-1, R 3 It is methyl (Embodiment 5-3).

[0561] In certain embodiments of Formula (V) or Embodiments 5-1 to 5-3, R 4 It is hydrogen (Implementation Option 5-4).

[0562] In certain embodiments of Formula (V) or Embodiments 5-1 to 5-3, R 4 It is methyl (Embodiment 5-5).

[0563] In certain embodiments of Formula (V) or Embodiments 5-1 to 5-3, R 4is fluorine (Embodiment 5-6).

[0564] In certain embodiments of Formula (V) or Embodiments 5-1 to 5-3, R 4 is chlorine (Embodiment 5-7).

[0565] In certain embodiments of Formula (V) or Embodiments 5-1 to 5-3, R 4 is fluoromethyl (Embodiment 5-8).

[0566] In certain embodiments of Formula (V) or Embodiments 5-1 to 5-3, R 4 is difluoromethyl (Embodiment 5-9).

[0567] In certain embodiments of Formula (V) or Embodiments 5-1 to 5-3, R 4 is trifluoromethyl (Embodiment 5-10).

[0568] In certain embodiments of Formula (V) or Embodiments 5-1 to 5-3, R 4 is bromine (Embodiment 5-11).

[0569] In certain embodiments of Formula (V) or Embodiments 5-1 to 5-11, V is CR 12 (Implementation Plan 5-12).

[0570] In certain embodiments of Formula (V) or Embodiments 5-1 to 5-11, V is N (Embodiment 5-13).

[0571] In certain embodiments of Formula (V) or Embodiments 5-1 to 5-12, V is CH, a is 1, and R 12 is hydrogen, C1-C3 alkyl or halogen (Embodiments 5-14).

[0572] In certain embodiments of Formula (V) or Embodiments 5-1 to 5-12, V is CH, a is 1, and R 12 is hydrogen, methyl, chlorine, bromine or fluorine (Embodiments 5-15).

[0573] In certain embodiments of Formula (V) or Embodiments 5-1 to 5-12, V is CH, a is 1, and R 12 It is hydrogen (Implementation Options 5-16).

[0574] In certain embodiments of Formula (V) or Embodiments 5-1 to 5-12, V is CH, a is 1, and R 12 is methyl (Embodiment 5-17).

[0575] In certain embodiments of Formula (V) or Embodiments 5-1 to 5-12, V is CH, a is 1, and R 12 is chlorine (Embodiment 5-18).

[0576] In certain embodiments of Formula (V) or Embodiments 5-1 to 5-12, V is CH, a is 1, and R 12 is bromine (Embodiment 5-19).

[0577] In certain embodiments of Formula (V) or Embodiments 5-1 to 5-12, V is CH, a is 1, and R 12 is fluorine (Embodiment 5-20).

[0578] In certain embodiments of Formula (V) or Embodiments 5-1 to 5-11 or 5-13, V is N, a is 1, and R 12 is hydrogen, C1-C3 alkyl or halogen (Embodiment 5-21).

[0579] In certain embodiments of Formula (V) or Embodiments 5-1 to 5-11 or 5-13, V is N, a is 1, and R 12 is hydrogen, methyl, chlorine, bromine or fluorine (Embodiments 5-22).

[0580] In certain embodiments of Formula (V) or Embodiments 5-1 to 5-11 or 5-13, V is N, a is 1, and R 12 is hydrogen (Implementation Option 5-23).

[0581] In certain embodiments of Formula (V) or Embodiments 5-1 to 5-11 or 5-13, V is N, a is 1, and R 12 is chlorine (Embodiment 5-24).

[0582] In certain embodiments of Formula (V) or Embodiments 5-1 to 5-11 or 5-13, V is N, a is 1, and R 12 is bromine (Embodiment 5-25).

[0583] In certain embodiments of Formula (V) or Embodiments 5-1 to 5-11 or 5-13, V is N, a is 1, and R 12 is methyl (Embodiment 5-26).

[0584] In certain embodiments of Formula (V) or Embodiments 5-1 to 5-11 or 5-13, V is N, a is 1, and R 12 is fluorine (Embodiment 5-27).

[0585] In certain embodiments of Formula (V) or Embodiments 5-1 to 5-27, the group express (Implementation Plan 5-28).

[0586] In certain embodiments of Formula (V) or Embodiments 5-1 to 5-28, R 31 is a 4-, 5- or 6-membered heterocyclic group, which is optionally substituted by one or two R 39 group substituted, where each R 39 is independently C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, halo-C1-C3 alkyl, hydroxy-C1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino. (Embodiments 5-29).

[0587] In certain embodiments of Formula (V) or Embodiments 5-1 to 5-28, R 31 is optionally independently replaced by one or two R 39 Substituted tetrahydrofuranyl (Embodiment 5-30).

[0588] In certain embodiments of Formula (V) or Embodiments 5-1 to 5-28, R 31 is tetrahydrofuranyl optionally substituted independently with one or two methyl, cyano or trifluoromethyl groups (embodiment 5-31).

[0589] In certain embodiments of Formula (V) or Embodiments 5-1 to 5-28, R 31 is optionally independently replaced by one or two R 39 Substituted tetrahydropyranyl (Embodiment 5-32).

[0590] In certain embodiments of Formula (V) or Embodiments 5-1 to 5-28, R 31 is tetrahydropyranyl optionally substituted independently with one or two methyl, cyano or trifluoromethyl groups (embodiments 5-33).

[0591] In certain embodiments of Formula (V) or Embodiments 5-1 to 5-28, R 31 is optionally replaced by one or two R 39 a pyridyl group substituted with a group, wherein each R 39 Independently C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, halogenated C1-C3 alkyl, hydroxy C1-C6 alkyl (embodiments 5-34).

[0592] In one embodiment, the compound of formula (I) is selected from the compounds disclosed in Table 1 below.

[0593] Table 1

[0594]

[0595]

[0596]

[0597]

[0598]

[0599]

[0600]

[0601]

[0602]

[0603]

[0604]

[0605]

[0606]

[0607]

[0608]

[0609]

[0610]

[0611]

[0612]

[0613]

[0614]

[0615]

[0616]

[0617]

[0618]

[0619]

[0620]

[0621]

[0622]

[0623]

[0624]

[0625]

[0626]

[0627]

[0628]

[0629]

[0630]

[0631]

[0632]

[0633]

[0634]

[0635]

[0636]

[0637]

[0638]

[0639] and pharmaceutically acceptable salts of the aforementioned compounds.

[0640] Pharmaceutical composition

[0641] The compounds of formula I may be formulated into pharmaceutical compositions.

[0642] In another aspect, the present invention provides a pharmaceutical composition comprising a PI3Kα inhibitor of the present invention and a pharmaceutically acceptable carrier, excipient or diluent. 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 a hospital setting. In certain other embodiments, administration may preferably be by oral route.

[0643] The characteristics of the carrier will depend on the route of administration. As used herein, the term "pharmaceutically acceptable" refers to a non-toxic substance that is compatible with biological systems such as cells, cell cultures, tissues or organisms and does not interfere with the effectiveness of the biological activity of the active ingredient. Therefore, in addition to the inhibitor, the composition of the present invention may contain diluents, fillers, salts, buffers, stabilizers, solubilizers and other substances well known in the art. The preparation of pharmaceutically acceptable formulations is described in, for example, Remington's Pharmaceutical Sciences, 18th edition, edited by A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

[0644] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the above-mentioned compound and exhibits minimal or no undesirable 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 can also be administered in the form of pharmaceutically acceptable quaternary salts known to those skilled in the art, specifically including quaternary ammonium salts of the formula -NR+Z-, wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion including chloride, bromide, iodide, -O-alkyl, tosylate, methanesulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamate, mandelate, benzyloate, and diphenylacetate).

[0645] The active compound is contained in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective amount to the patient without causing severe toxic effects in the treated patient. For all of the above-mentioned conditions, the dosage range of the active compound is about 0.01 to 300 mg / kg, preferably 0.1 to 100 mg / kg / day, more typically 0.5 to about 25 mg / kg recipient body weight / day. Typical local dosage ranges in suitable carriers are 0.01-3% wt / wt. The effective dose range of the pharmaceutically acceptable derivative can be calculated based on the weight of the parent compound to be delivered. If the derivative itself shows activity, the effective dose can be estimated using the weight of the derivative as described above or by other methods known to those skilled in the art.

[0646] Pharmaceutical compositions comprising compounds of the invention can be used in the methods described herein.

[0647] How to use

[0648] In another aspect, the present disclosure generally relates to methods for treating cancer. These methods include administering a therapeutically effective amount of a PI3K inhibitor (eg, a PI3Kα inhibitor or a PI3Kα H1047R mutation inhibitor) to an individual in need thereof.

[0649] In some embodiments, the PI3K inhibitor (e.g., a PI3Kα inhibitor or a PI3Kα H1047R mutation inhibitor) is a compound of Formula (I), (IIa), (IIb), (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.

[0650] In another aspect, the disclosure provides compounds obtainable or obtained by a method of making a compound as described herein (eg, a method comprising one or more steps described in a scheme).

[0651] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (I), (IIIa), (IIb), (IIc) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, and a pharmaceutically acceptable diluent or carrier.

[0652] In another aspect, the disclosure provides intermediates as described herein, which are suitable for use in methods of preparing compounds as described herein (eg, the intermediate is selected from the intermediates described in the Examples).

[0653] In another aspect, the present disclosure provides a method (e.g., in vitro or in vivo) of modulating PI3K (e.g., PI3Kα) activity, comprising contacting a cell with a therapeutically effective amount of a compound of Formula (I), (IIa), (IIb), (IIc), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof.

[0654] In certain embodiments, the PI3K associated with the disease or disorder has an H1047R mutation. For example, in certain embodiments as otherwise described herein, the compound has high selectivity for inhibiting H1047R-mutated PI3Kα compared to wild-type PI3Kα. This unexpected finding suggests that certain compounds may allow for targeted inhibition of PI3Kα with a novel binding mechanism compared to conventional wild-type PI3Kα inhibitors. Without wishing to be bound by theory, H1047R-mutated PI3Kα has a change away from the active site of wild-type PI3Kα. Therefore, it is believed that compounds that are selective for H1047R-mutated PI3Kα compared to wild-type PI3Kα do not bind strongly at the PI3Kα active site, but are advantageously considered to target other binding pockets. Since the active site of PI3K-type proteins is believed to be better conserved between different variants, compounds that effectively bind at a position different from the active site can provide high selectivity for PI3Kα inhibition compared to other PI3K proteins (such as PI3Kβ).

[0655] In another aspect, provided is a method for treating cancer, comprising administering to a patient suffering from cancer a therapeutically effective amount of a compound of Formula I, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof.

[0656] The compositions and methods provided herein can be used to treat a variety of cancers, including tumors, such as prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, testicular cancer, etc. More particularly, cancers that can be treated by the compositions and methods of the present invention include, but are not limited to, tumor types such as astrocytic carcinoma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer, and thyroid cancer, as well as sarcomas. More specifically, these compounds can be used to treat: Heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyomas, fibromas, lipomas, and teratomas; Lung: bronchogenic carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma, hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma); small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyomas, hemangiomas, lipomas, neurofibromas, fibromas); large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: 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, adenomatoid tumor, lipoma); Liver: Hepatocellular carcinoma (hepatocellular carcinoma), bile duct carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: Gallbladder carcinoma, ampullary carcinoma, bile duct carcinoma; Bone: Osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteocartilaginous exostosis) exostoses), benign enchondromas, chondroblastomas, chondromyxofibromas, osteoid osteomas, and giant cell tumors; nervous system: skull (osteomas, hemangiomas, granulomas, xanthoma, osteitis deformans), meninges (meningiomas, meningosarcomas, gliomatosis), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors (pinealomas), glioblastomas multiforme, oligodendrogliomas, schwannomas, retinoblastomas, congenital tumors), spinal neurofibromas, meningiomas, gliomas, sarcomas);Gynecology: Uterus (endometrial cancer), cervix (cervical cancer, precancerous cervical dysplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors Tumors), dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma); Hematologic system: blood (myeloid leukemia (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, molesdysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis, and adrenal gland: neuroblastoma. In certain embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL).

[0657] In one embodiment, the cancer is selected from hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, and head and neck cancer.

[0658] In another embodiment, the cancer is selected from breast cancer, uterine carcinosarcoma, endometrial cancer, colorectal adenocarcinoma, gastric adenocarcinoma, head and neck squamous cell carcinoma, bile duct cancer, esophageal adenocarcinoma, bladder cancer, lung squamous cell carcinoma, glioma, adrenocortical carcinoma, hepatocellular carcinoma, sarcoma, prostate adenocarcinoma, renal cell carcinoma, lung adenocarcinoma, ovarian cystadenocarcinoma, glioblastoma multiforme, melanoma.

[0659] In another embodiment, the cancer is gastric cancer, breast cancer, colorectal cancer, or endometrial cancer.

[0660] In another embodiment, the cancer is gastric cancer.

[0661] In another embodiment, the cancer is breast cancer.

[0662] In another embodiment, the cancer is colorectal cancer.

[0663] In another embodiment, the cancer is endometrial cancer.

[0664] Thus, in certain embodiments, the present disclosure provides a method of treating cancer, comprising administering to a patient in need thereof a compound of formula (I) or a pharmaceutical composition thereof and a KRAS inhibitor, wherein the cancer is breast cancer, uterine carcinosarcoma, endometrial cancer, colorectal adenocarcinoma, gastric adenocarcinoma, head and neck squamous cell carcinoma, bile duct cancer, esophageal adenocarcinoma, bladder cancer, lung squamous cell carcinoma, glioma, adrenocortical carcinoma, hepatocellular carcinoma, sarcoma, prostate adenocarcinoma, renal cell carcinoma, lung adenocarcinoma, ovarian cystadenocarcinoma, glioblastoma multiforme, or melanoma.

[0665] In other embodiments, the present disclosure provides a method for treating cancer, comprising administering to a patient in need thereof a compound of formula (I) or a pharmaceutical composition thereof and a mutant-selective KRAS inhibitor, wherein the cancer is breast cancer, uterine carcinosarcoma, endometrial cancer, colorectal adenocarcinoma, gastric adenocarcinoma, head and neck squamous cell carcinoma, bile duct cancer, esophageal adenocarcinoma, bladder cancer, lung squamous cell carcinoma, glioma, adrenocortical carcinoma, hepatocellular carcinoma, sarcoma, prostate adenocarcinoma, renal cell carcinoma, lung adenocarcinoma, ovarian cystadenocarcinoma, glioblastoma multiforme, or melanoma.

[0666] In another embodiment, the present disclosure provides a compound of formula (I) and a pharmaceutical composition thereof for use in combination with a KRAS inhibitor for treating cancer, wherein the cancer is breast cancer, uterine carcinosarcoma, endometrial cancer, colorectal adenocarcinoma, gastric adenocarcinoma, head and neck squamous cell carcinoma, bile duct cancer, esophageal adenocarcinoma, bladder cancer, lung squamous cell carcinoma, glioma, adrenocortical carcinoma, hepatocellular carcinoma, sarcoma, prostate adenocarcinoma, renal cell carcinoma, lung adenocarcinoma, ovarian cystadenocarcinoma, glioblastoma multiforme, or melanoma.

[0667] The concentration and route of administration to the patient will vary depending on the cancer to be treated. The compounds, pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising such compounds and salts can also be co-administered with other anti-tumor compounds (e.g., chemotherapeutic agents), or used in combination with other therapies (such as radiation or surgical intervention) as a pre- or post-operative adjunct.

[0668] The present disclosure provides methods for treating, preventing, or ameliorating diseases or disorders in which PI3K plays a role by administering a therapeutically effective amount of a PI3K inhibitor to a patient in need thereof. The methods of the present disclosure can be used to treat a variety of PI3K-dependent diseases and disorders.

[0669] In some embodiments, the disease disorder is cancer (e.g., breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, and head and neck cancer). In some embodiments, the diseases or disorders associated with PI3K include, but are not limited to, CLOVES syndrome (congenital lipomatous overgrowth, vascular malformation, epidermal nevus, scoliosis / bone and 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, schwannoma, head and neck squamous cell carcinoma, melanoma, esophagogastric adenocarcinoma, soft tissue sarcoma, prostate cancer, fibrolamellar carcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, bile duct cancer, B-cell lymphoma, mesothelioma, adrenocortical carcinoma, renal non-clear cell carcinoma, renal clear cell carcinoma, germ cell carcinoma, thymoma, pheochromocytoma, miscellaneous neuroepithelial tumors, and leukemia. neuroepithelial tumor), thyroid cancer, leukemia, and encapsulated glioma.

[0670] The details of the present disclosure are described in the following appended description. In the practice or testing of the present disclosure, methods and materials similar or equivalent to those described herein can be used, but illustrative methods and materials are now described. Other features, objects and advantages of the present disclosure will be apparent from the specification and claims. In the specification and the appended claims, unless the context clearly provides otherwise, the singular also includes the plural. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present disclosure belongs. All patents and publications cited in this specification are incorporated herein by reference in their entirety.

[0671] General Reaction Schemes, Intermediates and Examples

[0672] The compounds of the present invention can be prepared according to the synthetic methods and reaction schemes described herein using commercially available reagents and intermediates, or can be prepared using other reagents and conventional methods well known to those skilled in the art.

[0673] Unless otherwise specifically stated, when referring to the "first eluting enantiomer" or the "second eluting enantiomer," the specific stereochemistry of such enantiomers has not been determined, and any stereochemistry depicted in the corresponding compound structures is arbitrarily assigned.

[0674] For example, intermediates used to prepare compounds of the present invention and compounds of formula (I) can be prepared according to general reaction schemes I, II, III and IV.

[0675] General Reaction Scheme I

[0676]

[0677] For general reaction scheme 1, compound 10 is an example of formula (I). In this general reaction scheme 1, compound 1 is reacted with ethyl chloroformate at elevated temperature to give compound 2. Compound 2 is reacted with an appropriate hydrazine at elevated temperature to produce compound 3. Compound 3 can then undergo activation, such as reaction with phosphorus oxychloride to give an aryl chloride capable of reacting with amines, or can be catalyzed by using a coupling reagent such as benzotriazol-1-yloxytripyrrolidino In situ activation of hexafluorophosphate followed by addition of the desired amine yields compound 4. Using an enol ether coupling partner, compound 4 can undergo Heck or Stille coupling to form the ketone product 5 after acidic workup. Compound 5 can then undergo a cross-coupling, such as a Suzuki reaction using an alkylboronic acid, to produce compound 6. Condensation with a chiral sulfonamide, such as an Ellman auxiliary, using a Lewis acid such as titanium(IV) ethoxide can yield imine 7. Compound 7 can be reduced to form sulfenamide 8 using a reducing agent such as diisobutylaluminum hydride, sodium borohydride, or zirconocene chloride hydride. Following acidic deprotection of 8 using, for example, hydrochloric acid in dioxane, the amine salt 9 can be substituted to produce compound 10 by nucleophilic substitution or metal-catalyzed reactions in the presence of an appropriate base.

[0678] General Reaction Scheme II

[0679]

[0680] For general reaction scheme II, compound 19 is an example of formula (I). In this general reaction scheme II, 11 is reacted with methanolic ammonia to produce compound 12. Compound 12 can undergo condensation with a suitable α-haloaldehyde or ketone at elevated temperature to produce 13. Subsequently, compound 13 is reacted with a substituted amine at elevated temperature in the presence of a suitable base (such as diisopropylethylamine) to provide 14. Using an enol ether coupling partner, aryl bromide 14 can undergo Heck or Stille coupling to form vinyl ether 15, which will provide 16 when exposed to a suitable acid such as trifluoroacetic acid hydrogen chloride. Reduction of ketone 16 can be achieved using common reducing agents (such as sodium borohydride) to provide compound 17. Conversion of alcohol 17 to chloride 18 can be achieved using chlorinating agents (such as thionyl chloride). Compound 19 can be obtained by nucleophilic displacement of the alkyl chloride using the desired aniline in the presence of a salt (such as potassium iodide) and a suitable base (such as diisopropylethylamine).

[0681] General Reaction Scheme III

[0682]

[0683] For general reaction scheme III, compound 29 is an example of formula (I). In this general reaction scheme III, compound 12 is prepared in the same manner as general reaction scheme II. Compound 12 is then reacted with a substituted amine at elevated temperature in the presence of a suitable base (e.g., diisopropylethylamine) to provide 20. Compound 20 can undergo condensation with a 3-halo-2-oxopropanoate to provide ester 21. Aminolysis of the ester can be achieved using reagents such as methanolic ammonia to produce amide 22. Reaction of 22 with a suitable dehydrating reagent such as trifluoroacetic anhydride can provide 23. Using an enol ether coupling partner, aryl bromide 23 can undergo Heck or Stille coupling to form vinyl ether 24, which, upon exposure to a suitable acid (e.g., trifluoroacetic acid / hydrochloric acid), will provide 25. Using a Lewis acid such as titanium (IV) ethoxide, condensation with a chiral sulfonamide such as an Ellman auxiliary can produce imine 26. Compound 26 can be reduced using a reducing agent such as diisobutylaluminum hydride, sodium borohydride, or zirconocene hydrochloride to form sulfenamide 27. Following oxidative deprotection of 27 using, for example, molecular iodine, the resulting amine 28 can be substituted to prepare compound 29 by nucleophilic substitution or metal-catalyzed reactions in the presence of an appropriate base.

[0684] General Reaction Scheme IV

[0685]

[0686] For general reaction scheme IV, compound 37 is an example of formula (I). In this general reaction scheme IV, compound 30 can undergo nucleophilic aromatic substitution and condensation with an appropriate hydrazine in the presence of a suitable base (such as diisopropylethylamine) and a dehydrating agent (such as phosphorus oxychloride) to provide 31. Substituted amines can be used for nucleophilic aromatic substitution of compound 31 in the presence of a suitable base (such as diisopropylethylamine) to provide compound 32. Using an enol ether coupling partner, aryl bromide 32 can undergo Heck or Stille coupling to form ketone product 33 after acidic workup. Using a Lewis acid such as titanium (IV) ethoxide, condensation with a chiral sulfonamide such as Ellman's auxiliary can produce imine 34. Compound 34 can be reduced to form sulfenamide 35 using a reducing agent such as diisobutylaluminum hydride, sodium borohydride or zirconocene hydrochloride. After acidic deprotection of 35 using, for example, hydrochloric acid in dioxane, the amine salt 36 can be substituted to prepare compound 37 by nucleophilic substitution or metal-catalyzed reaction in the presence of an appropriate base.

[0687] The substituents shown in Schemes I, II, III and IV have the same definitions as described above for formula (I).

[0688] Intermediate A

[0689] Ethyl (4-bromo-2-cyano-6-iodophenyl)carbamate

[0690]

[0691] Step A: To a flask equipped 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 stirring bar. The flask was heated to 100 ° C for 3 days and then allowed to cool to room temperature. After cooling, the reaction was concentrated by rotary evaporation. The residue was then suspended in diethyl ether and heptane was slowly added to induce crystallization. The suspension was filtered and rinsed with heptane to obtain 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.

[0692] 1 H NMR (500MHz, CDCl3) δppm=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).

[0693] Intermediate B

[0694]

[0695] Step A: A mixture of ethyl (4-bromo-2-cyano-6-iodophenyl)carbamate (204 mg, 1.0 eq., 516 μmol) and formic hydrazide (31 mg, 1.0 eq., 520 μmol) in N-methyl-2-pyrrolidone (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 poured into 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.

[0696] 1 H NMR (400MHz, CDCl3) δppm=8.56 (br s, 1H), 8.48 (d, J = 2.00Hz, 1H), 8.42 (s, 1H), 8.21 (d, J = 1.88Hz, 1H).

[0697] Step B: 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-yloxytripyrrolidino- To a solution of the hexafluorophosphate salt (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). The resulting mixture was stirred for 1 hour, at which point piperidine (22 mg, 25 μL, 1.1 eq., 0.25 mmol) was added dropwise, and the reaction was stirred for 12 hours. The reaction was quenched with 10% sodium carbonate and extracted with ethyl acetate. The combined organic layers were washed sequentially with water and brine, then dried over magnesium sulfate, filtered, and concentrated to a residue. The residue was purified by silica gel chromatography (0% to 70% ethyl acetate in heptane) to afford 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.

[0698] Step C: To a vial equipped with a stir bar was added 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). The flask was evacuated and backfilled with nitrogen three times. 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 then added, and the solution was purged with nitrogen. The vial was placed in 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 deprotection of the ketone was complete (ca. 1 hour). The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to a residue. The residue was purified via 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.

[0699] 1 H NMR (500MHz, CDCl3) δppm=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).

[0700] 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 vial was evacuated and backfilled with nitrogen three times. Then, 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 sequentially with water and brine and dried over magnesium sulfate. After filtration, the mixture was concentrated under reduced pressure and chromatographed on silica gel 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.

[0701] 1 H NMR (400MHz, CDCl3) δppm=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).

[0702] 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-sulfenamide (26 mg, 1.2 eq., 0.22 mmol) in tetrahydrofuran (0.72 mL) was added titanium tetraethoxide (0.21 g, 0.19 mL, 5.0 eq., 0.91 mmol). The mixture was stirred at 80°C for 4 hours and then cooled to room temperature. Once at room temperature, a very small amount of brine was added to form a suspension. The resulting suspension was diluted with ethyl acetate. Filtered through a plug of celite and the filter cake was washed 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-sulfenamide (92 mg, crude) as a yellow solid which was used in the next step without further purification.

[0703] Step F: To a 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-sulfenamide (92 mg, 1.0 eq., 0.22 mmol) in anhydrous dichloromethane (1.5 mL) was added Schwartz's reagent (63 mg, 1.1 eq., 0.25 mmol) as a solid in portions at room temperature. The reaction was stirred at this 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 via silica gel chromatography (0% to 10% methanol in dichloromethane) to afford (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-sulfenamide (47 mg, 0.11 mmol, 51% yield) as a white solid. LCMS [M+1] + =415.2.

[0704] Step G: To a 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-sulfenamide (47 mg, 1.0 eq., 0.11 mmol) in methanol (0.45 mL) was added 71 μL of HCl (4 M in 1,4-dioxane) at room temperature. The conversion of the reaction was monitored by LCMS and once complete, triturated with diethyl ether to provide (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.

[0705] Intermediate C

[0706]

[0707]

[0708] 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-pyrrolidone (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 poured into 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.

[0709] 1 H NMR (500MHz, DMSO-d6) δppm=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).

[0710] 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 stirring bar were added 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). 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 under reduced pressure to give a dark residue. Ice was added to the residue and the contents were mixed. After melting, 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 in heptane) to afford 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.

[0711] 1 H NMR (500MHz, DMSO-d6) δppm=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).

[0712] Step C: To a vial equipped with a 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 and dissolved in anhydrous 1,2-dichloroethane (2.25 mL). 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 then added sequentially. 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, which was purified via silica gel chromatography (0% to 70% ethyl acetate in heptane) to afford 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.

[0713] 1 H NMR (500MHz, DMSO-d6) δppm=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).

[0714] Step D: To a vial equipped with a 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. 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 then added, and the solution was purged with nitrogen. The vial was placed in 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 (5 mL) was added to the reaction. The reaction was stirred until deprotection of the ketone was complete (ca. 1 hour). The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to a residue. The residue was purified via 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.

[0715] 1 H NMR (400MHz, CDCl3) δppm 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).

[0716] 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 vial was evacuated and backfilled with nitrogen three times. Then, 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 sequentially with water and brine, and dried over magnesium sulfate. After filtration, the mixture was concentrated under reduced pressure and chromatographed on silica gel to yield 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.

[0717] 1 H NMR (400MHz, CDCl3) δppm = 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).

[0718] 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-sulfenamide (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 at 80°C for 4 hours and then cooled to room temperature. Once at room temperature, a very small amount of brine was added to form a suspension. The resulting suspension was diluted with ethyl acetate. Filtered through a plug of celite and the filter cake was washed several times with ethyl acetate. The filtrate was concentrated by rotary evaporation to afford (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-sulfenamide (52 mg, crude mass) as a crude yellow solid. The product was used in the next step without further purification.

[0719] Step G: To a 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-sulfenamide (52 mg, 1.0 eq., 0.11 mmol) in anhydrous dichloromethane (0.71 mL) was added Schwartz's reagent (30 mg, 1.1 eq., 0.12 mmol) as a solid in portions at room temperature. The reaction was stirred at this 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 via silica gel chromatography (0% to 10% methanol in dichloromethane) to afford (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-sulfenamide (17 mg, 35 μmol, 33% yield) as a white solid. LCMS [M+1] = 491.3.

[0720] Step H: To a 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-sulfenamide (17 mg, 1.0 eq., 35 μmol) in methanol (0.35 mL) was added 22 μL of HCl (4 molar in dioxane) at room temperature. The reaction was monitored and, upon completion, triturated with diethyl ether and dried under vacuum to afford (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.

[0721] Intermediate D

[0722]

[0723] Step A: A mixture of ethyl (4-bromo-2-cyano-6-iodophenyl)carbamate (500 mg, 1.00 eq., 1.27 mmol) and pyrazine-2-carboxylic acid hydrazide (184 mg, 1.05 eq., 1.33 mmol) in N-methyl-2-pyrrolidone (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 poured into 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.

[0724] 1 H NMR(500MHz,DMSO-d6)δppm=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).

[0725] 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 stirring bar were added phosphorus oxychloride (1.08 g, 656 μL, 10 eq., 7.04 mmol) and diisopropylethylamine (364 mg, 490 μL, 4 eq., 2.81 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 under reduced pressure to give a dark residue. Ice was added to the residue and the contents were mixed. After melting, 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 in 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.

[0726] 1 H NMR (500 MHz, DMSO-d6) δ ppm = 9.53 (d, J = 1.10 Hz, 1H), 8.90-8.94 (m, 1H), 8.88 (d, J = 2.19 Hz, 1H), 8.71 (d, J = 1.92 Hz, 1H), 8.67 (d, J = 1.92 Hz, 1H).

[0727] Step C: To a vial equipped with a 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 and dissolved in anhydrous 1,2-dichloroethane (2.56 mL). 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 then added sequentially. 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 via silica gel chromatography (0% to 70% ethyl acetate in heptane) to provide 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.

[0728] 1 H NMR (500MHz, DMSO-d6) δppm=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).

[0729] Step D: To a vial equipped with a 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. 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 then added, and the solution was purged with nitrogen. The vial was placed in 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 (5 mL) was added to the reaction. The reaction was stirred until deprotection of the ketone was complete (ca. 1 hour). The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to a residue. The residue was purified via 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.

[0730] 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 vial was evacuated and backfilled with nitrogen three times. Then, 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 sequentially with water, then brine, and dried over magnesium sulfate. After filtration, the mixture was concentrated under reduced pressure and chromatographed on silica gel to yield 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.

[0731] 1 H NMR (400MHz, CDCl3) δppm=9.62(d,J=1.38Hz,1H),8.82(dd,J=2.38,1.50Hz,1H),8.72(d,J=2.50Hz,1H),8.5 5(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).

[0732] 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-sulfenamide (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 very small amount of brine was added to form a suspension. The resulting suspension was diluted with ethyl acetate. Filtered through a plug of celite and the filter cake was washed several times with ethyl acetate. The filtrate was concentrated by rotary evaporation to afford (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-sulfenamide (55 mg, crude mass) as a crude yellow solid. The product was used in the next step without further purification.

[0733] Step G: To a 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-sulfenamide (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 portions at room temperature. The reaction was stirred at this 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 via silica gel chromatography (0% to 10% methanol in dichloromethane) to afford (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-sulfenamide (23 mg, 47 μmol, 42% yield) as a white solid. LCMS [M+1] + =493.3.

[0734] Step H: To a 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-sulfenamide (23 mg, 1.0 eq., 47 μmol) in methanol (0.23 mL) was added 29 μL of HCl (4 M in dioxane) at room temperature. The reaction was monitored and, upon completion, triturated with diethyl ether and dried under vacuum to afford (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.

[0735] Intermediate E

[0736]

[0737] Step A: A mixture of ethyl (4-bromo-2-cyano-6-iodophenyl)carbamate (500 mg, 1.00 eq., 1.27 mmol) and thiazole-4-carboxylic acid hydrazide (190 mg, 1.05 eq., 1.33 mmol) in N-methyl-2-pyrrolidone (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 poured into 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 by LCMS: [M+1]. + =473.9.

[0738] 1 H NMR (500MHz, DMSO-d6) δppm=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).

[0739] 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 stirring bar were added 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 its contents were concentrated under reduced pressure to give a dark residue. Ice was added to the residue and the contents were mixed. After melting, 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 in 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.

[0740] 1 H NMR (500MHz, DMSO-d6) δppm=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).

[0741] Step C: To a vial equipped with a 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 and dissolved in anhydrous 1,2-dichloroethane (2.45 mL). 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 then added sequentially. 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. Purification via silica gel chromatography (0% to 70% ethyl acetate in heptane) afforded 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.

[0742] 1H NMR (500MHz, DMSO-d6) δppm=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).

[0743] Step D: To a vial equipped with a 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. 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 then added, and the solution was purged with nitrogen. The vial was placed in 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 (5 mL) was added to the reaction. The reaction was stirred until deprotection of the ketone was complete (ca. 1 hour). The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to obtain a residue. The residue was purified via silica gel chromatography to afford 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.

[0744] 1 H NMR (400MHz, CDCl3) δppm = 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).

[0745] 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 vial was evacuated and backfilled with nitrogen three times. Then, 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 sequentially with water and then brine, and dried over magnesium sulfate. After filtration, the mixture was concentrated under reduced pressure and chromatographed on silica gel to yield 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.

[0746] 1 H NMR (400MHz, CDCl3) δppm = 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).

[0747] 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-sulfenamide (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 very small amount of brine was added to form a suspension. The resulting suspension was diluted with ethyl acetate. Filtered through a plug of celite and the filter cake was washed several times with ethyl acetate. The filtrate was concentrated by rotary evaporation to afford (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-sulfenamide (93 mg, crude mass) as a crude yellow solid. The product was used in the next step without further purification.

[0748] Step G: To a 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-sulfenamide (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 portions at room temperature. The reaction was stirred at this 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 via silica gel chromatography (0% to 10% methanol in dichloromethane) to afford (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-sulfenamide (38 mg, 76 μmol, 41% yield) as a white solid. LCMS [M+1] + =498.2.

[0749] Step H: To a 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-sulfenamide (38 mg, 1.0 eq., 76 μmol) in methanol (0.31 mL) was added 48 μL of HCl (4.0 M in dioxane) at room temperature. The reaction was monitored and, upon completion, triturated with diethyl ether and dried under vacuum to afford (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 as a salt, which was used without further purification. LCMS [M+1] + =394.2.

[0750] Intermediate F8-bromo-2,4-dichloro-6-methylquinazoline

[0751]

[0752] 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, and then a solution of sodium cyanate (25.4 g, 391 mmol, 3.00 eq.) in water (400 mL) was added to the mixture. The mixture was stirred at 35°C for 12 hours, and then sodium hydroxide (235 g, 5.87 mol, 45.0 eq.) was added to the mixture. The mixture was stirred at 35°C for 0.2 hours. After the reaction was completed, the pH of the reaction mixture was adjusted to 4 with hydrochloric acid at 0°C, the mixture was filtered, rinsed with water (1 L), and then the crude product was purified by recrystallization from ethyl acetate (30 mL) at 25°C for 10 minutes to give 8-bromo-6-methyl-1H-quinazoline-2,4-dione (30 g) as a white solid. LCMS [M+2] + =257.0.

[0753] 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. At 0 ° C, the reaction mixture was quenched by adding water (100 mL), and then extracted with ethyl acetate (100 mL × 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.

[0754] Intermediate G7-bromo-5-chloro-9-methyl-[1,2,4]triazolo[4,3-c]quinazoline

[0755]

[0756] 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 hours, followed by the addition of formic hydrazide (884 mg, 14.7 mmol, 1.00 eq.), and the mixture was stirred at 0°C. Once the conversion to the intermediate arylhydrazine was complete, 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 hours. After completion of the reaction, the reaction solution was carefully poured into 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), extracted with ethyl acetate (100 mL × 2), and then the aqueous phase was adjusted to pH = 10 with aqueous sodium hydroxide solution and extracted with ethyl acetate (100 mL × 2). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel chromatography (0% to 100% ethyl acetate in petroleum ether) to give 7-bromo-5-chloro-9-methyl-[1,2,4]triazolo[4,3-c]quinazoline (6 g, crude product) as a yellow solid. LCMS [M+2] + =299.0.

[0757] Example 1-1

[0758] (R)-2-((1-(9-methyl-5-(piperidin-1-yl)-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)ethyl)amino)benzoic acid

[0759]

[0760] To a vial equipped with a stir bar was 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 inserted through the septum to expose the reaction to ambient pressure, and the reaction was stirred at room temperature for 12 hours. 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 sequentially 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 in heptane) to provide (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.

[0761] 1 H NMR (400MHz, CDCl3) δppm = 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(brm,J=1.63Hz,1H),3.99(br m,4H),2.47(s,3H),1.73-1.89(m,9H).

[0762] The compounds in Table 2 were prepared essentially according to the procedures described in the Schemes and Examples above.

[0763] Table 2

[0764]

[0765] Example 2-1

[0766] 2-((1-(9-methyl-5-(piperidin-1-yl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzoic acid

[0767]

[0768] 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 methanolic ammonia (7 M). The mixture was stirred at 25 ° C for 16 hours. After completion, the reaction mixture was concentrated under vacuum 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-quinazoline-4-amine (3.06 g, 10.7 mmol, 98% yield) as a white solid. LCMS [M+3] + =273.8.

[0769] 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) was added 2-chloroacetaldehyde (19.4 g, 99.1 mmol, 15.9 mL, 40% purity, 9.00 eq.), and the mixture was stirred at 100 ° C for 16 hours. After completion, the mixture was cooled to 25 ° C and concentrated under reduced pressure to obtain a residue. The residue was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (50 mL × 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.

[0770] 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),

[0771] 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 uL, 1.00 eq.) and the mixture was stirred at 60°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 purified by flash silica gel chromatography (0% to 40% ethyl acetate in petroleum ether) to give 7-bromo-9-methyl-5-(1-piperidinyl)imidazo[1,2-c]quinazoline (2.16 g, 4.38 mmol, 44% yield) as a yellow solid. LCMS [M+3] + =346.8.

[0772] 1 H NMR (400MHz, CDCl3) δppm=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).

[0773] Step D: A mixture of 7-bromo-9-methyl-5-(1-piperidinyl)imidazo[1,2-c]quinazoline (400 mg, 1.16 mmol, 1.00 eq.), butyl vinyl ether (116 mg, 1.16 mmol, 149 uL, 1.00 eq.), N,N-dicyclohexylmethylamine (231 mg, 1.27 mmol, 254 uL, 1.10 eq.) and [(tri-tert-butylphosphine)-2-(2-aminodiphenyl)]palladium(II) chloride (89.1 mg, 174 umol, 0.15 eq.) in dioxane (5.0 mL) was degassed, purged with nitrogen three times, and then stirred at 100° C. under nitrogen atmosphere for 12 hours. After 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.

[0774] Step E: To a solution of 7-(1-butoxyvinyl)-9-methyl-5-(1-piperidinyl)imidazo[1,2-c]quinazoline (325 mg, 892 umol, 1.00 eq.) in tetrahydrofuran (2.00 mL) was added 2.00 mL of aqueous hydrochloric acid (3 M in water), and the mixture was stirred at 25°C for 3 hours. Upon completion, the mixture was adjusted to pH 8 with saturated sodium bicarbonate solution and then extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over sodium sulfate, and concentrated in vacuo to obtain a residue. The residue was purified by flash silica gel chromatography (0% to 50% ethyl acetate in petroleum ether) to afford 1-(9-methyl-5-(piperidin-1-yl)imidazo[1,2-c]quinazolin-7-yl)ethan-1-one (65.0 mg, 179 umol, 20% yield) as a yellow solid. LCMS[M+1] + =309.0.

[0775] Step F: Sodium borohydride (8 mg, 200 umol, 1.1 eq.) was added 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 umol, 1.0 eq.) in methanol (1.0 mL) at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The mixture was quenched by the addition of water (5 mL) and then extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (5 mL x 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 umol, 66% yield) as a yellow solid. LCMS [M+1] + =310.9.

[0776] 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 umol, 1.0 eq.) in thionyl chloride (1.64 g, 14 mmol, 1.0 mL, 86 eq.) was stirred at 50°C for 30 minutes. 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 light brown gum.

[0777] Step H: A mixture of 7-(1-chloroethyl)-9-methyl-5-(piperidin-1-yl)imidazo[1,2-c]quinazoline (40 mg, 120 umol, 1.0 eq.), tert-butyl 2-aminobenzoate (47 mg, 240 umol, 44 uL, 2.0 eq.), potassium iodide (20 mg, 120 umol, 1.0 eq.) and diisopropylethylamine (63 mg, 490 umol, 85 uL, 4.0 eq.) in dimethylformamide (2.0 mL) was stirred at 80° C. under a nitrogen atmosphere for 4 hours. After completion, the mixture was cooled to 25° C., diluted with ethyl acetate (20 mL), and the resulting mixture was washed with brine (10 mL×3). The separated organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (0% to 20% ethyl acetate in petroleum ether) to provide tert-butyl 2-((1-(9-methyl-5-(piperidin-1-yl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzoate (15 mg, 24 umol, 20% yield) as a light yellow solid. LCMS [M+1] + =486.2.

[0778] 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 umol, 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 obtain a residue. The residue was purified by preparative HPLC (Phenomenex C18 × 80 × 40 mm 3 μm column, mobile phase A: water (NH3H2O ​​+ NH4HCO3), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient conditions from 30% B to 60%) to provide 2-((1-(9-methyl-5-(piperidin-1-yl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzoic acid (5 mg, 11 μmol, 36% yield) as a white solid. LCMS [M+1] + =430.1.

[0779] 1H NMR (400MHz, CD3OD) δppm=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),7.14-7.0 5(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).

[0780] Example 2-2

[0781] (R)-2-((1-(2-Cyano-9-methyl-5-(piperidin-1-yl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzoic acid

[0782]

[0783] Step A: 8-bromo-2-chloro-6-methyl-quinazolin-4-amine (3.70 g, 13.6 mmol, 1.00 eq.) was added to piperidine (5.78 g, 67.9 mmol, 6.70 mL, 5.00 eq.) in solid form. The mixture was heated and stirred at 130 ° C for 1 hour. After the reaction was completed, the mixture was cooled to 25 ° C and the reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (0% to 50% ethyl acetate in 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.

[0784] 1 H NMR (400MHz, DMSO-d6) δppm=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)

[0785] 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) were added ethyl 3-bromo-2-oxopropanoate (9.11 g, 46.7 mmol, 5.84 mL, 5.00 eq.) and Molecular sieves (40.0 g). The mixture was sealed and stirred at 140 ° C for 15 hours. After the reaction was completed, the mixture was cooled to 25 ° C, and the reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (0% to 100% ethyl acetate in petroleum ether) to give 7-bromo-9-methyl-5-(piperidin-1-yl)imidazo[1,2-c]quinazoline-2-carboxylic acid ethyl ester (3.50 g, 8.39 mmol) as a yellow solid. LCMS [M+3] + =419.1.

[0786] 1 H NMR (400MHz, DMSO-d6) δppm=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 (brd, J=4.4Hz, 2H), 1.35 (t, J=7.2Hz, 3H).

[0787] 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 methanolic ammonia (7.00 M). The mixture was stirred at 35 ° C for 48 hours. 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 in 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.

[0788] 1 H NMR (400MHz, DMSO-d6) δppm=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).

[0789] 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 by the addition of water (20 mL) at 25°C and then extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with 30 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (0% to 30% ethyl acetate in petroleum ether) to afford 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.

[0790] 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.), [(tri-tert-butylphosphine)-2-(2-aminodiphenyl)]palladium(II) chloride (37.4 mg, 72.9 μmol, 0.10 eq.) was evacuated and backfilled with nitrogen three times, deoxygenated dioxane (6.00 mL) was added, and the mixture was stirred at 100° C. under nitrogen atmosphere for 10 hours. After the reaction was complete, the mixture was cooled to 25°C, 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.

[0791] 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 hour. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to a residue. The residue was purified by silica gel chromatography (10% to 20% ethyl acetate in petroleum ether) to afford 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.

[0792] 1 H NMR (400MHz, CDCl3) δppm=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).

[0793] 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) was added (R)-2-methylpropane-2-sulfenamide (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.). The mixture was stirred at 95°C for 12 hours. After the reaction was complete, the mixture was cooled to 25°C, and the reaction mixture was added to water (15 mL) and stirred for 30 minutes. 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 (20 mL x 3) of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield a residue. The residue was purified by flash silica gel chromatography (0% to 100% ethyl acetate in petroleum ether) to yield (R)-N-(1-(2-cyano-9-methyl-5-(piperidin-1-yl)imidazo[1,2-c]quinazolin-7-yl)ethylidene)-2-methylpropane-2-sulfenamide (160 mg, 360 μmol, 63% yield, 98% purity) as a yellow solid. LCMS [M+1] + =437.4.

[0794] 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-sulfenamide (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.) portionwise. The mixture was stirred at 25°C for 1 hour. The reaction mixture was partitioned between 30.0 mL of ethyl acetate and 30.0 mL of water. The organic phase was separated, washed with 90 mL of brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (0% to 100% ethyl acetate in 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-sulfenamide (80 mg, 170 μmol, 57% yield) as a yellow solid. LCMS [M+1] + =439.2.

[0795] 1 H NMR (400MHz, CDCl3) δppm=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).

[0796] 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-sulfenamide (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.

[0797] 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) were 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 Molecular sieves (40.0 mg). The mixture was stirred at 25 ° C for 12 hours. At 25 ° C, 20 mL of a saturated aqueous solution of ammonium chloride was added to the reaction mixture and extracted with ethyl acetate (20 mL × 3). The combined organic layer was washed with brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (33% ethyl acetate in petroleum ether) to obtain a residue. The residue was purified by preparative HPLC (FA conditions; column: Phenomenex Luna C18 150×25 mm×10 μm; mobile phase: [water (FA)-ACN]; gradient: 62%-92% B over 9 minutes) to afford (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.

[0798] 1 H NMR (400MHz, CDCl3) δppm=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(br d,J=6.8Hz,3H).

[0799] Example 3-1

[0800] (R)-2-((1-(5-(Piperidin-1-yl)-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid

[0801]

[0802]

[0803] Step A: To a reaction flask containing tetrahydrofuran (36.0 mL) and a stir bar, 8-bromo-2,4-dichloroquinazoline (3.00 g, 1.0 eq. 10.8 mmol) and diisopropylethylamine (1.40 g, 1.88 mL, 1.0 eq. 10.8 mmol) were added as solids. After dissolution, the vial was cooled to 0°C and formic hydrazide (648 mg, 1.0 eq. 10.8 mmol) was added portionwise. Once the addition was complete, the cooling bath was removed and the reaction was stirred at room temperature for 12 hours. After complete conversion to the intermediate arylhydrazine (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 and rinsed with water, dried, and purified by silica gel chromatography (0% to 100% ethyl acetate in 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.

[0804] 1 H NMR (500MHz, CDCl3) δppm=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).

[0805] Step B: 7-bromo-5-chloro-[1,2,4]triazolo[4,3-c]quinazoline (500 mg, 1 eq. 1.76 mmol) was added as a solid to a vial equipped with a stir bar and dissolved in anhydrous 1,2-dichloroethane (7.05 mL). Diisopropylethylamine (456 mg, 614 μL, 2.0 eq. 3.53 mmol) and piperidine (165 mg, 192 μL, 1.1 eq. 1.94 mmol) were then added sequentially. The reaction mixture 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, and concentrated. Purification via silica gel chromatography (0% to 70% ethyl acetate in heptane) afforded 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.

[0806] 1 H NMR (500MHz, CDCl3) δppm=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).

[0807] Step C: To a vial equipped with a stir bar, 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. The flask was evacuated and backfilled with nitrogen three times. 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 then added, and the solution was purged with nitrogen. The vial was placed in 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 deprotection of the ketone was complete (ca. 1 hour). The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to a residue. The 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.

[0808] 1 H NMR (400MHz, CDCl3) δppm=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).

[0809] 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-sulfenamide (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 very small amount of brine was added to form a suspension. The resulting suspension was diluted with ethyl acetate. Filtered through a plug of celite and the filter cake was washed several times with ethyl acetate. The filtrate was concentrated by evaporation under reduced pressure, and the yellow residue was purified by flash silica gel chromatography (30% to 100% ethyl acetate in heptane) to afford (R)-2-methyl-N-(1-(5-(piperidin-1-yl)-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethylidene)propane-2-sulfenamide (145 mg, 364 μmol, 69% yield) as a yellow solid.

[0810] Step E: To a solution of (R)-2-methyl-N-(1-(5-(piperidin-1-yl)-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethylidene)propane-2-sulfenamide (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 portions at room temperature. The reaction was stirred at this 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 via silica gel chromatography (0% to 10% methanol in dichloromethane) to afford (R)-2-methyl-N-((R)-1-(5-(piperidin-1-yl)-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)propane-2-sulfenamide (8.8 mg, 22 μmol, 6% yield) as a white solid. LCMS [M+1] + =401.1.

[0811] Step F: To a 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-sulfenamide (8.8 mg, 1.0 eq. 22 μmol) in methanol (0.22 mL) was added 14 μL of HCl (4.0 M in dioxane) at room temperature. The reaction was monitored and, upon completion, triturated with diethyl ether and dried under vacuum to afford (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.

[0812] Step G: To a vial equipped with a stir bar was added (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) as solids. 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 inserted through the septum to expose the reaction to ambient pressure, and the reaction was stirred at room temperature for 12 hours. 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 sequentially 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 yield (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. LCMS [M+1] + =417.2.

[0813] 1H NMR (400MHz, CDCl3) δppm=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=7.7 5Hz,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).

[0814] Example 4-1

[0815] (R)-2-((1-(9-methyl-5-(piperidin-1-yl)-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)benzoic acid

[0816]

[0817] 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 hours. Upon completion, the mixture was cooled to 25°C, filtered, and the filter residue was washed with acetonitrile (30 mL) to give a residue, which was triturated with water (150 mL) at 20°C for 30 minutes, 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.

[0818] 1 H NMR (400MHz, DMSO-d6) δppm = 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).

[0819] 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.), [(tri-tert-butylphosphino)-2-(2-aminodiphenyl)]palladium(II) chloride (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. under a nitrogen atmosphere for 2 hours. 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.

[0820] Step C: To a solution of 7-(1-butoxyvinyl)-9-methyl-5-(piperidin-1-yl)-[1,2,4]triazolo[4,3-c]quinazoline (2.10 g, 5.75 mmol, 1.00 eq.) in tetrahydrofuran (30 mL) was added 5.75 mL of HCl (3 M in 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 filter residue, which was triturated with ethyl acetate (50 mL) at 20°C for 30 minutes, filtered, and dried under reduced pressure to give 1-(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. LCMS [M+1] + =310.3.

[0821] 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.) and (R)-2-methylpropane-2-sulfenamide (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 a residue that was used in the next step without further purification. LCMS [M+1] + =413.3.

[0822] 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-sulfenamide (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.) portionwise. The reaction was stirred at 25 °C for 3 hours. The mixture was concentrated under reduced pressure to give a residue which was used in the next step without further purification. LCMS [M+1] + =415.3.

[0823] 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-sulfenamide (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 chromatography (0% to 40% acetonitrile in water (0.3% FA)), and lyophilized to afford (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.

[0824] 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 at 25° C. under an oxygen atmosphere for 12 hours. The mixture was filtered and then purified by preparative HPLC (column: Phenomenex luna C18 150×25 mm×10 μm; mobile phase: [water (FA)-ACN]; gradient: 52%-82% B over 9 minutes) and lyophilized to afford (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, 18 μmol, 3% yield) as a yellow solid. LCMS [M+1] + =431.3.

[0825] 1 H NMR (400MHz, CD3OD) δppm = 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).

[0826] Examples 5-1 to 5-50

[0827] The following compounds were prepared essentially according to the procedures described in Schemes I-IV above and Examples 1-1, 2-1, 2-2, 3-1 and 4-1.

[0828]

[0829]

[0830]

[0831]

[0832]

[0833]

[0834]

[0835]

[0836]

[0837]

[0838]

[0839]

[0840]

[0841]

[0842]

[0843]

[0844]

[0845] Intermediate H

[0846]

[0847] 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, followed by the dropwise addition of a solution of potassium cyanate (5.79 g, 67.9 mmol, 3.00 eq.) in water (10.0 mL) over 5 minutes. Stirring was continued at 45°C for 1 hour. Upon completion, the reaction solution was cooled to 25°C and adjusted to pH 6 using 10% aqueous sodium hydroxide solution. The precipitate was collected by filtration and then dried under vacuum to afford 8-bromo-6-methylquinazoline-2,4(1H,3H)-dione (3.00 g, 9.41 mmol, 42% yield) as a white solid.

[0848] 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. After 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.

[0849] 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 a methanolic ammonia solution (7 M, 15.5 mL, 10.0 eq.). The mixture was stirred at 25 ° C for 16 hours. After completion, the reaction mixture was concentrated under vacuum 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-methylquinazoline-4-amine (3.06 g, 10.7 mmol, 98% yield) as a white solid. LCMS [M+3] + =273.8.

[0850] 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 hours. After the reaction was completed, the reaction mixture was cooled to 25 ° C and concentrated under reduced pressure to obtain 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.

[0851] Example 6-1

[0852] (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

[0853]

[0854] 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). The mixture was stirred at 80 ° C for 1 hour. After the reaction was completed, the reaction mixture was cooled to 25 ° C, diluted with water (100 mL), 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 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.

[0855] 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 (10.0 mL) was evacuated and backfilled with nitrogen three times, and then the mixture was stirred at 100° C. under nitrogen atmosphere for 2 hours. After the reaction was complete, the mixture was poured into a saturated aqueous solution of potassium fluoride (100 mL) at 25° C. and stirred for 1 hour. The aqueous phase was extracted with dichloromethane (50.0 mL x 3), and the combined organic phases 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.

[0856] 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 at 25 ° C for 1 hour. After completion of the reaction, the reaction mixture was diluted with water (100 mL) 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 = 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.

[0857] 1 H NMR (400MHz, CDCl3) δppm=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).

[0858] 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-sulfenamide (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 obtained 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 (SiO2, petroleum ether:ethyl acetate = 6:1 to 4:1) to afford (R)-N-(1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethylidene)-2-methylpropane-2-sulfenamide (810 mg, 1.49 mmol, 57% yield) as a yellow solid. LCMS [M+1]+ =516.2.

[0859] 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-sulfenamide (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 at 25°C for 1.5 hours. After completion of the reaction, the pH of the mixture was adjusted to ~pH=8 using saturated aqueous sodium bicarbonate solution. The obtained solution was then extracted with dichloromethane (30.0 mL x 3), 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-sulfenamide was purified by SFC (column: (S,S) WHELK-O1 (250 mm × 30 mm, 10 μm); mobile phase: [CO2-EtOH]; B%: 25%, isocratic elution mode) 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-sulfenamide as a white solid. LCMS [M+1] + =518.1.

[0860] 1 H NMR (400MHz, DMSO-d6) δppm=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).

[0861] 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-sulfenamide (540 mg, 1.04 mmol, 1.00 eq.) in ethyl acetate was added hydrochloric acid in ethyl acetate (10.0 mL, 2 M) and stirred at 25° C. for 1.5 hours. After completion of the reaction, the pH of the mixture was adjusted to ~pH=8 with saturated aqueous sodium bicarbonate solution. 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 afford (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.

[0862] 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.) and 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 obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 7:1 to 5:1) to afford (R)-methyl 6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinate (450 mg, 687 μmol, 68% yield) as a white solid. LCMS [M+1] + =583.1.

[0863] Step H: To a solution of (R)-methyl 6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)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 at 40 °C for 1 hour. After completion of the reaction, the mixture was adjusted to ~pH=5 with aqueous citric acid solution, and the solution was 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 in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150×25 mm×10 μm; mobile phase: [water(formic acid)-acetonitrile]; gradient: 60%-90% acetonitrile over 9 minutes) to afford (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.

[0864] 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=9.2 Hz, 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).

[0865] 19 F NMR (377MHz, CD3OD) δppm=-64.0, -64.2.

[0866] Example 6-2

[0867] (R)-6-Chloro-3-((1-(9-methyl-5-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid

[0868]

[0869] Step A: To a mixture of 7-bromo-5-chloro-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazoline (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 hr. 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 afford the crude product. The crude product was purified by silica gel chromatography (SiO2, petroleum ether:ethyl acetate = 10 / 1 to 2 / 1) to afford 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.

[0870] 1 H NMR (400MHz, CDCl3) δppm=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).

[0871] 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 hours. Upon completion, the mixture was quenched with saturated aqueous potassium fluoride solution (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.

[0872] Step C: To a solution 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 aqueous hydrochloric acid (4 M, 24.1 mL, 1.00 eq) and the mixture was stirred at 25 °C for 1 hour. Upon completion, the mixture was diluted with water (1000 mL) to give a suspension, which was collected by filtration and dried under vacuum to give 1-(9-methyl-5-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethan-1-one (32.0 g, 84.6 mmol, 88% yield) as a yellow solid.

[0873] Step D: To a solution of 1-(9-methyl-5-(morpholin-4-yl)-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-sulfenamide (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 hours. 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-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethylidene)propane-2-sulfenamide (40.7 g, crude) as a yellow oil, which was used in the next step without further purification.

[0874] Step E: To a mixture of (R)-2-methyl-N-(1-(9-methyl-5-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethylidene)propane-2-sulfenamide (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) at 25 °C, and then sodium cyanoborohydride (21.3 g, 338 mmol, 4.00 eq) was added portionwise to the mixture. The mixture was stirred at 25 °C for 2 hours. Upon completion, the mixture was diluted with water (1000 mL) and extracted with dichloromethane (500 mL). The organic layer was concentrated in vacuo to obtain a crude solid. The crude solid was purified by silica gel chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to afford (R)-2-methyl-N-((R)-1-(9-methyl-5-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)propane-2-sulfenamide (27.0 g, 51.4 mmol, 61% yield) as a yellow solid. LCMS [M+1] + =484.3.

[0875] 1 H NMR (400MHz, CDCl3) δppm=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).

[0876] Step F: To a solution of (R)-2-methyl-N-((R)-1-(9-methyl-5-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)propane-2-sulfenamide (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 at 25 °C for 1 hour. Upon completion, the mixture was concentrated in vacuo to afford a yellow solid. The solid was triturated with ethyl acetate (50 mL), filtered, and dried under vacuum to afford (R)-1-(9-methyl-5-(morpholin-4-yl)-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.

[0877] Step G: To a solution of (R)-1-(9-methyl-5-(morpholin-4-yl)-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 hours. Upon completion, the mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL). The combined organic layers were washed with brine (50 mL) and concentrated in vacuo to give (R)-methyl 6-chloro-3-((1-(9-methyl-5-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinate (7.10 g, crude) as a light yellow solid which was used in the next step without further purification. LCMS [M+1] + =549.1.

[0878] Step H: To a solution of (R)-6-chloro-3-((1-(9-methyl-5-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid methyl ester (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 hours. After 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×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 to dichloromethane / methanol = 10 / 1) and further purified by preparative HPLC (column: Phenomenex luna C18 250*50mm*10um; mobile phase: [water (0.1% formic acid)-acetonitrile]; gradient: 50%-80% acetonitrile over 20 minutes) to afford (R)-6-chloro-3-((1-(9-methyl-5-(morpholin-4-yl)-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.

[0879] 1H NMR (400MHz, DMSO-d6) δppm=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).

[0880] 19 F NMR (377MHz, DMSO-d6) δppm=-61.15.

[0881] Example 6-3

[0882] (R)-6-Chloro-3-((1-(9-methyl-5-(2-oxa-6-azaspiro[3.3]hept-6-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid

[0883]

[0884] 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 hours. After completion, the mixture was poured into water and extracted with ethyl acetate (400 mL × 4). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 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.

[0885] 1 H NMR (400MHz, CDCl3) δppm=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).

[0886] Step B: Under nitrogen, 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). The mixture was stirred at 100 ° C under a nitrogen atmosphere for 10 hours. After completion, the mixture was cooled to 20 ° C and quenched with potassium fluoride aqueous solution (10%, 1.5 L). Then, ethyl acetate (2 L) was added to the mixture and stirred for 10 minutes. The mixture was filtered and the filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 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.

[0887] 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 aqueous hydrochloric acid (1 M, 25.5 mL, 1.00 eq). The mixture was stirred at 20 °C for 1 hour. 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]hept-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.

[0888] Step D: To a mixture of 1-(9-methyl-5-(2-oxa-6-azaspiro[3.3]hept-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-sulfenamide (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 hours. After 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 minutes. The mixture was filtered and the filtrate was separated, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford (R)-2-methyl-N-(1-(9-methyl-5-(2-oxa-6-azaspiro[3.3]hept-6-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethylidene)propane-2-sulfenamide (10 g, crude) as a yellow oil which was used without further purification.

[0889] Step E: To a mixture of (R)-2-methyl-N-(1-(9-methyl-5-(2-oxa-6-azaspiro[3.3]hept-6-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethylidene)propane-2-sulfenamide (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 at 20 °C for 2 hours. After completion, the mixture was poured into water (500 mL) and extracted with dichloromethane (200 mL x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to obtain 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]hept-6-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)propane-2-sulfenamide (8.00 g, 15.3 mmol, 76% yield) as a yellow solid. LCMS [M+1] + =496.1.

[0890] Step F: To a mixture of (R)-2-methyl-N-((R)-1-(9-methyl-5-(2-oxa-6-azaspiro[3.3]hept-6-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)propane-2-sulfenamide (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 minutes. After completion, the mixture was filtered and the filter cake was washed with ethyl acetate (50 mL) and dried under vacuum to give (R)-1-(9-methyl-5-(2-oxa-6-azaspiro[3.3]hept-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.

[0891] Step G: To a mixture of (R)-1-(9-methyl-5-(2-oxa-6-azaspiro[3.3]hept-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) was added diisopropylethylamine (12.1 g, 93.5 mmol, 16.3 mL, 5.00 eq). The mixture was stirred at 90 °C for 10 hours. Upon completion, the mixture was cooled to 25 °C, poured into water (500 mL) and stirred for 10 minutes. The suspension was filtered, and the filter cake was washed with water (100 mL x 2) and dried under vacuum to give (R)-methyl 6-chloro-3-((1-(9-methyl-5-(2-oxa-6-azaspiro[3.3]hept-6-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinate (8.00 g, crude) as a yellow solid.

[0892] Step H: To a mixture of (R)-6-chloro-3-((1-(9-methyl-5-(2-oxa-6-azaspiro[3.3]hept-6-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid methyl ester (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. After completion, the mixture was poured into water (300 mL) and the mixture was adjusted to ~pH=6 by aqueous hydrochloric acid solution (0.5 M). The aqueous solution was extracted with ethyl acetate (200 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was further purified by preparative HPLC (column: Phenomenex luna C18 250*70mm*10um; mobile phase: [water (0.1% trifluoroacetic acid)-acetonitrile]; gradient: 52%-82% acetonitrile over 20 minutes) to afford (R)-6-chloro-3-((1-(9-methyl-5-(2-oxa-6-azaspiro[3.3]hept-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. 1 H NMR (400MHz, CDCl3) δppm=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).

[0893] Example 6-4

[0894] (R)-6-Chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methylimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid

[0895] 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) were 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 hour. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography ( 80g Silica gel flash column, 0-100% ethyl acetate / petroleum ether gradient elution @ 60 mL / min) afforded 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.

[0896] 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 (16.0 mL) was evacuated and backfilled with nitrogen three times, and then the mixture was stirred at 100° C. under a nitrogen atmosphere for 6 hours. After the reaction was complete, the mixture was cooled to 25° C., poured into a saturated solution of potassium fluoride (80.0 mL) and stirred for 1 hour. The aqueous phase was extracted with dichloromethane (80.0 mL x 3), and the combined organic phases 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.

[0897] 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 obtain a residue. The residue was dissolved in dichloromethane (80.0 mL), washed with saturated aqueous sodium bicarbonate solution (80.0 mL×3) and brine (80.0 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a residue. The residue was purified by flash silica gel chromatography ( 12g Silica gel flash column, 0-60% ethyl acetate / petroleum ether gradient elution @ 36 mL / min) to afford 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.

[0898] 1 H NMR (400MHz, CDCl3) δppm=8.43(d,J=1.2Hz,1H),7.75(d,J=2.0Hz,1H),7.63(d,J=1.2Hz,1 H),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).

[0899] 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) were added (R)-2-methylpropane-2-sulfenamide (563 mg, 4.65 mmol, 2.00 eq.) and titanium (IV) ethoxide (1.80 g, 7.88 mmol, 1.63 mL, 3.39 eq.). 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 obtained mixture was filtered, and the filter cake was washed with dichloromethane (50.0 mL×3). The combined organic layers were concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography ( 12g Silica gel flash column, gradient elution with 0-100% ethyl acetate / petroleum ether @ 36 mL / min) afforded (R)-N-(1-(5-(4,4-difluoropiperidin-1-yl)-9-methylimidazo[1,2-c]quinazolin-7-yl)ethylidene)-2-methylpropane-2-sulfenamide (900 mg, 2.01 mmol, 87% yield) as a yellow oil. LCMS [M+1] + =448.1.

[0900] 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-sulfenamide (800 mg, 1.79 mmol, 1.00 eq.) in dichloromethane (4.00 mL) and methanol (4.00 mL) was 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 pH = 7 with saturated aqueous sodium bicarbonate solution (15.0 mL). The resulting mixture was concentrated under reduced pressure to remove methanol and dichloromethane, and then diluted with dichloromethane (20.0 mL). The organic phase was separated, washed with brine (20.0 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 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%-65% acetonitrile over 15 minutes) to obtain (R)-N-((R)-1-(5-(4,4-difluoropiperidin-1-yl)-9-methylimidazo[1,2-c]quinazolin-7-yl)ethyl)-2-methylpropane-2-sulfenamide (500 mg, 1.10 mmol, 62% yield, 99% purity) as a yellow solid. LCMS [M+1] + =450.2.

[0901] 1 H NMR (400MHz, CDCl3) δppm=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).

[0902] 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-sulfenamide (121 mg, 267 μmol, 1.00 eq.) in acetonitrile (1.00 mL) was added a solution of hydrochloric acid in ethyl acetate (2.00 M, 1.33 mL, 10.0 eq.). The mixture was stirred at 25 °C for 1 hour. Upon completion, the reaction mixture was concentrated under reduced pressure to give 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 afford (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.

[0903] 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 the reaction was completed, the mixture was cooled to 25 ° C and partitioned between ethyl acetate (30.0 mL) and water (30.0 mL). The organic phase 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 ( 4g Silica gel flash column, gradient elution with 0-100% ethyl acetate / petroleum ether @ 36 mL / min) afforded (R)-methyl 6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methylimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinate (100 mg, 194 μmol, 74% yield) as a yellow solid. LCMS [M+1] + =515.1.

[0904] Step H: To a solution of (R)-methyl 6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methylimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)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 150×25mm×5um; mobile phase: [water(formic acid)-acetonitrile]; gradient: 45%-75% acetonitrile over 40 minutes) to afford (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.

[0905] 1 H NMR (400MHz, CDCl3) δppm = 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,1 H), 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).

[0906] 19 F NMR (377MHz, CDCl3) δppm=-97.4.

[0907] Example 6-5

[0908] (R)-6-Chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-2,9-dimethylimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid

[0909]

[0910] 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 hours. After the reaction was complete, the reaction mixture was cooled to 25°C to obtain a suspension, which was filtered. The filter cake was triturated with petroleum ether / ethyl acetate = 1 / 1 (25.0 mL) at 25°C for 5 minutes and filtered. The filter cake was collected and dried under vacuum to obtain 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.

[0911] 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 hours. After completion of the reaction, the mixture was cooled to 25°C and concentrated under reduced pressure to obtain a solid. The solid was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to obtain 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.

[0912] 1 H NMR (400MHz, CDCl3) δppm=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).

[0913] 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. under a nitrogen atmosphere for 3.5 hours. After the reaction was complete, the mixture was cooled to 25° C. and quenched by the addition of a saturated aqueous solution of 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×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.

[0914] 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 at 25°C for 1 hour. After the reaction was complete, the mixture was adjusted to pH = 7 with saturated aqueous sodium bicarbonate solution, then diluted with water (20.0 mL) and extracted 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 obtain 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.

[0915] 1H NMR (400MHz, CDCl3) δppm=8.39(d,J=0.8Hz,1H),7.72(d,J=1.6Hz,1H),7.24(d,J=0.8Hz,1 H),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).

[0916] 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-sulfenamide (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 hours. 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 retained, and the filter cake was collected, triturated with dichloromethane / methanol = 10 / 1 (70.0 mL x 3) and filtered. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1 to dichloromethane / methanol = 10 / 1) to obtain (R)-N-(1-(5-(4,4-difluoropiperidin-1-yl)-2,9-dimethylimidazo[1,2-c]quinazolin-7-yl)ethylidene)-2-methylpropane-2-sulfenamide (1.10 g, 2.38 mmol, 85% yield) as a yellow solid. LCMS [M+1] + =462.2.

[0917] 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-sulfenamide (1.10 g, 2.38 mmol, 1.00 eq.) in dichloromethane (10.0 mL) and methanol (10.0 mL) were added 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.). The mixture was stirred at 25 °C for 2 hours. After completion of the reaction, the mixture was quenched by adjusting the pH to ~pH=7 by adding aqueous sodium bicarbonate at 25 °C. The obtained solution was extracted with dichloromethane / methanol=10 / 1 (90.0 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 yield 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%-60% acetonitrile over 15 minutes) to yield (R)-N-((R)-1-(5-(4,4-difluoropiperidin-1-yl)-2,9-dimethylimidazo[1,2-c]quinazolin-7-yl)ethyl)-2-methylpropane-2-sulfenamide (750 mg, 1.62 mmol, 68% yield) as a yellow solid. LCMS [M+1] + =464.3.

[0918] 1 H NMR (400MHz, CDCl3) δppm=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).

[0919] 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-sulfenamide (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 at 0°C for 1 hour. After completion of the reaction, the mixture was concentrated in vacuo to a residue. The residue was triturated with ethyl acetate (3.00 mL) at 25°C for 5 minutes 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.

[0920] 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 the reaction was completed, the mixture was cooled to 25 ° C, diluted with water (10.0 mL), and extracted with dichloromethane (30 mL × 3). The combined organic layers were washed with brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to give (R)-methyl 6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-2,9-dimethylimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinate (150 mg, 284 μmol, 75% yield) as a yellow solid. LCMS [M+1] + =529.3.

[0921] Step I: To a solution of (R)-methyl 6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-2,9-dimethylimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)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 completion of the reaction, the reaction mixture was directly filtered to obtain a filtrate. The filtrate was purified by preparative HPLC (column: Welch Xtimate C18 150×25mm×5um; mobile phase: [water(formic acid)-acetonitrile]; gradient: 35%-65% acetonitrile over 15 minutes) to afford (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.

[0922] 1 H NMR (400MHz, CD3OD) δppm=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=9.2H z,1H),5.58(q,J=6.8Hz,1H),3.68(brt,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).

[0923] 19 F NMR (377MHz, CD3OD) δppm=-98.7.

[0924] Example 6-6

[0925] (R)-6-Chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-3,9-dimethylimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid

[0926]

[0927] 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 completed, the reaction mixture was cooled to 25 ° C to obtain a suspension, which was filtered. The filter cake was triturated with petroleum ether / ethyl acetate = 1 / 1 (50.0 mL) at 25 ° C for 5 minutes and filtered. 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.

[0928] 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.). The mixture was stirred at 60°C for 12 hours. After the reaction was complete, the mixture was cooled to 25°C and water (100 mL) was added to obtain a suspension, which was then filtered and the filter cake was dried under vacuum to afford 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.

[0929] 1 H NMR (400MHz, DMSO-d6) δppm=8.06(d,J=0.8Hz,1H),7.77(d,J=1.6Hz,1H),7.3 7(d,J=0.8Hz,1H),3.46(s,4H),2.70(s,3H),2.46(s,3H),2.33-2.24(m,4H).

[0930] 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-trimethylsilylethyl ketone (1.47 g, 12.6 mmol, 2.00 eq.) in 1,2-dichloroethane (10.0 mL) were 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 the reaction was completed, the mixture was cooled to 25 ° C, filtered and concentrated under reduced pressure to obtain a solid. The solid was purified by flash silica gel chromatography ( 20g Silica gel flash column, gradient elution with 0-50% ethyl acetate / petroleum ether @ 40 mL / min) afforded 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.

[0931] 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-sulfenamide (1.49 g, 12.2 mmol, 2.00 eq.) in tetrahydrofuran (20.0 mL) were added 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.). The mixture was stirred at 70° C. under a nitrogen atmosphere for 2 hours. After the reaction was complete, the mixture was cooled to 25° C. and water (2.00 mL) was added to give a suspension. The suspension was filtered and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography ( 20g Silica gel flash column, gradient elution with 0-50% ethyl acetate / petroleum ether at 40 mL / min) afforded (R)-N-(1-(5-(4,4-difluoropiperidin-1-yl)-3,9-dimethylimidazo[1,2-c]quinazolin-7-yl)ethylidene)-2-methylpropane-2-sulfenamide (2.00 g, 4.33 mmol, 71% yield) as a yellow solid. LCMS [M+1] + =462.1.

[0932] 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 at 0 ° C for 1 hour. After completion of the reaction, the reaction mixture was quenched by adding water (2 mL) at 25 ° C, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography ( 20g Silica gel flash column, gradient elution of 0-80% ethyl acetate / petroleum ether @ 40 mL / min) afforded (R)-N-((R)-1-(5-(4,4-difluoropiperidin-1-yl)-3,9-dimethylimidazo[1,2-c]quinazolin-7-yl)ethyl)-2-methylpropane-2-sulfenamide (2.00 g, 4.31 mmol, 99% yield) as a white solid. LCMS [M+1] + =464.2.

[0933] 1 H NMR (400MHz, CDCl3) δppm=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).

[0934] Step F: (R)-N-((R)-1-(5-(4,4-difluoropiperidin-1-yl)-3,9-dimethylimidazo[1,2-c]quinazolin-7-yl)ethyl)-2-methylpropane-2-sulfenamide (800 mg, 1.73 mmol, 1.00 eq.) and a 4.0 M hydrochloric acid solution in dioxane (5.00 mL) were stirred at 25°C for 2 hours. After completion of the reaction, the reaction mixture was concentrated in vacuo to afford (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.

[0935] 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 hours. After the reaction was complete, the mixture was cooled to 25°C and 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 obtain a residue. The residue was purified by flash silica gel chromatography ( 12g Silica gel flash column, gradient elution with 0-50% ethyl acetate / petroleum ether at 40 mL / min) afforded (R)-methyl 6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-3,9-dimethylimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinate (400 mg, 756 μmol, 54% yield) as a white solid. LCMS [M+1] + =529.1.

[0936] 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)picolinic acid methyl ester (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 and diluted with water (10.0 mL) and extracted with dichloromethane (30.0 mL×3). The combined organic layers were washed with brine (10.0 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150×40 mm×15 μm; mobile phase: [water (0.1% formic acid)-acetonitrile]; gradient: 38%-68% acetonitrile over 15 minutes) to afford (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, 112 μmol, 19% yield) as a yellow solid. LCMS [M+1] +=515.2.

[0937] 1 H NMR (400MHz, CD3OD) δppm=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).

[0938] Examples 6-7 to 6-130

[0939] The following compounds were prepared essentially according to the procedures described in Schemes I-IV above and Examples 2-2, 3-1, 6-1, 6-2, 6-3, 6-4, 6-5 and 6-6.

[0940]

[0941]

[0942]

[0943]

[0944]

[0945]

[0946]

[0947]

[0948]

[0949]

[0950]

[0951]

[0952]

[0953]

[0954]

[0955]

[0956]

[0957]

[0958]

[0959]

[0960]

[0961]

[0962]

[0963]

[0964]

[0965]

[0966]

[0967]

[0968]

[0969]

[0970]

[0971]

[0972]

[0973]

[0974]

[0975]

[0976]

[0977]

[0978]

[0979]

[0980]

[0981]

[0982] Example A

[0983] This example demonstrates that representative compounds of the present invention inhibit the formation of phosphorylated AKT (pAKT) in cells.

[0984] The ability of compounds of formula (I) to inhibit pAKT formation was determined using the alphaLISA Surefire Ultra AKT 1 / 2 / 3 (pS473) Assay Kit (#ALSU-PAKT-B50K) obtained from Perkin Elmer (Waltham, MA).

[0985] To prepare assay plates for the pAKT alphaLISA assay, cells were trypsinized, resuspended in fresh culture 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 cells / w), SKBR3 (12,000 cells / w), or MKN1 (24,000 cells / w) cells were seeded at 12 μl per well in plain white flat-bottom 384 cell culture plates (Perkin Elmer #6007680).

[0986] Immediately after inoculation, cells were dosed using an Echo Liquid Handler (Beckman Coulter) with a starting concentration of 10.4 μM compound and serial dilutions (1:4) for a total of 10 concentrations. 14 vehicle (DMSO) and 14 positive control (Alpelisib@3.125 μM) wells were included on each assay plate. Cells were incubated with compound (dissolved in DMSO) at 37°C for approximately 1 hour or 24 hours. After 1 hour (or 24 hours) of treatment, cells were lysed with 3 μl of 5x lysis buffer (provided on a microtiter plate shaker and incubated at room temperature for 15 minutes). Once the cells were fully lysed, 7.5 μl of the acceptor bead mixture (prepared using the manufacturer's recommended diluent) was added to each well and placed on a microtiter plate shaker for 1 minute, and the plate was then incubated for one hour at room temperature in the dark. After incubation with the acceptor bead mixture for 1 hour, 7.5 μl of the donor bead mixture (prepared using the manufacturer's recommended diluent) was added to each well and placed on a microtiter plate shaker for 1 minute. The plate was then incubated overnight at room temperature in the dark. The plate was then imaged the next day using a CLARIOstar microplate reader (BMG Labtech, Germany).

[0987] The percentage of control values ​​was calculated by subtracting the mean signal of the positive control (alpelisib) treated wells from all treated wells (including the DMSO control wells) and then dividing by the mean signal of the vehicle DMSO treated control wells. The percentage of vehicle control values ​​was plotted as a log(inhibitor) vs. response curve – variable slope of the curve fit (four parameters) and IC was determined using XLfit. 50 value.

[0988] The results are shown in the table below.

[0989] Table A

[0990] Inhibition of pAKT in T47D (PI3Kα H1047R mutation) cells by representative compounds of formula (I)

[0991]

[0992] Table B

[0993] Inhibition of pAKT in MKN1 (PI3Kα E545K mutation) cells by representative compounds of formula (I)

[0994]

[0995] Table C

[0996] Inhibition of pAKT in SKBR3 (PI3Kα wild type) cells by representative compounds of formula (I)

[0997]

[0998] Example B

[0999] This example demonstrates that exemplary compounds of the invention reduce the viability of cells.

[1000] The ability of compounds of Formula (I) to reduce cell viability was determined using the CellTiter-Glo 2.0 (CTG) Luminescent Cell Viability Assay Kit (#G9241) obtained from Promega (Madison, WI).

[1001] To prepare assay plates for viability assays, cells were trypsinized, resuspended in fresh culture medium, and viable cells were counted using trypan blue exclusion. T47D, SKBR3, or MKN1 cells were seeded at 1000 cells per well in 30 μl of a plain white flat-bottom 384 cell culture plate (Perkin Elmer #6007680) and incubated overnight at 37°C.

[1002] On day 1 of the assay, cells were dosed using an Echo Liquid Handler (Beckman Coulter) with a starting concentration of 10 μM compound and serial dilutions (1:4) 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 equilibrated to room temperature and 15 μl of CTG was added to each well. The plates were then covered with aluminum foil to protect from light, incubated at room temperature for 30 minutes on a microtiter plate shaker, and luminescence readings were collected using a CLARIOstar microplate reader (BMG Labtech, Germany). The percentage of the vehicle control value was plotted as log(inhibitor) vs. response curve – variable slope of the curve fit (four parameters), and IC was determined using XLfit 50 value.

[1003] Table D

[1004] Representative compounds of formula (I) have an effect on the viability of T47D (PI3Kα H1047R mutation) cells

[1005]

[1006] Table F

[1007] Representative compounds of formula (I) have an effect on the viability of SKBR3 (PI3Kα wild type) cells

[1008]

[1009]

[1010] It should be understood that the embodiments and implementations described herein are for illustrative purposes only, and that those skilled in the art may make various modifications or changes based on these embodiments and implementations, and that these modifications or changes should be incorporated into the spirit and scope of this application and the scope of the appended claims. All publications, patents, and patent applications cited herein are incorporated herein by reference for all purposes.

Claims

1. Compounds of formula (I): or a pharmaceutically acceptable salt or deuterated form thereof, wherein: R 1 is H, C1-C3 alkyl or C3-C6 cycloalkyl; R 2 is phenyl or 5-6 membered heteroaryl, wherein each phenyl and heteroaryl is optionally substituted by 1-5 R 12 replace; 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 are independently H, -OH, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl; and R 3 is a C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 alkenyl, C2-C3 alkynyl or C5-C6 cycloalkenyl group which is optionally substituted, multi-substituted or fully substituted by fluorine; 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 halogen, wherein each C1-C3 alkyl and C3-C6 cycloalkyl is optionally substituted with 1-5 halo groups; T is N or CR 6 ,in R 6 is H or C1-C6 alkyl; Expression (E), (G), (J), (K), (L), or (M) in Each d represents the point of attachment of 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), X and Y are both N; Each R 5 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogen, halo-substituted C1-C6 alkyl, cyano, hydroxy, hydroxyC1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino, C3-C6 cycloalkyl, halo-substituted C3-C6 cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein each 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 groups, and each phenyl and heteroaryl is optionally substituted with 1-3 halo, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, cyano, amino, or mono- or di-(C1-C3)alkylamino groups; R 30 express -NR 7 NR 8 or R 31 , R 31 express (i) 5-7 membered heteroaryl, or (ii) a 3-8 membered monocyclic heterocyclic group linked to the tricyclic ring system via a carbon atom, wherein the heterocyclic group is saturated or unsaturated and is optionally fused to an aromatic or non-aromatic ring containing 3 to 6 ring members, wherein 1 or 2 of the ring members are optionally nitrogen atoms, oxygen atoms or sulfur atoms and the remaining ring members are carbon, or forms a spirocyclic ring system with a carbon atom from a monocyclic heterocyclyl and an additional carbon or nitrogen atom having up to 10 total ring members, wherein the ring members are carbon or nitrogen, and where R 31 Each heteroaryl and heterocyclic group in the aromatic or non-aromatic part is optionally replaced by 1-4 R 39 group substituted, where each R 39 is 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), 5-7 membered heterocyclyl, or 5-6 membered heteroaryl, wherein each phenyl, 5-7 membered heterocyclyl, and 5-6 membered heteroaryl is optionally substituted with C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxy, cyano, amino, or mono- or di-(C1-C3 alkyl)amino; R 7 represents H or C1-C3 alkyl; R 8 represents H, C1-C6 alkyl, C3-C6 cycloalkyl or C3-C6 cycloalkyl(C1-C3 alkyl) optionally substituted by 5-8 membered heterocyclyl; or R 7 and R 8 Together with the nitrogen to which they are attached, they form Ring Q, wherein Ring Q is A 3-8 membered monocyclic heterocyclic group containing one or two ring nitrogen atoms, wherein the heterocyclic group optionally fused to an aromatic or non-aromatic ring containing 3 to 6 ring members, wherein 1 or 2 of the ring members are optionally nitrogen atoms, oxygen atoms or sulfur atoms and the remaining ring members are carbon, or forms with the carbon atom from the monocyclic heterocyclyl and an additional carbon or nitrogen atom a spirocyclic ring system having up to 10 total ring members, wherein the ring members are carbon or nitrogen, and wherein each ring Q is optionally substituted with 1 to 4 R 9 group substituted, where each R 9 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), 5-7 membered heterocyclyl or 5-6 membered heteroaryl, wherein each phenyl, 5-7 membered heterocyclyl and 5-6 membered heteroaryl is optionally substituted with C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxy, cyano, amino or mono- or di-(C1-C3 alkyl)amino.

2. The compound according to claim 1, which has the formula (III): or a pharmaceutically acceptable salt or deuterated form thereof, wherein: 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 , where R A is H, C1-C6 alkyl or C3-C6 cycloalkyl, or (iv) -C(O)N(R B )2, where 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 heterocyclic 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 is 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), 5-7 membered heterocyclyl, or 5-6 membered heteroaryl, wherein each phenyl, 5-7 membered heterocyclyl, and 5-6 membered heteroaryl is optionally substituted with C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxy, cyano, amino, or mono- or di-(C1-C3 alkyl)amino; and R 51 and R 52 independently represents hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogen, halo-substituted C1-C6 alkyl, cyano, hydroxy, hydroxyC1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino, C3-C6 cycloalkyl, halo-substituted C3-C6 cycloalkyl, phenyl or 5-6 membered heteroaryl, wherein each 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 groups, and each 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 groups.

3. The compound according to claim 0, wherein R 1 It is H or CH3.

4. A compound according to claim 0 or claim 1, wherein R 3 is C1-C3 alkyl, wherein the alkyl group is unsubstituted, substituted with 1 to 5 halo groups or perfluorinated.

5. The compound according to claim 0 or claim 1, wherein R 3 It's methyl.

6. A compound according to any one of claims 0-0, wherein R 4 It's hydrogen.

7. A compound according to any one of claims 0-0, wherein R 4 It's methyl.

8. A compound according to any one of claims 0-0, wherein R 4 It's fluorine.

9. A compound according to any one of claims 0-0, wherein R 4 It's chlorine.

10. A compound according to any one of claims 0-0, wherein R 4 It is trifluoromethyl.

11. A compound according to any one of claims 0-0, wherein R 4 It is difluoromethyl.

12. A compound according to any one of claims 0-0, wherein R 4 It is fluoromethyl.

13. A compound according to any one of claims 0-0, wherein R 4 It's bromine.

14. A compound according to any one of claims 0-0, wherein V is CR 12 .

15. The compound according to any one of claims 0-0, wherein V is N.

16. A compound according to any one of claims 0-0, wherein V is CH, a is 1, and R 12 is hydrogen or a halogen.

17. A compound according to any one of claims 0-0, wherein V is CH, a is 1, and R 12 It is hydrogen or chlorine, bromine or fluorine.

18. A compound according to any one of claims 0-0, wherein V is CH, a is 1, and R 12 It's hydrogen.

19. A compound according to any one of claims 0-0, wherein V is CH, a is 1, and R 12 It's chlorine.

20. A compound according to any one of claims 0-0, wherein V is CH, a is 1, and R 12 It's bromine.

21. A compound according to any one of claims 0-0, wherein V is CH, a is 1, and R 12 It's fluorine.

22. A compound according to any one of claims 0-0, wherein V is CH, a is 1, and R 12 It's methyl.

23. A compound according to any one of claims 0-0, wherein V is N, a is 1, and R 12 is hydrogen or a halogen.

24. A compound according to any one of claims 0-0, wherein V is N, a is 1, and R 12 It is hydrogen or chlorine, bromine or fluorine.

25. A compound according to any one of claims 0-0, wherein V is N, a is 1, and R 12 It's hydrogen.

26. A compound according to any one of claims 0-0, wherein V is N, a is 1, and R 12 It's chlorine.

27. A compound according to any one of claims 0-0, wherein V is N, a is 1, and R 12 It's bromine.

28. A compound according to any one of claims 0-0, wherein V is N, a is 1, and R 12 It's methyl.

29. A compound according to any one of claims 0-0, wherein V is N, a is 1, and R 12 It's fluorine.

30. A compound according to any one of claims 0-0, wherein R 51 and R 52 independently represent hydrogen, C1-C3 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyano, halogen, cyclopropyl, halogenated C3-C6 cycloalkyl or halogenated (C1-C6) alkyl.

31. A compound according to any one of claims 0-0, wherein R 51 and R 52 One is hydrogen, and the other is methyl, ethyl, C2 alkenyl, C2 alkynyl, cyano, halogen, cyclopropyl, haloC3-C6 cycloalkyl or halo(C1-C6)alkyl.

32. A compound according to any one of claims 0-0, wherein R 51 is hydrogen and R 52 It is methyl, ethyl, C2 alkenyl, C2 alkynyl, cyano, halogen, cyclopropyl, halogenated C3-C6 cycloalkyl or halogenated (C1-C6) alkyl.

33. A compound according to any one of claims 0-0, wherein R 51 is hydrogen, and R 52 is methyl, ethyl, C2 alkenyl, C2 alkynyl, cyano, halogen, cyclopropyl, difluoromethyl, trifluoromethyl, trifluoroethyl, pentafluoroethyl, tetrafluorocyclopropyl or perfluorocyclopropyl, 34. A compound according to any one of claims 0-0, wherein R 52 is hydrogen, and R 51 It is methyl, ethyl, C2 alkenyl, C2 alkynyl, cyano, halogen, cyclopropyl, halogenated C3-C6 cycloalkyl or halogenated (C1-C6) alkyl.

35. A compound according to any one of claims 0-0, wherein R 52 is hydrogen, and R 51 is methyl, ethyl, C2 alkenyl, C2 alkynyl, cyano, halogen, cyclopropyl, difluoromethyl, trifluoromethyl, trifluoroethyl, pentafluoroethyl, tetrafluorocyclopropyl or perfluorocyclopropyl.

36. A compound according to any one of claims 0 to 0, wherein Q represents a group having the formula in Each b is 0, 1, or 2; D stands for C(R 29 )2, W represents 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 Independently, they are hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, halogenated C1-C3 alkyl, hydroxy C1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino.

37. A compound according to claim 0, wherein W is oxygen, b is 0 or 1, and R 9 It is methyl or cyano.

38. A compound according to any one of claims 0-0, wherein W is oxygen and b is 0.

39. The compound according to claim 0, wherein 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, halo-C1-C2 alkyl, hydroxy-C1-C2 alkyl, amino, mono- or di-(C1-C2 alkyl)amino.

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

41. The compound according to claim 0, wherein D and W are C(R 29 )2, b is 0, and each R 29 is independently chloro or fluoro.

42. The compound according to claim 0, wherein D and W are C(R 29 )2, b is 0, and each R 29 It's fluorine.

43. The compound according to claim 0, wherein D and W are C(R 29 )2, b is 0, and each R 29 It's hydrogen.

44. A compound according to any one of claims 0 to 0, wherein Q represents a group having the formula in Each b is 0, 1, or 2; and W represents O, NR 19 or C(R 29 )2, where 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 Independently, they are hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, halogenated C1-C3 alkyl, hydroxy C1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino.

45. A compound according to claim 0, wherein W is oxygen, b is 0 or 1, and R 9 It is methyl or cyano.

46. ​​A compound according to claim 0, wherein W is oxygen and b is O.

47. A compound according to claim 0, wherein 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, halo-C1-C2 alkyl, hydroxy-C1-C2 alkyl, amino, mono- or di-(C1-C2 alkyl)amino.

48. A compound according to claim 0, wherein W is C(R 29 )2, b is 0, and each R 29 and R is independently hydrogen, methyl, methoxy, cyano, hydroxy, chloro, fluoro, amino, methylamino, or dimethylamino.

49. A compound according to claim 0, wherein W is C(R 29 )2, b is 0, and each R 29 is independently chloro or fluoro.

50. A compound according to claim 0, wherein W is C(R 29 )2, b is 0, and each R 29 It's fluorine.

51. according to the compound of claim 0, wherein W is C (R 29 )2, b is 0, and each R 29 It's hydrogen.

52. A compound according to any one of claims 0-0, wherein Q represents a group having the formula in Each b is 0, 1, or 2; and W represents O, NR 19 or C(R 29 )2, where 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 Independently, they are hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, halogenated C1-C3 alkyl, hydroxy C1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino.

53. A compound according to claim 0, wherein W is oxygen, b is 0 or 1, and R 9 is methyl, chloro, fluoro or cyano.

54. A compound according to claim 0, wherein W is oxygen and b is O.

55. A compound according to claim 0, wherein 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, halo-C1-C2 alkyl, hydroxy-C1-C2 alkyl, amino, mono- or di-(C1-C2 alkyl)amino.

56. A compound according to claim 0, wherein W is C(R 29 )2, b is 0, and each R 29 and R is independently hydrogen, methyl, methoxy, cyano, hydroxy, chloro, fluoro, amino, methylamino, or dimethylamino.

57. A compound according to claim 0, wherein W is C(R 29 )2, b is 0, and each R 29 is independently chloro or fluoro.

58. A compound according to claim 0, wherein W is C(R 29 )2, b is 0, and each R 29 It's fluorine.

59. A compound according to claim 0, wherein W is C(R 29 )2, b is 0, and each R 29 It's hydrogen.

60. The compound according to claim 1, which has the formula (IV): or a pharmaceutically acceptable salt or deuterated form thereof, wherein: 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 , where R A is H, C1-C6 alkyl or C3-C6 cycloalkyl or (iv) -C(O)N(R B )2, where 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 heterocyclic 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 is 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), 5-7 membered heterocyclyl, or 5-6 membered heteroaryl, wherein each phenyl, 5-7 membered heterocyclyl, and 5-6 membered heteroaryl is optionally substituted with C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxy, cyano, amino, or mono- or di-(C1-C3 alkyl)amino; 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 5-6 membered heteroaryl, wherein each alkyl, cycloalkyl, phenyl and heteroaryl is optionally substituted by 1-3 halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, cyano, amino or mono- or di(C1-C3)alkylamino groups.

61. The compound according to claim 0, wherein R 1 It is H or CH3.

62. according to claim 0 or the compound of claim 0, wherein R 3 Is C1-C3 alkyl, wherein the alkyl group is unsubstituted, substituted with 1-5 halo groups or perfluorinated.

63. according to claim 0 or the compound of claim 0, wherein R 3 It's methyl.

64. A compound according to any one of claims 0-0, wherein R 4 It's hydrogen.

65. A compound according to any one of claims 0-0, wherein R 4 It's methyl.

66. A compound according to any one of claims 0-0, wherein R 4 It's ethyl.

67. A compound according to any one of claims 0-0, wherein R 4 It is cyclopropyl.

68. A compound according to any one of claims 0-0, wherein R 4 It's a methoxy group.

69. A compound according to any one of claims 0-0, wherein R 4 It's fluorine.

70. A compound according to any one of claims 0-0, wherein R 4 It's chlorine.

71. A compound according to any one of claims 0-0, wherein R 4 It is trifluoromethyl.

72. A compound according to any one of claims 0-0, wherein R 4 It is difluoromethyl.

73. A compound according to any one of claims 0-0, wherein R 4 It is fluoromethyl.

74. A compound according to any one of claims 0-0, wherein R 4 It's bromine.

75. A compound according to any one of claims 0-0, wherein V is CR 12 .

76. A compound according to any one of claims 0-0, wherein V is N.

77. A compound according to any one of claims 0-0, wherein V is CH, a is 1, and R 12 is hydrogen or a halogen.

78. A compound according to any one of claims 0-0, wherein V is CH, a is 1, and R 12 It is hydrogen or chlorine, bromine or fluorine.

79. A compound according to any one of claims 0-0, wherein V is CH, a is 1, and R 12 It's hydrogen.

80. A compound according to any one of claims 0-0, wherein V is CH, a is 1, and R 12 It's methyl.

81. A compound according to any one of claims 0-0, wherein V is CH, a is 1, and R 12 It's chlorine.

82. A compound according to any one of claims 0-0, wherein V is CH, a is 1, and R 12 It's bromine.

83. A compound according to any one of claims 0-0, wherein V is CH, a is 1, and R 12 It's fluorine.

84. A compound according to any one of claims 0-0, wherein V is N, a is 1, and R 12 is hydrogen or a halogen.

85. A compound according to any one of claims 0-0, wherein V is N, a is 1, and R 12 It is hydrogen or chlorine, bromine or fluorine.

86. A compound according to any one of claims 0-0, wherein V is N, a is 1, and R 12 It's hydrogen.

87. A compound according to any one of claims 0-0, wherein V is N, a is 1, and R 12 It's chlorine.

88. A compound according to any one of claims 0-0, wherein V is N, a is 1, and R 12 It's bromine.

89. A compound according to any one of claims 0-0, wherein V is N, a is 1, and R 12 It's methyl.

90. A compound according to any one of claims 0-0, wherein V is N, a is 1, and R 12 It's fluorine.

91. A compound according to any one of claims 0-0, wherein R 52 represents hydrogen, C1-C3 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyano, halogen, cyclopropyl or halo(C1-C6)alkyl.

92. A compound according to any one of claims 0-0, wherein R 52 It is hydrogen, methyl, ethyl, C2 alkenyl, C2 alkynyl, cyano, halogen, cyclopropyl or halo(C1-C6)alkyl.

93. A compound according to any one of claims 0-0, wherein R 52 It is methyl, ethyl, C2 alkenyl, C2 alkynyl, cyano, halogen, cyclopropyl or halo(C1-C6)alkyl.

94. A compound according to any one of claims 0-0, wherein R 52 is methyl, ethyl, cyano, halogen, cyclopropyl, fluoromethyl, difluoromethyl or trifluoromethyl.

95. A compound according to any one of claims 0-0, wherein R 52 It is a C2 alkenyl group or a C2 alkynyl group.

96. A compound according to any one of claims 0-0, wherein R 52 It's hydrogen.

97. A compound according to any one of claims 0-0, wherein R 52 is fluoromethyl, difluoromethyl or trifluoromethyl.

98. according to any one of the compounds of claim 0-0, wherein Q represents a group having the formula in Each b is 0, 1, or 2; and D stands for C(R 29 )2, W represents 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 Independently, they are hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, halogenated C1-C3 alkyl, hydroxy C1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino.

99. according to the compound of claim 0, wherein W is oxygen, b is 0 or 1, and R 9 It is methyl or cyano.

100. The compound according to claim 0, wherein W is oxygen and b is 0.

101. according to the compound of claim 0, wherein 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, halo-C1-C2 alkyl, hydroxy-C1-C2 alkyl, amino, mono- or di-(C1-C2 alkyl)amino.

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

103. according to the compound of claim 0, wherein D and W are C (R 29 )2, b is 0, and each R 29 is independently chloro or fluoro.

104. according to the compound of claim 0, wherein D and W are C (R 29 )2, b is 0, and each R 29 It's fluorine.

105. according to the compound of claim 0, wherein D and W are C (R 29 )2, b is 0, and each R 29 It's hydrogen.

106. A compound according to any one of claims 0-0, wherein Q represents a group having the formula in Each b is 0, 1, or 2; and W represents O, NR 19 or C(R 29 )2, where 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 Independently, they are hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, halogenated C1-C3 alkyl, hydroxy C1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino.

107. according to the compound of claim 0, wherein W is oxygen, b is 0 or 1, and R 9 It is methyl or cyano.

108. A compound according to claim 0, wherein W is oxygen and b is 0.

109. according to the compound of claim 0, wherein 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, halo-C1-C2 alkyl, hydroxy-C1-C2 alkyl, amino, mono- or di-(C1-C2 alkyl)amino.

110. A compound according to claim 0, wherein W is C(R 29 )2, b is 0, and each R 29 and R is independently hydrogen, methyl, methoxy, cyano, hydroxy, chloro, fluoro, amino, methylamino, or dimethylamino.

111. The compound according to claim 0, wherein W is C(R 29 )2, b is 0, and each R 29 is independently chloro or fluoro.

112. The compound according to claim 0, wherein W is C(R 29 )2, b is 0, and each R 29 It's fluorine.

113. according to the compound of claim 0, wherein W is C (R 29 )2, b is 0, and each R 29 It's hydrogen.

114. A compound according to any one of claims 0-0, wherein Q represents a group having the formula in Each b is 0, 1, or 2; and W represents O, NR 19 or C(R 29 )2, where 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 Independently, they are hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, halogenated C1-C3 alkyl, hydroxy C1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino.

115. A compound according to claim 1, wherein W is oxygen, b is 0 or 1, and R 9 is methyl, chloro, fluoro or cyano.

116. A compound according to claim 0, wherein W is oxygen and b is 0.

117. A compound according to claim 0, wherein 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, halo-C1-C2 alkyl, hydroxy-C1-C2 alkyl, amino, mono- or di-(C1-C2 alkyl)amino.

118. A compound according to claim 0, wherein W is C(R 29 )2, b is 0, and each R 29 and R is independently hydrogen, methyl, methoxy, cyano, hydroxy, chloro, fluoro, amino, methylamino, or dimethylamino.

119. A compound according to claim 0, wherein W is C(R 29 )2, b is 0, and each R 29 is independently chloro or fluoro.

120. A compound according to claim 0, wherein W is C(R 29 )2, b is 0, and each R 29 It's fluorine.

121. according to the compound of claim 0, wherein W is C (R 29 )2, b is 0, and each R 29 It's hydrogen.

122. The compound according to claim 1, which has the formula (III-A): or a pharmaceutically acceptable salt or deuterated form thereof, wherein: 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 , where R A is H, C1-C6 alkyl or C3-C6 cycloalkyl, or (iv) -C(O)N(R B )2, where 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 heterocyclic 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 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), 5-7 membered heterocyclyl or 5-6 membered heteroaryl, wherein each phenyl, 5-7 membered heterocyclyl and 5-6 membered heteroaryl is optionally substituted with C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxy, cyano, amino or mono- or di-(C1-C3 alkyl)amino.

123. according to the compound of claim 0, wherein R 1 It is H or CH3.

124. according to claim 0 or the compound of claim 0, wherein R 3 is C1-C3 alkyl, wherein the alkyl group is unsubstituted, substituted with 1 to 5 halo groups or perfluorinated.

125. according to claim 0 or the compound of claim 0, wherein R 3 It's methyl.

126. A compound according to any one of claims 0-0, wherein R 4 It's hydrogen.

127. A compound according to any one of claims 0-0, wherein R 4 It's methyl.

128. A compound according to any one of claims 0-0, wherein R 4 It's fluorine.

129. A compound according to any one of claims 0-0, wherein R 4 It's chlorine.

130. A compound according to any one of claims 0-0, wherein R 4 It is fluoromethyl.

131. A compound according to any one of claims 0-0, wherein R 4 It is difluoromethyl.

132. A compound according to any one of claims 0-0, wherein R 4 It is trifluoromethyl.

133. A compound according to any one of claims 0-0, wherein R 4 It's bromine.

134. A compound according to any one of claims 0-0, wherein V is CR 12 .

135. A compound according to any one of claims 0-0, wherein V is N.

136. A compound according to any one of claims 0-0, wherein V is CH, a is 1, and R 12 is hydrogen or a halogen.

137. A compound according to any one of claims 0-0, wherein V is CH, a is 1, and R 12 It is hydrogen or chlorine, bromine or fluorine.

138. A compound according to any one of claims 0-0, wherein V is CH, a is 1, and R 12 It's hydrogen.

139. A compound according to any one of claims 0-0, wherein V is CH, a is 1, and R 12 It's methyl.

140. A compound according to any one of claims 0-0, wherein V is CH, a is 1, and R 12 It's chlorine.

141. A compound according to any one of claims 0-0, wherein V is CH, a is 1, and R 12 It's bromine.

142. A compound according to any one of claims 0-0, wherein V is CH, a is 1, and R 12 It's fluorine.

143. A compound according to any one of claims 0-0, wherein V is N, a is 1, and R 12 is hydrogen or a halogen.

144. A compound according to any one of claims 0-0, wherein V is N, a is 1, and R 12 It is hydrogen or chlorine, bromine or fluorine.

145. A compound according to any one of claims 0-0, wherein V is N, a is 1, and R 12 It's hydrogen.

146. A compound according to any one of claims 0-0, wherein V is N, a is 1, and R 12 It's chlorine.

147. A compound according to any one of claims 0-0, wherein V is N, a is 1, and R 12 It's bromine.

148. A compound according to any one of claims 0-0, wherein V is N, a is 1, and R 12 It's methyl.

149. A compound according to any one of claims 0-0, wherein V is N, a is 1, and R 12 It's fluorine.

150. A compound according to any one of claims 0-0, wherein the group express 151. according to any one of the compounds of claim 0-0, wherein Q represents a group having the formula in Each b is 0, 1, or 2; D means C(R 29 )2, W represents 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 Independently, they are hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, halogenated C1-C3 alkyl, hydroxy C1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino.

152. according to the compound of claim 0, wherein W is oxygen, b is 0 or 1, and R 9 It is methyl or cyano.

153. A compound according to claim 0, wherein W is oxygen and b is 0.

154. according to the compound of claim 0, wherein 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, halo-C1-C2 alkyl, hydroxy-C1-C2 alkyl, amino, mono- or di-(C1-C2 alkyl)amino.

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

156. according to the compound of claim 0, wherein D and W are C (R 29 )2, b is 0, and each R 29 is independently chloro or fluoro.

157. according to the compound of claim 0, wherein D and W are C (R 29 )2, b is 0, and each R 29 It's fluorine.

158. according to the compound of claim 0, wherein D and W are C (R 29 )2, b is 0, and each R 29 It's hydrogen.

159. according to any one of the compounds of claim 0-0, wherein Q represents a group having the formula in Each b is 0, 1, or 2; and W represents O, NR 19 or C(R 29 )2, where 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 Independently, they are hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, halogenated C1-C3 alkyl, hydroxy C1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino.

160. A compound according to claim 0, wherein W is oxygen, b is 0 or 1, and R 9 It is methyl or cyano.

161. A compound according to claim 0, wherein W is oxygen and b is 0.

162. according to the compound of claim 0, wherein 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, halo-C1-C2 alkyl, hydroxy-C1-C2 alkyl, amino, mono- or di-(C1-C2 alkyl)amino.

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

164. according to the compound of claim 0, wherein W is C (R 29 )2, b is 0, and each R 29 is independently chloro or fluoro.

165. according to the compound of claim 0, wherein W is C (R 29 )2, b is 0, and each R 29 It's fluorine.

166. A compound according to claim 159, wherein W is C(R 29 )2, b is 0, and each R 29 It's hydrogen.

167. according to any one of the compounds of claim 0-0, wherein Q represents a group having the formula in Each b is 0, 1, or 2; and W represents O, NR 19 or C(R 29 )2, where 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 Independently, they are hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, halogenated C1-C3 alkyl, hydroxy C1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino.

168. according to the compound of claim 0, wherein W is oxygen, b is 0 or 1, and R 9 is methyl, chloro, fluoro or cyano.

169. A compound according to claim 0, wherein W is oxygen and b is 0.

170. According to the compound of claim 0, wherein 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, halo-C1-C2 alkyl, hydroxy-C1-C2 alkyl, amino, mono- or di-(C1-C2 alkyl)amino.

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

172. according to the compound of claim 0, wherein W is C (R 29 )2, b is 0, and each R 29 is independently chloro or fluoro.

173. According to the compound of claim 0, wherein W is C(R 29 )2, b is 0, and each R 29 It's fluorine.

174. according to the compound of claim 0, wherein W is C (R 29 )2, b is 0, and each R 29 It's hydrogen.

175. The compound according to claim 1, which has formula (V): or a pharmaceutically acceptable salt or deuterated form thereof, wherein: 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 , where R A is H, C1-C6 alkyl or C3-C6 cycloalkyl, or (iv) -C(O)N(R B )2, where 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.

176. A compound according to claim 0, wherein R 1 It is H or CH3.

177. according to claim 0 or the compound of claim 0, wherein R 3 is C1-C3 alkyl, wherein the alkyl group is unsubstituted, substituted with 1 to 5 halo groups or perfluorinated.

178. according to claim 0 or the compound of claim 0, wherein R 3 It's methyl.

179. A compound according to any one of claims 0-0, wherein R 4 It's hydrogen.

180. A compound according to any one of claims 0-0, wherein R 4 It's methyl.

181. A compound according to any one of claims 0-0, wherein R 4 It's fluorine.

182. A compound according to any one of claims 0-0, wherein R 4 It's chlorine.

183. A compound according to any one of claims 0-0, wherein R 4 It is fluoromethyl.

184. A compound according to any one of claims 0-0, wherein R 4 It is difluoromethyl.

185. A compound according to any one of claims 0-0, wherein R 4 It is trifluoromethyl.

186. A compound according to any one of claims 0-0, wherein R 4 It's bromine.

187. A compound according to any one of claims 0-0, wherein V is CR 12 .

188. A compound according to any one of claims 0-0, wherein V is N.

189. A compound according to any one of claims 0-0, wherein V is CH, a is 1, and R 12 is hydrogen or a halogen.

190. A compound according to any one of claims 0-0, wherein V is CH, a is 1, and R 12 It is hydrogen or chlorine, bromine or fluorine.

191. A compound according to any one of claims 0-0, wherein V is CH, a is 1, and R 12 It's hydrogen.

192. A compound according to any one of claims 0-0, wherein V is CH, a is 1, and R 12 It's methyl.

193. A compound according to any one of claims 0-0, wherein V is CH, a is 1, and R 12 It's chlorine.

194. A compound according to any one of claims 0-0, wherein V is CH, a is 1, and R 12 It's bromine.

195. A compound according to any one of claims 0-0, wherein V is CH, a is 1, and R 12 It's fluorine.

196. A compound according to any one of claims 0-0, wherein V is N, a is 1, and R 12 is hydrogen or a halogen.

197. A compound according to any one of claims 0-0, wherein V is N, a is 1, and R 12 It is hydrogen or chlorine, bromine or fluorine.

198. A compound according to any one of claims 0-0, wherein V is N, a is 1, and R 12 It's hydrogen.

199. A compound according to any one of claims 0-0, wherein V is N, a is 1, and R 12 It's chlorine.

200. A compound according to any one of claims 0-0, wherein V is N, a is 1, and R 12 It's bromine.

201. A compound according to any one of claims 0-0, wherein V is N, a is 1, and R 12 It's methyl.

202. A compound according to any one of claims 0-0, wherein V is N, a is 1, and R 12 It's fluorine.

203. according to any one of the compounds of claim 0-0, wherein the group express 204. A compound according to any one of claims 0-0, wherein R 31 is a 4-, 5- or 6-membered heterocyclic group, which is optionally substituted by one or two R 39 group substituted, where each R 39 Independently C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, halogenated C1-C3 alkyl, hydroxy C1-C6 alkyl, amino, mono- or di-(C1-C6 alkyl)amino.

205. The compound according to claim 0, wherein R 31 is optionally independently replaced by one or two R 39 Substituted tetrahydrofuranyl.

206. A compound according to claim 0, wherein R 31 is tetrahydrofuranyl optionally substituted independently with one or two methyl, cyano or trifluoromethyl groups.

207. The compound according to claim 0, wherein R 31 is optionally independently replaced by one or two R 39 Substituted tetrahydropyranyl.

208. The compound according to claim 0, wherein R 31 is tetrahydropyranyl optionally substituted independently with one or two methyl, cyano or trifluoromethyl groups.

209. A compound according to any one of claims 0-0, wherein R 31 is optionally independently replaced by one or two R 39 a pyridyl group substituted with a group, wherein each R 39 Independently C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxy, oxo, halogen, halogenated C1-C3 alkyl, hydroxy C1-C6 alkyl.

210. The compound of claim 1, which is: (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]hept-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]hept-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]hept-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]oct-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]hept-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]hept-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]hept-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]hept-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]hept-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]hept-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]hept-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]hept-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-(morpholin-4-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[3.3]hept-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-(morpholin-4-yl)-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]hept-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-(morpholin-4-yl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-2-Fluoro-6-((1-(9-methyl-5-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-5-Fluoro-2-((1-(9-methyl-5-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-4-Fluoro-2-((1-(9-methyl-5-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-3-Fluoro-2-((1-(9-methyl-5-(morpholin-4-yl)-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-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(9-fluoro-5-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(5-(morpholin-4-yl)-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-(morpholin-4-yl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(2-cyano-9-methyl-5-(morpholin-4-yl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(2-(difluoromethyl)-9-methyl-5-(morpholin-4-yl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(2-(fluoromethyl)-9-methyl-5-(morpholin-4-yl)imidazo[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-methyl-morpholin-4-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((1R)-1-(5-(2-ethyl-morpholin-4-yl)-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]hept-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]hept-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]hept-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]hept-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]hept-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]hept-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]hept-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-(morpholin-4-yl)-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-(morpholin-4-yl)-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)picolinic acid ethyl ester; (R)-ethyl 6-chloro-3-((1-(9-methyl-5-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinate; (R)-ethyl 2-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzoate; (R)-ethyl 2-((1-(9-methyl-5-(morpholin-4-yl)-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-(morpholin-4-yl)-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-(morpholin-4-yl)-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-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinamide; (R)-6-chloro-N-methyl-3-((1-(9-methyl-5-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinamide; (R)-6-chloro-N-hydroxy-3-((1-(9-methyl-5-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinamide; (R)-6-chloro-N-hydroxy-N-methyl-3-((1-(9-methyl-5-(morpholin-4-yl)-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-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzamide; (R)-N-methyl-2-((1-(9-methyl-5-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzamide; (R)-N-hydroxy-2-((1-(9-methyl-5-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzamide; (R)-N-Hydroxy-N-methyl-2-((1-(9-methyl-5-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzamide; (R)-N-Hydroxy-N-methyl-2-((1-(9-methyl-5-(morpholin-4-yl)-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-(morpholin-4-yl)-2-(2,2,2-trifluoroethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-6-chloro-3-((1-(9-methyl-5-(morpholin-4-yl)-2-(2,2,2-trifluoroethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-2-((1-(9-methyl-5-(morpholin-4-yl)-2-(perfluoroethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-6-chloro-3-((1-(9-methyl-5-(morpholin-4-yl)-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-(morpholin-4-yl)-2,9-bis(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)benzoic acid; (R)-6-chloro-3-((1-(5-(morpholin-4-yl)-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-(morpholin-4-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-(fluoromethyl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(9-(fluoromethyl)-5-(morpholin-4-yl)-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-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; (R)-5-methyl-2-((1-(9-methyl-5-(morpholin-4-yl)-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-(morpholin-4-yl)-2-(2,2,3,3-tetrafluorocyclopropyl)imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinic acid; or or a pharmaceutically acceptable salt thereof.

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

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

213. The method of claim 212, wherein the PI3K is PI3Kα.

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

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

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

217. The method of any one of claims 212 to 214, wherein the disease or disorder is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevus, scoliosis / skeletal and spinal syndrome) or PIK3Cα-related overgrowth syndrome (PROS).

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

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

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

221. The method of claim 219, wherein the disorder is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevus, scoliosis / skeletal and spinal syndrome) or PIK3Ca-related overgrowth syndrome (PROS).

222. 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 cancer, colorectal adenocarcinoma, gastric adenocarcinoma, head and neck squamous cell carcinoma, bile duct cancer, esophageal adenocarcinoma, bladder cancer, lung squamous cell carcinoma, 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 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 mutant-selective KRAS inhibitor, wherein the cancer is breast cancer, uterine carcinosarcoma, endometrial cancer, colorectal adenocarcinoma, gastric adenocarcinoma, head and neck squamous cell carcinoma, bile duct cancer, esophageal adenocarcinoma, bladder cancer, lung squamous cell carcinoma, glioma, adrenocortical carcinoma, hepatocellular carcinoma, sarcoma, prostate adenocarcinoma, renal cell carcinoma, lung adenocarcinoma, ovarian cystadenocarcinoma, glioblastoma multiforme, or melanoma.

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

Images