Substituted spirocyclic pyrroloquinazolinones and spirocyclic piperidinoquinazolinones

Abstract

Substituted spirocyclic pyrroloquinazolinones and spirocyclic piperidinoquinazolinones, methods for their preparation and use are disclosed.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 478,858, filed January 6, 2023, the disclosures of each of which are incorporated herein by reference in their entireties. Technical Field The present invention relates to substituted spirocyclic pyrroloquinazolinones and spirocyclic piperidinoquinazolinones, and such compounds useful in the treatment of diseases or disorders associated with PI3K modulation. [Background technology]

[0002] Cellular activities are controlled by external signals that stimulate or inhibit intracellular events. The process by which stimulatory or inhibitory signals are transmitted within and within cells, resulting in an intracellular response, is called signal transduction. Over the past few decades, cascades of signaling events have been elucidated and found to play a central role in a variety of biological responses. Defects in various components of signaling pathways have been found to be the cause of a vast number of diseases, including various types of cancer, inflammatory diseases, metabolic disorders, vascular diseases, and neurological disorders.

[0003] Kinases are a type of important signaling molecule. Kinases are generally classified as protein kinases and lipid kinases, with certain kinases exhibiting dual specificity. Protein kinases are enzymes that phosphorylate other proteins or themselves (i.e., autophosphorylate). Protein kinases can generally be classified into three major groups based on substrate utilization: tyrosine kinases, which primarily phosphorylate substrates on tyrosine residues (e.g., erb2, PDGF receptor, EGF receptor, VEGF receptor, src, abl); serine / threonine kinases, which primarily phosphorylate substrates on serine and / or threonine residues (e.g., mTORC1, mTORC2, ATM, ATR, DNA-PK, Akt); and dual specificity kinases, which phosphorylate substrates on tyrosine, serine, and / or threonine residues.

[0004] Lipid kinases are enzymes that catalyze the phosphorylation of intracellular lipids. These enzymes, and the resulting phosphorylated lipids and lipid-derived bioactive organic molecules, play roles in a variety of physiological processes, including cell proliferation, migration, adhesion, and differentiation. A specific group of lipid kinases includes membrane lipid kinases, i.e., kinases that catalyze the phosphorylation of lipids contained in or associated with the cell membrane. Examples of such enzymes include phosphoinositide kinases (e.g., PI3 kinase, PI4 kinase), diacylglycerol kinase, and sphingosine kinase.

[0005] The phosphoinositide 3-kinase (PI3K) signaling pathway is one of the most highly mutated systems in human cancer. PI3K signaling is also involved in many other diseases, including allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, psoriasis, multiple sclerosis, asthma, diabetes-related complications, and cardiovascular inflammatory complications such as acute coronary syndromes.

[0006] PI3Ks belong to a unique and conserved family of intracellular lipid kinases that phosphorylate the 3'-OH group of phosphatidylinositols or phosphoinositides. The PI3K family consists of 15 kinases, each with distinct substrate specificities, expression patterns, and modes of regulation. Class I PI3Ks (PI10a, PI10b, PI106, and PI10g) are typically activated by tyrosine kinases or G protein-coupled receptors, generate PIP3, and bind downstream effectors in pathways such as Akt / PDK1, mTOR, Tec family kinases, and Rho family GTPases. Class II and III PI3Ks play important roles in intracellular trafficking through the synthesis of PI(3)P and PI(3,4)P2.

[0007] PI3K isoforms, for example, have been implicated in a variety of human cancers and diseases. Mutations in genes encoding PI3K isoforms or mutations leading to the upregulation of PI3K isoforms are thought to occur in many human cancers. Mutations in genes encoding PI3K isoforms are point mutations clustered within several hotspots in the helical and kinase domains. Due to the high incidence of PI3K mutations, targeting this pathway may provide valuable therapeutic opportunities.

[0008] Mutations in genes involved in PI3K signaling have been implicated in 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 carcinoma, nerve sheath tumor, head and neck squamous cell carcinoma, melanoma, esophagogastric adenocarcinoma, soft tissue sarcoma, prostate cancer, fibrolamellar carcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, cholangiocarcinoma, B-cell lymphoma, mesothelioma, adrenocortical carcinoma, renal non-clear cell carcinoma, renal clear cell carcinoma, germ cell carcinoma, thymic tumors, pheochromocytoma, other neuroepithelial tumors, thyroid cancer, leukemia, and encapsulated glioma.

[0009] The alpha (α) isoform of PI3K, for example, has been implicated in various human cancers. Angiogenesis has been shown to selectively require the alpha (α) isoform of PI3K to control endothelial cell migration. Mutations in the gene encoding PI3Kα, or mutations leading to upregulation of PI3Kα, are thought to occur in many human cancers, including lung, gastric, endometrial, ovarian, bladder, breast, colon, brain, prostate, and skin cancers. Mutations in the gene encoding PI3Kα are point mutations clustered within multiple hotspots in 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. Other PI3K isoforms, such as PI3Kδ or PI3Kγ, are expressed primarily in hematopoietic cells, whereas PI3Kα is constitutively expressed along with PI3Kβ.

[0010] Because PI3Kα plays a central role in regulating glucose homeostasis in the organism, PI3K inhibition in patients often leads to hyperglycemia and / or hyperinsulinemia. High circulating insulin levels may have mitogenic and / or antiapoptotic effects on cancer cells, counteracting the antiproliferative effects of PI3K inhibitors.

[0011] For cancers with mutant PI3Kα, one way to overcome the problem of compensatory insulin and / or glucose production caused by systemic PI3Kα inhibition is to develop inhibitors with enhanced selectivity for mutant PI3Kα over wild-type PI3Kα. This would broaden the drug dosing window to selectively inhibit the pathological signaling of mutant PI3Kα in cancer cells, limiting toxicity and allowing for higher doses and more complete inhibition of the drug target, without affecting wild-type PI3Kα in host tissues that regulate systemic metabolism. Summary of the Invention [Problem to be solved by the invention]

[0012] Existing PI3Kα inhibitors have roughly equivalent potency against wild-type and mutant PI3Kα. Because the location of PI3Kα mutations is far from the active site, it has been difficult to find mutation-selective inhibitors. Therefore, inhibitors targeting the second peripheral binding pocket close to known mutations (e.g., H1047R) may provide a path to selective PI3Kα inhibition. Therefore, targeting the mutated peripheral binding pocket of PI3Kα may provide a valuable therapeutic target for drug development. [Means for solving the problem]

[0013] Therefore, kinases, including lipid kinases such as PI3K, are prime targets for drug development. DETAILED DESCRIPTION OF THE INVENTION

[0014] overview In one aspect, the present invention provides a compound of formula (I): [ka] (I) [In the formula, R 1 is H, C1-C3 alkyl, or C3-C6 cycloalkyl; R 2 is a phenyl or 5-6 membered heteroaryl group, where the phenyl and heteroaryl each have 1-5 R 7 optionally replaced by; Each R 7 are independently C1-C4 alkyl; -OR A , -C(O)OR A , (C1-C3 alkyl)-OR A , -C(O)N(R B )2, cyano, halogen or tetrazolyl; Each R A are independently H, C1-C6 alkyl, or C3-C6 cycloalkyl; Each R B is independently H, —OH, C1-C6 alkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl; and R 3 is C1-C3 alkyl optionally substituted, polysubstituted or persubstituted with fluoro, C3-C6 cycloalkyl, C2-C3 alkenyl, C2-C3 alkynyl, or C5-C6 cycloalkenyl; R 4 is H, C1-C3 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C2-C3 alkenyl, C2-C3 alkynyl, or C5-C6 cycloalkenyl, cyano, or halo, wherein each of the C1-C3 alkyl and C3-C6 cycloalkyl is optionally substituted with 1-5 halo groups; [ka] (Formula (Z)) is the following formula (D), (G), (J) or (K): [ka] (Formula (D)), [ka] (Formula (G)), [ka] (Formula (J)) or [ka] (Formula (K)) (In the formula, Each ring A is a 3-8 membered carbocyclic ring or a 3-7 membered heterocyclic ring; m is 0, 1, 2, 3, 4 or 5; p and r are independently 1 or 2, with the proviso that the sum of p and r is 2 or 3; Each R 5are 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 cycloalkyl, phenyl, and heteroaryl are each optionally substituted with 1-3 halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, cyano, amino, or mono- or di(C1-C3)alkylamino; n is 0, 1 or 2; t is 0, 1, 2, 3, or 4; Each R 8 are independently C1-C6 alkyl, C1-C6 alkoxy, cyano, hydroxy, oxo, halogen, halo(C1-C6)alkyl, hydroxyC1-C6 alkyl, amino, or mono- or di(C1-C6 alkyl)amino; and Each R 10 are independently C1-C6 alkyl, C1-C6 alkoxy, cyano, hydroxy, oxo, halogen, halo(C1-C6)alkyl, hydroxyC1-C6 alkyl, amino, or mono- or di(C1-C6 alkyl)amino, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 or R 17 where: R 11 is aryl or aryl(C1-C6)alkyl, where each aryl is independently optionally substituted with up to four C1-C6 alkyl, C1-C6 alkoxy, cyano, hydroxy, oxo, halogen, halo(C1-C6)alkyl, hydroxyC1-C6 alkyl, amino, or mono- or di(C1-C6 alkyl)amino; R 12is a 5-8 membered heteroaryl or a 5-8 membered heteroaryl(C1-C6)alkyl, where each heteroaryl is independently optionally substituted with up to four C1-C6 alkyl, C1-C6 alkoxy, cyano, hydroxy, oxo, halogen, halo(C1-C6)alkyl, hydroxyC1-C6 alkyl, amino, or mono- or di(C1-C6 alkyl)amino; R 13 is aryl(C1-C6)alkoxy, aryl(C1-C6)alkoxy(C1-C6)alkyl, aryl(C1-C6)alkylamino, or aryl(C1-C6)alkylamino(C1-C6)alkoxy, where each aryl is independently optionally substituted with up to four C1-C6 alkyl, C1-C6 alkoxy, cyano, hydroxy, oxo, halogen, halo(C1-C6)alkyl, hydroxyC1-C6 alkyl, amino, or mono- or di(C1-C6 alkyl)amino; R 14 is a 5-8 membered heteroaryl(C-C)alkoxy, a 5-8 membered heteroaryl(C-C)alkoxy(C-C)alkyl, a 5-8 membered heteroaryl(C-C)alkylamino, or a 5-8 membered heteroaryl(C-C)alkylamino(C-C)alkyl, wherein each of up to four heteroaryls is independently optionally substituted with C-C alkyl, C-C alkoxy, cyano, hydroxy, oxo, halogen, halo(C-C)alkyl, hydroxyC-C alkyl, amino, or mono- or di(C-C alkyl)amino; R 15 is (C1-C6)cycloalkyl or (C1-C6)cycloalkyl(C1-C6)alkyl, where each cycloalkyl is independently optionally substituted with up to four C1-C6 alkyl, C1-C6 alkoxy, cyano, hydroxy, oxo, halogen, halo(C1-C6)alkyl, hydroxyC1-C6 alkyl, amino, or mono- or di(C1-C6 alkyl)amino; R 16is (C-C)cycloalkyl(C-C)alkoxy, (C-C)cycloalkyl(C-C)alkoxy(C-C)alkyl, (C-C)cycloalkyl(C-C)alkylamino, or (C-C)cycloalkyl(C-C)alkylamino(C-C)alkyl, where each cycloalkyl is independently optionally substituted with up to four C-C alkyl, C-C alkoxy, cyano, hydroxy, oxo, halogen, halo(C-C)alkyl, hydroxyC-C alkyl, amino, or mono- or di(C-C alkyl)amino; and R 17 is a 5-8-membered heterocyclyl, a 5-8-membered heterocyclyl(C-C)alkyl, a 5-8-membered heterocyclyl(C-C)alkoxy, a 5-8-membered heterocyclyl(C-C)alkoxy(C-C)alkyl, a 5-8-membered heterocyclyl(C-C)alkylamino, or a 5-8-membered heterocyclyl(C-C)alkylamino(C-C)alkyl, wherein each 5-8-membered heterocyclyl is independently optionally substituted with up to four C-C alkyl, C-C alkoxy, cyano, hydroxy, oxo, halogen, halo(C-C)alkyl, hydroxyC-C alkyl, amino, or mono- or di(C-C alkyl)amino). and pharmaceutically acceptable salts thereof, as well as prodrugs, solvates, hydrates, isomers, deuterated forms, and tautomers thereof.

[0015] In another aspect, the present invention provides a pharmaceutical composition comprising a compound or salt described herein, together with a pharmaceutically acceptable carrier, excipient, or diluent.

[0016] In another aspect, the present invention provides a method for treating a disease or disorder associated with the regulation of phosphoinositide 3-kinase (PI3K), the method comprising administering to a patient in need thereof a therapeutically effective amount of any compound described elsewhere herein or a pharmaceutical composition described elsewhere herein.

[0017] In another aspect, the present invention provides a method for inhibiting phosphoinositide 3-kinase (PI3K), the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound described elsewhere herein or a pharmaceutical composition described elsewhere herein.

[0018] In another aspect, the present invention provides a method of treating a cancer or disorder, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound described elsewhere herein or a pharmaceutical composition described elsewhere herein.

[0019] The compounds disclosed herein selectively bind to H1047R mutant PI3Kα and not to wild-type PI3Kα.

[0020] In another aspect, the present invention provides intermediates and synthetic methods useful in the preparation of compounds of formula (I).

[0021] Other aspects and embodiments of the present invention will be apparent in view of the detailed description provided herein.

[0022] Detailed Description of the Invention The present invention relates to inhibitors of PI3K alpha. In particular, the present invention relates to compounds that inhibit PI3K alpha activity, pharmaceutical compositions containing therapeutically effective amounts of the compounds, and methods of use thereof.

[0023] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs.All patents, patent applications, and publications referred to in this specification are incorporated by reference to the extent consistent with this disclosure.Terms and scopes have the definitions generally defined unless explicitly defined otherwise.

[0024] For simplicity, chemical moieties are defined and referred to throughout primarily as monovalent chemical moieties (e.g., alkyl, aryl, etc.). However, such terms may also be used to convey corresponding multivalent moieties under appropriate structural circumstances apparent to one of ordinary skill in the art. For example, an "alkyl" moiety generally refers to a monovalent radical (e.g., CH3-CH2-), although under certain circumstances a divalent linking moiety may be "alkyl," in which case one of ordinary skill in the art would understand that alkyl is a divalent radical (e.g., -CH2-CH2-) and is equivalent to the term "alkylene." (Similarly, in situations where a divalent moiety is required and "aryl" is described, one of skill in the art will understand that the term "aryl" refers to the corresponding divalent moiety, arylene.) All atoms are understood to have their normal valence numbers for bond formation (i.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S, depending on the oxidation state of S).

[0025] The term "amino" refers to -NH2. The term "acetyl" refers to -C(O)CH3.

[0026] As used herein, the term "acyl" refers to an alkylcarbonyl or arylcarbonyl substituent, where the alkyl and aryl moieties are as defined herein.

[0027] As used herein, the term "alkyl" refers to saturated straight- and branched-chain aliphatic groups having 1 to 12 carbon atoms. Thus, "alkyl" includes C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, 10 , C 11 and C 12 The alkyl groups may be branched or unbranched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0028] As used herein, the term "alkenyl" refers to an unsaturated straight- or branched-chain aliphatic group having 2 to 12 carbon atoms and one or more carbon-carbon double bonds. Thus, "alkenyl" includes C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C50, C51, C52, C5 10 , C 11 and C 12 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

[0029] As used herein, the term "alkynyl" refers to an unsaturated straight- or branched-chain aliphatic group having 2 to 12 carbon atoms and having one or more carbon-carbon triple bonds. Thus, "alkynyl" includes C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C50, C51, C52, C 10 , C 11 and C 12 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0030] An "alkylene," "alkenylene," or "alkynylene" group is an alkyl, alkenyl, or alkynyl group, as defined above, that is positioned between and serves to link two other chemical groups. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene groups. Representative alkenylene groups include, but are not limited to, ethenylene, propenylene, and butenylene groups. Representative alkynylene groups include, but are not limited to, ethynylene, propynylene, and butynylene groups.

[0031] The term "alkoxy" refers to -O(C1-C6 alkyl).

[0032] The term "cycloalkyl" as used herein refers to saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons. Thus, "cycloalkyl" includes C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26 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.

[0033] The term "heteroalkyl" refers to an alkyl group, as defined above, wherein one or more carbon atoms in the chain are independently O, S, or NR x is replaced by R x is hydrogen or C1-C3 alkyl. Examples of heteroalkyl groups include methoxymethyl, methoxyethyl, and methoxypropyl.

[0034] An "aryl" group is a C6-C14 aromatic moiety containing one to three aromatic rings. Thus, "aryl" includes C6, C 10 , C 13 , and C 14 It includes cyclic hydrocarbon groups. Typical aryl groups are C6-C 10 It is an aryl group. Particular aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and fluorenyl. "Aryl" groups also include fused polycyclic (e.g., bicyclic) ring systems, such as indenyl, in which one or more fused rings are non-aromatic, provided that at least one ring is aromatic.

[0035] An "aralkyl" or "arylalkyl" group comprises an aryl group covalently bonded to an alkyl group, which in turn is bonded to another group through the alkyl portion. Representative aralkyl groups include -(C1-C6)alkyl (C6-C 10) aryl, including, but not limited to, benzyl, phenethyl, and naphthylmethyl. For example, arylC1-C3 alkyl is an aryl group covalently linked to a C1-C3 alkyl.

[0036] A "heterocyclyl" or "heterocyclic" or "heterocycloalkyl" group is a saturated or unsaturated, non-aromatic, mono- or bicyclic (fused or spiro) ring structure having 3 to 12 atoms (3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 atoms), e.g., 4 to 8 atoms, wherein one or more ring atoms are independently -C(O)-, N, NR 4, O, or S, with the remaining ring atoms being quaternary carbons or carbonyl carbons. Examples of heterocyclic groups include, but are not limited to, epoxy, oxiranyl, oxetanyl, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, thiatanyl, dithianyl, trithianyl, azathianyl, oxathianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidonyl, thiomorpholinyl, dimethylmorpholinyl, and morpholinyl. Examples of heterocyclic groups that are spirocyclic ring systems are azaspiro[2.5]octan-6-yl, 5-azaspiro[2.4]heptan-5-yl, 6-azaspiro[3.4]octan-6-yl, 5-oxa-7-azaspiro[3.4]octan-7-yl, 5,5-dimethyl-4-oxa-7-azaspiro[2.5]octan-7-yl, and 7,7-dimethyl-5-azaspiro[2.5]octan-5-yl. Specifically excluded from the scope of this term are compounds having adjacent ring oxygen and / or sulfur atoms. A heterocyclic group can be attached to the parent group (i.e., the point of attachment) through any ring atom, including one of the heteroatoms or one of the carbon atoms in the heterocyclic group. If chemically necessary, a heterocycle may be attached to one or more other groups, for example, when functioning as a bridging group. The term "heterocyclic" also includes fused polycyclic (e.g., bicyclic) ring systems in which one or more of the fused rings are aromatic or non-aromatic, but at least one ring is non-aromatic containing an N, O, or S ring atom. Examples of such fused polycyclic ring systems include indolinyl, indolin-2-yl, 2,3-dihydrobenzofuran-2-yl, and 2,3,4,5-tetrahydrobenzo[d]oxazol-2-yl. All of these examples are nine-membered heterocyclyls.

[0037] 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, sharing 6, 10, or 14 π electrons in a ring, and having, in addition to carbon atoms, 1 to 3 heteroatoms, each 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 an N, O, or S ring atom. A heteroaryl group can be attached to the parent group (i.e., the point of attachment) through any ring atom, including one of the heteroatoms or one of the carbon atoms in the heteroaryl ring group. If chemically necessary, a heteroaryl can be attached to one or more other groups, for example, when functioning as a bridging group.

[0038] 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, furanyl, Furazanyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxa Zolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclinyl thiazinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

[0039] An "arylene," "heteroarylene," or "heterocyclylene" group is a divalent aryl, heteroaryl, or heterocyclyl group, respectively, as defined above, that is positioned between and serves to link two other chemical groups.

[0040] As used herein, when a moiety (e.g., cycloalkyl, aryl, heteroaryl, heterocyclyl, urea, etc.) is described as "optionally substituted" without explicitly reciting the substituents, it means that the group optionally has multiple non-hydrogen substituents, e.g., 1 to 5, 1 to 4, 1 to 3, or 1 or 2 non-hydrogen substituents.

[0041] As used herein, the term "halogen" or "halo" refers to chlorine, bromine, fluorine, or iodine.

[0042] The term "haloalkyl" refers to an alkyl chain in which one or more hydrogens have been replaced by halogen. Exemplary haloalkyls are trifluoromethyl, difluoromethyl, fluorochloromethyl, chloromethyl, and fluoromethyl.

[0043] The term "hydroxyalkyl" refers to -alkylene-OH.

[0044] In formula (I) and other embodiments as shown, ring A is defined as a 3- to 8-membered carbocyclic ring or a 3- to 7-membered heterocyclic ring, and ring A contains a spiro atom, i.e., an atom shared by two cyclic groups.

[0045] Groups such as -C(O)OR A or -C(O)N(R B )2 is R 2 R for the nitrogen atom to which 2 R in the alpha or ortho position relative to the attachment point of 2 It is understood that in embodiments of formula (I) linked to: [ka]

[0046] It is understood that each atom present in formula (I) and compounds within formula (I) may be present in any of its naturally occurring isotopic forms, with the most abundant isotopes being preferred. Thus, for example, each hydrogen atom present in formula (I) or in the formulae below may be: 1 H, 2 H (deuterium; D) or 3 It may be present as a H (tritium; T) atom, but preferably 1 H. Similarly, for example, each carbon atom present in formula (I) or in any formula below can be 2 C. 13 C or 14 It may be present as a C atom, but is preferably 12C.

[0047] As used herein, an "effective amount" of a compound is an amount sufficient to negatively regulate or inhibit the activity of PI3K alpha.

[0048] As used herein, a "therapeutically effective amount" of a compound is an amount sufficient to ameliorate or in any way alleviate symptoms, or to halt or reverse the progression of a disease state, or to negatively regulate or inhibit the activity of PI3K alpha. Such an amount can be administered as a single dose or according to a regimen whereby this is effective.

[0049] As used herein, "treatment" means any manner in which the symptoms or pathology of a patient's condition, disorder, or disease are ameliorated or otherwise beneficially altered. As used herein, "amelioration of the symptoms of a particular disorder by the administration of a particular compound or pharmaceutical composition" refers to any relief, whether permanent or temporary, lasting or transient, resulting from or associated with the administration of the composition.

[0050] compound In one aspect, the present invention provides a compound of formula (I): [ka] (I) [In the formula, R 1 is H, C1-C3 alkyl, or C3-C6 cycloalkyl; R 2 is a phenyl or 5-6 membered heteroaryl group, where each of phenyl and heteroaryl is 1-5 R 7 optionally replaced by; Each R 7 are independently C1-C4 alkyl; -OR A , -C(O)OR A , (C1-C3 alkyl)-OR A , -C(O)N(R B )2, cyano, halogen or tetrazolyl; Each R A are independently H, C1-C6 alkyl, or C3-C6 cycloalkyl; Each R B is independently H, —OH, C1-C6 alkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl; and R 3 is C1-C3 alkyl optionally substituted, polysubstituted or persubstituted with fluoro, C3-C6 cycloalkyl, C2-C3 alkenyl, C2-C3 alkynyl, or C5-C6 cycloalkenyl; R 4 is H, C1-C3 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C2-C3 alkenyl, C2-C3 alkynyl, or C5-C6 cycloalkenyl, cyano, or halo, wherein each C1-C3 alkyl and C3-C6 cycloalkyl is each optionally substituted with 1-5 halo groups; [ka] (Formula (Z)) is the following formula (D), (G), (J) or (K): [ka] (Formula (D)), [ka] (Formula (G)), [ka] (Formula (J)) or [ka] (Formula (K)) (In the formula, Each ring A is a 3-8 membered carbocyclic ring or a 3-7 membered heterocyclic ring; m is 0, 1, 2, 3, 4 or 5; p and r are independently 1 or 2, with the proviso that the sum of p and r is 2 or 3; Each R 5 are independently C1-C6 alkyl, C1-C6 alkoxy, halogen, cyano, hydroxy, hydroxyC1-C6 alkyl, amino, mono- or di(C1-C6 alkyl)amino, C3-C6 cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein cycloalkyl, phenyl, and heteroaryl are each optionally substituted with 1-3 halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, cyano, amino, or mono- or di(C1-C3)alkylamino; n is 0, 1 or 2; t is 0, 1, 2, 3, or 4; Each R 8 are independently C1-C6 alkyl, C1-C6 alkoxy, cyano, hydroxy, oxo, halogen, halo(C1-C6)alkyl, hydroxyC1-C6 alkyl, amino, or mono- or di(C1-C6 alkyl)amino; and Each R 10 are independently C1-C6 alkyl, C1-C6 alkoxy, cyano, hydroxy, oxo, halogen, halo(C1-C6)alkyl, hydroxyC1-C6 alkyl, amino, or mono- or di(C1-C6 alkyl)amino, R 11 , R 12 , R 13 , R 14 , R15 , R 16 or R 17 where: R 11 is aryl or aryl(C1-C6)alkyl, where each aryl is independently optionally substituted with up to four C1-C6 alkyl, C1-C6 alkoxy, cyano, hydroxy, oxo, halogen, halo(C1-C6)alkyl, hydroxyC1-C6 alkyl, amino, or mono- or di(C1-C6 alkyl)amino; R 12 is a 5-8 membered heteroaryl or a 5-8 membered heteroaryl(C1-C6)alkyl, where each heteroaryl is independently optionally substituted with up to four C1-C6 alkyl, C1-C6 alkoxy, cyano, hydroxy, oxo, halogen, halo(C1-C6)alkyl, hydroxyC1-C6 alkyl, amino, or mono- or di(C1-C6 alkyl)amino; R 13 is aryl(C1-C6)alkoxy, aryl(C1-C6)alkoxy(C1-C6)alkyl, aryl(C1-C6)alkylamino, or aryl(C1-C6)alkylamino(C1-C6)alkoxy, where each aryl is independently optionally substituted with up to four C1-C6 alkyl, C1-C6 alkoxy, cyano, hydroxy, oxo, halogen, halo(C1-C6)alkyl, hydroxyC1-C6 alkyl, amino, or mono- or di(C1-C6 alkyl)amino; R 14 is a 5-8 membered heteroaryl(C-C)alkoxy, a 5-8 membered heteroaryl(C-C)alkoxy(C-C)alkyl, a 5-8 membered heteroaryl(C-C)alkylamino, or a 5-8 membered heteroaryl(C-C)alkylamino(C-C)alkyl, wherein each of up to four heteroaryls is independently optionally substituted with C-C alkyl, C-C alkoxy, cyano, hydroxy, oxo, halogen, halo(C-C)alkyl, hydroxyC-C alkyl, amino, or mono- or di(C-C alkyl)amino; and R 15 is (C1-C6)cycloalkyl or (C1-C6)cycloalkyl(C1-C6)alkyl, where each cycloalkyl is independently optionally substituted with up to four C1-C6 alkyl, C1-C6 alkoxy, cyano, hydroxy, oxo, halogen, halo(C1-C6)alkyl, hydroxyC1-C6 alkyl, amino, or mono- or di(C1-C6 alkyl)amino; R 16 is (C-C)cycloalkyl(C-C)alkoxy, (C-C)cycloalkyl(C-C)alkoxy(C-C)alkyl, (C-C)cycloalkyl(C-C)alkylamino, or (C-C)cycloalkyl(C-C)alkylamino(C-C)alkyl, where each cycloalkyl is independently optionally substituted with up to four C-C alkyl, C-C alkoxy, cyano, hydroxy, oxo, halogen, halo(C-C)alkyl, hydroxyC-C alkyl, amino, or mono- or di(C-C alkyl)amino; and R 17 is a 5-8-membered heterocyclyl, a 5-8-membered heterocyclyl(C-C)alkyl, a 5-8-membered heterocyclyl(C-C)alkoxy, a 5-8-membered heterocyclyl(C-C)alkoxy(C-C)alkyl, a 5-8-membered heterocyclyl(C-C)alkylamino, or a 5-8-membered heterocyclyl(C-C)alkylamino(C-C)alkyl, wherein each 5-8-membered heterocyclyl is independently optionally substituted with up to four C-C alkyl, C-C alkoxy, cyano, hydroxy, oxo, halogen, halo(C-C)alkyl, hydroxyC-C alkyl, amino, or mono- or di(C-C alkyl)amino). and pharmaceutically acceptable salts thereof, as well as prodrugs, solvates, hydrates, isomers, deuterated forms, and tautomers thereof.

[0051] As described elsewhere herein, in certain embodiments of formula (I), formula (Z) represents formula (D).

[0052] As described elsewhere herein, in certain embodiments of formula (I), formula (Z) represents formula (G).

[0053] As described elsewhere herein, in certain embodiments of formula (I), formula (Z) represents formula (J).

[0054] As described elsewhere herein, in certain embodiments of Formula (I), ring A is a 5-7 membered carbocyclic ring.

[0055] As described elsewhere herein, in certain embodiments of Formula (I), ring A is a 5-7 membered heterocyclic ring.

[0056] As described elsewhere herein, in certain embodiments of Formula (I), ring A is cyclohexyl or cyclopentyl.

[0057] As described elsewhere herein, in certain embodiments of Formula (I), ring A is pyranyl or azetidinyl.

[0058] As described elsewhere herein, in certain embodiments of formula (I), R 1 is H or CH3.

[0059] As described elsewhere herein, in certain embodiments of formula (I), R 2 is optionally substituted phenyl or optionally substituted pyridyl.

[0060] As described elsewhere herein, in certain embodiments of formula (I), R 2 are 1-5 R 7is phenyl, pyridinyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyrazinyl, pyridazinyl or pyrimidinyl optionally substituted by

[0061] As described elsewhere herein, in certain embodiments of formula (I), R 2 are 1-5 R 7 is phenyl or pyridinyl, optionally substituted by

[0062] As described elsewhere herein, in certain embodiments of formula (I), R 2 are 1-5 R 7 phenyl or pyridinyl optionally substituted with one R 7 is -C(O)OR A or -C(O)N(R B )2, where -C(O)OR A or -C(O)N(R B )2 is R 2 R for the nitrogen atom to which is bonded 2 R in the alpha position, i.e., ortho position, relative to the attachment point of 2 Combine with.

[0063] As described elsewhere herein, in certain embodiments of formula (I), R 2 are 1-5 R 7 phenyl or pyridinyl optionally substituted with at least one R 7 is cyano, where at least one cyano is R 2 R for the nitrogen atom to which is bonded 2 R in the alpha position relative to the attachment point of 2 Combine with.

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

[0065] As described elsewhere herein, in certain embodiments of formula (I), R 2 is one, two or three R 7 The group is phenyl or 5-7 membered heteroaryl substituted with a group.

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

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

[0068] As described elsewhere herein, in certain embodiments of formula (I), R 2 has at least one -C(O)OR A where -C(O)OR A is R 2 R for the nitrogen atom to which is bonded 2 R in the alpha position relative to the attachment point of 2 Combine with.

[0069] As described elsewhere herein, in certain embodiments of formula (I), R 2 is phenyl or 5-7 membered heteroaryl, each of which is 1, 2, 3, or 4 R 7 group and at least one R 7 The group is -C(O)OR A where -C(O)OR A is R 2 R for the nitrogen atom to which is bonded2 R in the alpha position relative to the attachment point of 2 Combine with.

[0070] As described elsewhere herein, in certain embodiments of formula (I), R 2 is one, two or three R 7 phenyl or 5-7 membered heteroaryl substituted with a group, and at least one R 7 The group is -C(O)OR A , where -C(O)OR A is R 2 R for the nitrogen atom to which is bonded 2 R in the alpha position relative to the attachment point of 2 Combine with.

[0071] As described elsewhere herein, in certain embodiments of formula (I), R 3 is a C1-C3 alkyl group, where the alkyl group is unsubstituted, substituted with 1-5 halo groups, or perfluorinated.

[0072] As described elsewhere herein, in certain embodiments of Formula (I), m is 0, 1, or 2, and each R 5 is halogen, hydroxy, cyano or amino.

[0073] As described elsewhere herein, in certain embodiments of formula (I), R 2 is 1, 2, 3 or 4 R 7 and phenyl optionally substituted with a group.

[0074] As described elsewhere herein, in certain embodiments of formula (I), R 2 is 1, 2, 3 or 4 R 7 and pyridinyl optionally substituted with a group.

[0075] As described elsewhere herein, in certain embodiments of Formula (I), R is selected from 1, 2, 3, or 4 R 7and thienyl optionally substituted with a group.

[0076] As described elsewhere herein, in certain embodiments of formula (I), R 2 is 1, 2, 3 or 4 R 7 and thiazolyl optionally substituted with a group.

[0077] As described elsewhere herein, in certain embodiments of formula (I), R 2 is 1, 2, 3 or 4 R 7 and oxazolyl optionally substituted with a group.

[0078] As described elsewhere herein, in certain embodiments of formula (I), R 2 is 1, 2, 3 or 4 R 7 isoxazolyl optionally substituted with a group.

[0079] As described elsewhere herein, in certain embodiments of Formula (I), R is selected from 1, 2, 3, or 4 R 7 and imidazolyl optionally substituted with a group.

[0080] As described elsewhere herein, in certain embodiments of formula (I), R 2 is 1, 2, 3 or 4 R 7 and pyrazolyl optionally substituted with a group.

[0081] As described elsewhere herein, in certain embodiments of Formula (I), R is selected from 1, 2, 3, or 4 R 7 and pyrazinyl optionally substituted with a group.

[0082] As described elsewhere herein, in certain embodiments of formula (I), R 2 is 1, 2, 3 or 4 R 7 and pyridazinyl optionally substituted with a group.

[0083] As described elsewhere herein, in certain embodiments of Formula (I), R is selected from 1, 2, 3, or 4 R 7 and pyrimidinyl optionally substituted with a group.

[0084] As described elsewhere herein, in certain embodiments of formula (I), R 2 is one -C(O)OR A is optionally replaced by

[0085] As described elsewhere herein, in certain embodiments of formula (I), R 4 is hydrogen, fluoro, chloro, bromo, methyl, methoxy, ethyl, ethoxy, cyclopropyl, trifluoromethyl or cyano.

[0086] As described elsewhere herein, in certain embodiments of formula (I), R 4 is hydrogen, methyl, ethyl or cyano.

[0087] As described elsewhere herein, in certain embodiments of formula (I), R 4 is methoxy.

[0088] As described elsewhere herein, in certain embodiments of formula (I), R 4 is fluoro, chloro, or bromo.

[0089] As described elsewhere herein, in certain embodiments of formula (I), R 4 is hydrogen.

[0090] As described elsewhere herein, in certain embodiments of formula (I), R 4 is fluoro.

[0091] As described elsewhere herein, in certain embodiments of formula (I), R 4 is chloro.

[0092] As described elsewhere herein, in certain embodiments of formula (I), R 4 is bromo.

[0093] As described elsewhere herein, in certain embodiments of formula (I), R 4 is methyl.

[0094] As described elsewhere herein, in certain embodiments of formula (I), R 4 is ethyl.

[0095] As described elsewhere herein, in certain embodiments of formula (I), R 4 is cyano.

[0096] As described elsewhere herein, in certain embodiments of formula (I), R 4 is cyclopropyl.

[0097] As described elsewhere herein, in certain embodiments of formula (I), R 4 is trifluoromethyl.

[0098] As described elsewhere herein, in certain embodiments of Formula (I), m is 0.

[0099] As described elsewhere herein, in certain embodiments of Formula (I), m is 1 or 2, and each R 5 is 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.

[0100] As described elsewhere herein, in certain embodiments of Formula (I), m is 1 or 2, and each R 5is 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.

[0101] As described elsewhere herein, in certain embodiments of formula (I), R 8 is hydrogen or C1-C6 alkyl.

[0102] As described elsewhere herein, in certain embodiments of Formula (I), the compound has the formula: [ka] [6-chloro-3-((1-(2,6,6-trimethyl-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-4-yl)ethyl)amino)picolinic acid] It is not a compound represented by the formula:

[0103] As described elsewhere herein, in certain embodiments of Formula (I), the compound has the following formula (IIa-1), (IIa-2), (IIa-3), (IIb-1), (IIb-2), (IIb-3), (IIc-1), (IIc-2), (IIc-3), (IId-1), (IId-2), or (IId-3): [ka] [ka] [In the formula, R 1 is H, C1-C3 alkyl, or C3-C6 cycloalkyl; R 2 is phenyl or pyridinyl, where each phenyl and pyridinyl is selected from 1-5 R 7 optionally replaced by; Each R7 are independently C1-C4 alkyl; -OR A , -C(O)OR A , (C1-C3 alkyl)-OR A , -C(O)N(R B )2, cyano, halogen or tetrazolyl; Each R A are independently H, C1-C6 alkyl, or C3-C6 cycloalkyl; Each R B is independently H, —OH, C1-C6 alkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl; and R 3 is C1-C3 alkyl or C3-C6 cycloalkyl; R 4 is H, C1-C3 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, or halo, where each C1-C3 alkyl is optionally substituted with 1-5 halo groups; m is 0, 1, 2, 3, 4 or 5; Each R 5 are independently C1-C6 alkyl, C1-C6 alkoxy, halogen, cyano, hydroxy, hydroxyC1-C6 alkyl, amino, or 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; where R 5 Each non-spiro carbon in the ring having may be replaced with a heteroatom which is nitrogen, oxygen, or sulfur; n is 0, 1, or 2; and Each R 8 are independently C1-C6 alkyl, C1-C6 alkoxy, cyano, hydroxy, halogen, oxo, hydroxyC1-C6 alkyl, amino, or mono- or di(C1-C6 alkyl)amino. or a pharmaceutically acceptable salt thereof.

[0104] In certain embodiments described elsewhere herein, m is 0, 1, or 2, and each R 5 are independently halogen, hydroxy, cyano, or amino.

[0105] In certain embodiments of Formulas (IIa-1) through (IId-3) described elsewhere herein, n is 0 or 1, and each R 8 is halogen, hydroxy, cyano or amino.

[0106] In certain embodiments of formulas (IIa-1) to (IId-3) described elsewhere herein, R 3 is C1-C3 alkyl.

[0107] In certain embodiments of formulas (IIa-1) to (IId-3) described elsewhere herein, R 3 is methyl.

[0108] In certain embodiments of formulas (IIa-1) to (IId-3) described elsewhere herein, R 4 is H, C1-C3 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, fluoro, chloro, bromo, cyclopropyl, trifluoromethyl or cyano.

[0109] In certain embodiments of formulas (IIa-1) to (IId-3) described elsewhere herein, R 4 is hydrogen, methyl, methoxy, ethyl, or cyano.

[0110] In certain embodiments of formulas (IIa-1) to (IId-3) described elsewhere herein, R 4 is fluoro, chloro, or bromo.

[0111] In certain embodiments of formulas (IIa-1) to (IId-3) described elsewhere herein, R 4 is hydrogen.

[0112] In certain embodiments of formulas (IIa-1) to (IId-3) described elsewhere herein, R 4 is methoxy.

[0113] In certain embodiments of formulas (IIa-1) to (IId-3) described elsewhere herein, R 4 is fluoro.

[0114] In certain embodiments of formulas (IIa-1) to (IId-3) described elsewhere herein, R 4 is chloro.

[0115] In certain embodiments of formulas (IIa-1) to (IId-3) described elsewhere herein, R 4 is bromo.

[0116] In certain embodiments of formulas (IIa-1) to (IId-3) described elsewhere herein, R 4 is methyl.

[0117] In certain embodiments of formulas (IIa-1) to (IId-3) described elsewhere herein, R 4 is ethyl.

[0118] In certain embodiments of formulas (IIa-1) to (IId-3) described elsewhere herein, R 4 is cyano.

[0119] In certain embodiments of formulas (IIa-1) to (IId-3) described elsewhere herein, R 4 is cyclopropyl.

[0120] In certain embodiments of formulas (IIa-1) to (IId-3) described elsewhere herein, R 4 is trifluoromethyl.

[0121] In certain embodiments of formulas (IIa-1) to (IId-3) described elsewhere herein, R 2are 1-5 R 7 is phenyl or pyridinyl optionally substituted with

[0122] In certain embodiments of formulas (IIa-1) to (IId-3) described elsewhere herein, R 2 is phenyl or pyridinyl, each of which has 1-5 R 7 where one R 7 is -C(O)OR A or -C(O)N(R B )2, where -C(O)OR A or -C(O)N(R B )2 is R 2 R for the nitrogen atom to which is bonded 2 R in the alpha position, i.e., ortho position, relative to the attachment point of 2 Combine with.

[0123] In certain embodiments of formulas (IIa-1) to (IId-3) described elsewhere herein, R 2 are 1-5 R 7 phenyl or pyridinyl optionally substituted with 7 is cyano, where at least one cyano is R 2 R for the nitrogen atom to which is bonded 2 R in the alpha position relative to the attachment point of 2 Combine with.

[0124] In certain embodiments of formulas (IIa-1) to (IId-3) described elsewhere herein, R 2 is 1, 2, 3 or 4 R 7 The aryl group is phenyl or 5-7 membered heteroaryl substituted with a group.

[0125] In certain embodiments of formulas (IIa-1) to (IId-3) described elsewhere herein, R 2 is one, two or three R 7 The aryl group is phenyl or 5-7 membered heteroaryl substituted with a group.

[0126] In certain embodiments of formulas (IIa-1) to (IId-3) described elsewhere herein, R 2 is 1, 2, 3 or 4 R 7 phenyl or 5-7 membered heteroaryl substituted with a group, and at least one R 7 The group is -C(O)OR A is.

[0127] In certain embodiments of formulas (IIa-1) to (IId-3) described elsewhere herein, R 2 is one, two or three R 7 phenyl or 5-7 membered heteroaryl substituted with a group, and at least one R 7 The group is -C(O)OR A is.

[0128] In certain embodiments of formulas (IIa-1) to (IId-3) described elsewhere herein, R 2 has at least one -C(O)OR A where -C(O)OR A is R 2 R for the nitrogen atom to which is bonded 2 R in the alpha position relative to the attachment point of 2 Combine with.

[0129] In certain embodiments of formulas (IIa-1) to (IId-3) described elsewhere herein, R 2 is 1, 2, 3 or 4 R 7 phenyl or 5-7 membered heteroaryl substituted with a group, and at least one R 7 The group is -C(O)OR A where -C(O)OR A is R 2 R for the nitrogen atom to which is bonded 2 R in the alpha position relative to the attachment point of 2 Combine with.

[0130] In certain embodiments of formulas (IIa-1) to (IId-3) described elsewhere herein, R 2is one, two or three R 7 phenyl or 5-7 membered heteroaryl substituted with a group, and at least one R 7 The group is -C(O)OR A where -C(O)OR A is R 2 R for the nitrogen atom to which is bonded 2 R in the alpha position relative to the attachment point of 2 Combine with.

[0131] In certain embodiments of formulas (IIa-1) to (IId-3) described elsewhere herein, R 2 is one -C(O)OR A is optionally replaced by

[0132] R 5 As a specific embodiment of formulas (IIa-1), (IIa-2), (IIa-3), (IIb-1), (IIb-2), (IIb-3), (IIc-1), (IIc-2), (IIc-3), (IId-1), (IId-2), and (IId-3), in which the non-spiro carbon in the ring having [ka] [ka] [In the formula, R 1 is H, C1-C3 alkyl, or C3-C6 cycloalkyl; R 2 is phenyl or pyridinyl, where phenyl and pyridinyl each have 1-5 R 7 optionally replaced by; Each R 7 are independently C1-C4 alkyl; -OR A , -C(O)OR A , (C1-C3 alkyl)-OR A , -C(O)N(R B)2, cyano, halogen or tetrazolyl; Each R A are independently H, C1-C6 alkyl, or C3-C6 cycloalkyl; Each R B is independently H, —OH, C1-C6 alkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl; and R 3 is C1-C3 alkyl or C3-C6 cycloalkyl; R 4 is H, C1-C3 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, or halo, where each C1-C3 alkyl is optionally substituted with 1-5 halo groups; m is 0 or 1; Each R 5 are independently C1-C6 alkyl, C1-C6 alkoxy, halogen, cyano, hydroxy, hydroxyC1-C6 alkyl, amino, or 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; R 9 is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, cyano, hydroxy, hydroxyC1-C6 alkyl, amino, or 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; n is 0, 1, or 2; and Each R 8are independently C1-C6 alkyl, C1-C6 alkoxy, cyano, hydroxy, halogen, oxo, hydroxyC1-C6 alkyl, amino, or mono- or di(C1-C6 alkyl)amino. or a pharmaceutically acceptable salt thereof.

[0133] In certain embodiments of Formulas (IIb-1A), (IIb-1B), (IIc-1A), (IIc-1B), (IId-1A), and (IId-1B), as described elsewhere herein, n is 0 or 1, and each R 8 is halogen, hydroxy, cyano or amino.

[0134] In certain embodiments of formulas (IIb-1A), (IIb-1B), (IIc-1A), (IIc-1B), (IId-1A), and (IId-1B), as described elsewhere herein, R 3 is C1-C3 alkyl.

[0135] In certain embodiments of formulas (IIb-1A), (IIb-1B), (IIc-1A), (IIc-1B), (IId-1A), and (IId-1B), as described elsewhere herein, R 3 is methyl.

[0136] In certain embodiments of formulas (IIb-1A), (IIb-1B), (IIc-1A), (IIc-1B), (IId-1A), and (IId-1B), as described elsewhere herein, R 4 is H, C1-C3 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, fluoro, chloro, bromo, cyclopropyl, trifluoromethyl or cyano.

[0137] In certain embodiments of formulas (IIb-1A), (IIb-1B), (IIc-1A), (IIc-1B), (IId-1A), and (IId-1B), as described elsewhere herein, R 4 is hydrogen, methyl, methoxy, ethyl, ethoxy, cyclopropyl, trifluoromethyl or cyano.

[0138] In certain embodiments of formulas (IIb-1A), (IIb-1B), (IIc-1A), (IIc-1B), (IId-1A), and (IId-1B), as described elsewhere herein, R 4 is fluoro, chloro, or bromo.

[0139] In certain embodiments of formulas (IIb-1A), (IIb-1B), (IIc-1A), (IIc-1B), (IId-1A), and (IId-1B), as described elsewhere herein, R 4 is methoxy.

[0140] In certain embodiments of formulas (IIb-1A), (IIb-1B), (IIc-1A), (IIc-1B), (IId-1A), and (IId-1B), as described elsewhere herein, R 4 is hydrogen.

[0141] In certain embodiments of formulas (IIb-1A), (IIb-1B), (IIc-1A), (IIc-1B), (IId-1A), and (IId-1B), as described elsewhere herein, R 4 is fluoro.

[0142] In certain embodiments of formulas (IIb-1A), (IIb-1B), (IIc-1A), (IIc-1B), (IId-1A), and (IId-1B), as described elsewhere herein, R 4 is chloro.

[0143] In certain embodiments of formulas (IIb-1A), (IIb-1B), (IIc-1A), (IIc-1B), (IId-1A), and (IId-1B), as described elsewhere herein, R 4 is bromo.

[0144] In certain embodiments of formulas (IIb-1A), (IIb-1B), (IIc-1A), (IIc-1B), (IId-1A), and (IId-1B), as described elsewhere herein, R 4 is methyl.

[0145] In certain embodiments of formulas (IIb-1A), (IIb-1B), (IIc-1A), (IIc-1B), (IId-1A), and (IId-1B), as described elsewhere herein, R 4 is ethyl.

[0146] In certain embodiments of formulas (IIb-1A), (IIb-1B), (IIc-1A), (IIc-1B), (IId-1A), and (IId-1B), as described elsewhere herein, R 4 is cyano.

[0147] In certain embodiments of formulas (IIb-1A), (IIb-1B), (IIc-1A), (IIc-1B), (IId-1A), and (IId-1B), as described elsewhere herein, R 4 is cyclopropyl.

[0148] In certain embodiments of formulas (IIb-1A), (IIb-1B), (IIc-1A), (IIc-1B), (IId-1A), and (IId-1B), as described elsewhere herein, R 4 is trifluoromethyl.

[0149] In certain embodiments of formulas (IIb-1A), (IIb-1B), (IIc-1A), (IIc-1B), (IId-1A), and (IId-1B), as described elsewhere herein, R 2 is one -C(O)OR A is optionally replaced by

[0150] In certain embodiments of formulas (IIb-1A), (IIb-1B), (IIc-1A), (IIc-1B), (IId-1A), and (IId-1B), as described elsewhere herein, R 2 are 1-5 R 7 is phenyl or pyridinyl optionally substituted with

[0151] In certain embodiments of formulas (IIb-1A), (IIb-1B), (IIc-1A), (IIc-1B), (IId-1A), and (IId-1B), as described elsewhere herein, R 2 is phenyl or pyridinyl, each of which has 1-5 R 7 where one R 7 is -C(O)OR A or -C(O)N(R B )2, where -C(O)OR A or -C(O)N(R B )2 is R 2 R for the nitrogen atom to which is bonded 2 R in the alpha position, i.e., ortho position, relative to the attachment point of 2 Combine with.

[0152] In certain embodiments of formulas (IIb-1A), (IIb-1B), (IIc-1A), (IIc-1B), (IId-1A), and (IId-1B), as described elsewhere herein, R 2 is phenyl or pyridinyl, each of which has 1-5 R 7 where at least one R 7 is cyano, where at least one cyano is R 2 R for the nitrogen atom to which is bonded 2 R in the alpha position relative to the attachment point of 2 Combine with.

[0153] In certain embodiments of formulas (IIb-1A), (IIb-1B), (IIc-1A), (IIc-1B), (IId-1A), and (IId-1B), as described elsewhere herein, R 2 is phenyl or 5-7 membered heteroaryl, each of which is 1, 2, 3, or 4 R 7 The group is substituted.

[0154] In certain embodiments of formulas (IIb-1A), (IIb-1B), (IIc-1A), (IIc-1B), (IId-1A), and (IId-1B), as described elsewhere herein, R 2is one, two or three R 7 The group is phenyl or 5-7 membered heteroaryl substituted with a group.

[0155] In certain embodiments of formulas (IIb-1A), (IIb-1B), (IIc-1A), (IIc-1B), (IId-1A), and (IId-1B), as described elsewhere herein, R 2 is phenyl or 5-7 membered heteroaryl, each of which is 1, 2, 3, or 4 R 7 group and at least one R 7 The group is -C(O)OR A is.

[0156] In certain embodiments of formulas (IIb-1A), (IIb-1B), (IIc-1A), (IIc-1B), (IId-1A), and (IId-1B), as described elsewhere herein, R 2 is one, two or three R 7 phenyl or 5-7 membered heteroaryl substituted with a group, and at least one R 7 The group is -C(O)OR A is.

[0157] In certain embodiments of formulas (IIb-1A), (IIb-1B), (IIc-1A), (IIc-1B), (IId-1A), and (IId-1B), as described elsewhere herein, R 2 has at least one -C(O)OR A where -C(O)OR A is R 2 R for the nitrogen atom to which is bonded 2 R in the alpha position relative to the attachment point of 2 Combine with.

[0158] In certain embodiments of formulas (IIb-1A), (IIb-1B), (IIc-1A), (IIc-1B), (IId-1A), and (IId-1B), as described elsewhere herein, R 2 is phenyl or 5-7 membered heteroaryl, each of which is 1, 2, 3, or 4 R 7group and at least one R 7 The group is -C(O)OR A where -C(O)OR A is R 2 R for the nitrogen atom to which is bonded 2 R in the alpha position relative to the attachment point of 2 Combine with.

[0159] In certain embodiments of formulas (IIb-1A), (IIb-1B), (IIc-1A), (IIc-1B), (IId-1A), and (IId-1B), as described elsewhere herein, R 2 is one, two or three R 7 phenyl or 5-7 membered heteroaryl substituted with a group, and at least one R 7 The group is -C(O)OR A where -C(O)OR A is R 2 R for the nitrogen atom to which is bonded 2 R in the alpha position relative to the attachment point of 2 Combine with.

[0160] As described elsewhere herein, in certain embodiments of Formula (I), the compound has the following formula (IIIa) or (IIIb): [ka] [In the formula, R 1 is H, C1-C3 alkyl, or C3-C6 cycloalkyl; R 2 is phenyl or pyridinyl, where phenyl and pyridinyl each have 1-5 R 7 optionally replaced by; Each R 7 are independently C1-C4 alkyl; -OR A , -C(O)OR A , (C1-C3 alkyl)-OR A , -C(O)N(R B )2, cyano, halogen or tetrazolyl; Each RA are independently H, C1-C6 alkyl, or C3-C6 cycloalkyl; Each R B is independently H, —OH, C1-C6 alkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl; and R 3 is C1-C3 alkyl or C3-C6 cycloalkyl; and R 4 is H, C1-C3 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, or halo, where each C1-C3 alkyl is optionally substituted with 1-5 halo groups. or a pharmaceutically acceptable salt thereof.

[0161] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, each R 10 are independently C1-C6 alkyl, C1-C6 alkoxy, cyano, hydroxy, oxo, halogen, halo(C1-C6)alkyl, hydroxyC1-C6 alkyl, amino, or mono- or di(C1-C6 alkyl)amino.

[0162] In certain embodiments of Formula (IIIa) or Formula (IIIb), described elsewhere herein, t is 1.

[0163] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, t is 2 and both R 10 The groups are attached to the same carbon atom.

[0164] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, t is 2 and R 10 The groups are attached to different carbon atoms.

[0165] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, each R 10are independently C1-C6 alkyl, C1-C6 alkoxy, cyano, hydroxy, oxo, halogen, halo(C1-C3)alkyl, hydroxyC1-C3 alkyl, amino, or mono- or di(C1-C3 alkyl)amino.

[0166] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, each R 10 is independently C1-C2 alkyl, C1-C2 alkoxy, cyano, hydroxy, halogen, or halo(C1-C2)alkyl.

[0167] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, each R 10 is independently C1-C2 alkyl, chloro, fluoro, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0168] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, t is 1 and R 10 is C1-C2 alkyl, chloro, fluoro, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0169] In certain embodiments of Formula (IV) or Formula (V) described elsewhere herein, t is 2 and both R 10 The groups are identical and are C1-C2 alkyl, chloro, fluoro, or fluoromethyl.

[0170] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, t is 1 and R 10 is C1-C2 alkyl, fluoro, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0171] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, t is 1 and R 10is C1-C2 alkyl, fluoro or trifluoromethyl.

[0172] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, t is 2 and both R 10 The groups are identical and are methyl, ethyl or fluoro.

[0173] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, t is 2 and both R 10 The groups are identical and are C1-C2 alkyl, fluoro, or fluoromethyl.

[0174] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, t is 1 and R 10 is R 11 , R 12 , R 13 , R 14 , R 15 , R 16 or R 17 is.

[0175] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, t is 2 and one R 10 is C1-C6 alkyl, halogen or halo(C1-C2)alkyl, and the other is R 11 , R 12 , R 13 , R 14 , R 15 , R 16 or R 17 is.

[0176] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, t is 2 and one R 10 is C1-C2 alkyl, halogen or halo(C1-C2)alkyl, and the other is R 11 , R 12 , R 13 , R 14 , R 15 , R16 or R 17 is.

[0177] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, t is 2 and one R 10 is C1-C2 alkyl, chloro, fluoro, or halo(C1-C2)alkyl, and the other is R 11 , R 12 , R 13 , R 14 , R 15 , R 16 or R 17 is.

[0178] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, t is 2 and both R 10 The R groups are attached to the same carbon atom, and one R 10 is C1-C2 alkyl, chloro, fluoro, or halo(C1-C2)alkyl, and the other is R 11 , R 12 , R 13 , R 14 , R 15 , R 16 or R 17 is.

[0179] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, t is 2 and R 10 The groups are attached to different carbon atoms, and one R 10 is C1-C2 alkyl, chloro, fluoro, or halo(C1-C2)alkyl, and the other is R 11 , R 12 , R 13 , R 14 , R 15 , R 16 or R 17 is.

[0180] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, t is 1 and R 10 is R 11 is.

[0181] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, t is 1 and R 10 is R 12 is.

[0182] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, t is 1 and R 10 is R 13 is.

[0183] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, t is 1 and R 10 is R 14 is.

[0184] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, t is 1 and R 10 is R 15 is.

[0185] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, t is 1 and R 10 is R 16 is.

[0186] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, t is 1 and R 10 is R 17 is.

[0187] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, R 10 is R 11 or R 12 is.

[0188] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, R 11 and R 12 is non-substituted.

[0189] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, R 11 and R 12 is substituted with C1-C2 alkyl, bromo, chloro, fluoro, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0190] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, t is 2 and one R 10 is C1-C6 alkyl, halogen or halo(C1-C2)alkyl, and the other is R 11 where R 11 is phenyl(C1-C6)alkyl, wherein said phenyl is optionally substituted with one, two, or three C1-C6 alkyl, C1-C6 alkoxy, cyano, hydroxy, oxo, halogen, halo(C1-C6)alkyl, hydroxyC1-C6 alkyl, amino, or mono- or di(C1-C6 alkyl)amino.

[0191] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, t is 2 and one R 10 is C1-C6 alkyl, halogen or halo(C1-C2)alkyl, and the other is R 11 where R 11 is a 5- or 6-membered heteroaryl(C1-C6)alkyl, wherein said heteroaryl is optionally substituted with one, two, or three C1-C6 alkyl, C1-C6 alkoxy, cyano, hydroxy, oxo, halogen, halo(C1-C6)alkyl, hydroxyC1-C6 alkyl, amino, or mono- or di(C1-C6 alkyl)amino.

[0192] In certain embodiments of Formula (IIIa) or Formula (IIIb), described elsewhere herein, heteroaryl is optionally substituted with pyridyl, thiazolyl, imidazolyl, oxazolyl, or isoxazolyl.

[0193] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, R 3 is C1-C3 alkyl.

[0194] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, R 3 is methyl.

[0195] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, R 4 is H, C1-C3 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, fluoro, chloro, bromo, cyclopropyl, trifluoromethyl or cyano.

[0196] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, R 4 is hydrogen, methyl, ethyl, ethoxy or cyano.

[0197] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, R 4 is methoxy.

[0198] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, R 4 is fluoro, chloro, or bromo.

[0199] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, R 4 is hydrogen.

[0200] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, R 4 is fluoro.

[0201] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, R 4 is chloro.

[0202] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, R 4 is bromo.

[0203] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, R 4 is methyl.

[0204] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, R 4 is ethyl.

[0205] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, R 4 is cyano.

[0206] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, R 4 is cyclopropyl.

[0207] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, R 4 is trifluoromethyl.

[0208] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, R 2 is phenyl or pyridinyl, each of which has 1-5 R 7 is optionally replaced by

[0209] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, R 2 is phenyl or pyridinyl, each of which has 1-5 R 7 where one R 7 is -C(O)OR A or -C(O)N(R B )2, where -C(O)OR Aor -C(O)N(R B )2 is R 2 R for the nitrogen atom to which is bonded 2 R in the alpha position, i.e., ortho position, relative to the attachment point of 2 Combine with.

[0210] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, R 2 is phenyl or pyridinyl, each of which has 1-5 R 7 where at least one R 7 is cyano, where at least one cyano is R 2 R for the nitrogen atom to which is bonded 2 R in the alpha position relative to the attachment point of 2 Combine with.

[0211] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, R 2 is phenyl or 5-7 membered heteroaryl, each of which is 1, 2, 3, or 4 R 7 The group is substituted.

[0212] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, R 2 is one, two or three R 7 The group is phenyl or 5-7 membered heteroaryl substituted with a group.

[0213] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, R 2 is phenyl or 5-7 membered heteroaryl, each of which is 1, 2, 3, or 4 R 7 group and at least one R 7 The group is -C(O)OR A is.

[0214] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, R 2 is one, two or three R7 phenyl or 5-7 membered heteroaryl substituted with a group, and at least one R 7 The group is -C(O)OR A is.

[0215] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, R 2 has at least one -C(O)OR A where -C(O)OR A is R 2 R for the nitrogen atom to which is bonded 2 R in the alpha position relative to the attachment point of 2 Combine with.

[0216] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, R 2 is phenyl or 5-7 membered heteroaryl, each of which is 1, 2, 3, or 4 R 7 group and at least one R 7 The group is -C(O)OR A where -C(O)OR A is R 2 R for the nitrogen atom to which is bonded 2 R in the alpha position relative to the attachment point of 2 Combine with.

[0217] In certain embodiments of Formula (IIIa) or Formula (IIIb) described elsewhere herein, R 2 is one, two or three R 7 phenyl or 5-7 membered heteroaryl substituted with a group, and at least one R 7 The group is -C(O)OR A where -C(O)OR A is R 2 R for the nitrogen atom to which is bonded 2 R in the alpha position relative to the attachment point of 2 Combine with.

[0218] As described elsewhere herein, in certain embodiments of Formula (I), the compound has the following formula (IIIa) or (IIIb): In certain embodiments, the compound of formula (IIIa) has formula (IVa), (IVb) or (IVc): [ka] [In the formula, R 1 is H, C1-C3 alkyl, or C3-C6 cycloalkyl; R 2 is phenyl or pyridinyl, where phenyl and pyridinyl each have 1-5 R 7 optionally replaced by; Each R 7 are independently C1-C4 alkyl; -OR A , -C(O)OR A , (C1-C3 alkyl)-OR A , -C(O)N(R B )2, cyano, halogen or tetrazolyl; Each R A are independently H, C1-C6 alkyl, or C3-C6 cycloalkyl; Each R B is independently H, —OH, C1-C6 alkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl; and R 3 is C1-C3 alkyl or C3-C6 cycloalkyl; R 4 is H, C1-C3 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, or halo, where each C1-C3 alkyl is optionally substituted with 1-5 halo groups; R 20 and R 21 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, cyano, hydroxy, oxo, halogen, halo(C1-C6)alkyl, hydroxyC1-C6 alkyl, amino, or mono- or di(C1-C6 alkyl)amino; or R 20is hydrogen or C1-C6 alkyl; and R 21 is R 11 , R 12 , R 13 , R 14 , R 15 , R 16 or R 17 where: R 11 is aryl or aryl(C1-C6)alkyl, where each aryl is independently optionally substituted with up to four C1-C6 alkyl, C1-C6 alkoxy, cyano, hydroxy, oxo, halogen, halo(C1-C6)alkyl, hydroxyC1-C6 alkyl, amino, or mono- or di(C1-C6 alkyl)amino; R 12 is a 5-8 membered heteroaryl or a 5-8 membered heteroaryl(C1-C6)alkyl, where each heteroaryl is independently optionally substituted with up to four C1-C6 alkyl, C1-C6 alkoxy, cyano, hydroxy, oxo, halogen, halo(C1-C6)alkyl, hydroxyC1-C6 alkyl, amino, or mono- or di(C1-C6 alkyl)amino; R 13 is aryl(C1-C6)alkoxy, aryl(C1-C6)alkoxy(C1-C6)alkyl, aryl(C1-C6)alkylamino, or aryl(C1-C6)alkylamino(C1-C6)alkyl, where each aryl is independently optionally substituted with up to four C1-C6 alkyl, C1-C6 alkoxy, cyano, hydroxy, oxo, halogen, halo(C1-C6)alkyl, hydroxyC1-C6 alkyl, amino, or mono- or di(C1-C6 alkyl)amino; R 14is a 5-8 membered heteroaryl(C-C)alkoxy, a 5-8 membered heteroaryl(C-C)alkoxy(C-C)alkyl, a 5-8 membered heteroaryl(C-C)alkylamino, or a 5-8 membered heteroaryl(C-C)alkylamino(C-C)alkyl, wherein each heteroaryl is independently optionally substituted with up to four C-Calkyl, C-Calkoxy, cyano, hydroxy, oxo, halogen, halo(C-C)alkyl, hydroxyC-Calkyl, amino, or mono- or di(C-Calkyl)amino; R 15 is (C1-C6)cycloalkyl or (C1-C6)cycloalkyl(C1-C6)alkyl, where each cycloalkyl is independently optionally substituted with up to four C1-C6 alkyl, C1-C6 alkoxy, cyano, hydroxy, oxo, halogen, halo(C1-C6)alkyl, hydroxyC1-C6 alkyl, amino, or mono- or di(C1-C6 alkyl)amino; R 16 is (C-C)cycloalkyl(C-C)alkoxy, (C-C)cycloalkyl(C-C)alkoxy(C-C)alkyl, (C-C)cycloalkyl(C-C)alkylamino, or (C-C)cycloalkyl(C-C)alkylamino(C-C)alkyl, where each cycloalkyl is independently optionally substituted with up to four C-C alkyl, C-C alkoxy, cyano, hydroxy, oxo, halogen, halo(C-C)alkyl, hydroxyC-C alkyl, amino, or mono- or di(C-C alkyl)amino; and R 17is a 5-8-membered heterocyclyl, a 5-8-membered heterocyclyl(C-C)alkyl, a 5-8-membered heterocyclyl(C-C)alkoxy, a 5-8-membered heterocyclyl(C-C)alkoxy(C-C)alkyl, a 5-8-membered heterocyclyl(C-C)alkylamino, or a 5-8-membered heterocyclyl(C-C)alkylamino(C-C)alkyl, wherein each 5-8-membered heterocyclyl is independently optionally substituted with up to four C-C alkyl, C-C alkoxy, cyano, hydroxy, oxo, halogen, halo(C-C)alkyl, hydroxyC-C alkyl, amino, or mono- or di(C-C alkyl)amino. or a pharmaceutically acceptable salt thereof.

[0219] In certain embodiments of formulas (IVa), (IVb), and (IVc), R 20 and R 21 are C1-C2 alkyl, fluoro, chloro, or trifluoromethyl.

[0220] In certain embodiments of formulas (IVa), (IVb), and (IVc), R 20 and R 21 Both of are C1-C2 alkyl.

[0221] In certain embodiments of formulas (IVa), (IVb), and (IVc), R 20 and R 21 Both of the groups are fluoro.

[0222] In certain embodiments of formulas (IVa), (IVb), and (IVc), R 20 and R 21 Both are hydrogen.

[0223] In certain embodiments of formulas (IVa), (IVb), and (IVc), R 20 and R 21 Both of are trifluoromethyl.

[0224] In certain embodiments of formulas (IVa), (IVb), and (IVc), R 20 is hydrogen or methyl, and R 21 is C1-C2 alkyl.

[0225] In certain embodiments of formulas (IVa), (IVb), and (IVc), R 20 is hydrogen or methyl, and R 21 is fluoro.

[0226] In certain embodiments of formulas (IVa), (IVb), and (IVc), R 20 is hydrogen or methyl, and R 21 is chloro.

[0227] In certain embodiments of formulas (IVa), (IVb), and (IVc), R 20 is hydrogen and R 21 is trifluoromethyl.

[0228] In certain embodiments of formulas (IVa), (IVb), and (IVc), R 20 is hydrogen or methyl, and R 21 is R 11 is.

[0229] In certain embodiments of formulas (IVa), (IVb), and (IVc), R 20 is hydrogen or methyl, and R 21 is R 11 where R 11 The aryl is optionally substituted with one or two C1-C2 alkyl, C1-C2 alkoxy, cyano, hydroxy, oxo, halogen, halo(C1-C2)alkyl, hydroxyC1-C2 alkyl, amino, or mono- or di(C1-C2 alkyl)amino.

[0230] In certain embodiments of formulas (IVa), (IVb), and (IVc), R 20 is hydrogen or methyl, and R 21 is R 12 is.

[0231] In certain embodiments of formulas (IVa), (IVb), and (IVc), R 20 is hydrogen or methyl, and R 21 is R 12 where R 12 The heteroaryl is optionally substituted with one or two C1-C2 alkyl, C1-C2 alkoxy, cyano, hydroxy, oxo, halogen, halo(C1-C2)alkyl, hydroxyC1-C2 alkyl, amino, or mono- or di(C1-C2 alkyl)amino.

[0232] In certain embodiments of formulas (IVa), (IVb), and (IVc) described elsewhere herein, R 3 is C1-C3 alkyl.

[0233] In certain embodiments of formulas (IVa), (IVb), and (IVc) described elsewhere herein, R 3 is methyl.

[0234] In certain embodiments of formulas (IVa), (IVb), and (IVc) described elsewhere herein, R 4 is H, C1-C3 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, fluoro, chloro, bromo, cyclopropyl, trifluoromethyl or cyano.

[0235] In certain embodiments of formulas (IVa), (IVb), and (IVc) described elsewhere herein, R 4 is hydrogen, methyl, methoxy, ethyl, ethoxy or cyano.

[0236] In certain embodiments of formulas (IVa), (IVb), and (IVc) described elsewhere herein, R 4 is fluoro, chloro, or bromo.

[0237] In certain embodiments of formulas (IVa), (IVb), and (IVc) described elsewhere herein, R 4 is hydrogen.

[0238] In certain embodiments of formulas (IVa), (IVb), and (IVc) described elsewhere herein, R 4 is fluoro.

[0239] In certain embodiments of formulas (IVa), (IVb), and (IVc) described elsewhere herein, R 4 is chloro.

[0240] In certain embodiments of formulas (IVa), (IVb), and (IVc) described elsewhere herein, R 4 is bromo.

[0241] In certain embodiments of formulas (IVa), (IVb), and (IVc) described elsewhere herein, R 4 is methyl.

[0242] In certain embodiments of formulas (IVa), (IVb), and (IVc) described elsewhere herein, R 4 is ethyl.

[0243] In certain embodiments of formulas (IVa), (IVb), and (IVc) described elsewhere herein, R 4 is methoxy.

[0244] In certain embodiments of formulas (IVa), (IVb), and (IVc) described elsewhere herein, R 4 is cyano.

[0245] In certain embodiments of formulas (IVa), (IVb), and (IVc) described elsewhere herein, R 4 is cyclopropyl.

[0246] In certain embodiments of formulas (IVa), (IVb), and (IVc) described elsewhere herein, R 4 is trifluoromethyl.

[0247] In certain embodiments of formulas (IVa), (IVb), and (IVc) described elsewhere herein, R 2 is phenyl or pyridinyl, each of which has 1-5 R 7 is optionally replaced by

[0248] In certain embodiments of formulas (IVa), (IVb), and (IVc) described elsewhere herein, R 2 is phenyl or pyridinyl, each of which has 1-5 R 7 where one R 7 is -C(O)OR A or -C(O)N(R B )2, where -C(O)OR A or -C(O)N(R B )2 is R 2 R for the nitrogen atom to which is bonded 2 R in the alpha position, i.e., ortho position, relative to the attachment point of 2 Combine with.

[0249] In certain embodiments of formulas (IVa), (IVb), and (IVc) described elsewhere herein, R 2 is phenyl or pyridinyl, each of which has 1-5 R 7 where at least one R 7 is cyano, where at least one cyano is R 2 R for the nitrogen atom to which is bonded 2 R in the alpha position relative to the attachment point of 2 Combine with.

[0250] In certain embodiments of formulas (IVa), (IVb), and (IVc) described elsewhere herein, R 2 is phenyl or 5-7 membered heteroaryl, each of which is 1, 2, 3, or 4 R 7 The group is substituted.

[0251] In certain embodiments of formulas (IVa), (IVb), and (IVc) described elsewhere herein, R 2is one, two or three R 7 The group is phenyl or 5-7 membered heteroaryl substituted with a group.

[0252] In certain embodiments of formulas (IVa), (IVb), and (IVc) described elsewhere herein, R 2 is phenyl or 5-7 membered heteroaryl, each of which is 1, 2, 3, or 4 R 7 group and at least one R 7 The group is -C(O)OR A is.

[0253] In certain embodiments of formulas (IVa), (IVb), and (IVc) described elsewhere herein, R 2 is one, two or three R 7 phenyl or 5-7 membered heteroaryl substituted with a group, and at least one R 7 The group is -C(O)OR A is.

[0254] In certain embodiments of formulas (IVa), (IVb), and (IVc) described elsewhere herein, R 2 has at least one -C(O)OR A where -C(O)OR A is R 2 R for the nitrogen atom to which is bonded 2 R in the alpha position relative to the attachment point of 2 Combine with.

[0255] In certain embodiments of formulas (IVa), (IVb), and (IVc) described elsewhere herein, R 2 is phenyl or 5-7 membered heteroaryl, each of which is 1, 2, 3, or 4 R 7 group and at least one R 7 The group is -C(O)OR A where -C(O)OR A is R 2 R for the nitrogen atom to which is bonded 2 R in the alpha position relative to the attachment point of 2Combine with.

[0256] In certain embodiments of formulas (IVa), (IVb), and (IVc) described elsewhere herein, R 2 is one, two or three R 7 phenyl or 5-7 membered heteroaryl substituted with a group, and at least one R 7 The group is -C(O)OR A where -C(O)OR A is R 2 R for the nitrogen atom to which is bonded 2 R in the alpha position relative to the attachment point of 2 Combine with.

[0257] In certain embodiments, the compound of formula (IIIb) is represented by the following formula (Va), (Vb), (Vc) or (Vd): [ka] [In the formula, R 1 is H, C1-C3 alkyl, or C3-C6 cycloalkyl; R 2 is phenyl or pyridinyl, where phenyl and pyridinyl each have 1-5 R 7 optionally replaced by; Each R 7 are independently C1-C4 alkyl; -OR A , -C(O)OR A , (C1-C3 alkyl)-OR A , -C(O)N(R B )2, cyano, halogen or tetrazolyl; Each R A are independently H, C1-C6 alkyl, or C3-C6 cycloalkyl; Each R B is independently H, —OH, C1-C6 alkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl; and R 3is C1-C3 alkyl or C3-C6 cycloalkyl; R 4 is H, C1-C3 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, or halo, wherein each C1-C3 alkyl is optionally substituted with 1-5 halo groups; R 20 and R 21 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, cyano, hydroxy, oxo, halogen, halo(C1-C6)alkyl, hydroxyC1-C6 alkyl, amino, or mono- or di(C1-C6 alkyl)amino; or R 20 is hydrogen or C1-C6 alkyl; and R 21 is R 11 , R 12 , R 13 , R 14 , R 15 , R 16 or R 17 and where: R 11 is aryl or aryl(C1-C6)alkyl, where each aryl is independently optionally substituted with up to four C1-C6 alkyl, C1-C6 alkoxy, cyano, hydroxy, oxo, halogen, halo(C1-C6)alkyl, hydroxyC1-C6 alkyl, amino, or mono- or di(C1-C6 alkyl)amino; R 12 is a 5-8 membered heteroaryl, a 5-8 membered heteroaryl(C1-C6)alkyl, where each heteroaryl is independently optionally substituted with up to four C1-C6 alkyl, C1-C6 alkoxy, cyano, hydroxy, oxo, halogen, halo(C1-C6)alkyl, hydroxyC1-C6 alkyl, amino, or mono- or di(C1-C6 alkyl)amino; R 13is aryl(C1-C6)alkoxy, aryl(C1-C6)alkoxy(C1-C6)alkyl, aryl(C1-C6)alkylamino, or aryl(C1-C6)alkylamino(C1-C6)alkyl, where each aryl is independently optionally substituted with up to four C1-C6 alkyl, C1-C6 alkoxy, cyano, hydroxy, oxo, halogen, halo(C1-C6)alkyl, hydroxyC1-C6 alkyl, amino, or mono- or di(C1-C6 alkyl)amino; R 14 is a 5-8 membered heteroaryl(C-C)alkoxy, a 5-8 membered heteroaryl(C-C)alkoxy(C-C)alkyl, a 5-8 membered heteroaryl(C-C)alkylamino, or a 5-8 membered heteroaryl(C-C)alkylamino(C-C)alkyl, wherein up to four heteroaryls are independently optionally substituted with C-C alkyl, C-C alkoxy, cyano, hydroxy, oxo, halogen, halo(C-C)alkyl, hydroxyC-C alkyl, amino, or mono- or di(C-C alkyl)amino; R 15 is (C1-C6)cycloalkyl or (C1-C6)cycloalkyl(C1-C6)alkyl, where each cycloalkyl is independently optionally substituted with up to four C1-C6 alkyl, C1-C6 alkoxy, cyano, hydroxy, oxo, halogen, halo(C1-C6)alkyl, hydroxyC1-C6 alkyl, amino, or mono- or di(C1-C6 alkyl)amino; R 16is (C-C)cycloalkyl(C-C)alkoxy, (C-C)cycloalkyl(C-C)alkoxy(C-C)alkyl, (C-C)cycloalkyl(C-C)alkylamino, or (C-C)cycloalkyl(C-C)alkylamino(C-C)alkyl, where each cycloalkyl is independently optionally substituted with up to four C-C alkyl, C-C alkoxy, cyano, hydroxy, oxo, halogen, halo(C-C)alkyl, hydroxyC-C alkyl, amino, or mono- or di(C-C alkyl)amino; and R 17 is a 5-8-membered heterocyclyl, a 5-8-membered heterocyclyl(C-C)alkyl, a 5-8-membered heterocyclyl(C-C)alkoxy, a 5-8-membered heterocyclyl(C-C)alkoxy(C-C)alkyl, a 5-8-membered heterocyclyl(C-C)alkylamino, or a 5-8-membered heterocyclyl(C-C)alkylamino(C-C)alkyl, wherein each 5-8-membered heterocyclyl is independently optionally substituted with up to four C-C alkyl, C-C alkoxy, cyano, hydroxy, oxo, halogen, halo(C-C)alkyl, hydroxyC-C alkyl, amino, or mono- or di(C-C alkyl)amino. or a pharmaceutically acceptable salt thereof.

[0258] In certain embodiments of formulas (Va), (Vb), (Vc), and (Vd), R 20 and R 21 are C1-C2 alkyl, fluoro, chloro, or trifluoromethyl.

[0259] In certain embodiments of formulas (Va), (Vb), (Vc), and (Vd), R 20 and R 21 Both of are C1-C2 alkyl.

[0260] In certain embodiments of formulas (Va), (Vb), (Vc), and (Vd), R 20and R 21 Both are hydrogen.

[0261] In certain embodiments of formulas (Va), (Vb), (Vc), and (Vd), R 20 and R 21 Both of the groups are fluoro.

[0262] In certain embodiments of formulas (Va), (Vb), (Vc), and (Vd), R 20 and R 21 Both of are trifluoromethyl.

[0263] In certain embodiments of formulas (Va), (Vb), (Vc), and (Vd), R 20 is hydrogen or methyl, and R 21 is C1-C2 alkyl.

[0264] In certain embodiments of formulas (Va), (Vb), (Vc), and (Vd), R 20 is hydrogen or methyl, and R 21 is fluoro.

[0265] In certain embodiments of formulas (Va), (Vb), (Vc), and (Vd), R 20 is hydrogen or methyl, and R 21 is chloro.

[0266] In certain embodiments of formulas (Va), (Vb), (Vc), and (Vd), R 20 is hydrogen and R 21 is trifluoromethyl.

[0267] In certain embodiments of formulas (Va), (Vb), (Vc), and (Vd), R 20 is hydrogen or methyl, and R 21 is R 11 is.

[0268] In certain embodiments of formulas (Va), (Vb), (Vc), and (Vd), R 20 is hydrogen or methyl, and R21 is R 11 where R 11 The aryl is optionally substituted with one or two C1-C2 alkyl, C1-C2 alkoxy, cyano, hydroxy, oxo, halogen, halo(C1-C2)alkyl, hydroxyC1-C2 alkyl, amino, or mono- or di(C1-C2 alkyl)amino.

[0269] In certain embodiments of formulas (Va), (Vb), (Vc), and (Vd), R 20 is hydrogen or methyl, and R 21 is R 12 is.

[0270] In certain embodiments of formulas (Va), (Vb), (Vc), and (Vd), R 20 is hydrogen or methyl, and R 21 is R 12 where R 12 The heteroaryl is optionally substituted with one or two C1-C2 alkyl, C1-C2 alkoxy, cyano, hydroxy, oxo, halogen, halo(C1-C2)alkyl, hydroxyC1-C2 alkyl, amino, or mono- or di(C1-C2 alkyl)amino.

[0271] As described elsewhere herein, in certain embodiments of formulas (Va), (Vb), (Vc), and (Vd), R 3 is C1-C3 alkyl.

[0272] As described elsewhere herein, in certain embodiments of formulas (Va), (Vb), (Vc), and (Vd), R 3 is methyl.

[0273] As described elsewhere herein, in certain embodiments of formulas (Va), (Vb), (Vc), and (Vd), R 4 is H, C1-C3 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, fluoro, chloro, bromo or cyano.

[0274] As described elsewhere herein, in certain embodiments of formulas (Va), (Vb), (Vc), and (Vd), R 4 is hydrogen, methyl, methoxy, ethyl, ethoxy or cyano.

[0275] As described elsewhere herein, in certain embodiments of formulas (Va), (Vb), (Vc), and (Vd), R 4 is fluoro, chloro, or bromo.

[0276] As described elsewhere herein, in certain embodiments of formulas (Va), (Vb), (Vc), and (Vd), R 4 is hydrogen.

[0277] As described elsewhere herein, in certain embodiments of formulas (Va), (Vb), (Vc), and (Vd), R 4 is fluoro.

[0278] As described elsewhere herein, in certain embodiments of formulas (Va), (Vb), (Vc), and (Vd), R 4 is chloro.

[0279] As described elsewhere herein, in certain embodiments of formulas (Va), (Vb), (Vc), and (Vd), R 4 is bromo.

[0280] As described elsewhere herein, in certain embodiments of formulas (Va), (Vb), (Vc), and (Vd), R 4 is methyl.

[0281] As described elsewhere herein, in certain embodiments of formulas (Va), (Vb), (Vc), and (Vd), R 4 is ethyl.

[0282] As described elsewhere herein, in certain embodiments of formulas (Va), (Vb), (Vc), and (Vd), R 4 is methoxy.

[0283] As described elsewhere herein, in certain embodiments of formulas (Va), (Vb), (Vc), and (Vd), R 4 is cyano.

[0284] As described elsewhere herein, in certain embodiments of formulas (Va), (Vb), (Vc), and (Vd), R 4 is cyclopropyl.

[0285] As described elsewhere herein, in certain embodiments of formulas (Va), (Vb), (Vc), and (Vd), R 4 is trifluoromethyl.

[0286] As described elsewhere herein, in certain embodiments of formulas (Va), (Vb), (Vc), and (Vd), R 2 is phenyl or pyridinyl, each of which has 1-5 R 7 is optionally replaced by

[0287] As described elsewhere herein, in certain embodiments of formulas (Va), (Vb), (Vc), and (Vd), R 2 is phenyl or pyridinyl, each of which has 1-5 R 7 where one R 7 is -C(O)OR A or -C(O)N(R B )2, where -C(O)OR A or -C(O)N(R B )2 is R 2 R for the nitrogen atom to which is bonded 2 R in the alpha position, i.e., ortho position, relative to the attachment point of 2 Combine with.

[0288] As described elsewhere herein, in certain embodiments of formulas (Va), (Vb), (Vc), and (Vd), R 2 is phenyl or pyridinyl, each of which has 1-5 R 7 where at least one R 7 is cyano, where at least one cyano is R 2 R for the nitrogen atom to which is bonded 2 R in the alpha position relative to the attachment point of 2 Combine with.

[0289] As described elsewhere herein, in certain embodiments of formulas (Va), (Vb), (Vc), and (Vd), R 2 is phenyl or 5-7 membered heteroaryl, each of which is 1, 2, 3, or 4 R 7 The group is substituted.

[0290] As described elsewhere herein, in certain embodiments of formulas (Va), (Vb), (Vc), and (Vd), R 2 is one, two or three R 7 The group is phenyl or 5-7 membered heteroaryl substituted with a group.

[0291] As described elsewhere herein, in certain embodiments of formulas (Va), (Vb), (Vc), and (Vd), R 2 is phenyl or 5-7 membered heteroaryl, each of which is 1, 2, 3, or 4 R 7 group and at least one R 7 The group is -C(O)OR A is.

[0292] As described elsewhere herein, in certain embodiments of formulas (Va), (Vb), (Vc), and (Vd), R 2 is one, two or three R 7 phenyl or 5-7 membered heteroaryl substituted with a group, and at least one R 7 The group is -C(O)OR A is.

[0293] As described elsewhere herein, in certain embodiments of formulas (Va), (Vb), (Vc), and (Vd), R 2 is substituted with at least one -C(O)OR A , where -C(O)OR A is R 2 R for the nitrogen atom to which is bonded 2 R in the alpha position relative to the attachment point of 2 Combine with.

[0294] As described elsewhere herein, in certain embodiments of formulas (Va), (Vb), (Vc), and (Vd), R 2 is phenyl or 5-7 membered heteroaryl, each of which is 1, 2, 3, or 4 R 7 group and at least one R 7 The group is -C(O)OR A where -C(O)OR A is R 2 R for the nitrogen atom to which is bonded 2 R in the alpha position relative to the attachment point of 2 Combine with.

[0295] As described elsewhere herein, in certain embodiments of formulas (Va), (Vb), (Vc), and (Vd), R 2 is one, two or three R 7 phenyl or 5-7 membered heteroaryl substituted with a group, and at least one R 7 The group is -C(O)OR A where -C(O)OR A is R 2 R for the nitrogen atom to which is bonded 2 R in the alpha position relative to the attachment point of 2 Combine with.

[0296] In one embodiment, the compound of formula (I) is selected from the group consisting of: [Table 1] Table 2 Table 3 Table 4 Table 5 Table 6 Table 7 Table 8 Table 9 Table 10 Table 11 Table 12 Table 13 Table 14 Table 15 Table 16 Table 17 Table 18 Table 19 Table 20 Table 21 Table 22 Table 23 Table 24 Table 25 Table 26 Table 27 Table 28 Table 29 Table 30 [Table 31] [Table 32] [Table 33] [Table 34] [Table 35] [Table 36] [Table 37] [Table 38] [Table 39] [Table 40] [Table 41] [Table 42] or a pharmaceutically acceptable salt thereof.

[0297] Pharmaceutical Composition The compounds of formula I can be formulated into pharmaceutical compositions.

[0298] In another aspect, the present invention provides a pharmaceutical composition comprising a PI3K alpha inhibitor according to 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 hospitals.In other specific embodiments, administration is preferably via the oral route.

[0299] The characteristics of the carrier depend on the route of administration. As used herein, the term "pharmaceutically acceptable" refers to a non-toxic material that is compatible with a biological system, such as a cell, cell culture, tissue, or organism, and does not inhibit the effectiveness of the biological activity of the active ingredient. Thus, 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, for example, in Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

[0300] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that maintains the desired biological activity of the compound and has minimal or no undesired toxic effects.Examples of such salts include, but are not limited to, acid addition salts with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), and salts with organic acids such as 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, polygalacturonic acid, etc. These compounds may also be administered as pharmaceutically acceptable quaternary salts known to those of skill in the art, specifically salts of the formula -NRZ- (where R is hydrogen, alkyl, or benzyl, and Z is a counterion), including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamate, mandelate, benzilate, and diphenylacetate).

[0301] The active compound is contained in a pharmaceutically acceptable carrier or diluent in an amount sufficient to administer a therapeutically effective amount without causing serious toxic effects to the patient being treated. The dosage of the active compound for all of the above conditions ranges from about 0.01 to 300 mg / kg, preferably 0.1 to 100 mg / kg / day, and more commonly 0.5 to about 25 mg / kg / day. Typical topical dosages range from 0.01 to 3% (w / w) in a suitable carrier. The effective dosage range of pharmaceutically acceptable derivatives can be calculated based on the weight of the parent compound administered. If the derivative is active in itself, the effective dosage can be estimated using the weight of the derivative as described above or by other methods known to those skilled in the art.

[0302] Pharmaceutical compositions containing the compounds of the invention can be used in the methods described herein.

[0303] How to use In another aspect, the present disclosure relates generally to methods for treating cancer, which methods include administering to a subject in need thereof a therapeutically effective amount of a PI3K inhibitor (e.g., a PI3K alpha inhibitor or a PI3K alpha H1047R mutation inhibitor).

[0304] In some embodiments, the PI3K inhibitor (e.g., a PI3K alpha inhibitor or a PI3K alpha H1047R mutation inhibitor) is a compound of Formula (I), 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.

[0305] In another aspect, the present invention provides compounds obtained by or obtained by a method for preparing a compound described herein (e.g., a method comprising one or more steps described in a reaction scheme).

[0306] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, and a pharmaceutically acceptable diluent or carrier.

[0307] In another aspect, the present invention provides intermediates described herein that are suitable for use in the methods of making the compounds described herein (e.g., the intermediates are selected from the intermediates described in the Examples).

[0308] In another aspect, the present invention provides a method (e.g., in vitro or in vivo) of modulating PI3K (e.g., PI3Kα) activity, the method comprising contacting a cell with a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof.

[0309] In certain embodiments, the PI3K associated with a disease or disorder has an H1047R mutation. For example, in certain embodiments described elsewhere herein, the compound has high selectivity for inhibiting H1047R mutant PI3Kα compared to wild-type PI3Kα. This unexpected discovery suggests that certain compounds may be able to target and inhibit PI3Kα through a novel binding mechanism compared to conventional wild-type PI3Kα inhibitors. Without being bound by theory, H1047R mutant PI3Kα has a modification at a position away from the active site of wild-type PI3Kα. Therefore, it is believed that compounds that are selective for H1047R mutant PI3Kα over wild-type PI3Kα advantageously do not bind strongly to the active site of PI3Kα, but rather target other binding pockets. Because the active site of PI3K proteins is thought to be more conserved among different mutants, compounds that effectively bind to a site other than the active site may exhibit high selectivity for inhibiting PI3Kα over other PI3K proteins, such as PI3Kβ.

[0310] In another aspect, there is provided a method of treating cancer, comprising administering to a patient having cancer a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound or a pharmaceutically acceptable salt thereof.

[0311] The compositions and methods provided herein can be used to treat a wide variety of cancers, including tumors such as prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, testicular cancer, etc. More specifically, cancers that may be treated by the compositions and methods of the present invention include, but are not limited to, tumor types such as astrocytic cancer, 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 and sarcoma. Specifically, these compounds can be used to treat the following: cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung: bronchial carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar carcinoma (bronchiolar carcinoma), bronchial adenoma, sarcoma, lymphoma, chondroitin hamartoma, mesothelioma; gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (pancreatic ductal adenocarcinoma, islet cell carcinoma, glucagonoma, gastrinoma, carcinoid tumor, VIP tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colon (adenocarcinoma, tubular adenoma) , villous adenoma, hamartoma, leiomyoma); genitourinary system: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver: hepatocellular carcinoma (hepatocellular carcinoma) ), bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gallbladder cancer, ampulla cancer, bile duct cancer; Bone: osteosarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid and giant cell tumor;Nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); gynecology: uterus (endometrial cancer), cervix (cervical cancer, precancerous cervical dysplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (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; skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles, dysplastic nevi, lipomas, hemangiomas, dermatofibromas, keloids, psoriasis; adrenal gland: neuroblastoma. In certain embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL);

[0312] 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.

[0313] In another embodiment, the cancer is selected from breast cancer, uterine carcinosarcoma, endometrial carcinoma, colorectal adenocarcinoma, gastric adenocarcinoma, head and neck squamous cell carcinoma, bile duct carcinoma, esophageal adenocarcinoma, bladder carcinoma, lung squamous cell carcinoma, brain glioma, adrenocortical carcinoma, liver hepatocellular carcinoma, sarcoma, prostate adenocarcinoma, kidney renal cell carcinoma, lung adenocarcinoma, ovarian cystadenocarcinoma, glioblastoma multiforme, and melanoma.

[0314] In another embodiment, the cancer is gastric cancer, breast cancer, colon cancer, or endometrial cancer. In another embodiment, the cancer is gastric cancer. In another embodiment, the cancer is breast cancer. In another embodiment, the cancer is colon cancer. In another embodiment, the cancer is endometrial cancer.

[0315] Thus, in certain embodiments, the present disclosure provides methods of treating cancer, comprising administering a compound of Formula (I), a pharmaceutical composition thereof, and a KRAS inhibitor to a patient in need thereof, wherein the cancer is breast cancer, uterine carcinosarcoma, endometrial carcinoma, colorectal adenocarcinoma, gastric adenocarcinoma, head and neck squamous cell carcinoma, bile duct carcinoma, esophageal adenocarcinoma, bladder carcinoma, lung squamous cell carcinoma, brain glioma, adrenocortical carcinoma, liver hepatocellular carcinoma, sarcoma, prostate adenocarcinoma, kidney renal cell carcinoma, lung adenocarcinoma, ovarian cystadenocarcinoma, glioblastoma multiforme, or melanoma.

[0316] In other embodiments, the present disclosure provides methods of treating cancer, comprising administering a compound of Formula (I), a pharmaceutical composition thereof, and a mutation-selective KRAS inhibitor to a patient in need thereof, wherein the cancer is breast cancer, uterine carcinosarcoma, endometrial carcinoma, colorectal adenocarcinoma, gastric adenocarcinoma, head and neck squamous cell carcinoma, bile duct carcinoma, esophageal adenocarcinoma, bladder carcinoma, lung squamous cell carcinoma, brain glioma, adrenocortical carcinoma, liver hepatocellular carcinoma, sarcoma, prostate adenocarcinoma, kidney renal cell carcinoma, lung adenocarcinoma, ovarian cystadenocarcinoma, glioblastoma multiforme, or melanoma.

[0317] In another embodiment, the disclosure provides a compound of Formula (I), or a pharmaceutical composition thereof, for use in combination with a KRAS inhibitor in the treatment of cancer, wherein the cancer is breast cancer, uterine carcinosarcoma, endometrial carcinoma, colorectal adenocarcinoma, gastric adenocarcinoma, head and neck squamous cell carcinoma, bile duct carcinoma, esophageal adenocarcinoma, bladder carcinoma, lung squamous cell carcinoma, brain glioma, adrenocortical carcinoma, liver hepatocellular carcinoma, sarcoma, prostate adenocarcinoma, kidney renal cell carcinoma, lung adenocarcinoma, ovarian cystadenocarcinoma, glioblastoma multiforme, or melanoma.

[0318] The concentration and route of administration to a patient will vary depending on the cancer being treated. The compounds, their pharmaceutically acceptable salts, and pharmaceutical compositions containing these compounds and salts can be used in combination with other anti-tumor compounds (e.g., chemotherapy) or in combination with other treatments, such as radiation therapy or surgical intervention, as adjuvant therapy before or after surgery.

[0319] The present disclosure provides methods for treating, preventing, or ameliorating a disease or disorder involving PI3K by administering a therapeutically effective amount of a PI3K inhibitor to a patient in need thereof. The methods of the disclosure can be used to treat a variety of PI3K-dependent diseases and disorders.

[0320] In some embodiments, the disease or disorder is cancer (e.g., breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colon cancer, lung cancer, ovarian cancer, skin cancer, and head and neck cancer). In some embodiments, diseases or disorders associated with PI3K include, but are not limited to, CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis / skeletal and spinal syndrome), PIK3CA-associated overgrowth syndrome (PROS), endometrial cancer, breast cancer, esophageal squamous cell carcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, bladder urothelial carcinoma, glioblastoma, ovarian cancer, non-small cell lung cancer, esophagogastric cancer, nerve sheath tumor, head and neck squamous cell carcinoma, malignant melanoma, esophagogastric adenocarcinoma, soft tissue sarcoma, prostate cancer, fibrolamellar carcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, cholangiocarcinoma, B-cell lymphoma, mesothelioma, adrenocortical carcinoma, renal non-clear cell carcinoma, renal clear cell carcinoma carcinoma, germ cell carcinoma, thymic tumors, pheochromocytoma, other neuroepithelial tumors, thyroid cancer, leukemia, and encapsulated glioma.

[0321] Details of the present disclosure are described in the following description. Although methods and materials similar or equivalent to those described herein can be used in practicing or testing the present disclosure, exemplary methods and materials are described herein. Other features, objects, and advantages of the present disclosure will be apparent from the specification and claims. In this specification and the appended claims, unless otherwise defined, the singular forms include the plural forms unless clearly indicated otherwise by the context, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited herein are incorporated herein by reference in their entirety.

[0322] General Reaction Schemes, Intermediates and Examples The compounds of the invention can be prepared using commercially available reagents and intermediates in the synthetic methods and reaction schemes described herein, or can be prepared using other reagents and conventional methods well known to those skilled in the art.

[0323] When referring to the "fastest-eluting enantiomer" or the "second-eluting enantiomer," unless specifically indicated otherwise, the specific stereochemistry of such enantiomers is not determined, and the stereochemistry shown in the structure of the corresponding compound is arbitrarily assigned.

[0324] For example, intermediates for preparing compounds of formula (I) of the present invention can be prepared according to general reaction schemes I and II. General Reaction Scheme I [ka] [where R 2 , R 4 , A, p and r are as defined for formula (I), and R 18 is hydrogen or R as defined for formula (I). 8 ]

[0325] In General Reaction Scheme I, compound 8 is an example of formula (I). In this General Reaction Scheme I, compound 1 is condensed with compound 2 using a dehydrating agent such as phosphorus oxychloride to produce compound 3. Compounds with a quaternary carbon at the spiro center in a position different from that shown in Scheme I can be prepared using different spirocyclic pyrrolidines 2. Compound 3 can undergo an acylation reaction, such as a Heck or Stille coupling using an enol ether coupling partner, followed by acidic treatment to produce ketone 4. Compound 4 can be condensed with a chiral sulfinamide, such as Ellman's auxiliary, using a Lewis acid such as titanium(IV) ethoxide to give imine 5. Compound 5 can be reduced to sulfinamide 6 using a reducing agent such as diisobutylaluminum hydride, sodium borohydride, or zirconocene chloride hydride. Acidic deprotection of 6, for example, using hydrochloric acid in dioxane, followed by nucleophilic or metal-catalyzed substitution of amine 7 in the presence of a suitable base can give compound 8.

[0326] General Reaction Scheme II [ka] [where R 2 , R 4 , A, p and r are as defined for formula (I), and R 18 is hydrogen or R as defined for formula (I). 8 ]

[0327] In General Reaction Scheme II, compound 17 is an example of formula (I). In this General Reaction Scheme II, compound 9 is reacted with cyanogen bromide in the presence of a suitable base, e.g., sodium carbonate, to produce compound 10. Compounds in which the quaternary carbon of the spiro center is positioned differently from that shown in Scheme II can be prepared using different starting unsaturated amines 9. Compound 11 can be coupled with compound 10 after appropriate activation of the carboxylic acid. For example, in situ conversion to the acid chloride is performed using oxalyl chloride and dimethylformamide, Ghosez reagent, or thionyl chloride. This produces compound 12. Transition metal-catalyzed cross-coupling of aryl halides of compound 12 with redox-active esters (13) or similar alkyl electrophiles can be carried out using a suitable reducing agent, e.g., a sacrificial anode or metal powder, to give compound 14. Cyclization reactions, such as iron-catalyzed hydrogen atom transfer radical cyclization, can be used to construct compound 15. Acidic deprotection of the protected amine using hydrochloric acid or a similar Brønsted acid in dioxane gives compound 16. Amine 16 can be displaced by nucleophilic substitution or metal catalyzed reaction in the presence of a suitable base to prepare compound 17.

[0328] The substituents shown in Schemes I and II are the same as those defined above for Formula (I), with D indicating that Ring A is a 3- to 8-membered carbocyclic ring or a 4- to 7-membered heterocyclic ring. The pyrrolidine ring and Rings A and D may be substituted as described for Formula (I).

[0329] Intermediate A 2-Amino-5-bromo-3-iodobenzoic acid [ka]

[0330] Step A: To a suspension of 2-amino-5-bromobenzoic acid (5.0 g, 1.0 eq., 23 mmol) in acetic acid (23 mL) was added N-iodosuccinimide (6.25 g, 1.2 eq., 27.8 mmol). The mixture was stirred at room temperature overnight. The product was concentrated to dryness, dissolved in dichloromethane, and purified by silica gel chromatography to give 2-amino-5-bromo-3-iodobenzoic acid as a light brown solid. LCMS [M+H] + = 343.8. 1 H NMR (500 MHz, DMSO-d6) δ ppm 6.81 (br s, 2H) 7.86 (d, J = 2.46 Hz, 1H) 7.97 (d, J = 2.46 Hz, 1H).

[0331] Intermediate B [ka]

[0332] Step A: A solution of 2-azaspiro[4.5]decan-1-one (500 mg, 1.0 eq., 3.3 mmol) in 1,2-dichloroethane (12 mL) was placed in a flask, and phosphorus oxychloride (650 mg, 395 μL, 1.3 eq., 4.2 mmol) and diisopropylethylamine (422 mg, 568 μL, 1.0 eq., 3.3 mmol) were added. The reaction was heated at 50 °C for 1 h. 2-Amino-5-bromo-3-iodobenzoic acid (1.12 g, 1 eq., 3.3 mmol) was then added as a solid, and the reaction was heated at 100 °C. The reaction was stirred overnight, cooled to room temperature, and diluted with water. The aqueous layer was extracted with dichloromethane, and the combined organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The solid was purified by silica gel chromatography to give 7'-bromo-5'-iodo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (780 mg, 1.7 mmol, 52%) as a yellow solid. LCMS [M+H] += 461.0.

[0333] Step B: Palladium(II) acetate (17 mg, 0.05 eq., 74 μmol), 1,3-bis(diphenylphosphino)propane (61 mg, 0.10 eq., 15 μmol), and 7'-bromo-5'-iodo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (681 mg, 1.0 eq., 1.48 mmol) were added to a vial and stir bar. The flask was evacuated and backfilled with nitrogen three times. Next, ethylene glycol (3.7 mL), n-butyl vinyl ether (960 μL, 5.0 eq., 7.42 mmol), and N,N-dicyclohexylmethylamine (948 μL, 3.0 eq., 4.45 mmol) were added, and the solution was sparged with nitrogen. The flask was placed in a heating block and the mixture was heated to 115 °C with stirring. After the reaction was complete, the reaction was cooled to room temperature and 1N HCl (6 mL) was added. The reaction was stirred until the ketone deprotection was complete (approximately 1 h). The aqueous layer was extracted three times with ethyl acetate, and the combined organic phase was washed successively with water and saturated brine, dried over magnesium sulfate, filtered, and concentrated to give a residue. This residue was purified by silica gel chromatography to give 5'-acetyl-7'-bromo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (367 mg, 98 μmol, 66%) as a yellow solid. LCMS [M+H] + = 433.1.

[0334] Step C: A vial was charged with methylboronic acid (57 mg, 2.0 eq., 95 μmol), 5'-acetyl-7'-bromo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (179 mg, 1.0 eq., 477 μmol), potassium carbonate (132 mg, 2.0 eq., 954 μmol), and tetrakis(triphenylphosphine)palladium(0) (55 mg, 0.10 eq., 48 μmol). The vial was evacuated and refilled with nitrogen three times. Next, a solution of deoxygenated 1,4-dioxane (1.9 mL) and water (480 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 layer was washed with water and then saturated brine, dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel chromatography to give 5'-acetyl-7'-methyl-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (65 mg, 0.21 mmol, 44%) as a yellow solid. LCMS [M+H] + = 311.2.

[0335] Step D: To a solution of 5'-acetyl-7'-methyl-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (84 mg, 1.0 eq., 0.27 mmol) and (R)-2-methylpropane-2-sulfinamide (39 mg, 1.2 eq., 0.32 mmol) in tetrahydrofuran (1.1 mL) was added titanium(IV) ethoxide (0.31 g, 0.28 mL, 5 eq., 1.4 mmol). The mixture was stirred at 70 °C for 4 h and then cooled to room temperature. After returning to room temperature, a small amount of saturated brine was added to form a suspension. The resulting suspension was diluted with ethyl acetate and filtered through Celite. The filter cake was washed several times with ethyl acetate. The filtrate was concentrated under reduced pressure, and the resulting yellow residue was quickly purified by silica gel chromatography (30% to 100% ethyl acetate in heptane) to give (R)-2-methyl-N-(1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethylidene)propane-2-sulfinamide (53 mg, 0.13 mmol, 47%) as a yellow solid.

[0336] Step E: To a solution of (R)-2-methyl-N-(1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethylidene)propane-2-sulfinamide (53 mg, 1.0 eq., 0.13 mmol) in anhydrous dichloromethane (0.85 mL) was added Schwartz's reagent (36 mg, 1.1 eq., 0.14 mmol) as a solid in small 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 phases were washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a residue. The solid was purified by silica gel chromatography (0% to 10% methanol in dichloromethane) to give (R)-2-methyl-N-((R)-1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)propane-2-sulfinamide (47 mg, 0.11 mmol, 88%) as a white solid. LCMS [M+H] + = 416.2.

[0337] Step F: To a solution of (R)-2-methyl-N-((R)-1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazolin]-5'-yl)ethyl)propane-2-sulfinamide (57 mg, 1.0 eq., 0.14 mmol) in methanol (0.30 mL) was added 86 μL of HCl (4 M dioxane solution) at 0 °C. The reaction was monitored by LCMS. Upon completion of the reaction, the product was triturated with diethyl ether to give (R)-5'-(1-aminoethyl)-7'-methyl-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one hydrochloride (48 mg), which was used without further purification. LCMS [M+H] + = 312.2.

[0338] Intermediate C [ka]

[0339] Step A: A solution of 8,8-difluoro-2-azaspiro[4.5]decan-1-one (500 mg, 1.0 eq., 2.64 mmol) in 1,2-dichloroethane (9.9 mL) was placed in a flask, and phosphorus oxychloride (320 μL, 1.3 eq., 3.44 mmol) and diisopropylethylamine (460 μL, 1.0 eq., 2.6 mmol) were added. The reaction was then heated at 50 °C for 1 h. 2-Amino-5-bromo-3-iodobenzoic acid (904 mg, 1.0 eq., 2.64 mmol) was then added as a solid, and the reaction was heated at 100 °C. The reaction was stirred overnight, cooled to room temperature, and diluted with water. The aqueous layer was extracted with dichloromethane, and the combined organics were washed with saturated brine, dried over magnesium sulfate, and concentrated. The resulting solid was purified by silica gel chromatography to give 7'-bromo-4,4-difluoro-5'-iodo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (759 mg, 1.5 mmol, 58%) as a yellow solid. LCMS [M+H] + = 496.8. 1 H NMR(500 MHz, CDCl3)δ ppm 1.88 - 1.96(m, 2H)1.96 - 2.07(m, 2H)2.12(dt, J = 13.7, 4.8 Hz, 2H)2.15 - 2.19(m, 2H)2.70 - 2.86(m, 2H)4.10 - 4.16(m, 2H)8.35(d, J = 2.19 Hz, 1H)8.39(d, J = 2.19 Hz, 1H).

[0340] Step B: Palladium(II) acetate (17 mg, 0.05 eq., 77 μmol), 1,3-bis(diphenylphosphino)propane (63 mg, 0.10 eq., 150 μmol), and 7'-bromo-4,4-difluoro-5'-iodo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (759 mg, 1.0 eq., 1.53 mmol) were added to a vial and stir bar. The vial was evacuated and backfilled with nitrogen three times. Next, ethylene glycol (3.8 mL), N,N-dicyclohexylmethylamine (980 μL, 3.0 eq., 4.6 mmol), and n-butyl vinyl ether (992 μL, 5.0 eq., 7.66 mmol) were added, and the solution was sparged with nitrogen. The vial was placed in a heating block and the mixture was heated to 115 °C with stirring. After the reaction was complete, the reaction was cooled to room temperature and 1N HCl (10 mL) was added. The reaction was stirred until deprotection of the ketone was complete (approximately 1 h). The aqueous layer was extracted three times with ethyl acetate, and the combined organic phase was washed successively with water and saturated brine, dried over magnesium sulfate, filtered, and concentrated to give a residue. The residue was purified by silica gel chromatography to give 5'-acetyl-7'-bromo-4,4-difluoro-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (435 mg, 1.1 mmol, 69%) as a yellow solid. LCMS [M+H] + = 467.1, 469.1 (before acid treatment). 1 H NMR(400 MHz, CDCl3)δ ppm 1.79 - 1.89(m, 2H)1.90 - 2.06(m, 2H)2.13 - 2.20(m, 2H)2.21 - 2.27(m, 2H)2.31 - 2.46(m, 2H)2.82(s, 3H)4.13 - 4.22(m, 2H)8.06(d, J = 2.50 Hz, 1H)8.54(d, J = 2.38 Hz, 1H).

[0341] Step C: A vial was charged with methylboronic acid (78 mg, 2.5 eq., 1.3 mmol), 5'-acetyl-7'-bromo-4,4-difluoro-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (215 mg, 1.0 eq., 520 μmol), potassium carbonate (181 mg, 2.5 eq., 1.31 mmol), and tetrakis(triphenylphosphine)palladium(0) (60 mg, 0.10 eq., 52 μmol). The vial was evacuated and backfilled with nitrogen three times. Next, a solution of deoxygenated 1,4-dioxane (2.1 mL) and water (520 μL) was added, and the reaction was heated to 90 °C and stirred overnight. The reaction mixture was cooled to room temperature, quenched with saturated sodium bicarbonate, and extracted three times with dichloromethane. The combined organic layer was washed with water and then saturated brine, and dried over magnesium sulfate. After filtration and concentration under reduced pressure, the mixture was purified by silica gel chromatography to give 5'-acetyl-4,4-difluoro-7'-methyl-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (114 mg, 329 μmol, 63%) as a pale yellow solid. LCMS [M+H] + = 347.1. 1 H NMR(400 MHz, CDCl3)δ ppm 1.80 - 1.89(m, 2H)1.90 - 2.03(m, 2H)2.15 - 2.26(m, 4H)2.35 - 2.47(m, 2H)2.49(s, 3H)2.83(s, 3H)4.11 - 4.23(m, 2H)7.81(d, J = 2.25 Hz, 1H)8.23(d, J = 1.38 Hz, 1H).

[0342] Step D: To a solution of 5'-acetyl-4,4-difluoro-7'-methyl-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (114 mg, 1 eq., 329 μmol) and (R)-2-methylpropane-2-sulfinamide (48 mg, 1.2 eq., 400 μmol) in tetrahydrofuran (1.3 mL) was added titanium(IV) ethoxide (340 μL, 5.0 eq., 1.7 mmol). The mixture was stirred at 80 °C for 4 h and then cooled to room temperature. After returning to room temperature, a small amount of saturated brine was added to form a suspension. The resulting suspension was diluted with ethyl acetate and filtered through a Celite plug. The filter cake was washed several times with ethyl acetate. The filtrate was concentrated under reduced pressure to give (R)-N-(1-(4,4-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethylidene)-2-methylpropane-2-sulfinamide (167 mg) as a crude yellow solid, which was used in the next step without purification.

[0343] Step E: To a solution of (R)-N-(1-(4,4-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethylidene)-2-methylpropane-2-sulfinamide (167 mg, 1.0 eq., 371 μmol) in anhydrous dichloromethane (2.5 mL) was added Schwartz's reagent (105 mg, 1.10 eq., 409 μmol) as a solid in small portions at room temperature. The reaction mixture was stirred at this temperature for 15 minutes and then quenched with ammonium chloride. The aqueous layer was extracted with dichloromethane, and the combined organics were washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0% to 10% methanol in dichloromethane) to give (R)-N-((R)-1-(4,4-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)-2-methylpropane-2-sulfinamide (78 mg, 0.17 mmol, 46% over two steps) as a white solid. LCMS [M+H] + = 452.2.

[0344] Step F: To a solution of (R)-N-((R)-1-(4,4-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)-2-methylpropane-2-sulfinamide (78 mg, 1.0 eq., 0.17 mmol) in methanol (0.35 mL) was added 0.11 mL of HCl (4.0 mol) in dioxane at 0°C. The reaction was stirred at room temperature until complete, then triturated with diethyl ether to give (R)-5'-(1-aminoethyl)-4,4-difluoro-7'-methyl-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one hydrochloride as an off-white salt, which was used without further purification. LCMS [M+H] + = 348.2.

[0345] Intermediate D [ka]

[0346] Step A: A solution of 8-oxa-2-azaspiro[4.5]decan-1-one (500 mg, 1.0 eq., 3.2 mmol) in 1,2-dichloroethane (12 mL) was placed in a flask, and phosphorus oxychloride (390 μL, 1.3 eq., 4.2 mmol) and diisopropylethylamine (560 μL, 1.0 eq., 3.2 mmol) were added. The reaction was heated at 50 °C for 1 h. 2-Amino-5-bromo-3-iodobenzoic acid (1.1 g, 1.0 eq., 3.2 mmol) was then added as a solid, and the reaction was heated at 100 °C. The reaction was stirred overnight, cooled to room temperature, and diluted with water. The aqueous layer was extracted with dichloromethane, and the combined organic phase was washed with saturated brine, dried over magnesium sulfate, and concentrated. The resulting solid was purified by silica gel chromatography to give 7'-bromo-5'-iodo-1',2,2',3,5,6-hexahydro-9'H-spiro[pyran-4,3'-pyrrolo[2,1-b]quinazolin]-9'-one (501 mg, 1.10 mmol, 34%) as a solid. LCMS: [M+H] + = 462.8. 1 H NMR(500 MHz, CDCl3)δ ppm 1.70 - 1.76(m, 2H), 2.14 - 2.21(m, 2H)2.21 - 2.28(m, 2H)3.73(ddd, J = 11.64, 7.94, 3.42 Hz, 2H)4.11 - 4.17(m, 2H)4.25 - 4.34(m, 2H)8.36(d, J = 2.19 Hz, 1H)8.39(d, J = 2.19 Hz, 1H).

[0347] Step B: Palladium(II) acetate (12 mg, 0.05 eq., 54 μmol), 1,3-bis(diphenylphosphino)propane (45 mg, 0.10 eq., 110 μmol), and 7'-bromo-5'-iodo-1',2,2',3,5,6-hexahydro-9'H-spiro[pyran-4,3'-pyrrolo[2,1-b]quinazolin]-9'-one (500 mg, 1.0 eq., 1.10 mmol) were added to a vial and stir bar. The flask was evacuated and backfilled with nitrogen three times. Ethylene glycol (2.7 mL), N,N-dicyclohexylmethylamine (700 μL, 3.0 eq., 3.3 mmol), and n-butyl vinyl ether (700 μL, 5.0 eq., 5.4 mmol) were then added, and the solution was sparged with nitrogen. The vial was placed in a heating block and the mixture was heated to 115 °C with stirring. After the reaction had progressed completely, the reaction was cooled to room temperature and 1N HCl (9 mL) was added. The reaction was stirred until deprotection of the ketone was complete (approximately 1 h). The aqueous layer was extracted three times with ethyl acetate, and the combined organic phase was washed successively with water and saturated brine, dried over magnesium sulfate, filtered, and concentrated to give a residue. This residue was purified by silica gel chromatography to give 5'-acetyl-7'-bromo-1',2,2',3,5,6-hexahydro-9'H-spiro[pyran-4,3'-pyrrolo[2,1-b]quinazolin]-9'-one (300 mg, 795 μmol, 73%) as a red solid. LCMS: [M+H] + = 379.0. 1 H NMR(400 MHz, CDCl3)δ ppm 1.62(br d, J = 13.13 Hz, 2H)2.17 - 2.28(m, 2H)2.33(br t, J = 6.88 Hz, 2H)2.89(s, 3H)3.65(td, J = 11.51, 2.38 Hz, 2H)4.09(dt, J = 11.79, 3.74 Hz, 2H)4.18(br t, J = 6.94 Hz, 2H)8.10(br s, 1H)8.54(d, J = 2.13 Hz, 1H)

[0348] Step C: A vial was charged with methylboronic acid (60 mg, 2.5 eq., 990 μmol), 5'-acetyl-7'-bromo-1',2,2',3,5,6-hexahydro-9'H-spiro[pyran-4,3'-pyrrolo[2,1-b]quinazolin]-9'-one (150 mg, 1 eq., 398 μmol), potassium carbonate (137 mg, 2.5 eq., 994 μmol), and tetrakis(triphenylphosphine)palladium(0) (46 mg, 0.10 eq., 40 μmol). The vial was evacuated and backfilled with nitrogen three times. Next, a solution of deoxygenated 1,4-dioxane (1.6 mL) and water (400 μL) was added, and the reaction was heated to 90 °C and stirred overnight. The reaction mixture was cooled to room temperature, quenched with saturated sodium bicarbonate, and extracted three times with dichloromethane. The combined organic layer was washed sequentially with water and saturated brine, and dried over magnesium sulfate. After filtration, the mixture was concentrated under reduced pressure and purified by silica gel chromatography to give 5'-acetyl-7'-methyl-1',2,2',3,5,6-hexahydro-9'H-spiro[pyran-4,3'-pyrrolo[2,1-b]quinazolin]-9'-one (68 mg, 0.22 mmol, 55%) as a pale red solid. LCMS: [M+H] + = 313.2. 1 H NMR(400 MHz, CDCl3)δ ppm 1.62(br d, J = 13.51 Hz, 2H)1.59 - 1.66(m, 1H)2.06 - 2.06(m, 1H)2.17 - 2.27(m, 2H)2.28 - 2.34(m, 2H)2.49(s, 3H)2.90(s, 3H)3.61 - 3.71(m, 2H)4.10(dt, J = 11.91, 3.99 Hz, 2H)4.14 - 4.19(m, 2H)7.85(d, J = 2.00 Hz, 1H)8.23(d, J = 1.25 Hz, 1H).

[0349] Step D: To a solution of 5'-acetyl-7'-methyl-1',2,2',3,5,6-hexahydro-9'H-spiro[pyran-4,3'-pyrrolo[2,1-b]quinazolin]-9'-one (68 mg, 1 eq., 0.22 mmol) and (R)-2-methylpropane-2-sulfinamide (32 mg, 1.2 eq., 0.26 mmol) in tetrahydrofuran (0.90 mL) was added titanium(IV) ethoxide (0.23 mL, 5.0 eq., 1.1 mmol). The mixture was stirred at 80 °C for 4 h and then cooled to room temperature. After reaching room temperature, a small amount of saturated brine was added to form a suspension. The resulting suspension was diluted with ethyl acetate and filtered through a Celite plug. The filter cake was washed several times with ethyl acetate. The filtrate was concentrated under reduced pressure to give (R)-2-methyl-N-(1-(7'-methyl-9'-oxo-1',2,2',3,5,6-hexahydro-9'H-spiro[pyran-4,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethylidene)propane-2-sulfinamide (97 mg) as a crude yellow solid, which was used in the next step without further purification.

[0350] Step E: To a solution of (R)-2-methyl-N-(1-(7'-methyl-9'-oxo-1',2,2',3,5,6-hexahydro-9'H-spiro[pyran-4,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethylidene)propane-2-sulfinamide (97 mg, 1 eq., 0.23 mmol) in anhydrous dichloromethane (1.6 mL) was added Schwartz's reagent (66 mg, 1.1 eq., 0.26 mmol) as a solid in small portions at room temperature. The reaction was stirred at this temperature for 15 minutes before being quenched with ammonium chloride. The aqueous layer was extracted with dichloromethane, and the combined organics were washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0% to 10% methanol in dichloromethane) to give (R)-2-methyl-N-((R)-1-(7'-methyl-9'-oxo-1',2,2',3,5,6-hexahydro-9'H-spiro[pyran-4,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)propane-2-sulfinamide (32 mg, 77 μmol, 33% over two steps) as a white solid. LCMS [M+H] + = 418.2.

[0351] Step F: To a solution of (R)-2-methyl-N-((R)-1-(7'-methyl-9'-oxo-1',2,2',3,5,6-hexahydro-9'H-spiro[pyran-4,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)propane-2-sulfinamide (33 mg, 1.0 eq., 79 μmol) in methanol (0.3 mL) was added 49 μL of HCl (4.0 mol dioxane solution) at 0°C. The reaction was stirred at room temperature until complete, then triturated with diethyl ether to give (R)-5'-(1-aminoethyl)-7'-methyl-1',2,2',3,5,6-hexahydro-9'H-spiro[pyran-4,3'-pyrrolo[2,1-b]quinazolin]-9'-one hydrochloride as a yellow salt, which was used without further purification. LCMS [M+H] + = 314.2.

[0352] Intermediate E [ka]

[0353] Step A: A solution of 2-azaspiro[4.4]nonan-1-one (500 mg, 1.0 eq., 3.59 mmol) in 1,2-dichloroethane (14 mL) was placed in a flask, and phosphorus oxychloride (435 μL, 1.3 eq., 4.67 mmol) and diisopropylethylamine (626 μL, 1.0 eq., 3.59 mmol) were added. The reaction was heated at 50 °C for 1 h. 2-Amino-5-bromo-3-iodobenzoic acid (1.23 g, 1.0 eq., 3.59 mmol) was then added as a solid, and the reaction was heated to 100 °C. The reaction was stirred overnight, cooled to room temperature, and diluted with water. The aqueous layer was extracted with dichloromethane, and the combined organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The solid was purified by silica gel chromatography to give 7'-bromo-5'-iodo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (721 mg, 1.62 mmol, 45%) as a yellow solid. LCMS: [M+H] + = 446.7. 1 H NMR(499 MHz, CDCl3)δ ppm 1.77 - 1.85(m, 4H)2.03 - 2.11(m, 2H)2.15 - 2.18(m, 2H)2.18 - 2.24(m, 2H)4.06 - 4.13(m, 2H)8.33(d, J = 2.19 Hz, 1H)8.38(d, J = 2.19 Hz, 1H).

[0354] Step B: Palladium(II) acetate (18 mg, 0.05 eq., 81 μmol), 1,3-bis(diphenylphosphino)propane (67 mg, 0.10 eq., 160 μmol), and 7'-bromo-5'-iodo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (721 mg, 1.0 eq., 1.62 mmol) were added to a vial and stir bar. The vial was evacuated and backfilled with nitrogen three times. Ethylene glycol (4.05 mL), N,N-dicyclohexylmethylamine (1.00 mL, 3.0 eq., 4.9 mmol), and n-butyl vinyl ether (1.1 mL, 5.0 eq., 8.1 mmol) were then added, and the solution was sparged with nitrogen. The vial was placed in a heating block and the mixture was heated to 115 °C with stirring. After the reaction was complete, the reaction was cooled to room temperature and 1N HCl (9 mL) was added to the reaction mixture. The reaction mixture was stirred until deprotection of the ketone was complete (approximately 1 hour). The aqueous layer was extracted three times with ethyl acetate, and the combined organic phase was washed successively with water and saturated brine, dried over magnesium sulfate, filtered, and concentrated to give a residue. The residue was purified by silica gel chromatography to give 5'-acetyl-7'-bromo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (449 mg, 1.24 mmol, 77%) as a yellow solid. LCMS: [M+H] + = 419.1 (before acid treatment). 1 H NMR(400 MHz, CDCl3)δ ppm 1.78 - 1.88(m, 4H)1.91 - 2.03(m, 2H)2.14(br dd, J = 4.88, 2.13 Hz, 2H)2.16 - 2.21(m, 2H)2.86(s, 2H)4.04 - 4.21(m, 2H)8.09(d, J = 2.50 Hz, 1H)8.54(d, J = 2.50 Hz, 1H).

[0355] Step C: A vial was charged with methylboronic acid (62 mg, 2.5 eq., 1.00 mmol), 5'-acetyl-7'-bromo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (150 mg, 1.0 eq., 415 μmol), potassium carbonate (143 mg, 2.5 eq., 1.04 mmol), and tetrakis(triphenylphosphine)palladium(0) (48 mg, 0.10 eq., 42 μmol). The vial was evacuated and backfilled with nitrogen three times. Next, a solution of deoxygenated 1,4-dioxane (1.7 mL) and water (420 μL) was added, and the reaction was heated to 90 °C and stirred overnight. The reaction was then cooled to room temperature. The reaction mixture was cooled to room temperature, quenched with saturated sodium bicarbonate, and then extracted three times with dichloromethane. The combined organic layer was washed with water and then saturated brine, and dried over magnesium sulfate. After filtration and concentration under reduced pressure, the mixture was purified by silica gel chromatography to give 5'-acetyl-7'-methyl-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (65 mg, 0.22 mmol, 53%) as a pale yellow solid. LCMS: [M+H] + = 297.2.

[0356] Step D: To a solution of 5'-acetyl-7'-methyl-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (87 mg, 1.0 eq., 0.29 mmol) and (R)-2-methylpropane-2-sulfinamide (43 mg, 1.2 eq., 0.35 mmol) in tetrahydrofuran (1.2 mL) was added titanium(IV) ethoxide (0.33 g, 0.31 mL, 5.0 eq., 1.5 mmol). The mixture was stirred at 80 °C for 4 h and then cooled to room temperature. After returning to room temperature, a small amount of saturated brine was added to form a suspension. The resulting suspension was diluted with ethyl acetate and filtered through a Celite plug. The filter cake was washed several times with ethyl acetate. The filtrate was concentrated under reduced pressure, and the yellow residue was quickly purified by silica gel chromatography (30% to 100% ethyl acetate in heptane) to give (R)-2-methyl-N-(1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethylidene)propane-2-sulfinamide (57 mg, 0.14 mmol, 49%) as a yellow solid.

[0357] Step E: To a solution of (R)-2-methyl-N-(1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethylidene)propane-2-sulfinamide (57 mg, 1 eq., 0.14 mmol) in anhydrous dichloromethane (0.95 mL) was added Schwartz's reagent (40 mg, 1.1 eq., 0.16 mmol) as a solid in small portions at room temperature. The reaction mixture was stirred at this temperature for 15 minutes and then quenched with ammonium chloride. The aqueous layer was extracted with dichloromethane, and the combined organics were washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0% to 10% methanol in dichloromethane) to give (R)-2-methyl-N-((R)-1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)propane-2-sulfinamide (57 mg, 0.14 mmol, 99%) as a white solid. LCMS [M+H] + = 402.2.

[0358] Step F: To a solution of (R)-2-methyl-N-((R)-1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazolin]-5'-yl)ethyl)propane-2-sulfinamide (47 mg, 1.0 eq., 0.12 mmol) in methanol (0.2 mL) was added 73 μL of HCl (4.0 mol dioxane solution) at 0 °C. The reaction was stirred at room temperature until complete and then triturated with diethyl ether to give (R)-5'-(1-aminoethyl)-7'-methyl-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one hydrochloride as an off-white hydrochloride salt. LCMS [M+H] + = 298.2.

[0359] Intermediate F [ka]

[0360] Step A: The starting aryl bromide was prepared analogously to intermediate B. The desired Suzuki reaction was carried out using a procedure similar to Wallace, DJ, and Chen C.-Y. Tetrahedron Letters 43, 2002, 6987-6990. A vial containing cyclopropylboronic acid (44 mg, 1.3 eq., 510 μmol), 5'-acetyl-7'-bromo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (147 mg, 1.0 eq., 392 μmol), palladium(II) acetate (4 mg, 0.05 eq., 20 μmol), potassium phosphate tribasic (291 mg, 3.5 eq., 1.37 mmol), and tricyclohexylphosphine (11.0 mg, 0.1 eq., 39.2 μmol) was evacuated and backfilled with nitrogen three times. A solution of deoxygenated toluene (1.9 mL) and water (90 μL) was then added, and the reaction mixture was heated to 100 °C and stirred overnight. The reaction was quenched with saturated sodium bicarbonate and extracted three times with dichloromethane. The combined organics were washed sequentially with water and saturated brine, dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel chromatography to give 5'-acetyl-7'-cyclopropyl-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (92 mg, 0.27 mmol, 70%) as a white solid. LCMS [M+H] + = 337.2. 1H NMR(400 MHz, CDCl3)δ ppm 0.76 - 0.84(m, 2H)1.01 - 1.10(m, 2H)1.35 - 1.50(m, 3H)1.66(m, 2H)1.71 - 1.78(m, 1H)1.79 - 1.92(m, 4H)1.98 - 2.08(m, 1H)2.10 - 2.10(m, 1H)2.16 - 2.22(m, 2H)2.90(s, 3H)4.07 - 4.15(m, 2H)7.75(d, J = 2.25 Hz, 1H)8.09(d, J = 2.38 Hz, 1H).

[0361] Step B: To a solution of 5'-acetyl-7'-cyclopropyl-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (92 mg, 1 eq., 0.27 mmol) and (R)-2-methylpropane-2-sulfinamide (40 mg, 1.2 eq., 0.33 mmol) in tetrahydrofuran (1.1 mL) was added titanium(IV) ethoxide (0.31 g, 0.28 mL, 5 eq., 1.4 mmol). The mixture was stirred at 80 °C for 4 h and then cooled to room temperature. After returning to room temperature, a small amount of saturated brine was added to form a suspension. The resulting suspension was diluted with ethyl acetate and filtered through a Celite plug. The filter cake was washed several times with ethyl acetate. The filtrate was concentrated under reduced pressure to give (R)-N-(1-(7'-cyclopropyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethylidene)-2-methylpropane-2-sulfinamide (138 mg) as a crude yellow solid, which was used without further purification.

[0362] Step C: To a solution of (R)-N-(1-(7'-cyclopropyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethylidene)-2-methylpropane-2-sulfinamide (138 mg, 1 eq., 314 μmol) in anhydrous dichloromethane (2.1 mL) was added Schwartz's reagent (89 mg, 1.1 eq., 350 μmol) as a solid in small portions at room temperature. The reaction mixture 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 layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0% to 10% methanol in dichloromethane) to give (R)-N-((R)-1-(7'-cyclopropyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)-2-methylpropane-2-sulfinamide (60 mg, 0.14 mmol, 43%) as a white solid. LCMS [M+H] + = 442.3.

[0363] Step D: To a solution of (R)-N-((R)-1-(7'-cyclopropyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)-2-methylpropane-2-sulfinamide (60 mg, 1.0 eq., 0.14 mmol) in methanol (0.3 mL) was added 85 μL of HCl (4.0 M dioxane solution) at 0 °C. The reaction was stirred at room temperature until complete, then triturated with diethyl ether to give (R)-5'-(1-aminoethyl)-7'-cyclopropyl-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one hydrochloride (45 mg, 0.12 mmol, 89%) as an off-white salt, which was used without further purification. LCMS [M+H] + = 338.3.

[0364] intermediate G [ka]

[0365] Step A: To a solution of 5'-acetyl-7'-bromo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (296 mg, 1.0 eq., 819 μmol) and (R)-2-methylpropane-2-sulfinamide (119 mg, 1.2 eq., 983 μmol) in tetrahydrofuran (2.05 mL) was added titanium(IV) ethoxide (850 μL, 5.0 eq., 4.1 mmol). The mixture was stirred at 80 °C for 3 h and then cooled to room temperature. After returning to room temperature, a small amount of saturated brine was added to form a suspension. The resulting suspension was diluted with ethyl acetate and filtered through a Celite plug. The filter cake was washed several times with ethyl acetate. The filtrate was concentrated under reduced pressure, and the yellow residue was quickly purified by silica gel chromatography (30% to 100% ethyl acetate in heptane) to give (R)-N-(1-(7'-bromo-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethylidene)-2-methylpropane-2-sulfinamide (280 mg, 600 μmol, 74%) as a yellow solid.

[0366] Step B: To a solution of (R)-N-(1-(7'-bromo-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethylidene)-2-methylpropane-2-sulfinamide (280 mg, 1.0 eq., 600 μmol) in anhydrous dichloromethane (4.0 mL) was added Schwartz's reagent (171 mg, 1.1 eq., 663 μmol) as a solid in small portions at room temperature. The reaction was stirred at this temperature for 15 minutes before being quenched with ammonium chloride. The aqueous layer was extracted with dichloromethane, and the combined organics were washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (0% to 10% methanol in dichloromethane) to give (R)-N-((R)-1-(7'-bromo-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)-2-methylpropane-2-sulfinamide (249 mg, 530 μmol, 89%) as a white solid. LCMS: [M+H] + = 468.1.

[0367] Step C: Dimethylacetamide (0.9 mL) was added to a flask containing zinc cyanide (6 mg, 3.0 μL, 0.55 eq., 5 μmol), (R)-N-((R)-1-(7'-bromo-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)-2-methylpropane-2-sulfinamide (40 mg, 1.0 eq., 86 μmol), and Xantphos Pd G3 (4.0 mg, 0.05 eq., 4.0 μmol) under a nitrogen atmosphere. The reaction mixture was heated at 100 °C for 12 h. The reaction was quenched with 1 M sodium carbonate and extracted with ethyl acetate. The combined organic layer was washed with water, then saturated brine, dried over magnesium sulfate, filtered, and concentrated by rotary evaporation. The product was purified by silica gel chromatography to give (R)-N-((R)-1-(7'-cyano-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)-2-methylpropane-2-sulfinamide (18 mg, 44 μmol, 51%) as a yellow solid. LCMS: [M+H] + = 413.2.

[0368] Step D: To a solution of (R)-N-((R)-1-(7'-cyano-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)-2-methylpropane-2-sulfinamide (18 mg, 1 eq., 44 μmol) in methanol (0.2 mL) was added 16 μL of HCl (4.0 mol dioxane solution) at 0 °C. The reaction was stirred at room temperature until complete, and then triturated with diethyl ether to give (R)-5'-(1-aminoethyl)-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-7'-carbonitrile hydrochloride as an off-white salt, which was used directly without further purification. LCMS [M+H] + = 309.1.

[0369] Intermediate H [ka]

[0370] Step A: A procedure similar to Turner et al., Chemistry - A European Journal, 2020, 26, 3026-3029, was used. Diethyl ether (30 mL) was added to a flask containing cyanogen bromide (3.00 g, 1.77 mL, 1.0 eq., 28.3 mmol) and sodium carbonate (4.50 g, 1.5 eq., 42.5 mmol) at 0 °C. A solution of 2-(1-cyclohexenyl)ethylamine (3.55 g, 3.94 mL, 1.0 eq., 28.3 mmol) in tetrahydrofuran (30 mL) was then slowly added. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was filtered through Celite, the solid washed with ethyl acetate, and the organics dried under vacuum to give N-(2-(cyclohex-1-en-1-yl)ethyl)cyanamide (2.47 g, 16.4 mmol, 58%), which was purified by silica gel chromatography (ethyl acetate / heptane 0% to 40%). The product was visualized by TLC iodine staining. 1 H NMR(400 MHz, CDCl3)δ ppm 1.52 - 1.59(m, 2H)1.60 - 1.69(m, 2H)1.90(br d, J = 1.25 Hz, 2H)1.97 - 2.06(m, 2H)2.22(t, J = 6.57 Hz, 2H)3.12 - 3.21 (m, 2H) 3.32 (br s, 1H) 5.53 (br s, 1H).

[0371] Step B: To a suspension of 3-bromo-5-iodobenzoic acid (4.35 g, 2.0 eq., 13.3 mmol) in dichloromethane (10 mL) was added Gose's reagent (1.78 g, 1.76 mL, 2.0 eq., 13.3 mmol). The mixture was stirred at room temperature for 15 min. After the solution became clear, a solution of N-(2-(cyclohex-1-en-1-yl)ethyl)cyanamide (1.00 g, 1.0 eq., 6.66 mmol), 4-(dimethylamino)pyridine (81.3 mg, 0.10 eq., 666 μmol), and pyridine (2.63 g, 2.69 mL, 5.0 eq., 33.3 mmol) in dichloromethane (20 mL) was added with stirring. The reaction mixture was stirred until the reaction was complete (approximately 1 h). The reaction mixture was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate and saturated brine, and dried over magnesium sulfate. The organic matter was filtered and concentrated, and the target product was purified by silica gel chromatography to give 3-bromo-N-cyano-N-(2-(cyclohex-1-en-1-yl)ethyl)-5-iodobenzamide. LCMS: [M + HO + Na] + = 500.9. 1 H NMR(400 MHz, CDCl3)δ ppm 1.55 - 1.71(m, 4H)1.93 - 2.11(m, 4H)2.40(t, J = 6.75 Hz, 2H)3.83(t, J = 6.82 Hz, 2H)5.61(br s, 1H)7.81(t, J = 1.50 Hz, 1H)7.96(d, J = 1.25 Hz, 1H)8.06(d, J = 1.50 Hz, 1H).

[0372] Step C: A procedure similar to that of Harwood et al., Science, 2022, 745-752 was used. To a 5 mL electrasyn vial and stir bar was added 4,4'-di-tert-butyl-2,2'-dipyridyl (81 mg, 0.2 eq., 300 μmol), nickel chloride hexahydrate (71 mg, 0.2 eq., 300 μmol), 1,3-dioxoisoindolin-2-yl(tert-butoxycarbonyl)alaninate (627 mg, 1.25 eq., 1.88 mmol), silver nitrate (76 mg, 0.30 eq., 450 μmol), and 3-bromo-N-cyano-N-(2-(cyclohex-1-en-1-yl)ethyl)-5-iodobenzamide (689 mg, 1.0 eq., 1.50 mmol). A standard ElectraXin cap equipped with a magnesium anode and an RVC (100 ppi) cathode was then attached to the vial. The vial was then evacuated and backfilled with nitrogen three times. Anhydrous, deoxygenated dimethylformamide (4.0 mL) was then added. The vial was placed in ElectraXin 2.0 with the following parameters: 1.50 mmol, 2.3 F / mol, 45 mA. After completion of the reaction, the reaction was evaluated by LCMS and quenched with 1N HCl. The organic matter was extracted with ethyl acetate, washed sequentially with water and saturated brine, dried over magnesium sulfate, concentrated, and purified by silica gel chromatography (0% to 45% ethyl acetate in heptane) to give tert-butyl (1-(3-bromo-5-(cyano(2-(cyclohex-1-en-1-yl)ethyl)carbamoyl)phenyl)ethyl)carbamate (421 mg, 880 μmol, 59%) as a white solid. LCMS [M- tBu + H] + = 422.0.

[0373] Step D: A procedure similar to Turner et al., Chemistry - A European Journal, 2020, 26, 3026-3029, was used. tert-Butyl (1-(3-bromo-5-(cyano(2-(cyclohex-1-en-1-yl)ethyl)carbamoyl)phenyl)ethyl)carbamate (606 mg, 1.0 eq., 1.27 mmol) and iron(III) acetylacetonate (45 mg, 0.1 eq., 130 μmol) were added to a vial, followed by a solution of phenylsilane (145 mg, 166 μL, 1.05 eq., 1.34 mmol) in isopropanol (5.09 mL). The reaction mixture was stirred at 50 °C in the open atmosphere. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The crude regioisomers were separated by silica gel chromatography (0% to 60% ethyl acetate in heptane) to give tert-butyl (1-(7'-bromo-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazolin]-5'-yl)ethyl)carbamate (219 mg, 561 μmol, 36%) as a white solid and the unwanted regioisomer, tert-butyl (1-(5'-bromo-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazolin]-7'-yl)ethyl)carbamate (186 mg, 390 μmol, 31%) in a 1.17:1 ratio. LCMS [M+H] + = 478.1.

[0374] Step E: A vial was charged with methylboronic acid (38 mg, 2.0 eq., 630 μmol), tert-butyl (1-(7'-bromo-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazolin]-5'-yl)ethyl)carbamate (150 mg, 1.0 eq., 315 μmol), potassium carbonate (87 mg, 2.0 eq., 630 μmol), and tetrakis(triphenylphosphine)palladium(0) (36 mg, 0.1 eq., 32 μmol), and the reaction mixture was evacuated and backfilled with nitrogen three times. Next, a degassed solution of 1,4-dioxane (1.3 mL) and water (320 μL) was added, and the reaction mixture was heated to 90 °C and stirred overnight. After cooling to room temperature, the reaction was quenched with saturated sodium bicarbonate and extracted three times with dichloromethane. The combined organics were washed sequentially with water and saturated brine, and dried over magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and purified by silica gel chromatography to give tert-butyl (1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazolin]-5'-yl)ethyl)carbamate (65 mg, 0.16 mmol, 50%) as a white solid. LCMS [M+H] + = 412.2.

[0375] Step F: To a vial containing tert-butyl (1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazolin]-5'-yl)ethyl)carbamate (67 mg, 1.0 eq., 0.16 mmol) was added 0.50 mL of HCl (4 M in dioxane). The reaction was stirred at room temperature until complete (3 h), after which it was triturated with diethyl ether and the solid was washed three times with diethyl ether to give 5'-(1-aminoethyl)-7'-methyl-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one hydrochloride as a white salt, which was used in the next step without further purification. LCMS [M+H] + = 312.2.

[0376] Intermediate I [ka]

[0377] Step A: To a vial containing tert-butyl (1-(7'-bromo-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazolin]-5'-yl)ethyl)carbamate (50 mg, 1.0 eq., 0.10 mmol) was added HCl (4.0 mol in dioxane) (0.5 mL). The reaction was stirred at room temperature until complete (3 h), then triturated with diethyl ether. The solid was washed three times with diethyl ether to give 5'-(1-aminoethyl)-7'-bromo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one hydrochloride (34 mg, 98 μmol, 93%) as a white salt. LCMS [M+H] + = 377.95.

[0378] Intermediate J [ka]

[0379] Step A: The reaction of Intermediate H, Step E also produced tert-butyl (1-(9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazolin]-5'-yl)ethyl)carbamate (7.0 mg, 18 μmol, 5.6%) as a minor product. LCMS [M+H] + = 398.3.

[0380] Step B: To a vial containing tert-butyl (1-(9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazolin]-5'-yl)ethyl)carbamate (8.0 mg, 1 eq., 20 μmol) was added HCl (4.0 M in dioxane) (0.3 mL). The reaction was stirred at room temperature until complete (3 h), then triturated with diethyl ether. The resulting solid was washed three times with diethyl ether to give 5'-(1-aminoethyl)-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one hydrochloride (7 mg, 20 μmol, quantitative yield) as a white salt. LCMS [M+H] + = 298.1. [Example]

[0381] Example 1-1 (R)-2-((1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid [ka]

[0382] To the vial and stir bar were added (R)-5'-(1-aminoethyl)-7'-methyl-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one hydrochloride (48 mg, 1 eq., 0.14 mmol), 2-carboxyphenylboronic acid (69 mg, 3.0 eq., 0.41 mmol), and copper(II) acetate (38 mg, 1.5 eq., 0.21 mmol) as solids. The vial was then sealed with a septum cap, and dimethylformamide (0.69 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.10 mL, 5.0 eq., 0.69 mmol) were added sequentially. A vent needle was inserted into the septum, and the reaction was returned to ambient atmosphere and stirred at room temperature for 12 h. The reaction was quenched with aqueous ammonium chloride and diluted with ethyl acetate. The aqueous layer was extracted three times with ethyl acetate, and the combined organic phase was washed successively with saturated aqueous ammonium chloride and saturated brine, then dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The reaction residue was purified by silica gel chromatography (heptane solution, 0-75% ethyl acetate) to give (R)-2-((1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid (8.0 mg, 19 μmol, 13%) as a white solid. LCMS [M+H] + = 432.2. 1 H NMR(400 MHz, CDCl3)δ ppm 1.41 - 1.56(m, 3H)1.60 - 1.76(m, 6H)1.84 - 1.99(m, 4H)2.19(t, J = 7.19 Hz, 2H)2.40(s, 3H)4.12(t, J = 7.19 Hz, 2H)5.61 - 5.75(m, 1H)6.53(br d, J = 8.50 Hz, 1H)6.58(br t, J = 7.13 Hz, 1H)7.13 - 7.21(m, 1H)7.57(br s, 1H)7.96(d, J = 1.50 Hz, 1H)7.98(s, 1H).

[0383] Example 1-2 2-((1-(9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid [ka]

[0384] To a vial containing 2-iodobenzoic acid (9 mg, 1.5 eq., 40 μmol), sarcosine (1 mg, 0.6 eq., 10 μmol), potassium carbonate (10 mg, 3.0 eq., 70 μmol), copper(I) iodide (1 mg, 0.3 eq., 7 μmol), and 5'-(1-aminoethyl)-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (7 mg, 1.0 eq., 20 μmol) was added dimethyl sulfoxide (0.5 mL) under a nitrogen atmosphere. The reaction was stirred for 5 minutes and then heated to 40 °C for 18 hours. The reaction was cooled, quenched with saturated ammonium chloride, and extracted with ethyl acetate. The combined organics were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by preparative TLC to give 2-((1-(9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid (2 mg, 4 μmol, 15%). LCMS [M+H] + = 418.2. 1H NMR(400 MHz, CDCl3)δ ppm 1.46 - 1.53(m, 3H)1.66(d, J = 6.75 Hz, 4H)1.67 - 1.75(m, 3H)1.85 - 2.02(m, 4H)2.20(t, J = 7.38 Hz, 2H)4.13(t, J = 7.32 Hz, 2H)6.46(d, J = 8.63 Hz, 1H)6.53(t, J = 7.50 Hz, 1H)7.15(td, J = 7.85, 1.69 Hz, 1H)7.33(t, J = 7.75 Hz, 1H)7.68 - 7.76(m, 1H)7.92(dd, J = 7.94, 1.56 Hz, 1H)8.17(dd, J = 7.88, 1.38 Hz, 1H).

[0385] Examples 1-3 to 1-90 The following compounds are prepared essentially according to the procedures described above and below in the Schemes and Examples.

[0386] [Table 43] [Table 44] [Table 45] [Table 46] [Table 47] [Table 48] [Table 49] [Table 50] Table 51 Table 52 Table 53 Table 54 Table 55 Table 56 Table 57 Table 58 Table 59 Table 60 Table 61 Table 62 Table 63 Table 64 [Table 65] [Table 66] [Table 67] [Table 68] [Table 69] [Table 70] [Table 71] [Table 72] [Table 73] [Table 74] [Table 75] [Table 76]

[0387] Examples 1-91 2-((1-(3,3-difluoro-7-methyl-9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-5-yl)ethyl)amino)benzoic acid [ka]

[0388] Step A: To a mixture of 2-amino-3-bromo-5-methylbenzoic acid (10.0 g, 43.5 mmol, 1.00 eq.) in toluene (50.0 mL) was added thionyl chloride (25.9 g, 217 mmol, 15.8 mL, 5.00 eq.) dropwise at 25° C. The reaction mixture was degassed and purged with nitrogen three times, and then the mixture was stirred under a nitrogen atmosphere at 100° C. for 3 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the solvent was removed to give 2-amino-3-bromo-5-methylbenzoyl chloride (10.5 g, 97% yield) as a brown oil, which was used in the next step without further purification.

[0389] Step B: A solution of 2-amino-3-bromo-5-methylbenzoyl chloride (1.50 g, 6.04 mmol, 1.83 eq.) in chloroform (5.00 mL) was added dropwise to a solution of 3,3-difluoropyrrolidin-2-one (400 mg, 3.30 mmol, 1.00 eq.) in chloroform (10.0 mL). The mixture was degassed and purged with nitrogen three times, and then stirred under a nitrogen atmosphere at 25 °C for 16 h. After completion of the reaction, the reaction was quenched by the addition of aqueous sodium hydroxide (2 M, 20.0 mL) at 25 °C. The resulting solution was then extracted with DCM (10.0 mL × 2). The combined organic layers were washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 5-bromo-3,3-difluoro-7-methyl-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one (250 mg, 22% yield, 90% purity) as a yellow solid. LCMS [M+3] + = 317.3.

[0390] Step C: A mixture of 5-bromo-3,3-difluoro-7-methyl-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one (250 mg, 793 μmol, 1.00 eq.), tributyl(1-ethoxyvinyl)stannane (287 mg, 793 μmol, 268 μL, 1.00 eq.), and tetrakis(triphenylphosphine)palladium(0) (91.7 mg, 79.3 μmol, 0.10 eq.) in dioxane (5.00 mL) was degassed and purged with nitrogen three times. The mixture was then stirred at 100 °C under a nitrogen atmosphere for 16 h. After completion of the reaction, the reaction mixture was cooled to 25 °C and quenched with saturated aqueous potassium fluoride (20.0 mL) at 20 °C. The mixture was then filtered, and the filtrate was extracted with ethyl acetate (10.0 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product 5-(1-ethoxyvinyl)-3,3-difluoro-7-methyl-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one (200 mg, 82% yield) as a yellow oil, which was used directly in the next step.

[0391] Step D: A mixture of 5-(1-ethoxyvinyl)-3,3-difluoro-7-methyl-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one (200 mg, 653 μmol, 1.00 eq.) and hydrochloric acid (4 M, 2.00 mL, 12.3 eq.) in tetrahydrofuran (2.00 mL) was stirred at 25 °C for 2 h. After stirring was complete, the reaction mixture was partitioned between water (10.0 mL) and dichloromethane (10.0 mL × 2). The organic phase was separated, washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to dichloromethane / methanol = 1 / 0) to obtain 5-acetyl-3,3-difluoro-7-methyl-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one (220 mg, yield 97%, purity 80%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ = 8.29(br s, 1H), 7.95(br s, 1H), 4.26(br s, 2H), 2.91(br s, 3H), 2.87 - 2.75(m, 2H), 2.54(br s, 3H).

[0392] Step E: A solution of 5-acetyl-3,3-difluoro-7-methyl-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one (110 mg, 395 μmol, 1.00 eq.) and ammonium acetate (305 mg, 3.95 mmol, 10.0 eq.) in ethanol (5.00 mL) was stirred at 70° C. for 1 hour. Sodium cyanoborohydride (49.7 mg, 791 μmol, 2.00 eq.) was then added to the mixture. The reaction mixture was stirred at 70° C. for an additional 1 hour. After completion of the reaction, the reaction mixture was cooled to 25°C and diluted with dichloromethane (30.0 mL). The organic solution was washed with water (30.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a residue. The residue was purified by preparative TLC (dichloromethane / methanol = 10 / 1) to give 5-(1-aminoethyl)-3,3-difluoro-7-methyl-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one (17.0 mg, 15.4% yield) as a pale yellow solid. LCMS [M+H] + = 280.4.

[0393] Step F: A blue suspension of 2-iodobenzoic acid (18.9 mg, 76.1 μmol, 1.25 eq.), 5-(1-aminoethyl)-3,3-difluoro-7-methyl-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one (17.0 mg, 60.9 μmol, 1.00 eq.), cuprous iodide (2.32 mg, 12.2 μmol, 0.20 eq.), L-proline (2.80 mg, 24.35 μmol, 0.4 eq.), and potassium carbonate (12.6 mg, 91.3 μmol, 1.50 eq.) in dimethyl sulfoxide (2.00 mL) was degassed, purged with nitrogen three times, and then stirred at 100 °C under nitrogen for 2 h. After the reaction was complete, the reaction mixture was cooled to 250°C and filtered. Acetic acid (2.00 mL) was added to the filtrate and the mixture was directly concentrated in vacuo to obtain a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1, 4 g silica gel column) to obtain 2-((1-(3,3-difluoro-7-methyl-9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-5-yl)ethyl)amino)benzoic acid (8.00 mg, 19.2 μmol, 32% yield, 96% purity) as a pale yellow solid. LCMS [M+3] + = 400.1. 1 H NMR(400 MHz, CD3OD)δ = 7.98(s, 1H), 7.88(d, J = 8.0 Hz, 1H), 7.68(s, 1H), 7.07(t, J = 7.2 Hz, 1H), 6.49(t, J = 7.6 Hz, 1H), 6.36(d, J = 8.4 Hz, 1H), 5.67(q, J = 6.4 Hz, 1H), 4.24(br t, J = 7.2 Hz, 2H), 2.98 - 2.81(m, 2H), 2.42(s, 3H), 1.61(d, J = 6.8 Hz, 3H).

[0394] Examples 1-92 (R)-3-((1-(4,4-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)thiophene-2-carboxylic acid [ka]

[0395] Step A: The procedure used was similar to that in Tetrahedron Letters, 2000, 7731. (R)-5'-(1-aminoethyl)-4,4-difluoro-7'-methyl-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one·HCl (10 mg, 1.0 eq., 26 μmol), methyl 3-iodothiophene-2-carboxylate (10 mg, 1.50 eq., 39 μmol), cesium carbonate (29 mg, 3.4 eq., 89 μmol), tris(dibenzylideneacetone)dipalladium(0) (1.2 mg, 0.05 eq., 1.3 μmol), and (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (1.6 mg, 0.10 eq., 2.6 μmol) were dissolved in toluene (0.26 μmol) under a nitrogen atmosphere. mL) was added and the reaction was stirred at 100° C. for 20 hours. After cooling to room temperature, the reaction mixture was pre-absorbed onto silica and purified by flash chromatography to give methyl (R)-3-((1-(4,4-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)thiophene-2-carboxylate (9.5 mg, 19 μmol, 75% yield). LCMS [M+H] + = 488.3.

[0396] Step B: Methyl (R)-3-((1-(4,4-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)thiophene-2-carboxylate (12 mg, 1 eq., 25 μmol) was dissolved in tetrahydrofuran (98 μL), methanol (98 μL), and water (49 μL) at room temperature in a vial. Solid sodium hydroxide (3.9 mg, 4 eq., 98 μmol) was added in one portion. The reaction mixture was stirred for 24 hours and then quenched with 1N hydrochloric acid to adjust the pH to approximately 5. The aqueous layer was extracted three times with ethyl acetate, and the combined organics were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to give a residue that was purified by silica gel chromatography to give (R)-3-((1-(4,4-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)thiophene-2-carboxylic acid as a tan solid. LCMS [M+H] + = 474.1. 1 H NMR(400 MHz, CDCl3,)δ = 7.99(s, 1H), 7.55(s, 1H), 7.25(d, J = 5.6 Hz, 1H), 6.38(d, J = 5.4 Hz, 1H), 5.59 - 5.47(m, 1H), 4.16(t, J = 7.1 Hz, 2H), 2.61 - 2.46(m, 2H), 2.44(s, 3H), 2.30 - 2.13(m, 4H), 2.10 - 1.92(m, 2H), 1.92 - 1.82(m, 2H), 1.63(d, J = 6.6 Hz, 3H).

[0397] Examples 1-93 (R)-2-((1-(4,4-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)thiophene-3-carboxylic acid [ka]

[0398] Step A: The procedure used was similar to that in Tetrahedron Letters, 2000, 7731. (R)-5'-(1-aminoethyl)-4,4-difluoro-7'-methyl-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one·HCl (10 mg, 1.0 eq., 26 μmol), methyl 2-bromothiophene-3-carboxylate (8.6 mg, 1.50 eq., 39 μmol), cesium carbonate (29 mg, 3.4 eq., 89 μmol), tris(dibenzylideneacetone)dipalladium(0) (1.2 mg, 0.05 eq., 1.3 μmol), and (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (1.6 mg, 0.10 eq., 2.6 μmol) were dissolved in toluene (0.26 μmol) under a nitrogen atmosphere. mL) was added and the reaction was stirred at 100° C. for 20 hours. After cooling to room temperature, the reaction mixture was pre-absorbed onto silica and purified by flash chromatography to give methyl (R)-2-((1-(4,4-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)thiophene-3-carboxylate (10 mg, 21 μmol, 79% yield). LCMS [M+H] + = 488.3.

[0399] Step B: To a vial containing methyl (R)-2-((1-(4,4-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)thiophene-3-carboxylate (10.08 mg, 1 eq., 20.67 μmol) in tetrahydrofuran (82.70 μL), methanol (82.70 μL), and water (41.35 μL) at room temperature, solid sodium hydroxide (3.308 mg, 4 eq., 82.70 μmol) was added in one portion. The reaction was stirred for 36 h and then quenched with 1N hydrochloric acid to a pH of approximately 5. The aqueous layer was extracted three times with ethyl acetate and the combined organics were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give a residue which was purified by silica gel chromatography to give (R)-2-((1-(4,4-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)thiophene-3-carboxylic acid as a tan solid. LCMS [M+H] + = 474.2. 1 H NMR(400 MHz, CDCl3,)δ = 8.01(s, 1H), 7.54(s, 1H), 7.02(d, J = 5.6 Hz, 1H), 6.10(d, J = 5.8 Hz, 1H), 5.34 - 5.22(m, 1H), 4.15(t, J = 6.9 Hz, 2H), 2.65 - 2.47(m, 2H), 2.45(s, 3H), 2.31 - 2.14(m, 4H), 2.09 - 1.93(m, 2H), 1.91 - 1.80(m, 2H), 1.70(d, J = 6.8 Hz, 3H).

[0400] Intermediate K (R)-5'-(1-aminoethyl)-7'-methyl-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one hydrochloride [ka]

[0401] Step A: A solution of 6-azaspiro[3.4]octan-5-one (485 mg, 1.0 eq., 3.9 mmol) in 1,2-dichloroethane (19 mL) was placed in a flask, and phosphorus oxychloride (772 mg, 469 μL, 1.3 eq., 5.0 mmol) and diisopropylethylamine (501 mg, 675 μL, 1.0 eq., 3.9 mmol) were added. The reaction was heated at 50 °C for 1 h. 2-Amino-5-bromo-3-iodobenzoic acid (891 mg, 1 eq., 3.9 mmol) was then added as a solid, and the reaction was heated at 100 °C. The reaction was stirred overnight, cooled to room temperature, and diluted with water. The aqueous layer was extracted with dichloromethane, and the combined organic phase was washed with saturated brine, dried over magnesium sulfate, and concentrated. The solid was purified by silica gel chromatography to give 5'-bromo-7'-methyl-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (495 mg, 1.6 mmol, 40% yield) as a yellow solid. LCMS [M+H] + = 319.0.

[0402] Step B: Palladium(II) acetate (17 mg, 0.05 eq., 78 μmol), 1,3-bis(diphenylphosphino)propane (64 mg, 0.10 eq., 155 μmol), and 5'-bromo-7'-methyl-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (495 mg, 1.0 eq., 1.55 mmol) were added to a vial and stir bar. The flask was evacuated and backfilled with nitrogen three times. Ethylene glycol (3.9 mL), n-butyl vinyl ether (777 μL, 5.0 eq., 7.75 mmol), and N,N-dicyclohexylmethylamine (909 μL, 3.0 eq., 4.65 mmol) were then added, and the solution was sparged with nitrogen. The flask was placed in a heating block and the mixture was heated to 115 °C with stirring. After complete conversion, the reaction was cooled to room temperature and 1N HCl (8 mL) was added. The reaction was stirred until deprotection of the ketone was complete (approximately 1 h). The aqueous layer was extracted three times with ethyl acetate, and the combined organic phase was washed successively with water and saturated brine, dried over magnesium sulfate, filtered, and concentrated to give a residue. This residue was purified by silica gel chromatography to give 5'-acetyl-7'-methyl-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (283 mg, 1.00 mmol, 65% yield) as a yellow solid. LCMS [M+H] + = 283.1.

[0403] Step C: To a solution of 5'-acetyl-7'-methyl-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (239 mg, 1.0 eq., 846 μmol) and (R)-2-methylpropane-2-sulfinamide (123 mg, 1.2 eq., 1.02 mmol) in tetrahydrofuran (2.1 mL) was added titanium(IV) ethoxide (965 mg, 881 μL, 5 eq., 4.23 mmol). The mixture was stirred at 80 °C for 4 h and then cooled to room temperature. After returning to room temperature, a small amount of brine was added to form a suspension. The resulting suspension was diluted with ethyl acetate and filtered through a Celite plug. The filter cake was washed several times with ethyl acetate. The filtrate was concentrated under reduced pressure, and the resulting yellow residue was quickly purified by silica gel chromatography (heptane solution, 30% to 100% ethyl acetate) to give (R)-2-methyl-N-(1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethylidene)propane-2-sulfinamide (179 mg, 464 μmol, 55% yield) as a yellow solid.

[0404] Step D: To a solution of (R)-2-methyl-N-(1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethylidene)propane-2-sulfinamide (179 mg, 1.0 eq., 464 μmol) in anhydrous dichloromethane (3.10 mL) was added Schwartz's reagent (132 mg, 1.1 eq., 511 μL) as a solid in small portions at room temperature. The reaction was stirred at this temperature for 15 min and then quenched with ammonium chloride. The aqueous layer was extracted with dichloromethane, and the combined organics were washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a residue. The solid was purified by silica gel chromatography (dichloromethane solution, 0-10% methanol). Dilution with dichloromethane gave (R)-2-methyl-N-((R)-1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)propane-2-sulfinamide (119 mg, 307 μmol, 66% yield) as a white solid. LCMS [M+H] + = 388.2.

[0405] Step E: To a solution of (R)-2-methyl-N-((R)-1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazolin]-5'-yl)ethyl)propane-2-sulfinamide (119 mg, 1.0 eq., 307 μmol) in methanol (614 μL) was added 192 μL of HCl (4 M dioxane solution) at 0 °C. The reaction mixture was monitored by LCMS. After completion of the reaction, the mixture was triturated with diethyl ether to give (R)-5'-(1-aminoethyl)-7'-methyl-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one hydrochloride (89 mg), which was used without further purification. LCMS [M+H] + = 284.1.

[0406] Examples 1-94 (R)-3-((1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)pyrazine-2-carboxylic acid [ka]

[0407] Step A: A mixture of the starting materials (R)-5'-(1-aminoethyl)-7'-methyl-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one hydrochloride (20 mg, 1 eq., 63 μmol) and methyl 3-bromopyrazine-2-carboxylate (20 mg, 1.5 eq., 94 μmol), and diisopropylethylamine in isopropanol (500 μL) was heated at 90°C for 21 hours. After the reaction was complete by LCMS, the reaction was concentrated and the crude material was purified by preparative HPLC (Shimadzu Prep-HPLC; column: Phenomenex Gemini® 5uM NX-C18 110 Å; 150 x 30 mm; gradient: 5% acetonitrile (0.035% TFA) / 95% water (0.05% TFA) to 95% acetonitrile (0.035% TFA) / 5% water (0.05% TFA)) to give methyl (R)-3-((1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)pyrazine-2-carboxylate (12 mg, 29 μmol, 46% yield). LCMS [M+H] + = 420.4.

[0408] Step B: To a vial was added methyl (R)-3-((1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)pyrazine-2-carboxylate (12 mg, 1 eq., 29 μmol) in methanol (0.15 mL) and tetrahydrofuran (0.15 mL). The solution was stirred for 10 minutes, after which sodium hydroxide (5.7 mg, 5 eq., 0.14 mmol) and water (0.7 mL) were added. The reaction was stirred at room temperature for 4 hours. The reaction was concentrated, and 1 M HCl was added until the pH of the solution reached approximately 4. The solution was stirred until precipitation occurred, and the solid was filtered, washed with water, and dried under vacuum to give (R)-3-((1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)pyrazine-2-carboxylic acid (5.0 mg, 12 μmol, 43% yield) as a yellow solid. LCMS [M+H] + = 406.2. 1 H NMR (400 MHz, CDCl3)δ = 9.12-9.22(m, 1H), 8.30(s, 1H), 7.99(s, 1H), 7.68(s, 1H), 7.54(s, 1H), 5.93-6.05(m, 1H), 3.9 8-4.15(m, 2H), 2.86-2.93(m, 1H), 2.70-2.80(m, 1H), 2.44(s, 4H), 2.06-2.36(m, 5H), 1.82(br d, J = 6.6 Hz, 4H).

[0409] Examples 1-95 (R)-5-((1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)thiazole-4-carboxylic acid [ka]

[0410] Step A: To a vial and stir bar was added tris(dibenzylideneacetone)dipalladium(0) (2.9 mg, 0.05 eq., 3.1 μmol), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (3.9 mg, 0.10 eq., 6.3 μmol), (R)-5'-(1-aminoethyl)-7'-methyl-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one hydrochloride (20 mg, 1 eq., 63 μmol), methyl 5-bromothiazole-4-carboxylate (21 mg, 1.5 eq., 94 μmol), and cesium carbonate (71 mg, 3.5 eq., 0.22 mmol). The vial was sealed with a Teflon screw cap and evacuated and backfilled with nitrogen three times. Anhydrous, deoxygenated toluene (0.26 mL) was then added, and the reaction was stirred at room temperature until the dark red color changed to yellow / orange (approximately 15 minutes). The reaction was then heated at 100°C overnight. The reaction was cooled to room temperature, diluted with water and dichloromethane, and the aqueous layer was extracted three times with dichloromethane. The combined organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated to a residue that was purified by preparative HPLC (Shimadzu Prep-HPLC; column: Phenomenex Gemini® 5uM NX-C18 110 Å; 150 x 30 mm; gradient: 5% acetonitrile (0.035% TFA) / 95% water (0.05% TFA) to 95% acetonitrile (0.035% TFA) / 5% water (0.05% TFA)) to give methyl (R)-5-((1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)thiazole-4-carboxylate (10 mg, 24 μmol, 38% yield). LCMS [M+H] + = 425.5.

[0411] Step B: To a vial was added methyl (R)-5-((1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)thiazole-4-carboxylate (9.0 mg, 1 eq., 21 μmol), methanol (0.10 mL), and tetrahydrofuran (0.10 mL). The solution was stirred for 10 minutes, after which sodium hydroxide (4.2 mg, 5 eq., 0.11 mmol) and water (0.12 mL) were added. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated, and 1 M HCl was added until the pH of the solution reached approximately 4. The reaction was stirred until precipitation occurred, and the solid was filtered, washed with water, and dried under vacuum to give (R)-5-((1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)thiazole-4-carboxylic acid as a yellow fluffy solid. LCMS [M+H] + = 411.2.

[0412] 1 H NMR(400 MHz, CDCl3)δ = 8.14-8.28(m, 1H), 8.02(s, 1H), 7.71(s, 1H), 7.48(s, 1H), 5.11-5.19(m, 1H), 4.06(td, J = 6.8, 2.0 Hz, 2H), 2.72-2.82(m, 1H), 2.61-2.72(m, 1H), 2.45(s, 3H), 2.39(br d, J = 4.5 Hz, 2H), 2.06-2.31(m, 5H), 1.80(d, J = 6.8 Hz, 3H).

[0413] Intermediates L-1 and L-2 [ka]

[0414] Step A: A solution of 3-benzyl-3-methylpyrrolidin-2-one (1 g, 1.0 eq., 5.3 mmol) in 1,2-dichloroethane (26 mL) was placed in a flask, and phosphorus oxychloride (1.05 g, 640 μL, 1.3 eq., 6.9 mmol) and diisopropylethylamine (683 mg, 920 μL, 1.0 eq., 5.3 mmol) were added. The reaction was heated at 50 °C for 1 h. 2-Amino-3-bromo-5-methylbenzoic acid (1.22 g, 1 eq., 5.3 mmol) was then added as a solid, and the reaction was heated to 100 °C. The reaction was stirred overnight, cooled to room temperature, and diluted with water. The aqueous layer was extracted with dichloromethane, and the combined organics were washed with saturated brine, dried over sodium sulfate, and concentrated. The solid was purified by silica gel chromatography to give 3-benzyl-5-bromo-3,7-dimethyl-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one (780 mg, 2.0 mmol, 38% yield) as a yellow solid. LCMS [M+H] + = 382.9. 1 H NMR(400 MHz, CDCl3)δ = 8.02(s, 1H), 7.88(s, 1H), 7.23 - 7.17(m, 3H), 7.13 - 7.07(m, 2H), 3.95-3.87(m, 1H), 3.54-3.44(m, 1H), 3.29(d, J = 13.3 Hz, 1H), 2.95(d, J = 13.4 Hz, 1H), 2.46(s, 3H), 2.36 - 2.27(m, 1H), 1.99 - 1.90(m, 1H), 1.50(s, 3H).

[0415] Step B: Palladium(II) acetate (22.8 mg, 0.05 eq., 102 μmol), 1,3-bis(diphenylphosphino)propane (83.9 mg, 0.10 eq., 204 μmol), and 3-benzyl-5-bromo-3,7-dimethyl-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one (780 mg, 1.0 eq., 2.04 mmol) were added to a vial and stir bar. The flask was evacuated and backfilled with nitrogen three times. Ethylene glycol (8.1 mL), n-butyl vinyl ether (1.84 mL, 7.0 eq., 14.2 mmol), and N,N-dicyclohexylmethylamine (1.30 μL, 3.0 eq., 6.11 mmol) were then added, and the solution was sparged with nitrogen. The flask was placed in a heating block and the mixture was heated to 115 °C with stirring. After the reaction was complete, the reaction was cooled to room temperature and 1N HCl (6 mL) was added. The reaction was stirred until deprotection of the ketone was complete (approximately 1 h). The aqueous layer was extracted three times with ethyl acetate, and the combined organic phase was washed successively with water and saturated brine, dried over sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by silica gel chromatography to give 5-acetyl-3-benzyl-3,7-dimethyl-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one (430 mg, 2.04 mmol, 61% yield) as a yellow solid. LCMS [M+H] + = 347.4. 1 H NMR(400 MHz, CDCl3)δ = 8.22(s, 1H), 7.89(s, 1H), 7.23 - 7.15(m, 3H), 7.04 - 6.97(m, 2H), 4.01 - 3.90(m, 1H), 3.50 - 3.40(m, 1H), 3.18(d, J = 13.3 Hz, 1H), 2.97 - 2.88 (m, 4H), 2.50 (s, 3H), 2.38 - 2.26 (m, 1H), 2.05 - 1.93 (m, 1H), 1.49 (s, 3H).

[0416] Step C: To a solution of 5-acetyl-3-benzyl-3,7-dimethyl-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one (430 mg, 1.0 eq., 1.24 mmol) and (R)-2-methylpropane-2-sulfinamide (181 mg, 1.2 eq., 1.49 mmol) in tetrahydrofuran (3.1 mL) was added titanium(IV) ethoxide (1.42 g, 1.29 mL, 5 eq., 6.21 mmol). The mixture was stirred at 80 °C for 4 h and then cooled to room temperature. After returning to room temperature, a small amount of saturated brine was added to form a suspension. The resulting suspension was diluted with ethyl acetate and filtered through a Celite plug. The filter cake was washed several times with ethyl acetate. The filtrate was concentrated under reduced pressure, and the resulting yellow residue was immediately purified. Purification by silica gel chromatography (0% to 80% ethyl acetate in heptane) afforded (R)-N-(1-(3-benzyl-3,7-dimethyl-9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-5-yl)ethylidene)-2-methylpropane-2-sulfinamide (290 mg, 645 μmol, 52% yield) as a yellow solid.

[0417] Step D: To a solution of (R)-N-(1-(3-benzyl-3,7-dimethyl-9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-5-yl)ethylidene)-2-methylpropane-2-sulfinamide (290 mg, 1.0 eq., 645 μmol) in anhydrous dichloromethane (4.30 mL) was added Schwartz's reagent (216 mg, 1.3 eq., 839 μmol) as a solid in small portions at room temperature. The reaction was stirred at this temperature for 15 min and then quenched with ammonium chloride. The aqueous layer was extracted with dichloromethane, and the combined organic phase was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give a residue. The solid was purified by silica gel chromatography (0% to 5% methanol in dichloromethane) to give the separated diastereomers.

[0418] Step E: To a solution of the first eluting isomer (87 mg, 1.0 eq., 0.19 mmol) in methanol (0.96 mL) was added 120 μL of HCl (4 M in dioxane). The reaction mixture was monitored by LCMS. Upon completion, the mixture was triturated with diethyl ether to give intermediate L-1 (71 mg), which was used without further purification. LCMS [M+H] + = 348.2. 1 H NMR (400 MHz, CDCl3)δ = 8.99(br s, 2H), 8.07(s, 1H), 7.57(s, 1H), 7.23(m, 3H), 7.02 - 6.98(m, 2H), 4.96 - 4.87(m, 1H), 4.08 - 3.97(m, 1H), 3.54 - 3.44(m, 1H), 3.09(br d, J = 13.6 Hz, 1H), 2.98(d, J = 13.6 Hz, 1H), 2.47(s, 3H), 2.39 - 2.28(m, 1H), 2.06 - 1.96(m, 1H), 1.92(br d, J = 6.3 Hz, 3H), 1.51(s, 3H).

[0419] Step E': To a solution of the second eluting isomer (87 mg, 1.0 eq., 0.19 mmol) in methanol (0.96 mL) was added 120 μL of HCl (4 M in dioxane). The reaction mixture was monitored by LCMS. Upon completion, the mixture was triturated with diethyl ether to give intermediate L-2 (74 mg), which was used without further purification. LCMS [M+H] + = 348.2. 1H NMR (400 MHz, CDCl3)δ = 8.92(br s, 2H), 8.06(s, 1H), 7.57(s, 1H), 7.27 - 7.22(m, 3H), 7.04 - 6.95(m, 2H), 5.00 - 4.89(m, 1H), 4.07-4.00(m, 1H), 3.60 - 3.47(m, 1H), 3.09(d, J = 13.4 Hz, 1H), 2.95(d, J = 13.4 Hz, 1H), 2.46(s, 3H), 2.39 - 2.29(m, 1H), 2.04 - 1.97(m, 1H), 1.90(d, J = 6.8 Hz, 3H), 1.51(s, 3H).

[0420] Examples 1-96 and 1-97 3-(((R)-1-((R)-3-benzyl-3,7-dimethyl-9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-5-yl)ethyl)amino)-6-chloropicolinic acid and 3-(((R)-1-((S)-3-benzyl-3,7-dimethyl-9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-5-yl)ethyl)amino)-6-chloropicolinic acid [ka]

[0421] Step A: To the vial was added L-1 (46 mg, 1 eq., 0.12 mmol), methyl 6-chloro-3-fluoropicolinate (38 mg, 1.65 eq., 0.20 mmol), and dimethylformamide (0.66 mL). Finally, diisopropylethylamine (0.12 mL, 5.5 eq., 0.66 mmol) was added, and the vial was sealed and stirred at 100 °C for 12 h. The mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted twice more with ethyl acetate. The combined organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (Gemini 150 x 30 mm column, 5-95%, 0.035% acetonitrile / trifluoroacetic acid in 0.05% water / trifluoroacetic acid) and then lyophilized to give the methyl picolinic acid product as a white solid trifluoroacetate salt (28 mg, 44 μmol, 37% yield). LCMS [M+H] + = 517.2. 1 H NMR (400 MHz, CD3OD)δ = 7.91(s, 1H), 7.66(s, 1H), 7.28 - 7.21(m, 2H), 7.21 - 7.14(m, 3H), 7.09 - 7.02(m, 2H), 5.60(q, J = 6.7 Hz, 1H), 3.96 - 3.88(m, 4H), 3.40 - 3.34(m, 1H), 3.18 - 3.11(m, 1H), 3.07 - 2.99(m, 1H), 2.44(s, 3H)2.43 - 2.35(m, 1H), 2.09 - 2.01(m, 1H), 1.73(d, J = 6.6 Hz, 3H), 1.51(s, 3H).

[0422] Step B: To a vial containing a solution of methyl picolinate (26 mg, 1 eq., 41 μmol) in methanol (0.2 mL) and tetrahydrofuran (0.2 mL), 2M lithium hydroxide (0.13 mL, 6.5 eq., 0.27 mmol) was added. The reaction mixture was stirred for 1 hour. The methanol and lithium hydroxide were removed using a rotary evaporator. The residue was taken up in dichloromethane and washed with water. The solution was adjusted to pH 5 with 1N hydrochloric acid. The aqueous layer was extracted twice more with dichloromethane, then washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was taken up in water, frozen, and lyophilized to give Example 1-96 (19 mg, 37 μmol, 90% yield) as a white solid. LCMS [M+H] + = 503.2. 1 H NMR (400 MHz, CD3OD)δ = 7.90(s, 1H), 7.66(s, 1H), 7.22 - 7.14(m, 5H), 7.09 - 7.03(m, 2H), 5.62(q, J = 6.5 Hz, 1H), 3.97 - 3.85(m, 1H), 3.40 - 3.33(m, 1H), 3.17(d, J = 13.3 Hz, 1H), 3.02(d, J = 13.3 Hz, 1H), 2.43(s, 3H), 2.42 - 2.35(m, 1H), 2.10 - 2.01(m, 1H), 1.70(d, J = 6.8 Hz, 3H), 1.52(s, 3H).

[0423] Step C: To the vial was added intermediate L-2 (49 mg, 1.0 eq., 0.13 mmol), methyl 6-chloro-3-fluoropicolinate (40 mg, 1.65 eq., 0.21 mmol), and dimethylformamide (0.71 mL). Finally, diisopropylethylamine (0.12 mL, 5.5 eq., 0.70 mmol) was added, and the vial was sealed and stirred at 100 °C for 12 h. The mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted twice more with ethyl acetate. The combined organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (Gemini 150 x 30 mm column, 5-95%, 0.035% acetonitrile / trifluoroacetic acid in 0.05% water / trifluoroacetic acid) and lyophilized to give the methyl picolinate product as the trifluoroacetate salt (23 mg, 36 μmol, 29% yield) as a white solid. LCMS [M+H] + = 517.2. 1 H NMR (400 MHz, CD3OD)δ = 7.90(s, 1H), 7.68(s, 1H), 7.22(s, 2H), 7.20 - 7.07(m, 3H), 6.97(d, J = 7.4 Hz, 2H), 5.50(q, J = 6.8 Hz, 1H), 3.94-3.88(m, 1H), 3.84(s, 3H), 3.28(m, 1H), 3.21 - 3.13(m, 1H), 2.98(d, J = 13.1 Hz, 1H), 2.46 - 2.37(m, 4H), 2.12-2.04(m, 1H), 1.78(d, J = 6.8 Hz, 3H), 1.57(s, 3H).

[0424] To a vial containing a solution of methyl picolinate (21 mg, 1.0 eq., 33 μmol) in methanol (0.2 mL) and tetrahydrofuran (0.2 mL), 2M lithium hydroxide (0.10 mL, 6 eq., 0.20 mmol) was added. The reaction mixture was stirred for 1 hour. The methanol and lithium hydroxide were removed using a rotary evaporator. The residue was dissolved in dichloromethane and washed with water. The solution was adjusted to pH 5 with 1N hydrochloric acid. The aqueous layer was extracted twice more with dichloromethane, then washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was dissolved in water and lyophilized to give Example 1-97 (17 mg, 37 μmol, 100%) as a white solid. LCMS [M+H] + = 503.1. 1 H NMR(400 MHz, CD3OD)δ = 7.89(s, 1H), 7.68(s, 1H), 7.20 - 7.08(m, 5H), 6.98(d, J = 7.4 Hz, 2H), 5.57(q, J = 6.3 Hz, 1H), 3.97 - 3.86(m, 1H), 3.25(d, J = 13.1 Hz, 1H), 3.22 - 3.12(m, 1H), 2.97(d, J = 13.1 Hz, 1H), 2.47 - 2.38(m, 4H), 2.12 - 2.05(m, 1H), 1.74(d, J = 6.6 Hz, 3H), 1.56(s, 3H).

[0425] Examples 1-98 (R)-2-((1-(10'-oxo-7',8'-dihydro-10'H-spiro[cyclobutane-1,6'-pyrido[4,3-d]pyrrolo[1,2-a]pyrimidin]-4'-yl)ethyl)amino)benzoic acid [ka]

[0426] Step A: A solution of 6-azaspiro[3.4]octan-5-one (500 mg, 1.0 eq., 3.99 mmol) in 1,2-dichloroethane (20.0 mL) was placed in a flask, and phosphorus oxychloride (735 mg, 447 μL, 1.2 eq., 4.79 mmol) and diisopropylethylamine (516 mg, 696 μL, 1.0 eq., 3.99 mmol) were added. The reaction mixture was heated at 50 °C for 1 h. 4-Amino-5-bromonicotinic acid (867 mg, 1.0 eq., 3.99 mmol) was then added as a solid. The flask was fitted with a reflux condenser and the reaction mixture was heated to 100 °C. The reaction mixture was stirred overnight, cooled to room temperature, and diluted with water. The aqueous layer was extracted with dichloromethane, and the combined organic phase was washed with saturated brine, dried over magnesium sulfate, and concentrated. The resulting solid was purified by silica gel chromatography to give 4'-bromo-7',8'-dihydro-10'H-spiro[cyclobutane-1,6'-pyrido[4,3-d]pyrrolo[1,2-a]pyrimidin]-10'-one (228 mg, 745 μmol, 19% yield) as a yellow solid. 1 H NMR(400 MHz, CDCl3)δ(ppm)= 9.38(s, 1H), 8.98(s, 1H), 4.11(t, J = 7.1 Hz, 2H), 2.80 - 2.66(m, 2H), 2.44(t, J = 7.0 Hz, 2H), 2.37 - 2.27(m, 1H), 2.26 - 2.08(m, 3H).

[0427] Step B: Palladium(II) acetate (3.67 mg, 0.05 eq., 16.3 μmol), 1,3-bis(diphenylphosphino)propane (13.5 mg, 0.10 eq., 32.7 μmol), and 4'-bromo-7',8'-dihydro-10'H-spiro[cyclobutane-1,6'-pyrido[4,3-d]pyrrolo[1,2-a]pyrimidin]-10'-one (100 mg, 1.0 eq., 327 μmol) were added to a vial and stir bar. The vial was evacuated and backfilled with nitrogen three times. Next, ethylene glycol (817 μL), N,N-dicyclohexylmethylamine (191 mg, 209 μL, 3.0 eq., 980 μmol), and n-butyl vinyl ether (164 mg, 211 μL, 5.0 eq., 1.63 mmol) were injected, and the solution was sparged with nitrogen. The vial was placed in a heating block, and the mixture was heated to 115 °C with stirring. After the reaction was complete, the reaction solution was cooled to room temperature, and 1 N HCl (2 mL; approximately three times the volume of ethylene glycol) was added to the reaction solution. The reaction solution was stirred until the ketone deprotection was complete (approximately 1 h). The aqueous layer was extracted three times with ethyl acetate, and the combined organic phase was washed successively with water and saturated brine, dried over magnesium sulfate, filtered, and concentrated to give a residue. The residue was purified by silica gel chromatography to give 4'-acetyl-7',8'-dihydro-10'H-spiro[cyclobutane-1,6'-pyrido[4,3-d]pyrrolo[1,2-a]pyrimidin]-10'-one (89 mg, 0.33 mmol, 100% yield) as a yellow solid. LCMS [M+H] + = 270.1.

[0428] Step C: A solution of 4'-acetyl-7',8'-dihydro-10'H-spiro[cyclobutane-1,6'-pyrido[4,3-d]pyrrolo[1,2-a]pyrimidin]-10'-one (89 mg, 1.0 eq., 0.33 mmol) and (R)-2-methylpropane-2-sulfinamide (48 mg, 1.2 eq., 0.40 mmol) in tetrahydrofuran (0.83 mL) was added to a sealed tube with titanium(IV) ethoxide (0.38 g, 0.34 mL, 5.0 eq., 1.7 mmol). The sealed tube was placed in a heating block and heated at 80 °C for 4 h, then cooled to room temperature. After returning to room temperature, a small amount of saturated brine was added to form a suspension. The resulting suspension was diluted with ethyl acetate and filtered through a Celite plug. The filter cake was washed several times with ethyl acetate. The filtrate was concentrated under reduced pressure to give a crude yellow solid, which was quickly purified by silica gel chromatography to give (R)-2-methyl-N-(1-(10'-oxo-7',8'-dihydro-10'H-spiro[cyclobutane-1,6'-pyrido[4,3-d]pyrrolo[1,2-a]pyrimidin]-4'-yl)ethylidene)propane-2-sulfinamide (90 mg, 0.24 mmol, 73% yield).

[0429] Step D: To a solution of (R)-2-methyl-N-(1-(10'-oxo-7',8'-dihydro-10'H-spiro[cyclobutane-1,6'-pyrido[4,3-d]pyrrolo[1,2-a]pyrimidine]-4'-yl)ethylidene)propane-2-sulfinamide (89 mg, 1.0 eq., 0.24 mmol) in anhydrous dichloromethane (1.2 mL) was added Schwartz's reagent (68 mg, 1.1 eq., 0.26 mmol) as a solid in small portions at room temperature (Note: slight effervescence was observed). The reaction was stirred at this temperature for 15 min before being quenched with ammonium chloride. The aqueous layer was extracted with dichloromethane, and the combined organic phases were washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10% methanol in dichloromethane) to give (R)-2-methyl-N-((R)-1-(10'-oxo-7',8'-dihydro-10'H-spiro[cyclobutane-1,6'-pyrido[4,3-d]pyrrolo[1,2-a]pyrimidin]-4'-yl)ethyl)propane-2-sulfinamide (30 mg, 80 μmol, 34% yield) as a white solid. LCMS [M+H] + = 375.2.

[0430] Step E: To a solution of (R)-2-methyl-N-((R)-1-(10'-oxo-7',8'-dihydro-10'H-spiro[cyclobutane-1,6'-pyrido[4,3-d]pyrrolo[1,2-a]pyrimidin]-4'-yl)ethyl)propane-2-sulfinamide (30 mg, 1.0 eq., 80 μmol) in methanol (0.27 mL) was added HCl (4 M dioxane solution) (4.4 mg, 30 μL, 4.0 mol, 1.5 eq., 0.12 mmol) at 0 °C. The reaction was stirred at room temperature until complete, then triturated with diethyl ether to give (R)-4'-(1-aminoethyl)-7',8'-dihydro-10'H-spiro[cyclobutane-1,6'-pyrido[4,3-d]pyrrolo[1,2-a]pyrimidin]-10'-one·HCl as an off-white salt, which was used without further purification. LCMS [M+H] + = 271.2.

[0431] Step F: To a vial and stir bar were added (R)-4'-(1-aminoethyl)-7',8'-dihydro-10'H-spiro[cyclobutane-1,6'-pyrido[4,3-d]pyrrolo[1,2-a]pyrimidin]-10'-one·HCl (15 mg, 1.0 eq., 49 μmol), 2-boronobenzoic acid (24 mg, 3.0 eq., 0.15 mmol), and copper(II) acetate (13 mg, 1.5 eq., 73 μmol) as solids. The vial was then sealed with a septum cap, and dimethylformamide (0.24 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (37 mg, 37 μL, 5.0 eq., 0.24 mmol) were added sequentially. The septum was pierced with a vent needle to expose the reaction to ambient air, 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 phase was washed sequentially with saturated aqueous ammonium chloride and saturated brine, then dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The reaction residue was purified by silica gel chromatography (0-75% ethyl acetate in heptane) to give (R)-2-((1-(10'-oxo-7',8'-dihydro-10'H-spiro[cyclobutane-1,6'-pyrido[4,3-d]pyrrolo[1,2-a]pyrimidin]-4'-yl)ethyl)amino)benzoic acid as a white solid. LCMS [M+H] + = 391.1. 1 H NMR (400 MHz, CDCl3)δ = 9.37(s, 1H), 8.99(s, 1H), 8.72 - 8.54(br s, 1H), 8.03 - 7.90(m, 1H), 7.21 - 7.12(m, 1H), 6.67 - 6.48(m, 2H), 5.70(m, 1H), 4.15 - 4.06(m, 2H), 2.82 - 2.66(m, 2H), 2.45(br t, J = 6.8 Hz, 2H), 2.37 - 2.08(m, 4H), 1.75(br d, J = 6.5 Hz, 3H).

[0432] Intermediate M [ka]

[0433] Step A: A solution of 8-oxa-2-azaspiro[4.5]decan-1-one (1.0 g, 1.0 eq., 6.4 mmol) in 1,2-dichloroethane (32 mL) was placed in a flask, and phosphorus oxychloride (1.3 g, 0.78 mL, 1.3 eq., 8.4 mmol) and diisopropylethylamine (0.83 g, 1.1 mL, 1.0 eq., 6.4 mmol) were added. The reaction was heated at 50 °C for 1 h. 2-Amino-3-bromo-5-fluorobenzoic acid (1.5 g, 1 eq., 6.4 mmol) was then added as a solid, and the reaction was heated to 100 °C. The reaction was stirred overnight, cooled to room temperature, and diluted with water. The aqueous layer was extracted with dichloromethane, and the combined organic phase was washed with saturated brine, dried over sodium sulfate, and concentrated. The resulting solid was purified by silica gel chromatography to give 5'-bromo-7'-fluoro-1',2,2',3,5,6-hexahydro-9'H-spiro[pyran-4,3'-pyrrolo[2,1-b]quinazolin]-9'-one (960 mg, 2.7 mmol, 42% yield) as a yellow solid. LCMS [M+H] + = 353.0. 1 H NMR(400 MHz, CD3OD)δ = 7.97 - 7.92(m, 1H), 7.87(dd, J = 2.4, 8.3 Hz, 1H), 4.24 - 4.11(m, 4H), 3.78 - 3.68(m, 2H), 2.33(t, J = 7.2 Hz, 2H), 2.22 - 2.10(m, 2H), 1.78-1.72(m, 2H).

[0434] Step B: Palladium(II) acetate (30.2 mg, 0.05 eq., 134 μmol), 1,3-bis(diphenylphosphino)propane (111 mg, 0.10 eq., 269 μmol), and 5'-bromo-7'-fluoro-1',2,2',3,5,6-hexahydro-9'H-spiro[pyran-4,3'-pyrrolo[2,1-b]quinazolin]-9'-one (950 mg, 1.0 eq., 2.69 mmol) were added to a vial and stir bar. The flask was evacuated and backfilled with nitrogen three times. Next, ethylene glycol (10.8 mL), n-butyl vinyl ether (1.74 mL, 5.0 eq., 13.4 mmol), and N,N-dicyclohexylmethylamine (1.72 mL, 3.0 eq., 8.07 mmol) were added, and the solution was sparged with nitrogen. The flask was placed in a heating block, and the mixture was stirred and heated to 115 °C. After the reaction was complete, the reaction was cooled to room temperature, and 1 N HCl (30 mL) was added to the reaction. The reaction was stirred until the deprotection of the ketone was complete (approximately 1 h). The aqueous layer was adjusted to pH = 5 with 2 M lithium hydroxide and extracted three times with ethyl acetate. The combined organic phase was washed successively with water and saturated brine, dried over sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by silica gel chromatography to give 5'-acetyl-7'-fluoro-1',2,2',3,5,6-hexahydro-9'H-spiro[pyran-4,3'-pyrrolo[2,1-b]quinazolin]-9'-one (680 mg, 2.15 mmol, 80% yield) as a yellow solid. LCMS [M+H] + = 317.1. 1 H NMR (400 MHz, DMSO-d6)δ = 7.98(dd, J = 3.0, 8.1 Hz, 1H), 7.78(dd, J = 2.9, 8.7 Hz, 1H), 4.09(t, J = 7.1 Hz, 2H), 3.94-3.87(m, 2H), 3.56(br t, J = 11.1 Hz, 2H), 2.81(s, 3H), 2.29(t, J = 7.1 Hz, 2H), 2.03 - 1.92(m, 2H), 1.70 - 1.62(m, 2H).

[0435] Step C: To a solution of 5'-acetyl-7'-fluoro-1',2,2',3,5,6-hexahydro-9'H-spiro[pyran-4,3'-pyrrolo[2,1-b]quinazolin]-9'-one (675 mg, 1.0 eq., 2.13 mmol) and (R)-2-methylpropane-2-sulfinamide (310 mg, 1.2 eq., 2.56 mmol) in tetrahydrofuran (7.11 mL) was added titanium(IV) ethoxide (2.43 g, 2.22 mL, 5 eq., 10.7 mmol). The mixture was stirred at 80 °C for 4 h and then cooled to room temperature. After returning to room temperature, a small amount of saturated brine was added to form a suspension. The resulting suspension was diluted with ethyl acetate and filtered through a Celite plug. The filter cake was washed several times with ethyl acetate. The filtrate was concentrated under reduced pressure, and the resulting yellow residue was quickly purified by silica gel chromatography (0–10% methanol in dichloromethane) to give (R)—N-(1-(7′-fluoro-9′-oxo-1′,2,2′,3,5,6-hexahydro-9′H-spiro[pyran-4,3′-pyrrolo[2,1-b]quinazoline]-5′-yl)ethylidene)-2-methylpropane-2-sulfinamide (895 mg, 2.13 mmol, 100% yield) as a yellow oil.

[0436] Step D: To a solution of (R)-N-(1-(7'-fluoro-9'-oxo-1',2,2',3,5,6-hexahydro-9'H-spiro[pyran-4,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethylidene)-2-methylpropane-2-sulfinamide (895 mg, 1.0 eq., 2.13 mmol) in anhydrous dichloromethane (14.2 mL) was added Schwartz's reagent (688 mg, 1.25 eq., 2.67 mmol) as a solid in small portions at room temperature. The reaction mixture 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 layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give a residue. The solid was purified by silica gel chromatography (0% to 10% methanol in dichloromethane) to give (R)-N-((R)-1-(7'-fluoro-9'-oxo-1',2,2',3,5,6-hexahydro-9'H-spiro[pyran-4,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)-2-methylpropane-2-sulfinamide (380 mg, 0.90 mmol, 42% yield) as a clear oil. LCMS [M+H] + = 422.2 1 H NMR(400 MHz, CD3OD)δ = 7.76(dd, J = 2.8, 8.3 Hz, 1H), 7.68(dd, J = 2.6, 9.2 Hz, 1H), 5.28(q, J = 7.1 Hz, 1H), 4.17(t, J = 7.2 Hz, 2H), 4.13 - 4.02(m, 2H), 3.72(br t, J = 10.7 Hz, 2H), 2.37(t, J = 7.2 Hz, 2H), 2.24 - 2.10(m, 2H), 1.73(br d, J = 13.1 Hz, 2H), 1.62(d, J = 6.9 Hz, 3H), 1.24(s, 9H).

[0437] Step E: To a solution of (R)-N-((R)-1-(7'-fluoro-9'-oxo-1',2,2',3,5,6-hexahydro-9'H-spiro[pyran-4,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)-2-methylpropane-2-sulfinamide (380 mg, 1.0 eq., 0.90 mmol) in methanol (3.61 mL) was added 1.13 mL of HCl (4 M solution in dioxane). The reaction was monitored by LCMS. After completion of the reaction, the mixture was concentrated and triturated with diethyl ether to give (R)-5'-(1-aminoethyl)-7'-fluoro-1',2,2',3,5,6-hexahydro-9'H-spiro[pyran-4,3'-pyrrolo[2,1-b]quinazolin]-9'-one hydrochloride (220 mg) as an off-white solid, which was used subsequently without further purification. LCMS [M+H] + = 318.1. 1 H NMR(400 MHz, CD3OD)δ = 7.92(dd, J = 2.3, 8.3 Hz, 1H), 7.73(dd, J = 2.2, 8.9 Hz, 1H), 5.31(q, J = 6.8 Hz, 1H), 4.19(t, J = 7.2 Hz, 2H), 4.09 - 4.00(m, 2H), 3.72(br t, J = 11.5 Hz, 2H), 2.41(t, J = 7.3 Hz, 2H), 2.28 - 2.14(m, 2H), 1.77(d, J = 6.9 Hz, 3H), 1.71(br d, J = 13.5 Hz, 2H).

[0438] Examples 1-99 (R)-7'-Fluoro-5'-(1-((3-(hydroxymethyl)phenyl)amino)ethyl)-1',2,2',3,5,6-hexahydro-9'H-spiro[pyran-4,3'-pyrrolo[2,1-b]quinazolin]-9'-one [ka]

[0439] Step A: To the vial and stir bar, (R)-5'-(1-aminoethyl)-7'-fluoro-1',2,2',3,5,6-hexahydro-9'H-spiro[pyran-4,3'-pyrrolo[2,1-b]quinazolin]-9'-one hydrochloride (40 mg, 1 eq., 0.11 mmol), (3-(hydroxymethyl)phenyl)boronic acid (17 mg, 1.0 eq., 0.11 mmol), and copper(II) acetate (31 mg, 1.5 eq., 0.17 mmol) were added as solids. The vial was then sealed with a septum cap, and dimethylformamide (0.57 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.08 mL, 5.0 eq., 0.57 mmol) were added sequentially. The reaction was exposed to ambient air by piercing the septum with a vent needle and 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 phases were washed sequentially with saturated aqueous ammonium chloride and saturated brine, then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The reaction residue was purified by reverse-phase preparative HPLC (0.035% acetonitrile / trifluoroacetic acid solution in 0.05% water / trifluoroacetic acid, 5%–95%) and lyophilized to give (R)-7'-fluoro-5'-(1-((3-(hydroxymethyl)phenyl)amino)ethyl)-1',2,2',3,5,6-hexahydro-9'H-spiro[pyran-4,3'-pyrrolo[2,1-b]quinazolin]-9'-one trifluoroacetic acid (17.7 mg, 33 μmol, 29% yield) as a white solid. LCMS [M+H] + = 424.2. 1H NMR (400 MHz, CD3OD)δ = 7.72(dd, J = 3.0, 8.4 Hz, 1H), 7.62(dd, J = 3.0, 9.4 Hz, 1H), 7.04(t, J = 7.8 Hz, 1H), 6.75(s, 1H), 6.71(d, J = 7.6 Hz, 1H), 6.57(dd, J = 1.5, 8.0 Hz, 1H), 5.60(q, J = 6.8 Hz, 1H), 4.43(s, 2H), 4.21 - 4.09(m, 4H), 3.79 - 3.69(m, 2H), 2.42 - 2.35(m, 2H), 2.27-2.17(m, 2H), 1.81-1.73(m, 2H), 1.62(d, J = 6.8 Hz, 3H) 19 F NMR (377 MHz, CD3OD) δ = -77.23, -115.26.

[0440] Examples 1-100 (R)-6-Methyl-3-((1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid [ka]

[0441] Step A: A mixture of (R)-5'-(1-aminoethyl)-7'-methyl-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one hydrochloride (148 mg, 1 eq., 463 μmol), methyl 6-chloro-3-fluoropicolinate (132 mg, 1.5 eq., 694 μmol), and diisopropylethylamine (299 mg, 403 μL, 5 eq., 2.31 mmol) in dimethylformamide (2.31 mL) was stirred at 100 °C for 21 h. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to give the product, methyl (R)-6-chloro-3-((1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinate (130 mg, 287 μmol, 62% yield). LCMS [M+H] + = 453.2.

[0442] Step B: To a vial was added methylboronic acid (28 mg, 2.5 eq., 0.47 mmol), methyl (R)-6-chloro-3-((1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinate (85 mg, 1 eq., 0.19 mmol), potassium carbonate (65 mg, 2.5 eq., 0.47 mmol), and tetrakis(triphenylphosphine)palladium(0) (22 mg, 0.1 eq., 19 μmol). The vial was evacuated and backfilled with nitrogen three times. Next, a solution of deoxygenated 1,4-dioxane (0.75 mL) and water (0.19 mL) was added, and the reaction was heated to 100 °C and stirred overnight. The reaction was quenched with saturated sodium bicarbonate and extracted three times with dichloromethane. The combined organics were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to give the product, methyl (R)-6-methyl-3-((1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinate (35 mg, 81 μmol, 43% yield). LCMS [M+H] + = 433.2.

[0443] Step C: To the vial was added methyl (R)-6-methyl-3-((1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinate (18 mg, 1 eq., 42 μmol), followed by methanol (0.10 mL) and tetrahydrofuran (0.10 mL). The solution was stirred for 10 minutes, after which sodium hydroxide (8.3 mg, 5 eq., 0.21 mmol) and water (0.5 mL) were added. The reaction was stirred at room temperature for 4 hours. The reaction was then concentrated in vacuo to a more concentrated solution, and 1 M HCl was added until the pH of the solution reached approximately 4. The solution was directly purified by preparative HPLC (Shimadzu Prep-HPLC; Column: Phenomenex Gemini® 5uM NX-C18 110 Å; 150 x 30 mm; Gradient: 5% acetonitrile (0.035% TFA) / 95% water (0.05% TFA) to 95% acetonitrile (0.035% TFA) / 5% water (0.05% TFA)) to give (R)-6-methyl-3-((1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid. LCMS [M+H] + = 419.2. 1 H NMR(400 MHz, CDCl3)δ = 7.99(s, 1H), 7.97(br s, 1H), 7.54(d, J = 1.6 Hz, 1H), 7.29(d, J = 9.0 Hz, 1H), 7.11-7.18(m, 1H), 5.70-5.79(m, 1H), 4.09(t, J = 6.9 Hz, 2H), 2.73(s, 1H), 2.60-2.71(m, 2H), 2.57(s, 2H), 2.36-2.46(m, 5H), 2.10-2.29(m, 5H), 1.67-1.74(m, 3H).

[0444] Example 1-101 (R)-6-chloro-3-((1-(7'-chloro-3,3-difluoro-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid [ka]

[0445] Step A: A solution of 2,2-difluoro-6-azaspiro[3.4]octan-5-one (1.000 g, 1.0 eq., 6.205 mmol) in 1,2-dichloroethane (31.03 mL) was placed in a flask, and phosphorus oxychloride (1.142 g, 694.0 μL, 1.2 eq., 7.446 mmol) and diisopropylethylamine (802.0 mg, 1.08 mL, 1.0 eq., 6.205 mmol) were added. The reaction was stirred at 19 °C for 1 h. 2-Amino-3-bromo-5-chlorobenzoic acid (1.554 g, 1.0 eq., 6.205 mmol) was then added as a solid. The flask was fitted with a reflux condenser and the reaction was heated to 100 °C. The reaction was stirred overnight, cooled to room temperature, and diluted with water. The aqueous layer was extracted with dichloromethane, and the combined organic layers were washed with saturated brine, dried over magnesium sulfate, and concentrated. The resulting solid was purified by silica gel chromatography to give 5'-bromo-7'-chloro-3,3-difluoro-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (976 mg, 2.60 mmol, 42% yield) as a yellow solid. LCMS [M+H] + = 376.9.

[0446] Step B: Palladium(II) acetate (35.06 mg, 0.05 eq., 156.2 μmol), 1,3-bis(diphenylphosphino)propane (128.8 mg, 0.10 eq., 312.3 μmol), and 5'-bromo-7'-chloro-3,3-difluoro-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (1.173 g, 1.0 eq., 3.123 mmol) were added to a vial and stir bar. The vial was evacuated and backfilled with nitrogen three times. Next, ethylene glycol (7.808 mL), N,N-dicyclohexylmethylamine (1.830 g, 2.00 mL, 3.0 eq., 9.369 mmol), and n-butyl vinyl ether (1.564 g, 2.02 mL, 5.0 eq., 15.62 mmol) were added. The vial was placed in a heating block, and the mixture was stirred and heated to 115 °C. After the reaction was complete, the reaction mixture was cooled to room temperature, and 1 N HCl (2 mL; approximately three times the volume of ethylene glycol) was added to the reaction mixture. The reaction mixture was stirred until the ketone deprotection was complete (approximately 1 h). The aqueous layer was extracted three times with ethyl acetate, and the combined organic phase was washed successively with water and saturated brine, dried over magnesium sulfate, filtered, and concentrated to a residue. The residue was purified by silica gel chromatography to give 5'-acetyl-7'-chloro-3,3-difluoro-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (868 mg, 2.56 mmol, 82% yield) as a yellow solid. LCMS [M+H] + = 339.0.

[0447] Step C: Titanium(IV) ethoxide (2.92 g, 2.67 mL, 5.0 eq., 12.8 mmol) was added to a solution of 5'-acetyl-7'-chloro-3,3-difluoro-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (868 mg, 1.0 eq., 2.56 mmol) and (R)-2-methylpropane-2-sulfinamide (373 mg, 1.2 eq., 3.07 mmol) in tetrahydrofuran (6.41 mL) in a sealed tube. The sealed tube was placed in a heating block and heated at 80 °C for 12 h, then cooled to room temperature. After returning to room temperature, a small amount of saturated brine was added to form a suspension. The resulting suspension was diluted with ethyl acetate and filtered through a Celite plug. The filter cake was washed several times with ethyl acetate. The filtrate was concentrated under reduced pressure to give a crude yellow solid, which was quickly purified by silica gel chromatography to give (R)-N-(1-(7'-chloro-3,3-difluoro-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethylidene)-2-methylpropane-2-sulfinamide (1.027 g, 2.324 mmol, 91% yield).

[0448] Step D: To a solution of (R)-N-(1-(7'-chloro-3,3-difluoro-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethylidene)-2-methylpropane-2-sulfinamide (1.027 g, 1.0 eq., 2.324 mmol) in anhydrous dichloromethane (15.49 mL) was added Schwartz's reagent (779.1 mg, 1.3 eq., 3.021 mmol) as a solid in small portions at room temperature (Note: slight effervescence was observed). The reaction was stirred at this temperature for 1 hour and then quenched with aqueous ammonium chloride. The aqueous layer was extracted with dichloromethane, and the combined organics were washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0% to 10% methanol in dichloromethane) to give (R)-N-((R)-1-(7'-chloro-3,3-difluoro-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)-2-methylpropane-2-sulfinamide (818 mg, 1.84 mmol, 79% yield) as a white solid. LCMS [M+H] + = 444.3.

[0449] Step E: To a solution of (R)-N-((R)-1-(7'-chloro-3,3-difluoro-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)-2-methylpropane-2-sulfinamide (818 mg, 1.0 eq., 1.84 mmol) in methanol (7.37 mL) was added HCl (4 mol in dioxane) (101 mg, 691 μL, 4.0 mol, 1.5 eq., 2.76 mmol). The reaction was stirred at room temperature until complete and then triturated with diethyl ether to give (R)-5'-(1-aminoethyl)-7'-chloro-3,3-difluoro-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one HCl (601 mg, 1.60 mmol, 87% yield) as an off-white salt, which was used without further purification. LCMS [M+H] + = 340.1.

[0450] Step F: A solution of (R)-5'-(1-aminoethyl)-7'-chloro-3,3-difluoro-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one·HCl (606 mg, 1.0 eq., 1.61 mmol), methyl 6-chloro-3-fluoropicolinate (458 mg, 1.5 eq., 2.42 mmol), and diisopropylethylamine (1.04 g, 1.39 mL, 5.00 eq., 8.05 mmol) in dimethyl sulfoxide (8.05 mL) was stirred at 100 °C for 12 h. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0% to 70% ethyl acetate in heptane) to give methyl (R)-6-chloro-3-((1-(7'-chloro-3,3-difluoro-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinate (699 mg, 1.37 mmol, 85% yield). LCMS [M+H] + = 509.1.

[0451] Step G: To a vial containing methyl (R)-6-chloro-3-((1-(7'-chloro-3,3-difluoro-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinate (674 mg, 1 eq., 1.32 mmol) and a stir bar, tetrahydrofuran (2.12 mL), methanol (2.12 mL), and water (1.06 mL) were added, followed by solid sodium hydroxide (159 mg, 3 eq., 3.97 mmol). The reaction mixture was stirred at room temperature for 1 hour, then 1N HCl was added and the mixture was diluted with ethyl acetate and saturated brine. The aqueous layer was extracted three times, and the combined organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated to give a residue that was purified by silica gel chromatography (0% to 100% ethyl acetate in heptane) to give (R)-6-chloro-3-((1-(7'-chloro-3,3-difluoro-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid (662 mg, 1.34 mmol, 100% yield). LCMS [M+H] + = 495.1. 1 H NMR(400 MHz, CDCl3)δ ppm = 8.35(br d, J = 6.5 Hz, 1H), 8.18(d, J = 2.4 Hz, 1H), 7.65(d, J = 2.4 Hz, 1H), 7.15(d, J = 9.0 Hz, 1H), 6.89(d, J = 8.9 Hz, 1H), 5.54(quin, J = 6.6 Hz, 1H), 4.17(dt, J = 1.4, 7.0 Hz, 2H), 3.42 - 3.27(m, 1H), 3.25 - 3.11(m, 1H), 2.88 - 2.72(m, 2H), 2.55(t, J = 7.0 Hz, 2H), 1.69(d, J = 6.8 Hz, 3H). 19 F NMR (377 MHz, CDCl3) δ ppm = -85.5, -86.0, -95.1, -95.6.

[0452] Intermediates N-1 and N-2 [ka]

[0453] Step A: Methyl 3-oxocyclopentanecarboxylate (50.0 g, 351 mmol, 1.00 eq.) was dissolved in (diethylamino)sulfur trifluoride (150 mL). The mixture was degassed and purged with nitrogen three times, then stirred under a nitrogen atmosphere at 25 °C for 12 h. After completion of the reaction, the reaction mixture was quenched by adding saturated aqueous sodium bicarbonate (1.00 L) and extracted with ethyl acetate (500 mL × 2). The combined organic layers were washed with saturated brine (1.00 L) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 4 / 1) to give methyl 3,3-difluorocyclopentanecarboxylate (27.3 g, 158 mmol, 45% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ = 3.68 (s, 3H), 3.07 - 2.91 (m, 1H), 2.45 - 2.28 (m, 2H), 2.24 - 2.00 (m, 4H). 19 F NMR (377 MHz, CDCl3) δ = -90.8, -91.4, -93.8, -94.4.

[0454] Step B: A solution of methyl 3,3-difluorocyclopentanecarboxylate (27.3 g, 158 mmol, 1.00 eq.) in anhydrous tetrahydrofuran (500 mL) was cooled to -78 °C. Lithium diisopropylamine (2 M, 86.9 mL, 1.10 eq.) was added dropwise under a nitrogen atmosphere. The reaction mixture was stirred at -78 °C for 1.5 hours. Next, a solution of 2-iodoacetonitrile (31.7 g, 190 mmol, 1.20 eq.) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (10.1 g, 79.0 mmol, 9.52 mL, 0.50 eq.) in tetrahydrofuran (20.0 mL) was added dropwise while maintaining the internal temperature at -78 °C. The reaction mixture was warmed to 25 °C and stirred for 16 hours. After the reaction was completed, hydrochloric acid (1N, 300 mL) was added at 0°C under a nitrogen atmosphere to quench the reaction. The resulting aqueous solution was extracted with ethyl acetate (500 mL × 2). The combined organic phase was washed with saturated brine (1.00 L), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give methyl 1-(cyanomethyl)-3,3-difluorocyclopentanecarboxylate (14.5 g, 71.4 mmol, 45% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3)δ = 3.80(s, 3H), 2.83 - 2.71(m, 3H), 2.43 - 2.34(m, 1H), 2.31 - 2.15(m, 3H), 1.98 - 1.87(m, 1H).

[0455] Step C: To a solution of Raney nickel (6.11 g, 71.4 mmol, 1.00 eq.) in methanol (200 mL) under a nitrogen atmosphere, methyl 1-(cyanomethyl)-3,3-difluorocyclopentanecarboxylate (14.5 g, 71.4 mmol, 1.00 eq.) was added. The flask was evacuated and refilled with hydrogen three times. The reaction mixture was stirred under hydrogen (15 psi) at 25 °C for 6 h. After completion of the reaction, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to give 7,7-difluoro-2-azaspiro[4.4]nonan-1-one (5 g, 28.5 mmol, 40.0% yield) as a yellow solid. 1 H NMR(400 MHz, CDCl3)δ = 6.85(br s, 1H), 3.43 - 3.18(m, 2H), 2.63 - 2.47(m, 1H), 2.43 - 2.27(m, 1H), 2.25 - 2.13(m, 4H), 2.10 - 1.97(m, 1H), 1.86 - 1.71(m, 1H).

[0456] Step D: A solution of 7,7-difluoro-2-azaspiro[4.4]nonan-1-one (5 g, 28.5 mmol, 1.00 eq.) in 1,2-dichloroethane (100 mL) was placed in a flask, and phosphorus oxychloride (5.69 g, 37.1 mmol, 3.46 mL, 1.30 eq.) and diisopropylethylamine (3.69 g, 28.5 mmol, 4.97 mL, 1.00 eq.) were added. The reaction mixture was heated to 50 °C for 1 h. The reaction mixture was then heated to 85 °C, and 2-amino-3-bromo-5-methylbenzoic acid (7.22 g, 31.4 mmol, 1.10 eq.) was added as a solid. The reaction mixture was stirred at 85 °C for 12 h. After completion of the reaction, the reaction mixture was cooled to 25 °C and diluted with water (30.0 mL). The aqueous layer was extracted with dichloromethane (50.0 mL × 2), and the combined organic phases were washed with saturated brine (100 mL), dried over sodium sulfate, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give 5'-bromo-3,3-difluoro-7'-methyl-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (8.1 g, 13.6 mmol, 48% yield, 62% purity) as a yellow solid. LCMS [M+H] + = 369.0.

[0457] Step E: 5'-Bromo-3,3-difluoro-7'-methyl-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (8.10 g, 13.6 mmol, 1.00 eq.), 1-vinyloxybutane (4.08 g, 40.74 mmol, 5.24 mL, 3 eq.), methanesulfonato(di-tert-butyl)methylphosphino(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (696 mg, 1.36 mmol, 0.10 eq.), and dicyclohexylamine (2.95 g, 16.3 mmol, 3.25 mL, 1.20 eq.) in dioxane (50.0 The mixture in 1 mL of hexane was evacuated and filled with nitrogen three times, and then the mixture was stirred at 100° C. under a nitrogen atmosphere for 1 hour. After completion of the reaction, the mixture was cooled to 25° C., diluted with ethyl acetate (100 mL), filtered, and the filtrate was concentrated under reduced pressure to give 5'-(1-butoxyvinyl)-3,3-difluoro-7'-methyl-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (8 g, crude) as a yellow oil, which was used in the next step without further purification. LCMS [M+H] + = 389.2.

[0458] Step F: To a solution of 5'-(1-butoxyvinyl)-3,3-difluoro-7'-methyl-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (8.00 g, 20.6 mmol, 1.00 eq.) in tetrahydrofuran (80.0 mL) was added hydrochloric acid (4 M, 51.5 mL, 10.0 eq.). The mixture was stirred at 45°C for 1 hour. After completion of the reaction, the reaction solution was cooled to 25°C and quenched with saturated aqueous sodium bicarbonate (200 mL). The resulting mixture was extracted with ethyl acetate (100 mL × 2). The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give 5'-acetyl-3,3-difluoro-7'-methyl-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (1.80 g, 3.20 mmol, 16% yield, 59% purity) as a yellow oil. LCMS [M+H] + = 333.0.

[0459] Step G: To a solution of 5'-acetyl-3,3-difluoro-7'-methyl-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (1.80 g, 3.20 mmol, 1.00 eq.) and (R)-2-methylpropane-2-sulfinamide (582 mg, 4.80 mmol, 1.50 eq.) in 2-methyltetrahydrofuran (20.0 mL) was added titanium(IV) ethoxide (2.19 g, 9.60 mmol, 1.99 mL, 3.00 eq.). The mixture was stirred at 90 °C for 12 h. After completion of the reaction, the reaction was quenched with water (2.00 mL), diluted with ethyl acetate (100 mL), filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to give (R)-N-(1-(3,3-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethylidene)-2-methylpropane-2-sulfinamide (1.20 g, 2.61 mmol, 81% yield, 95% purity) as a yellow oil. LCMS [M+H] + = 436.2.

[0460] Step H: To a solution of (R)-N-(1-(3,3-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethylidene)-2-methylpropane-2-sulfinamide (1.20 g, 2.61 mmol, 1.00 eq.) in dichloromethane (10.0 mL) and methanol (10.0 mL) was added sodium cyanoborohydride (409 mg, 6.52 mmol, 2.50 eq.) and acetic acid (157 mg, 2.61 mmol, 149 μL, 1.00 eq.). The mixture was stirred at 25 °C for 12 hours. After completion of the reaction, the reaction was quenched with saturated aqueous ammonium chloride (20.0 mL). The resulting mixture was extracted with dichloromethane (20.0 mL × 2). The combined organic phase was washed with water (40.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give (R)-N-((1R)-1-(3,3-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)-2-methylpropane-2-sulfinamide (870 mg, 1.88 mmol, 72% yield, 94% purity) as a yellow solid. LCMS [M+H] + = 438.1. 1 H NMR(400 MHz, CDCl3)δ = 8.00(d, J = 0.8 Hz, 1H), 7.47(d, J = 2.0 Hz, 1H), 5.01(dd, J = 8.4, 15.6 Hz, 1H), 4.90 - 4.75 (m, 1H), 4.21 (m, 1H), 4.03 (m, 1H), 2.96 - 2.73 (m, 1H), 2.64 - 2.49 (m, 1H), 2.46 (s, 3H), 2.38 - 2.26 (m, 5H), 2.09 - 2.05(m, 1H), 1.63(d, J = 6.8 Hz, 3H), 1.22(d, J = 3.2 Hz, 9H).

[0461] Step I: (R)-N-((1R)-1-(3,3-Difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)-2-methylpropane-2-sulfinamide was separated by SFC (Conditions: Column: REGIS(R,R) WHELK-O1 (250 mm × 25 mm, 10 μm); Mobile phase: [CO₂-MeOH (0.1% NH₃·HO)]; B%: 65%, isocratic elution mode). The desired fractions from peak 1 were collected and concentrated in vacuo to give the first-eluting isomer (340 mg, 757 μmol, 40% yield, 97% purity) as a yellow solid. The desired fractions of peak 2 were collected and concentrated in vacuo to give the second eluting isomer (400 mg, 913 μmol, 49% yield, 99.9% purity).

[0462] Step J: To a solution of the first-eluting isomer (340 mg, 777 μmol, 1.00 eq.) in ethyl acetate (2.00 mL), hydrochloric acid / ethyl acetate (2 M, 1.55 mL, 4.00 eq.) was added. The mixture was stirred at 25°C for 30 minutes. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was triturated with petroleum ether / ethyl acetate = 10 / 1 (20.0 mL) at 25°C for 1 hour. After filtration, the filter cake was dried under vacuum to obtain Intermediate N-1 (250 mg, 675 μmol, 87% yield, 99.9% purity) as a yellow hydrochloride salt. LCMS [M+H] + = 334.1.

[0463] Step K: To a solution of the second-eluting isomer (400 mg, 914 μmol, 1.00 eq.) in ethyl acetate (2.00 mL), hydrochloric acid / ethyl acetate (2 M, 1.83 mL, 4.00 eq.) was added. The mixture was stirred at 25°C for 30 minutes. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was triturated with petroleum ether / ethyl acetate = 10 / 1 (20.0 mL) at 25°C for 1 hour. After filtration, the filter cake was dried under vacuum to obtain Intermediate N-1 (330 mg, 890 μmol, 97% yield, 99.7% purity) as a yellow hydrochloride salt. LCMS [M+H] + = 334.1.

[0464] Examples 1-102 and 1-103 6-chloro-3-(((R)-1-((R)-3,3-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid and 6-chloro-3-(((R)-1-((S)-3,3-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid [ka]

[0465] Step A: To intermediate N-2 (100 mg, 270 μmol, 1.00 eq.) in dimethylformamide (1.00 mL) was added diisopropylethylamine (105 mg, 810 μmol, 141 μL, 3.00 eq.) and methyl 6-chloro-3-fluoro-pyridine-2-carboxylate (56.3 mg, 297 μmol, 1.10 eq.). The mixture was stirred at 100°C for 12 hours. After the reaction was complete, the mixture was cooled to 25°C, diluted with water (10.0 mL), and extracted with ethyl acetate (10.0 mL × 3). The combined organic phases were washed with brine (30.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the methyl picolinic acid product (116 mg, 176 μmol, 66% yield, 77% purity) as a yellow solid, which was used in the next step without further purification. LCMS [M+H] + = 503.2.

[0466] Step B: To a solution of the methyl picolinate product (50.0 mg, 76.1 μmol, 1.00 eq.) in methanol (0.20 mL) and tetrahydrofuran (0.20 mL), sodium hydroxide (2 M, 145 μL, 4.00 eq.) was added. The mixture was stirred at 25°C for 1 hour. After the reaction was completed, the pH was adjusted to approximately 4 with aqueous hydrochloric acid (1 M). The solution was then extracted with ethyl acetate (10.0 mL × 2), and the combined organic layer was washed with saturated brine (20.0 mL) and dried over anhydrous sodium sulfate. The mixture was filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 x 25 mm x 10 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 55%-85% acetonitrile over 9 min) to give Example 1-102 (12.5 mg, 25.5 μmol, 34% yield, 99.9% purity) as a white solid. LCMS [M+H] + = 489.3. 1H NMR(400 MHz, CD3OD)δ = 7.93(s, 1H), 7.61(d, J = 1.6 Hz, 1H), 7.19(d, J = 9.2 Hz, 1H), 7.07(d, J = 9.2 Hz, 1H), 5.58(q, J = 6.8 Hz, 1H), 4.22 - 4.15(m, 1H), 4.14 - 4.05(m, 1H), 2.89(m, 1H), 2.62 - 2.42(m, 2H), 2.42(s, 3H), 2.39 - 2.29(m, 4H), 2.20 - 2.05(m, 1H), 1.68(d, J = 6.8 Hz, 3H). 19 F NMR (377 MHz, CD3OD) δ = -88.4, -89.0, -93.5, -94.1.

[0467] Step C: To a solution of intermediate N-1 (100 mg, 270 μmol, 1.00 eq.) in DMF (1.00 mL), DIEA (105 mg, 810 μmol, 141 μL, 3.00 eq.) and methyl 6-chloro-3-fluoro-pyridine-2-carboxylate (56.3 mg, 297 μmol, 1.10 eq.) were added. The mixture was stirred at 100 °C for 12 h. After the reaction was completed, the mixture was cooled to 25 °C, diluted with water (10.0 mL), and extracted with ethyl acetate (10.0 mL × 3). The combined organic phase was washed with saturated brine (30.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the methyl picolinic acid product (100 mg, 145 μmol, 54% yield, 73% purity) as a yellow solid, which was used in the next step without further purification. LCMS [M+H] + = 503.2.

[0468] Step D: To a solution of the methyl picolinate product (50.0 mg, 72.6 μmol, 1.00 eq.) in methanol (0.20 mL) and tetrahydrofuran (0.20 mL), sodium hydroxide (2 M, 145 μL, 4.00 eq.) was added. The mixture was stirred at 25°C for 1 hour. After the reaction was completed, the mixture was adjusted to pH = approximately 4 with hydrochloric acid (1 M). The solution was then extracted with ethyl acetate (10.0 mL × 2), and the combined organic layer was washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (FA conditions; column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 55% to 85% acetonitrile over 9 min) to give Example 1-103 (8.01 mg, 16.4 μmol, 23% yield, 99.9% purity) as an off-white solid. LCMS [M+H] + = 489.3. 1 H NMR(400 MHz, CD3OD)δ = 7.93(s, 1H), 7.62(s, 1H), 7.22(d, J = 8.8 Hz 1H), 7.06(d, J = 9.2 Hz 1H), 5.56(q, J = 6.8 Hz, 1H), 4.24 - 4.14 (m, 1H), 4.14 - 4.04 (m, 1H), 2.86 (m, 1H), 2.67 - 2.50 (m, 1H), 2.49 - 2.42 (m, 1H), 2.42 (s, 3H), 2.38 - 2.31 (m, 4H), 2.19 - 2.06(m, 1H), 1.68(d, J = 6.8 Hz, 3H). 19 F NMR (377 MHz, CD3OD) δ = -88.0, -88.6, -93.4, -94.0.

[0469] Examples 1-104 6-chloro-3-(((R)-1-((R)-1',7'-dimethyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid [ka]

[0470] Step A: A solution of (R)-7-methyl-6-azaspiro[3.4]octan-5-one (500 mg, 1.0 eq., 3.59 mmol) in 1,2-dichloroethane (18.0 mL) was added to a vial, followed by phosphorus oxychloride (716 mg, 435 μL, 1.3 eq., 4.67 mmol) and diisopropylethylamine (464 mg, 626 μL, 1.0 eq., 3.59 mmol). The reaction was stirred at room temperature for 1 hour. 2-Amino-3-bromo-5-methylbenzoic acid (826 mg, 1.0 eq., 3.59 mmol) was then added as a solid, and the reaction was heated to 100 °C. The reaction was stirred overnight, cooled to room temperature, and diluted with water. The aqueous layer was extracted with dichloromethane, and the combined organics were washed with saturated brine, dried over magnesium sulfate, and concentrated. The resulting solid was purified by silica gel chromatography to give (R)-5'-bromo-1',7'-dimethyl-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (682 mg, 2.05 mmol, 36% yield) as a yellow solid. 1 H NMR(400 MHz, CDCl3)δ ppm = 8.03(d, J = 1.0 Hz, 1H), 7.84(d, J = 1.9 Hz, 1H), 4.61-4.76(m, 1H), 2.78-2.89(m, 1H), 2.59-2.71(m, 1H), 2.45(s, 3H), 2.39-2.44(m, 1H), 2.25-2.39(m, 2H), 2.18(dd, J = 13.1, 2.2 Hz, 1H), 2.01-2.15(m, 2H), 1.47(d, J = 6.5 Hz, 3H).

[0471] Step B: Palladium(II) acetate (23.0 mg, 0.05 eq., 102 μmol), 1,3-bis(diphenylphosphino)propane (84.4 mg, 0.10 eq., 205 μmol), and (R)-5'-bromo-1',7'-dimethyl-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (682 mg, 1.0 eq., 2.05 mmol) were added to a vial and stir bar. The vial was evacuated and backfilled with nitrogen three times. Next, ethylene glycol (3.41 mL), N,N-dicyclohexylmethylamine (1.20 g, 1.31 mL, 3.0 eq., 6.14 mmol), and n-butyl vinyl ether (1.02 g, 1.32 mL, 5.0 eq., 10.2 mmol) were added. The vial was placed in a heating block, and the mixture was heated to 115 °C with stirring. After the reaction was complete, the reaction mixture was cooled to room temperature, and 1 N HCl (2 mL; approximately three times the volume of ethylene glycol) was added to the reaction mixture. The reaction mixture was stirred until the ketone deprotection was complete (approximately 1 h). The aqueous layer was extracted three times with ethyl acetate, and the combined organic phase was washed successively with water and saturated brine, dried over magnesium sulfate, filtered, and concentrated to a residue. The residue was purified by silica gel chromatography to give (R)-5'-acetyl-1',7'-dimethyl-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (508 mg, 1.71 mmol, 84% yield) as a yellow solid. 1 H NMR(400 MHz, CDCl3)δ ppm = 8.23(d, J = 1.4 Hz, 1H), 7.87(d, J = 2.1 Hz, 1H), 4.65-4.79(m, 1H), 2.98(s, 3H), 2.68-2.80(m, 1H), 2.54-2.66(m, 1H), 2.49(s, 3H), 2.45(dd, J = 13.1, 8.4 Hz, 1H), 2.24-2.39(m, 2H), 2.03-2.23(m, 3H), 1.48(d, J = 6.5 Hz, 3H).

[0472] Step C: Titanium(IV) ethoxide (1.95 g, 1.78 mL, 5.0 eq., 8.57 mmol) was added to a solution of (R)-5'-acetyl-1',7'-dimethyl-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (508 mg, 1.0 eq., 1.71 mmol) and (R)-2-methylpropane-2-sulfinamide (249 mg, 1.2 eq., 2.06 mmol) in tetrahydrofuran (2.86 mL) in a sealed tube. The sealed tube was placed in a heating block and heated at 80 °C for 12 h, then cooled to room temperature. After returning to room temperature, a small amount of saturated brine was added to form a suspension. The resulting suspension was diluted with ethyl acetate and filtered. The mixture was filtered through a Celite plug, and the filter cake was washed several times with ethyl acetate. The filtrate was concentrated under reduced pressure to give a crude yellow solid, which was quickly purified by silica gel chromatography to give (R)-N-(1-((R)-1',7'-dimethyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethylidene)-2-methylpropane-2-sulfinamide (494 mg, 1.24 mmol, 72% yield).

[0473] Step D: To a solution of (R)-N-((Z)-1-((R)-1',7'-dimethyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethylidene)-2-methylpropane-2-sulfinamide (494 mg, 1.0 eq., 1.24 mmol) in anhydrous dichloromethane (6.18 mL) was added Schwartz's reagent (414 mg, 1.3 eq., 1.61 mmol) as a solid in small portions at room temperature (Note: slight effervescence was observed). The reaction was stirred at this temperature for 1 h and then quenched with aqueous ammonium chloride. The aqueous layer was extracted with dichloromethane, and the combined organics were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0% to 10% methanol in dichloromethane) to give (R)-N-((R)-1-((R)-1',7'-dimethyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)-2-methylpropane-2-sulfinamide (373 mg, 929 μmol, 75% yield) as a white solid. LCMS [M+H] + = 402.3.

[0474] Step E: To a solution of (R)-N-((R)-1-((R)-1',7'-dimethyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)-2-methylpropane-2-sulfinamide (373 mg, 1.0 eq., 929 μmol) in methanol (1.86 mL) was added HCl (4 M solution in dioxane) (50.8 mg, 348 μL, 4.0 mol, 1.5 eq., 1.39 mmol). The reaction was stirred at room temperature until completion, then triturated with diethyl ether to give (R)-5'-((R)-1-aminoethyl)-1',7'-dimethyl-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one·HCl (286 mg, 857 μmol, 92% yield) as an off-white salt, which was used without further purification. LCMS [M+H] + = 298.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm = 8.39(br s, 3H), 7.97(s, 1H), 7.81(d, J = 1.8 Hz, 1H), 5.28(dt, J = 12.2, 6.2 Hz, 1H), 4.55-4.72(m, 1H), 2.62-2.75(m, 1H), 2.54(m, 1H), 2.48(s, 3H), 2.41-2.46(m, 1H), 2.29-2.39(m, 1H), 2.03-2.26(m, 4H), 1.64(d, J = 6.9 Hz, 3H), 1.38(d, J = 6.5 Hz, 3H).

[0475] Step F: A mixture of (R)-5'-((R)-1-aminoethyl)-1',7'-dimethyl-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one hydrochloride (15 mg, 1.0 eq., 45 μmol), methyl 6-chloro-3-fluoropicolinate (13 mg, 1.5 eq., 67 μmol), and diisopropylethylamine (29 mg, 39 μL, 5.00 eq., 0.22 mmol) in dimethyl sulfoxide (0.22 mL) was stirred at 100 °C for 12 h. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0% to 70% ethyl acetate in heptane) to give methyl 6-chloro-3-(((R)-1-((R)-1',7'-dimethyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinate (12 mg, 26 μmol, 57% yield). LCMS [M+H] + = 467.4.

[0476] Step G: To a vial containing methyl 6-chloro-3-(((R)-1-((R)-1',7'-dimethyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinate (12 mg, 1 eq., 26 μmol) and a stir bar, tetrahydrofuran (0.10 mL), methanol (0.10 mL), and water (51 μL) were added, followed by solid sodium hydroxide (4.1 mg, 4 eq., 0.10 mmol). The reaction mixture was stirred at room temperature for 1 hour, then 1N hydrochloric acid was added and the mixture was diluted with ethyl acetate and saturated brine. The aqueous layer was extracted three times, and the combined organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated to give a residue that was purified by silica gel chromatography (0% to 100% ethyl acetate in heptane) to give 6-chloro-3-(((R)-1-((R)-1',7'-dimethyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid (9.7 mg, 21 μmol, 83% yield). LCMS [M+H] + = 453.4. 1 H NMR(400 MHz, CDCl3)δ ppm = 7.99(d, J = 1.1 Hz, 1H), 7.49(d, J = 1.9 Hz, 1H), 7.12-7.16(m, 1H), 7.08-7.11(m, 1H), 5.74(q, J = 6.2 Hz, 1H), 4.67-4.81(m, 1H), 2.79-2.92(m, 1H), 2.53-2.65(m, 1H), 2.46(dd, J = 13.1, 8.4 Hz, 1H), 2.41(s, 3H), 2.26-2.39(m, 2H), 2.22(dd, J = 13.1, 1.9 Hz, 1H), 2.09-2.19(m, 2H), 1.70(d, J = 6.6 Hz, 3H), 1.51(d, J = 6.5 Hz, 3H).

[0477] Examples 1-105 6-chloro-3-(((R)-1-((S)-1',7'-dimethyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid [ka]

[0478] Step A: A solution of (S)-7-methyl-6-azaspiro[3.4]octan-5-one (500 mg, 1.0 eq., 3.59 mmol) in 1,2-dichloroethane (18.0 mL) was added to a vial, followed by phosphorus oxychloride (716 mg, 435 μL, 1.3 eq., 4.67 mmol) and diisopropylethylamine (464 mg, 626 μL, 1.0 eq., 3.59 mmol). The reaction was stirred at room temperature for 1 hour. 2-Amino-3-bromo-5-methylbenzoic acid (826 mg, 1.0 eq., 3.59 mmol) was then added as a solid, and the reaction was heated to 100 °C. The reaction was stirred overnight, cooled to room temperature, and diluted with water. The aqueous layer was extracted with dichloromethane, and the combined organic phase was washed with saturated brine, dried over magnesium sulfate, and concentrated. The solid was purified by silica gel chromatography to give (S)-5'-bromo-1',7'-dimethyl-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (702 mg, 2.11 mmol, 59% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3)δ ppm = 8.03(d, J = 0.9 Hz, 1H), 7.84(d, J = 1.8 Hz, 1H), 4.64-4.74(m, 1H), 2.78-2.89(m, 1H), 2.59-2.70(m, 1H), 2.45(s, 3H), 2.39-2.44(m, 1H), 2.25-2.39(m, 2H), 2.18(dd, J = 13.1, 2.2 Hz, 1H), 2.02-2.15(m, 2H), 1.47(d, J = 6.6 Hz, 3H).

[0479] Step B: Palladium(II) acetate (23.6 mg, 0.05 eq., 105 μmol), 1,3-bis(diphenylphosphino)propane (86.9 mg, 0.10 eq., 211 μmol), and (S)-5'-bromo-1',7'-dimethyl-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (702 mg, 1.0 eq., 2.11 mmol) were added to a vial and stir bar. The vial was evacuated and backfilled with nitrogen three times. Next, ethylene glycol (3.51 mL), N,N-dicyclohexylmethylamine (1.23 g, 1.35 mL, 3.0 eq., 6.32 mmol), and n-butyl vinyl ether (1.06 g, 1.36 mL, 5.0 eq., 10.5 mmol) were added. The vial was placed in a heating block, and the mixture was heated to 115 °C with stirring. After the reaction was complete, the reaction was cooled to room temperature, and 1 N HCl (2 mL; approximately three times the volume of ethylene glycol) was added to the reaction. The reaction was stirred until deprotection of the ketone was complete (approximately 1 h). The aqueous layer was extracted three times with ethyl acetate, and the combined organic phase was washed successively with water and saturated brine, dried over magnesium sulfate, filtered, and concentrated to a residue. The residue was purified by silica gel chromatography to give (S)-5'-acetyl-1',7'-dimethyl-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (527 mg, 1.78 mmol, 84% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3)δ ppm = 8.23(d, J = 1.4 Hz, 1H), 7.87(d, J = 2.0 Hz, 1H), 4.64-4.78(m, 1H), 2.98(s, 3H), 2.70-2.79(m, 1H), 2.53-2.62(m, 1H), 2.49(s, 3H), 2.44(dd, J = 13.1, 8.4 Hz, 1H), 2.25-2.39(m, 2H), 2.14-2.23(m, 2H), 2.03-2.13(m, 1H), 1.48(d, J = 6.6 Hz, 3H).

[0480] Step C: To a solution of (S)-5'-acetyl-1',7'-dimethyl-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (527 mg, 1.0 eq., 1.78 mmol) and (R)-2-methylpropane-2-sulfinamide (259 mg, 1.2 eq., 2.13 mmol) in tetrahydrofuran (2.96 mL) in a sealed tube, titanium(IV) ethoxide (2.03 g, 1.85 mL, 5.0 eq., 8.89 mmol) was added. The sealed tube was placed in a heating block and heated at 80 °C for 12 h, then cooled to room temperature. After returning to room temperature, a small amount of brine was added to form a suspension. The resulting suspension was diluted with ethyl acetate and filtered through a Celite plug, and the filter cake was washed several times with ethyl acetate. The filtrate was concentrated under reduced pressure to give a crude yellow solid, which was quickly purified by silica gel chromatography to give (R)-N-(1-((S)-1',7'-dimethyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethylidene)-2-methylpropane-2-sulfinamide (467 mg, 1.17 mmol, 66% yield).

[0481] Step D: To a solution of (R)-N-(1-((S)-1',7'-dimethyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethylidene)-2-methylpropane-2-sulfinamide (467 mg, 1.0 eq., 1.17 mmol) in anhydrous dichloromethane (5.84 mL) was added Schwartz's reagent (392 mg, 1.3 eq., 1.52 mmol) as a solid in small portions at room temperature (Note: slight effervescence was observed). The reaction was stirred at this temperature for 1 hour before being quenched with aqueous ammonium chloride. The reaction was stirred at this temperature for 1 hour before being quenched with aqueous ammonium chloride. The aqueous layer was extracted with dichloromethane, and the combined organic phases were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10% methanol in dichloromethane) to give (R)-N-((R)-1-((S)-1',7'-dimethyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)-2-methylpropane-2-sulfinamide (345 mg, 859 μmol, 74% yield) as a white solid. LCMS [M+H] + = 402.2.

[0482] Step E: To a solution of (R)-N-((R)-1-((S)-1',7'-dimethyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)-2-methylpropane-2-sulfinamide (345 mg, 1.0 eq., 859 μmol) in methanol (1.72 mL) was added HCl (4 M, dioxane solution) (47.0 mg, 322 μL, 4.0 mol, 1.5 eq., 1.29 mmol). The reaction was stirred at room temperature until complete, then triturated with diethyl ether to give (S)-5'-((R)-1-aminoethyl)-1',7'-dimethyl-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one·HCl (237 mg, 710 μmol, 83% yield) as an off-white salt, which was used without further purification. LCMS [M+H] + = 298.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm = 8.41(br s, 3H), 7.97(s, 1H), 7.81(d, J = 1.8 Hz, 1H), 5.26(br d, J = 6.0 Hz, 1H), 4.56-4.71(m, 1H), 2.63-2.75(m, 1H), 2.52-2.55(m, 1H), 2.48(s, 3H), 2.41-2.46(m, 1H), 2.29-2.38(m, 1H), 2.23(dd, J = 13.1, 2.1 Hz, 1H), 2.01-2.19(m, 3H), 1.64(d, J = 6.9 Hz, 3H), 1.38(d, J = 6.6 Hz, 3H).

[0483] Step F: A mixture of (S)-5'-((R)-1-aminoethyl)-1',7'-dimethyl-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one·HCl (15 mg, 1.0 eq., 45 μmol), methyl 6-chloro-3-fluoropicolinate (13 mg, 1.5 eq., 67 μmol), and diisopropylethylamine (29 mg, 39 μL, 5.0 eq., 0.22 mmol) in DMSO (0.30 mL) was stirred at 100 °C for 6 h. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0% to 70% ethyl acetate in heptane) to give methyl 6-chloro-3-(((R)-1-((S)-1',7'-dimethyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinate (12 mg, 26 μmol, 57% yield). LCMS [M+H] + = 467.4.

[0484] Step G: To a vial containing methyl 6-chloro-3-(((R)-1-((S)-1',7'-dimethyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinate (12 mg, 1 eq., 26 μmol) and a stir bar, tetrahydrofuran (0.10 mL), methanol (0.10 mL), and water (51 μL) were added, followed by solid sodium hydroxide (4.1 mg, 4 eq., 0.10 mmol). The reaction mixture was stirred at room temperature for 1 hour, then 1N HCl was added and the mixture was diluted with ethyl acetate and saturated brine. The aqueous layer was extracted three times, and the combined organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated to give a residue that was purified by silica gel chromatography (0% to 100% ethyl acetate in heptane) to give 6-chloro-3-(((R)-1-((S)-1',7'-dimethyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid (10 mg, 22 μmol, 86% yield). LCMS [M+H] + = 453.4. 1 H NMR(400 MHz, CDCl3)δ ppm = 8.33(br s, 1H), 7.98(d, J = 1.0 Hz, 1H), 7.49(d, J = 2.0 Hz, 1H), 7.08-7.13(m, 1H), 7.01-7.06(m, 1H), 5.64-5.77(m, 1H), 4.67-4.78(m, 1H), 2.74-2.84(m, 1H), 2.56-2.68(m, 1H), 2.47(dd, J = 13.1, 8.4 Hz, 1H), 2.40(s, 3H), 2.26-2.38(m, 2H), 2.21(dd, J = 13.1, 2.1 Hz, 1H), 2.07-2.25(m, 2H), 1.71(d, J = 6.8 Hz, 3H), 1.49(d, J = 6.5 Hz, 3H).

[0485] Intermediates O-1 and O-2 [ka]

[0486] Step A: To a solution of ethyl 2-oxocyclopentanecarboxylate (5.00 g, 32.0 mmol, 4.74 mL, 1.00 eq.) and 2-chloroacetonitrile (4.83 g, 64.0 mmol, 4.05 mL, 2.00 eq.) in acetonitrile (50.0 mL) was added potassium carbonate (13.2 g, 96.0 mmol, 3.00 eq.). The mixture was stirred at 60 °C for 12 h. After completion of the reaction, the reaction mixture was cooled to 25 °C, diluted with water (100 mL), and extracted with ethyl acetate (100 mL × 3). The combined organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent: 0–20% ethyl acetate / petroleum ether gradient, 40 mL / min) to give ethyl 1-(cyanomethyl)-2-oxocyclopentane-1-carboxylate (3.20 g, 16.3 mmol, 51% yield) as a clear oil. 1 H NMR(400 MHz, CDCl3)δ = 4.27 - 4.20(m, 2H), 2.94(d, J = 17.2 Hz, 1H), 2.76(d, J = 16.8 Hz, 1H), 2.69 - 2.52(m, 2H), 2.48 - 2.33(m, 1H), 2.30 - 2.17(m, 2H), 2.16 - 2.08(m, 1H), 1.29(t, J = 7.2 Hz, 3H).

[0487] Step B: A solution of ethyl 1-(cyanomethyl)-2-oxocyclopentane-1-carboxylate (3.20 g, 16.3 mmol, 1.00 eq.) in (diethylamino)sulfur trifluoride (5.00 mL) was stirred at 25 °C for 16 h. After completion of the reaction, water (100 mL) was added dropwise to the reaction mixture at 25 °C, and the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent: 0–20% ethyl acetate / petroleum ether, gradient, 40 mL / min) to give ethyl 1-(cyanomethyl)-2,2-difluorocyclopentane-1-carboxylate (2.50 g, 11.5 mmol, 70% yield) as a clear oil. 1 H NMR(400 MHz, CDCl3)δ = 4.38 - 4.23(m, 2H), 3.08 - 2.66(m, 2H), 2.66 - 2.59(m, 1H), 2.57 - 2.07(m, 3H), 2.07 - 1.80(m, 2H), 1.39 - 1.30(m, 3H). 19 F NMR (377 MHz, CDCl3) δ = -101.60, -102.01, -102.63, -131.67.

[0488] Step C: To a solution of ethyl 1-(cyanomethyl)-2,2-difluorocyclopentane-1-carboxylate (2.20 g, 10.1 mmol, 1.00 eq.) and cobalt(II) chloride (657 mg, 5.06 mmol, 0.50 eq.) in tetrahydrofuran (30.0 mL) and water (15.0 mL) was added sodium borohydride (3.07 g, 81.0 mmol, 8.00 eq.) at 0 °C. The mixture was stirred at 0 °C for 16 h. After completion of the reaction, water (100 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (100 mL × 3). The combined organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent 0–20% ethyl acetate / petroleum ether, gradient, 40 mL / min) to afford 6,6-difluoro-2-azaspiro[4.4]nonan-1-one (900 mg, 3.88 mmol, 38% yield) as a yellow oil. 1 H NMR(400 MHz, CDCl3)δ = 6.23(br s, 1H), 3.42 - 3.36(m, 1H), 3.36 - 3.26(m, 1H), 2.69 - 2.59(m, 1H), 2.58 - 2.40(m, 1H), 2.32 - 1.99(m, 4H), 1.89 - 1.72(m, 2H).

[0489] Step D: To a solution of 6,6-difluoro-2-azaspiro[4.4]nonan-1-one (678 mg, 3.87 mmol, 0.99 eq.) in 1,2-dichloroethane (10.0 mL), phosphorus oxychloride (899 mg, 5.87 mmol, 546 μL, 1.50 eq.) and diisopropylethylamine (1.01 g, 7.82 mmol, 1.36 mL, 2.00 eq.) were added and stirred at 50 °C for 1 h. Next, 2-amino-3-bromo-5-methylbenzoic acid (900 mg, 3.91 mmol, 1.00 eq.) was added at 50 °C. The mixture was stirred at 85 °C for 16 h. After completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluting with 0–50% ethyl acetate / petroleum ether, gradient, 40 mL / min) to give 5'-bromo-2,2-difluoro-7'-methyl-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (800 mg, 2.17 mmol, 55% yield) as a white solid. LCMS [M+3] + = 371.0.

[0490] Step E: To a solution of 5'-bromo-2,2-difluoro-7'-methyl-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (600 mg, 1.63 mmol, 1.00 eq.) and 1-vinyloxybutane (325 mg, 3.25 mmol, 417 μL, 2.00 eq.) in dioxane (5.00 mL) was added (t-Bu)2PMe-Pd-G3 (83.2 mg, 162 μmol, 0.10 eq.) and dicyclohexylamine (324 mg, 1.79 mmol, 356 μL, 1.10 eq.). The mixture was stirred at 90 °C for 6 h under a nitrogen atmosphere. After completion of the reaction, the reaction mixture was cooled to 25°C, filtered, and concentrated under reduced pressure to give 5'-(1-butoxyvinyl)-2,2-difluoro-7'-methyl-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (600 mg, crude) as a yellow solid. LCMS [M+1] + = 389.2.

[0491] Step F: To a solution of 5'-(1-butoxyvinyl)-2,2-difluoro-7'-methyl-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (600 mg, 1.54 mmol, 1.00 eq.) in tetrahydrofuran (5.00 mL) was added HCl (4.00 M, 1.93 mL, 5.00 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 × 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 5'-acetyl-2,2-difluoro-7'-methyl-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (500 mg, 1.50 mmol, 97% yield) as a yellow solid. LCMS [M+1] + = 333.1.

[0492] Step G: To a solution of 5'-acetyl-2,2-difluoro-7'-methyl-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (340 mg, 1.02 mmol, 1.00 eq.) and (R)-2-methylpropane-2-sulfinamide (247 mg, 2.05 mmol, 2.00 eq.) in tetrahydrofuran (3.00 mL), titanium(IV) ethoxide (700 mg, 3.07 mmol, 636 μL, 3.00 eq.) and 1,2-dimethoxyethane (101 mg, 1.13 mmol, 116 μL, 1.10 eq.) were added. The mixture was stirred at 70 °C for 2 h. After completion of the reaction, the reaction mixture was diluted with water (1.00 mL) and ethyl acetate (50.0 mL) and stirred for 5 min. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluting with 0-50% ethyl acetate / petroleum ether, gradient, 40 mL / min) to give (R)-N-(1-(2,2-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethylidene)-2-methylpropane-2-sulfinamide (310 mg, 711.78 μmol, 70% yield) as a white solid. LCMS [M+1] + = 436.2.

[0493] Step H: To a solution of (R)-N-(1-(2,2-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethylidene)-2-methylpropane-2-sulfinamide (300 mg, 688 μmol, 1.00 eq.) in dichloromethane (3.00 mL) was added Schwartz's reagent (675 mg, 3.44 mmol, 5.00 eq.). The mixture was stirred at 25°C for 2 hours. After completion of the reaction, the reaction was quenched with water (1.00 mL), filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent 0-20% ethyl acetate / petroleum ether, gradient, 40 mL / min) to afford (R)-N-((1R)-1-(2,2-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)-2-methylpropane-2-sulfinamide (220 mg, 502 μmol, 73% yield) as a yellow solid. LCMS [M+1] + = 438.1.

[0494] Step I: (R)-N-((1R)-1-(2,2-Difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)-2-methylpropane-2-sulfinamide (220 mg, 502 μmol, 1.00 eq.) was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm × 50 mm, 10 μm); mobile phase: [carbon dioxide-ethanol (neutral)]; gradient: 27% ethanol, isocratic elution mode). The desired fractions of the first peak were collected and concentrated to give the first-eluting isomer (50.0 mg, 114 μmol, 25.0% yield) as a white solid. The desired fractions of the second peak were collected and concentrated to give the second eluting isomer (80.0 mg, 183 μmol, 40% yield) as a white solid.

[0495] Step J: The first-eluting isomer (20.0 mg, 45.7 μmol, 1.00 eq.) was dissolved in HCl solution in ethyl acetate (2M, 1.00 mL) and stirred at 25 °C for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a residue. Saturated sodium bicarbonate solution (10.0 mL) was then added to the residue to adjust the pH to > 7, and the resulting aqueous solution was extracted with dichloromethane (10.0 mL × 3). The combined organic layer was washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate O-1 (15.0 mg, 44.9 μmol, 98% yield) as a white solid. LCMS [M+1] + = 334.2.

[0496] Step K: The second-eluting isomer (50.0 mg, 114 μmol, 1.00 eq.) was dissolved in a 2M HCl solution in ethyl acetate (1.00 mL) and stirred at 25 °C for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a residue. Saturated aqueous sodium bicarbonate solution (10.0 mL) was then added to the residue to adjust the pH to > 7, and the resulting aqueous solution was extracted with dichloromethane (10.0 mL × 3). The combined organic layer was washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate O-2 (35.0 mg, 104 μmol, 92% yield) as a white solid. LCMS [M+1] + = 334.2.

[0497] Examples 1-106 and 1-107 6-chloro-3-(((1R)-1-(2,2-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid and 6-chloro-3-(((R)-1-((R)-2,2-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid [ka]

[0498] Step A: To a solution of intermediate O-1 (72.0 mg, 216 μmol, 1.00 eq.) and methyl 6-chloro-3-fluoropyridine-2-carboxylate (81.9 mg, 432 μmol, 2.00 eq.) in dimethylformamide (1.00 mL) was added diisopropylethylamine (83.7 mg, 648 μmol, 113 μL, 3.00 eq.). The mixture was stirred at 100°C for 16 hours. After completion of the reaction, the reaction solution was cooled to 25°C. The reaction mixture was diluted with water (10.0 mL) and ethyl acetate (5.00 mL). The aqueous phase was extracted with ethyl acetate (10.0 mL × 2). The combined organic phase was washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by preparative TLC (silicon dioxide, petroleum ether:ethyl acetate=1:1) to give methyl picolinate (50.0 mg, 99.4 μmol, 46% yield) as a colorless oil. LCMS [M+1] + = 503.1.

[0499] Step B: To a solution of methyl picolinate (50.0 mg, 99.4 μmol, 1.00 eq.) in tetrahydrofuran (0.50 mL) and methanol (0.50 mL) was added lithium hydroxide (2.00 M, 357 μL, 7.18 eq.). The mixture was stirred at 25 °C for 2 hours. After completion of the reaction, the reaction mixture was adjusted to pH < 6 with hydrochloric acid (2.00 M, 1.00 mL) and extracted with dichloromethane (10.0 mL × 2). The combined organic layer was washed with saturated brine (10.00 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (formic acid conditions; column: YMC-Actus Triart C18 150 x 30 mm x 7 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 60%-90% acetonitrile over 10 min) to give Example 1-66 (30.0 mg, 61.3 μmol, 62% yield, 99.9% purity) as a white solid. LCMS [M+23] + = 511.1.

[0500] Step C: To a solution of Example 1-66 (15.0 mg, 30.7 μmol, 1.00 eq.) in methanol (1.00 mL) was added palladium on carbon (50.0 mg, 47.0 μmol, 10 wt%, 1.53 eq.) under a nitrogen atmosphere. The suspension was evacuated and filled with hydrogen three times. The mixture was stirred under hydrogen (15 psi) at 25°C for 30 minutes. Methanol (10.0 mL) was added to dilute the reaction mixture, which was then filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (YMC-Actus Triart C18 150 × 30 mm × 7 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 35%-65% acetonitrile over 10 minutes) to give Example 1-106. LCMS [M+1] + = 455.2. 1H NMR(400 MHz, CD3OD)δ = 7.96(s, 1H), 7.78 - 7.66(m, 2H), 7.45 - 7.30(m, 2H), 5.66(q, J = 6.4 Hz, 1H), 4.25 - 4.16(m, 1H), 4.08(td, J = 8.0, 12.0 Hz, 1H), 2.81 - 2.72 (m, 1H), 2.71 - 2.57 (m, 2H), 2.42 (s, 3H), 2.38 - 2.21 (m, 3H), 2.15 - 2.04 (m, 1H), 2.03 - 1.90(m, 1H), 1.71(d, J = 6.8 Hz, 3H).

[0501] Step D: To a solution of intermediate O-2 (70.0 mg, 210 μmol, 1.00 eq.) in dimethylformamide (1.00 mL) was added diisopropylethylamine (81.4 mg, 630 μmol, 110 μL, 3.00 eq.). The mixture was stirred at 100°C for 16 hours. The reaction mixture was cooled to 25°C and diluted with water (10.0 mL) and ethyl acetate (5.00 mL). The solution was extracted with ethyl acetate (10.0 mL × 2). The combined organic layer was washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by preparative TLC (silicon dioxide, petroleum ether:ethyl acetate = 1:1) to give methyl picolinate (50.0 mg, 92.5 μmol, 44% yield, 93% purity) as a colorless oil. LCMS [M+1] + = 503.3.

[0502] Step E: To a solution of methyl picolinate (50.0 mg, 99.4 μmol, 1.00 eq.) in tetrahydrofuran (0.50 mL) and methanol (0.50 mL), lithium hydroxide (2.00 M, 400 μL, 8.05 eq.) was added. The mixture was stirred at 25 °C for 1 hour. After completion of the reaction, the reaction mixture was adjusted to pH < 6 with hydrochloric acid (2.00 M) and extracted with ethyl acetate (10.0 mL × 2). The combined organic layer was washed with saturated brine (10.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18 150 × 30 mm × 7 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 60%-90% B over 10 min) to give Example 1-67 (25.0 mg, 51.1 μmol, 51.4% yield) as a yellow solid. LCMS [M+1] + = 489.0.

[0503] Step F: To a solution of Example 1-67 (80.0 mg, 164 μmol, 1.00 eq.) in methanol (1.00 mL) was added palladium on carbon (17.4 mg, 16.4 μmol, 10 wt%, 0.10 eq.) under a nitrogen atmosphere. The suspension was degassed and purged with hydrogen three times. The mixture was stirred under hydrogen (15 Psi) at 25°C for 0.5 h. After completion of the reaction, the reaction mixture was diluted with methanol (10 mL), filtered, and concentrated under reduced pressure to give 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: 32% - 62% B over 9 min) to give Example 1-107 (10.4 mg, 22.9 μmol, 14% yield, 99.8% purity) as an off-white solid. LCMS [M+1] + = 455.2. 1H NMR (400 MHz, CD3OD) δ = 7.95 (s, 1H), 7.75 (br d, J = 4.8 Hz, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.48 (dd, J = 4.8, 8.8 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 5.68 (q, J = 6.4 Hz, 1H), 4.25 - 4.19 (m, 1H), 4.10 - 4.03 (m, 1H), 2.81 - 2.73 (m, 1H), 2.73 - 2.52 (m, 2H), 2.41 (s, 3H), 2.38 - 2.21 (m, 3H), 2.00 - 1.93 (m, 1H), 2.00 - 1.97 (m, 1H), 1.68 (d, J = 6.8 Hz, 3H).

[0504] Intermediates P-1 and P-2 [ka]

[0505] Step A: A solution of methyl tetrahydrofuran-3-carboxylate (8.30 g, 63.78 mmol, 1.00 eq.) and allyl bromide (8.49 g, 70.2 mmol, 1.10 eq.) in anhydrous tetrahydrofuran (125 mL) was cooled to −78°C. Lithium diisopropylamine (2 M, 38.3 mL, 1.20 eq.) was then added dropwise. The reaction mixture was stirred at −78°C for 2 hours. The reaction was quenched with hydrochloric acid (1 N, 200 mL) at 0°C under a nitrogen atmosphere. The resulting mixture was extracted with ethyl acetate (100 mL × 2). The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give methyl 3-allyltetrahydrofuran-3-carboxylate (7.00 g, 41 mmol, yield 65%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ = 5.70 - 5.62 (m, 1H), 5.07 - 5.02 (m, 2H), 4.02 (d, J = 8.8 Hz, 1H), 3.87 - 3.79 (m, 2H), 3.68 (s, 3H), 3.60 (d, J = 8.8 Hz, 1H), 2.50 - 2.45 (m, 1H), 2.41 - 2.35 (m, 2H), 1.86 - 1.80 (m, 1H).

[0506] Step B: A solution of methyl 3-allyltetrahydrofuran-3-carboxylate (7.00 g, 41.1 mmol, 1.00 eq.) in dichloromethane (50.0 mL) and methanol (50.0 mL) was saturated with ozone at -78 °C and reacted until the blue color persisted. The atmosphere was then purged with nitrogen until the blue color disappeared, and triphenylphosphine (11.9 g, 45.2 mmol, 1.10 eq.) was added at 25 °C. The solution was warmed to 25 °C and stirred for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give methyl 3-(2-oxoethyl)tetrahydrofuran-3-carboxylate (4.80 g, 27.9 mmol, 68% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ = 9.71 (s, 1H), 4.12 - 4.09 (m, 1H), 3.95 - 3.84 (m, 2H), 3.70 (s, 3H), 3.64 (d, J = 9.2 Hz, 1H), 2.91 (s, 2H), 2.51 - 2.43 (m, 1H), 1.92 - 1.74 (m, 1H).

[0507] Step C: To a solution of methyl 3-(2-oxoethyl)tetrahydrofuran-3-carboxylate (4.60 g, 26.7 mmol, 1.00 eq.) in tetrahydrofuran (80.0 mL), 2,4-dimethoxybenzylamine (4.91 g, 29.4 mmol, 4.42 mL, 1.10 eq.) was added, followed by sodium triacetoxyborohydride (11.3 g, 53.4 mmol, 2.00 eq.). The mixture was stirred at 25 °C for 2 h. The reaction was quenched with hydrochloric acid (2 N, 50.0 mL) and diluted with water (100 mL). The mixture was extracted with ethyl acetate (100 mL × 2). The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 7-(3,4-dimethylbenzyl)-2-oxa-7-azaspiro[4.4]nonan-6-one (5.30 g, 16.4 mmol, 62% yield, 90% purity) as a yellow oil. LCMS [M+1] + = 292.1. 1 H NMR (400 MHz, CDCl3) δ = 7.14 - 7.07 (m, 1H), 6.52 - 6.43 (m, 2H), 4.54 - 4.34 (m, 2H), 4.00 (dt, J = 5.2, 8.4 Hz, 1H), 3.88 (d, J = 8.4 Hz, 1H), 3.80 (s, 6H), 3.68 - 3.66 (m, 1H), 3.23 - 3.11 (m, 2H), 2.42 - 2.31 (m, 2H), 2.10 - 2.01 (m, 1H), 1.98 - 1.90 (m, 1H), 1.83 - 1.72 (m, 1H).

[0508] Step D: To a solution of 7-(3,4-dimethylbenzyl)-2-oxa-7-azaspiro[4.4]nonan-6-one (5.30 g, 16.4 mmol, 1.00 eq.) in toluene (50.0 mL) was added p-toluenesulfonic acid (4.69 g, 24.6 mmol, 1.50 eq.). The mixture was stirred at 110 °C for 1 h. The mixture was cooled to 25 °C and water (100 mL) was added. The mixture was adjusted to pH = ∼9 with solid sodium carbonate and extracted with ethyl acetate (100 mL × 3). The combined organic layers were discarded. The aqueous phase was collected and filtered, and the filtrate was concentrated in vacuo to give a white solid. The crude product was triturated with dichloromethane (200 mL), filtered, and concentrated under reduced pressure to give 2-oxa-7-azaspiro[4.4]nonan-6-one (950 mg, 4.06 mmol, 25% yield, 60% purity) as a white solid. LCMS [M+1] + = 142.0. 1 H NMR (400 MHz, CDCl3) δ = 6.72 (br s, 1H), 3.99 (dt, J = 5.2, 8.4 Hz, 1H), 3.94 - 3.85 (m, 2H), 3.72 (d, J = 8.4 Hz, 1H), 3.50 - 3.26 (m, 2H), 2.34 (td, J = 8.0, 12.4 Hz, 1H), 2.27 - 2.17 (m, 1H), 2.16 - 2.06 (m, 1H), 1.86 - 1.79 (m, 1H).

[0509] Step E: A solution of 2-oxa-7-azaspiro[4.4]nonan-6-one (850 mg, 3.63 mmol, 1.00 eq.) in dichloroethane (15.0 mL) was placed in a flask, and phosphorus oxychloride (724 mg, 4.72 mmol, 440 μL, 1.30 eq.) and diisopropylethylamine (469 mg, 3.63 mmol, 632 μL, 1.00 eq.) were added. The reaction mixture was heated to 50°C for 1 h. The reaction mixture was then heated to 85°C, and 2-amino-3-bromo-5-methylbenzoic acid (919 mg, 3.99 mmol, 1.10 eq.) was added as a solid to the mixture. The reaction mixture was stirred at 85°C for 12 h. The reaction mixture was cooled to 25°C and diluted with warm water (20.0 mL). The aqueous layer was extracted with dichloromethane (20.0 mL), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give 5'-bromo-7'-methyl-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazolin]-9'-one (418 mg, 1.18 mmol, 33% yield, 95% purity) as a yellow solid. LCMS [M+3] + = 337.0. 1 H NMR (400 MHz, CDCl3) δ = 8.04 (d, J = 1.2 Hz, 1H), 7.85 (d, J = 1.6 Hz, 1H), 4.28 - 4.21 (m, 1H), 4.20 - 4.05 (m, 4H), 3.95 (d, J = 8.4 Hz, 1H), 2.72 - 2.57 (m, 1H), 2.46 (s, 3H), 2.43 - 2.34 (m, 1H), 2.32 - 2.22 (m, 1H), 2.15 - 2.05 (m, 1H).

[0510] Step F: A mixture of 5'-bromo-7'-methyl-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazolin]-9'-one (418 mg, 1.18 mmol, 1.00 eq.), 1-vinyloxybutane (237 mg, 2.37 mmol, 304 μL, 2.00 eq.), (t-Bu)2PMe-Pd-G3 (60.6 mg, 118 μmol, 0.10 eq.), and dicyclohexylamine (257 mg, 1.42 mmol, 283 μL, 1.20 eq.) in dioxane (4.00 mL) was evacuated and backfilled with nitrogen three times. The mixture was then stirred at 100 °C under a nitrogen atmosphere for 1 h. The reaction mixture was filtered at 25° C. and concentrated under reduced pressure to give 5′-(1-butoxyvinyl)-7′-methyl-1′,2′,4,5-tetrahydro-2H,9′H-spiro[furan-3,3′-pyrrolo[2,1-b]quinazolin]-9′-one (510 mg, crude) as a yellow oil, which was used in the next step without purification. LCMS [M+1] + = 355.2.

[0511] Step G: To a solution of 5'-(1-butoxyvinyl)-7'-methyl-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazolin]-9'-one (510 mg, 1.44 mmol, 1.00 eq.) in tetrahydrofuran (5.00 mL) was added hydrochloric acid (4 M, 1.44 mL, 4.00 eq.). The mixture was stirred at 25 °C for 0.5 h. The mixture was then poured into saturated aqueous sodium bicarbonate (30.0 mL) and extracted with ethyl acetate (20.0 mL × 2). The combined organic layer was washed with saturated brine (50.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 3) to give 5'-acetyl-7'-methyl-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazolin]-9'-one (350 mg, 1.11 mmol, 77% yield, 95% purity) as a yellow oil. LCMS [M+1]+ = 299.1.

[0512] Step H: To a solution of 5'-acetyl-7'-methyl-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazolin]-9'-one (300 mg, 951 μmol, 1.00 eq.) and (R)-2-methylpropane-2-sulfinamide (173 mg, 1.43 mmol, 1.50 eq.) in 2-methyltetrahydrofuran (5.00 mL) was added titanium(IV) ethoxide (651 mg, 2.85 mmol, 592 μL, 3.00 eq.). The mixture was stirred at 80 °C for 12 h. The reaction was quenched with water (0.60 mL), diluted with ethyl acetate (20.0 mL), filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give (R)-2-methyl-N-(1-(7'-methyl-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethylidene)propane-2-sulfinamide (336 mg, 485 μmol, 51% yield, 58% purity) as a yellow oil. [M+1] + = 402.2.

[0513] Step I: To a solution of (R)-2-methyl-N-(1-(7'-methyl-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethylidene)propane-2-sulfinamide (336 mg, 485 μmol, 1.00 eq.) in dichloromethane (3.00 mL) and methanol (3.00 mL) was added sodium cyanoborohydride (61.0 mg, 970 μmol, 2.00 eq.) and acetic acid (2.91 mg, 48.5 μmol, 2.78 μL, 0.10 eq.). The mixture was stirred at 25 °C for 1 h. The reaction was quenched with saturated sodium bicarbonate solution (50 mL). The resulting solution was extracted with dichloromethane (30.0 mL × 3). The combined organic phase was washed with saturated brine (50.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give (R)-2-methyl-N-((1R)-1-(7'-methyl-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)propane-2-sulfinamide (150 mg, 368 μmol, 76% yield, 99% purity) as a yellow solid. LCMS [M+1] + = 404.2.

[0514] Step J: (R)-2-Methyl-N-[(1R)-1-(7-methyl-9-oxo-spiro[1,2-dihydropyrrolo[2,1-b]quinazoline-3,3'-tetrahydrofuran]-5-yl)ethyl]propane-2-sulfinamide (150 mg, 368 μmol, 76% yield, 99% purity) was further separated by SFC (column: DAICEL CHIRALCEL OX (250 mm × 30 mm, 10 μm); mobile phase: [CO₂- EtOH (0.1% NH₃·HO)]; gradient: EtOH (0.1% NH₃·HO), 50%, isocratic elution mode). The fractions of interest from the first peak were collected and concentrated under vacuum to give the first-eluting isomer (50.0 mg, 115 μmol, 31% yield, 93% purity). The desired fractions of the second peak were collected and concentrated in vacuo to give the second eluting isomer (50.0 mg, 123 μmol, 34% yield, 99.5% purity) as an off-white solid.

[0515] Step K: To a solution of the second-eluting isomer (50.0 mg, 115 μmol, 1.00 eq.) in ethyl acetate (1.00 mL) was added a solution of hydrochloric acid in ethyl acetate (2 M, 229 μL, 4.00 eq.). The mixture was stirred at 25 °C for 30 min. The mixture was diluted with water (10.0 mL), and the pH of the mixture was adjusted to approximately 8 with saturated sodium bicarbonate solution. The solution was then extracted with dichloromethane / methane = 10 / 1 (10 mL × 3), and the combined organic phase was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to give intermediate P-2 (30.0 mg, 100 μmol, 87% yield, 99.9% purity) as a yellow oil. LCMS [M+1] + = 300.1.

[0516] Step L: To a solution of the first eluted isomer (50.0 mg, 123 μmol, 1.00 eq.) in ethyl acetate (1.00 mL) was added a solution of hydrochloric acid in ethyl acetate (2 M, 246 μL, 4.00 eq.). The mixture was stirred at 25°C for 30 minutes. The mixture was diluted with water (10.0 mL) and the pH was adjusted to approximately 8 with saturated aqueous sodium bicarbonate. The solution was then extracted with dichloromethane / methane = 10 / 1 (10 mL × 3), and the combined organic layer was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to give Intermediate P-1 (35.0 mg, 117 μmol, 95% yield) as a yellow oil. LCMS [M+1] + = 300.1.

[0517] Examples 1-108 and 1-109 6-chloro-3-(((R)-1-((S)-7'-methyl-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid and 6-chloro-3-(((R)-1-((R)-7'-methyl-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid [ka]

[0518] Step A: To a solution of intermediate P-2 (35.0 mg, 117 μmol, 1.00 eq.) and methyl 6-chloro-3-fluoropyridine-2-carboxylate (26.6 mg, 140 μmol, 1.20 eq.) in dimethylformamide (1.00 mL) was added diisopropylethylamine (30.2 mg, 234 μmol, 40.7 μL, 2.00 eq.). The mixture was stirred at 100 °C for 12 h. The mixture was diluted with water (10.0 mL) at 25 °C and extracted with ethyl acetate (10.0 mL × 3). The combined organic phase was washed with saturated brine (30.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 1 / 1) to give methyl picolinate (29.0 mg, 60.2 μmol, 52% yield, 97% purity) as an off-white solid. LCMS [M+1] + = 469.2.

[0519] Step B: To a solution of methyl picolinate (29.0 mg, 60.0 μmol, 1.00 eq.) in tetrahydrofuran (0.50 mL) and methanol (0.50 mL) was added aqueous lithium hydroxide (2 M, 60.2 μL, 2.00 eq.). The mixture was stirred at 40° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 250 × 50 mm × 15 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 42% - 72% acetonitrile over 9 min) to give Example 1-108 (15.3 mg, 33.6 μmol, 56% yield, 99.9% purity) as a white solid. LCMS [M+1] + = 455.2. 1H NMR (400 MHz, CD3OD) δ = 7.93 (s, 1H), 7.62 (d, J = 1.6 Hz, 1H), 7.25 - 7.16 (m, 1H), 7.13 - 7.08 (m, 1H), 5.56 (q, J = 6.8 Hz, 1H), 4.24 - 4.11 (m, 4H), 4.09 - 4.01 (m, 1H), 3.97 (d, J = 8.8 Hz, 1H), 2.57 (td, J = 7.6, 12.4 Hz, 1H), 2.42 (s, 3H), 2.41 - 2.29 (m, 2H), 2.25 - 2.16 (m, 1H), 1.67 (d, J = 6.8 Hz, 3H).

[0520] Step C: To a solution of intermediate P-1 (30.0 mg, 100 μmol, 1.00 eq.) and methyl 6-chloro-3-fluoropyridine-2-carboxylate (22.8 mg, 1208 μmol, 1.20 eq.) in dimethylformamide (1.00 mL) was added diisopropylethylamine (25.9 mg, 201 μmol, 34.9 μL, 2.00 eq.). The mixture was stirred at 100°C for 12 hours. The mixture was diluted with water (10.0 mL) at 25°C and extracted with ethyl acetate (10.0 mL × 3). The combined organic phase was washed with saturated brine (30.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 1 / 1) to give methyl picolinate (20.0 mg, 39.5 μmol, 40% yield, 93% purity) as an off-white solid. LCMS [M+1] + = 469.2.

[0521] Step D: To a solution of methyl picolinate (20.0 mg, 39.5 μmol, 1.00 eq.) in tetrahydrofuran (0.50 mL) and methanol (0.50 mL) was added lithium hydroxide (2 M, 39.5 μL, 2.00 eq.). The mixture was stirred at 40° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250 × 50 mm × 15 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 42% - 72% acetonitrile over 9 min) to give Example 1-109 (6.75 mg, 14.8 μmol, 37% yield, 99.5% purity) as a yellow solid. LCMS [M+1] + = 455.2. 1 H NMR (400 MHz, CD3OD) δ = 7.93 (d, J = 1.2 Hz, 1H), 7.62 (d, J = 1.6 Hz, 1H), 7.22 - 7.17 (m, 1H), 7.16 - 7.11 (m, 1H), 5.58 (q, J = 6.8 Hz, 1H), 4.23 (dt, J = 5.6, 8.4 Hz, 1H), 4.19 - 4.12 (m, 3H), 4.07 (q, J = 7.2 Hz, 1H), 3.97 (d, J = 8.4 Hz, 1H), 2.62 (td, J = 7.6, 12.4 Hz, 1H), 2.42 (s, 3H), 2.41 - 2.35 (m, 2H), 2.23 - 2.12 (m, 1H), 1.67 (d, J = 6.8 Hz, 3H).

[0522] Intermediates Q-1 and Q-2 [ka]

[0523] Step A: To a solution of 7,7-difluoro-2-azaspiro[4.4]nonan-1-one (2.40 g, 13.7 mmol, 1.34 eq.) in 1,2-dichloroethane (24.0 mL), diisopropylethylamine (3.98 g, 30.8 mmol, 5.36 mL, 3.00 eq.) and phosphorus oxychloride (3.14 g, 20.5 mmol, 1.91 mL, 2.00 eq.) were added. The mixture was stirred at 50 °C for 1 h, followed by the addition of 2-amino-3-bromo-5-fluorobenzoic acid (2.40 g, 10.3 mmol, 1.00 eq.), and the reaction mixture was heated at 80 °C for 15 min. After completion of the reaction, the reaction mixture was cooled to 25 °C, water (100 mL) was slowly added, and the mixture was stirred at 25 °C for 1 h. The aqueous layer was extracted with dichloromethane (100 mL), and the combined organic phases were washed with saturated aqueous sodium bicarbonate (60.0 mL × 2), dried over sodium sulfate, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give 5'-bromo-3,3,7'-trifluoro-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (1.35 g, 3.62 mmol, 35% yield) as a yellow solid. LCMS [M+3] + = 374.9. 1 H NMR (400 MHz, CDCl3) δ = 7.92 (dd, J = 2.8, 8.0 Hz, 1H), 7.79 (dd, J = 2.8, 8.0 Hz, 1H), 4.33 - 4.15 (m, 1H), 4.14 - 4.04 (m, 1H), 3.05 - 2.80 (m, 1H), 2.75 - 2.50 (m, 1H), 2.45 - 2.26 (m, 5H), 2.11 - 2.01 (m, 1H). 19 F NMR (377 MHz, CDCl3) δ = -87.254, -88.862 -93.638 -94.246, -111.958

[0524] Step B: A mixture of 5'-bromo-3,3,7'-trifluoro-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (1.50 g, 4.02 mmol, 1.00 eq.), tributyl(1-ethoxyvinyl)stannane (1.67 g, 4.62 mmol, 1.56 mL, 1.15 eq.), and bis(triphenylphosphine)palladium(II) dichloride (282 mg, 402 μmol, 0.10 eq.) in dioxane (36.0 mL) was evacuated and backfilled with nitrogen three times. The mixture was stirred at 100 °C under a nitrogen atmosphere for 4 h. After completion of the reaction, the reaction mixture was cooled to 25 °C and quenched by adding 50.0 mL of aqueous potassium fluoride solution, followed by stirring for 1 h. The mixture was filtered and extracted with ethyl acetate (40.0 mL × 2). The combined organic layers were washed with water (30.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 5'-(1-ethoxyvinyl)-3,3,7'-trifluoro-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (1.90 g, 4.02 mmol, 99.9% yield, 77% purity) as a yellow solid, which was used directly. LCMS [M+1] + = 365.3.

[0525] Step C: To a solution of 5'-(1-ethoxyvinyl)-3,3,7'-trifluoro-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (1.8 g, 3.80 mmol, 1.00 eq.) in tetrahydrofuran (20 mL) was added hydrochloric acid (1 M aqueous solution, 7.61 mL, 2.00 eq.). The mixture was stirred at 25 °C for 2.5 hours. Upon completion, saturated sodium bicarbonate solution (30 mL) was added to adjust the pH to approximately 7, and the solution was stirred at 25 °C for 5 minutes. The solution was extracted with ethyl acetate (80 mL × 2), and the combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to provide a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to give 5'-acetyl-3,3,7'-trifluoro-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (1.07 g, 3.18 mmol, 84% yield) as a yellow solid. LCMS [M+1] + = 337.1. 1 H NMR (400 MHz, CDCl3) δ = 8.08 (dd, J = 3.2, 8.0 Hz, 1H), 7.78 (dd, J = 3.0, 8.4 Hz, 1H), 4.34 - 4.18 (m, 1H), 4.17 - 4.05 (m, 1H), 2.98 - 2.74 (m, 4H), 2.62 - 2.43 (m, 1H), 2.43 - 2.26 (m, 5H), 2.15 - 2.01 (m, 1H). 19 F NMR (377 MHz, CDCl3) δ = -87.5, -88.1 -93.2, -93.8, -112.4.

[0526] Step D: To a mixture of 5'-acetyl-3,3,7'-trifluoro-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (1.07 g, 3.18 mmol, 1.00 eq.) and (R)-2-methylpropane-2-sulfinamide (1.54 g, 12.7 mmol, 4.00 eq.) in 2-methyltetrahydrofuran (20.0 mL) was added titanium(IV) ethoxide (2.90 g, 12.7 mmol, 2.64 mL, 4.0 eq.). The reaction was stirred at 80 °C for 24 h. After completion of the reaction, the mixture was cooled to 25 °C, and water (0.80 mL) was added, followed by ethyl acetate (80.0 mL). After stirring for 30 minutes, the mixture was filtered, the cake was washed with ethyl acetate (80.0 mL × 3), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to give (R)-2-methyl-N-(-1-(3,3,7'-trifluoro-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethylidene)propane-2-sulfinamide (1.34 g, 3.05 mmol, 96% yield) as a yellow oil. LCMS [M+1] + = 440.1.

[0527] Step E: To a solution of (R)-2-methyl-N-(-1-(3,3,7'-trifluoro-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethylidene)propane-2-sulfinamide (1.26 g, 2.87 mmol, 1.00 eq.) and acetic acid (866 mg, 14.4 mmol, 826 μL, 5.03 eq.) in dichloromethane (10.0 mL) and methanol (10.0 mL) was added sodium cyanoborohydride (721 mg, 11.5 mmol, 4.00 eq.) in portions. The mixture was stirred at 0 °C for 1 h. After the reaction was completed, saturated brine (10.0 ml) was added to the reaction mixture, and a mixed solvent of dichloromethane:methanol (10:1) (66 mL × 3) was added, and the combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150 × 40 mm × 15 μm; mobile phase: [water (formic acid)-acetonitrile]; elution: 45%-75% acetonitrile over 15 min) to give (R)-2-methyl-N-((1R)-1-(3,3,7'-trifluoro-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)propane-2-sulfinamide (921 mg, 2.03 mmol, 71% yield, 97% purity) as an off-white solid. LCMS [M+1] + = 442.2.

[0528] Step F: (R)-2-Methyl-N-((1R)-1-(3,3,7'-trifluoro-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazolin]-5'-yl)ethyl)propane-2-sulfinamide was purified by SFC (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase: [carbon dioxide-isopropanol (0.1% ammonium hydroxide)]; gradient: 20% isopropanol (0.1% ammonium hydroxide), isocratic elution mode). The desired fractions of the first peak were collected and concentrated to give the eluted isomer (408 mg, 902 μmol, 46% yield, 98% purity) as a white solid. The desired fractions of the second peak were collected and concentrated to give the second-eluting isomer (444 mg, 996 μmol, 50% yield, 99% purity) as a white solid. SFC conditions: Column: (S,S)Whelk-O1 50 × 4.6 mm ID, 3 μm. Gradient elution: 20% to 60% isopropanol + acetonitrile (0.05% diethylamine) in carbon dioxide, flow rate: 3 mL / min; Detector: PDA; Column temperature: 35 °C; Back pressure: 100 Bar.

[0529] Step G: To a solution of the first eluted isomer (150 mg, 332 μmol, 1.00 eq.) in ethyl acetate (1.50 mL) was added a solution of hydrochloric acid in ethyl acetate (2 M, 390 μL, 2.35 eq.). The mixture was stirred at 0°C for 1.5 h. The reaction mixture was warmed and concentrated directly at 25°C to give Intermediate Q-1 (120 mg, 321 μmol, 97% yield, hydrochloride salt) as a white solid, which was used directly. LCMS [M+1] + = 338.2.

[0530] Step H: To a solution of the second-eluting isomer (150 mg, 336 μmol, 1.00 eq.) in ethyl acetate (1.5 mL) was added a solution of hydrochloric acid in ethyl acetate (2 M, 396 μL, 2.35 eq.). The mixture was stirred at 0°C for 1.5 hours. After completion of the reaction, the reaction mixture was warmed and concentrated directly at 25°C to give intermediate Q-2 (120 mg, 321 μmol, 96% yield, hydrochloride salt) as a white solid, which was used directly. LCMS [M+1] + = 338.2.

[0531] Examples 1-110 and 1-111 6-chloro-3-(((R)-1-((S)-3,3,7'-trifluoro-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid and 6-chloro-3-(((R)-1-((R)-3,3,7'-trifluoro-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid [ka]

[0532] Step A: A mixture of intermediate Q-1 (120 mg, 321 μmol, 1.00 eq., hydrochloride), methyl 6-chloro-3-fluoropicolinate (169 mg, 802 μmol, 2.50 eq.), and diisopropylethylamine (290 mg, 2.24 mmol, 391 μL, 6.99 eq.) in dimethylformamide (1.50 mL) was stirred at 80 °C for 12 h. After completion of the reaction, the reaction mixture was cooled to 25 °C and purified by preparative HPLC (column: Phenomenex Luna C18 150 × 25 mm × 10 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 55%-85% acetonitrile over 1 min) to give the methyl picolinate product (93.0 mg, 183 μmol, 57% yield) as a white solid. LCMS [M+1] + = 507.1.

[0533] Step B: To a solution of methyl picolinate (93.0 mg, 183 μmol, 1.00 eq.) in tetrahydrofuran (1.00 mL) and methanol (1.00 mL) was added lithium hydroxide (2M aqueous solution, 183 μL, 2.00 eq.). The mixture was stirred at 25°C for 2 hours. After stirring, the reaction mixture was adjusted to pH 7 by adding formic acid. The mixture was purified by preparative HPLC (column: Phenomenex Luna C18 150 × 25 mm × 10 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 53%-83% acetonitrile over 15 min) to give Example 1-110 (61.5 mg, 122 μmol, 67% yield, 98% purity) as a white solid. LCMS [M+1] + = 493.1. 1H NMR (400 MHz, CD3OD) δ = 7.75 (dd, J = 2.8, 8.4 Hz, 1H), 7.56 (dd, J = 2.8, 8.8 Hz, 1H), 7.20 (d, J = 8.8 Hz, 1H), 7.05 (d, J = 8.8 Hz, 1H), 5.58 (q, J = 6.8 Hz, 1H), 4.28 - 4.16 (m, 1H), 4.16 - 4.05 (m, 1H), 2.87 (td, J = 14.8, 19.6 Hz, 1H), 2.68 - 2.50 (m, 1H), 2.48 - 2.27 (m, 5H), 2.19 - 2.08 (m, 1H), 1.69 (d, J = 6.8 Hz, 3H). 19 F NMR (377 MHz, CD3OD) δ = -88.024, -88.632, -93.364, -93.978, -114.807.

[0534] Step C: A mixture of intermediate Q-2 (120 mg, 321 μmol, 1.00 eq., hydrochloride), methyl 6-chloro-3-fluoropicolinate (169 mg, 802 μmol, 2.50 eq.), and diisopropylethylamine (290 mg, 2.25 mmol, 391 μL, 7.00 eq.) in dimethylformamide (1.00 mL) was stirred at 90 °C for 12 h. After completion of the reaction, the reaction mixture was cooled to 25 °C and purified by preparative HPLC (column: Welch Xtimate C18 150 × 25 mm × 5 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 60%-80% acetonitrile over 10 min) to give the methyl picolinate product (78.0 mg, 154 μmol, 48% yield) as a white solid. LCMS [M+1] + = 507.0.

[0535] Step D: To a solution of methyl picolinate (78.0 mg, 154 μmol, 1.00 eq.) in methanol (1.00 mL) and tetrahydrofuran (1.00 mL), lithium hydroxide (2M aqueous solution, 300 μL, 3.90 eq.) was added. The mixture was stirred at 25°C for 1.5 hours. After completion of the reaction, the reaction solution was adjusted to pH 7 by adding formic acid and purified by preparative HPLC (column: Welch Xtimate C18 150 × 25 mm × 5 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 55%-75% acetonitrile over 10 min) to give Example 1-111 (37.9 mg, 76.7 μmol, 50% yield, 99.8% purity) as an off-white solid. LCMS [M+1] + = 493.1. 1 H NMR (400 MHz, CD3OD) δ = 7.74 (br dd, J = 2.8, 8.4 Hz, 1H), 7.54 (dd, J = 2.8, 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 7.04 (d, J = 8.8 Hz, 1H), 5.59 (q, J = 6.8 Hz, 1H), 4.24 - 4.15 (m, 1H), 4.15 - 4.06 (m, 1H), 2.98 - 2.81 (m, 1H), 2.63 - 2.48 (m, 1H), 2.47 - 2.27 (m, 5H), 2.21 - 2.10 (m, 1H), 1.70 (d, J = 6.8 Hz, 3H). 19 F NMR (377 MHz, CD3OD) δ = -88.4, -89.0, -93.4, -94.0, -114.8.

[0536] Intermediates R-1 and R-1 [ka]

[0537] Step A: To a solution of 7,7-difluoro-2-azaspiro[4.4]nonan-1-one (600 mg, 3.43 mmol, 1.00 eq.) in 1,2-dichloroethane (6.00 mL), diisopropylethylamine (1.33 g, 10.3 mmol, 1.79 mL, 3.00 eq.) and phosphorus oxychloride (1.05 g, 6.85 mmol, 639 μL, 2.00 eq.) were added. The mixture was stirred at 50°C for 1 h. The reaction mixture was then heated to 80°C, and 2-amino-3-bromo-5-chlorobenzoic acid (858 mg, 3.43 mmol, 1.00 eq.) was added as a solid to the mixture. The reaction mixture was stirred at 80°C for 30 min. After the reaction was complete, the reaction mixture was cooled to 25 °C, water (40.0 mL) was added, and the resulting aqueous solution was extracted with dichloromethane (40.0 mL × 3). The combined organic layers were washed with saturated brine (120 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent 0–50% ethyl acetate / petroleum ether, gradient, 36 mL / min) to give 5'-bromo-7'-chloro-3,3-difluoro-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (350 mg, 898 μmol, 26% yield) as a yellow solid. LCMS [M+1] + = 391.0. 1H NMR (400 MHz, CDCl3) δ = 8.22 (d, J = 2.0 Hz, 1H), 7.99 (d, J = 2.4 Hz, 1H), 4.28 - 4.02 (m, 2H), 3.03 - 2.82 (m, 1H), 2.72 - 2.51 (m, 1H), 2.45 - 2.25 (m, 5H), 2.13 - 1.99 (m, 1H)

[0538] Step B: A mixture of 5'-bromo-7'-chloro-3,3-difluoro-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (1.50 g, 3.85 mmol, 1.00 eq.), tributyl(1-ethoxyvinyl)tin (2.01 g, 5.57 mmol, 1.88 mL, 1.45 eq.), and bis(triphenylphosphine)palladium(II) chloride (270 mg, 385 μmol, 0.10 eq.) in dioxane (15.0 mL) was evacuated and backfilled with nitrogen three times and then stirred at 100 °C under a nitrogen atmosphere for 2 h. After completion of the reaction, the mixture was cooled to 25 °C, poured into saturated aqueous potassium fluoride solution (60.0 mL), and stirred for 1 h. The aqueous phase was extracted with dichloromethane (60.0 mL × 3), and the combined organic phase was washed with saturated brine (180.0 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 7'-chloro-5'-(1-ethoxyvinyl)-3,3-difluoro-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (1.40 g, crude) as a yellow oil. LCMS [M+1] + = 381.1.

[0539] Step C: To a solution of 7'-chloro-5'-(1-ethoxyvinyl)-3,3-difluoro-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (1.40 g, 3.68 mmol, 1.00 eq.) in acetone (14.0 mL) was added 4-toluenesulfonic acid monohydrate (699 mg, 3.68 mmol, 1.00 eq.). The mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was then dissolved in dichloromethane (80.0 mL), washed with saturated aqueous sodium bicarbonate (80.0 mL × 3) and saturated brine (80.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent 0-70% ethyl acetate / petroleum ether, gradient, 60 mL / min) to give 5'-acetyl-7'-chloro-3,3-difluoro-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (1.10 g, 3.12 mmol, 85% yield) as a yellow solid. LCMS [M+1] + = 353.1.

[0540] Step D: To a solution of 5'-acetyl-7'-chloro-3,3-difluoro-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one (1.00 g, 2.83 mmol, 1.00 eq.) in 2-methyltetrahydrofuran (11.0 mL) was added (R)-2-methylpropane-2-sulfinamide (1.03 g, 8.50 mmol, 3.00 eq.) and titanium(IV) ethoxide (2.39 g, 10.5 mmol, 2.17 mL, 3.70 eq.). The mixture was stirred at 80 °C for 12 h. After completion of the reaction, the reaction mixture was cooled to 25 °C, and water (0.80 mL) and dichloromethane (30 mL) were added. The reaction mixture was stirred for 30 min. The mixture was then filtered, and the filter cake was washed with dichloromethane (50.0 mL × 3). The combined organics were concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent 0–100% ethyl acetate / petroleum ether, gradient, 60 mL / min) to give (R)-N-(1-(7'-chloro-3,3-difluoro-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethylidene)-2-methylpropane-2-sulfinamide (1.20 g, 2.63 mmol, 93% yield) as a yellow solid. LCMS [M+1] + = 456.1.

[0541] Step E: To a solution of (R)-N-(1-(7'-chloro-3,3-difluoro-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethylidene)-2-methylpropane-2-sulfinamide (1.00 g, 2.19 mmol, 1.00 eq.) in dichloromethane (5.00 mL) and methanol (5.00 mL) was added acetic acid (1.32 g, 21.9 mmol, 1.26 mL, 10.0 eq.) and sodium cyanoborohydride (413 mg, 6.58 mmol, 3.00 eq.). The mixture was stirred at 0°C for 2 hours. After completion of the reaction, the pH was adjusted to approximately 7 with saturated aqueous sodium bicarbonate and diluted with dichloromethane (45.0 mL). The organic phase was separated, washed with saturated brine (40.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 (250 × 70 mm, 10 μm); mobile phase: [water (formic acid)-acetonitrile]; gradient: 45%-75% acetonitrile over 20 min) to give (R)-N-((1R)-1-(7'-chloro-3,3-difluoro-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)-2-methylpropane-2-sulfinamide (900 mg, 1.89 mmol, 86% yield, 96% purity) as a yellow solid. LCMS [M+1] + = 458.2. 1 H NMR (400 MHz, CDCl3) δ = 8.16 (d, J = 2.8 Hz, 1H), 7.61 (d, J = 2.4 Hz, 1H), 5.00 - 4.93 (m, 1H), 4.24 - 4.14 (m, 1H), 4.13 - 4.04 (m, 1H), 2.95 - 2.73 (m, 1H), 2.63 - 2.44 (m, 1H), 2.42 - 2.24 (m, 5H), 2.11 - 2.06 (m, 1H), 1.63 (dd, J = 1.6, 6.4 Hz, 3H), 1.22 (d, J = 3.6 Hz, 9H).

[0542] Step F: (R)-N-((1R)-1-(7'-chloro-3,3-difluoro-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)-2-methylpropane-2-sulfinamide (900 mg, 1.89 mmol) was purified by SFC (Regis(S,S)WHELK-O1 column, 250 mm × 25 mm, 10 μm; isocratic elution, acetonitrile / isopropanol (0.1% ammonium hydroxide) in 50% carbon dioxide). The desired fractions of the first peak were pooled and concentrated to give the first-eluting isomer (400 mg, 873 μmol, 46% yield, 99.9% purity) as a yellow solid. Isocratic elution was continued and the desired fractions of the second peak were collected to give the second eluting isomer (420 mg, 824 μmol, 44% yield, 90% purity) as a yellow solid.

[0543] Step G: To a solution of the first-eluting isomer (150 mg, 327 μmol, 1.00 eq.) in ethyl acetate (1.50 mL) was added a solution of hydrochloric acid in ethyl acetate (2.00 M, 1.50 mL, 9.16 eq.). The mixture was stirred at 25°C for 30 minutes. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give Intermediate R-1 (120 mg, 307 μmol, 94% yield, HCl) as a yellow solid. LCMS [M+1] + = 354.1.

[0544] Step H: To a solution of the second-eluting isomer (150 mg, 294 μmol, 1.00 eq.) in ethyl acetate (1.50 mL) was added a solution of hydrochloric acid in ethyl acetate (2.00 M, 1.47 mL, 10.0 eq.). The mixture was stirred at 25°C for 30 minutes. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give intermediate R-2 (100 mg, 256 μmol, 87% yield, HCl) as a white solid. LCMS [M+1] + = 354.2.

[0545] Examples 1-112 and 1-113 6-chloro-3-(((R)-1-((S)-7'-chloro-3,3-difluoro-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid and 6-chloro-3-(((R)-1-((R)-7'-chloro-3,3-difluoro-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid [ka]

[0546] Step A: To a solution of intermediate R-1 (120 mg, 307 μmol, 1.00 eq., HCl) in N,N-dimethylformamide (1.00 mL), methyl 6-chloro-3-fluoro-pyridine-2-carboxylate (146 mg, 769 μmol, 2.50 eq.) and diisopropylethylamine (119 mg, 922 μmol, 161 μL, 3.00 eq.) were added. The mixture was stirred at 90 °C for 12 h. After the reaction was complete, 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 saturated brine (30.0 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, eluent 0-50% ethyl acetate / petroleum ether, gradient, 60 mL / min) to afford the methyl picolinic acid product (80.0 mg, 153 μmol, 50% yield) as a yellow solid. LCMS [M+23] + = 545.2.

[0547] Step B: To a solution of methyl picolinate (80.0 mg, 153 μmol, 1.00 eq.) in tetrahydrofuran (0.50 mL) and methanol (0.50 mL), lithium hydroxide (2.00 M, 153 μL, 2.00 eq.) was added. The mixture was stirred at 25°C for 2 hours. After completion of the reaction, the reaction mixture was adjusted to pH 7.0 with formic acid and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18 150 × 30 mm × 7 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 55%-85% acetonitrile over 10 min) to obtain Example 1-112 (35.1 mg, 68.8 μmol, 45% yield, 99.9% purity) as an off-white solid. LCMS [M+1] + = 509.1.7 1 H NMR (400 MHz, CDCl3) δ = 11.21 - 10.05 (m, 1H), 8.36 (br d, J = 6.4 Hz, 1H), 8.18 (d, J = 2.4 Hz, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.15 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 5.49 (quin, J = 6.8 Hz, 1H), 4.28 - 4.18 (m, 1H), 4.17 - 4.07 (m, 1H), 2.93 - 2.77 (m, 1H), 2.70 - 2.53 (m, 1H), 2.45 - 2.30 (m, 5H), 2.10 (br dd, J = 6.8, 12.0 Hz, 1H), 1.68 (d, J = 6.8 Hz, 3H).

[0548] Step C: To a solution of intermediate R-2 (100 mg, 256 μmol, 1.00 eq., HCl) in N,N-dimethylformamide (1.00 mL), methyl 6-chloro-3-fluoro-pyridine-2-carboxylate (121 mg, 641 μmol, 2.50 eq.) and diisopropylethylamine (99.4 mg, 769 μmol, 134 μL, 3.00 eq.) were a...

Claims

1. Formula (I): 【Chemistry 1】 (I) [In the formula, R 1 is H, C 1 -C 3 Alkyl, or C 3 -C 6 is cycloalkyl; R 2 is a phenyl or 5-6 membered heteroaryl group, where each phenyl and heteroaryl is selected from 1-5 R 7 optionally substituted with; Each R 7 independently, C 1 -C 4 Alkyl; -OR A , -C(O)OR A , (C 1 -C 3 alkyl)-OR A , -C(O)N(R B ) 2 , cyano, halogen or tetrazolyl; Each R A are independently H, C 1 -C 6 Alkyl, or C 3 -C 6 is cycloalkyl; Each R B are independently H, -OH, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or C 3 -C 6 is cycloalkyl; and R 3 Fluorocarbons, C 3 -C 6 Cycloalkyl, C 2 -C 3 Alkenyl, C 2 -C 3 Alkynyl, or C 5 -C 6 C optionally substituted, polysubstituted or persubstituted with cycloalkenyl 1 -C 3 is alkyl; R 4 is H, C 1 -C 3 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkyloxy, C 2 -C 3 Alkenyl, C 2 -C 3 Alkynyl, or C 5 -C 6 cycloalkenyl, cyano, or halo, where each C 1 -C 3 Alkyl and C 3 -C 6 Each cycloalkyl is optionally substituted with 1-5 halo groups; 【Chemistry 2】 (Formula (Z)) is the following formula (D), (G), (J) or (K): 【Transformation 3】 (Formula (D)), 【Chemistry 4】 (Formula (G)), 【Transformation 5】 (Formula (J)) or 【Transformation 6】 (Formula (K)) (In the formula, Each ring A is a 3-8 membered carbocyclic ring or a 3-7 membered heterocyclic ring; m is 0, 1, 2, 3, 4 or 5; p and r are independently 1 or 2, with the proviso that the sum of p and r is 2 or 3; Each R 5 independently, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen, cyano, hydroxy, hydroxy C 1 -C 6 Alkyl, amino, mono or di(C 1 -C 6 Alkyl)amino, C 3 -C 6 cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein the cycloalkyl, phenyl, and heteroaryl each contain 1-3 of halogen, hydroxy, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, cyano, amino, or mono- or di-(C 1 -C 3 ) optionally substituted with alkylamino; n is 0, 1 or 2; t is 0, 1, 2, 3 or 4; Each R 8 independently, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, cyano, hydroxy, oxo, halogen, halo(C 1 -C 6 ) Alkyl, Hydroxy C 1 -C 6 Alkyl, amino, or mono- or di-(C 1 -C 6 alkyl)amino; and Each R 10 independently, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, cyano, hydroxy, oxo, halogen, halo(C 1 -C 6 ) Alkyl, Hydroxy C 1 -C 6 Alkyl, amino, or mono- or di-(C 1 -C 6 alkyl)amino, R 11 , R 12 , R 13 , R 14 , R 15 or R 16 where: R 11 is an aryl or aryl(C 1 -C 6 ) alkyl, where each aryl is a group consisting of up to four C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, cyano, hydroxy, oxo, halogen, halo(C 1 -C 6 ) Alkyl, Hydroxy C 1 -C 6 Alkyl, amino, or mono- or di-(C 1 -C 6 alkyl)amino, independently optionally substituted; R 12 is a 5-8 membered heteroaryl or a 5-8 membered heteroaryl (C 1 -C 6 ) alkyl, wherein each heteroaryl is selected from up to four C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, cyano, hydroxy, oxo, halogen, halo(C 1 -C 6 ) Alkyl, Hydroxy C 1 -C 6 Alkyl, amino, or mono- or di-(C 1 -C 6 alkyl)amino, independently optionally substituted; R 13 is an aryl (C 1 -C 6 ) alkoxy, aryl (C 1 -C 6 )Alkoxy(C 1 -C 6 ) alkyl, aryl (C 1 -C 6 ) alkylamino or aryl (C 1 -C 6 ) Alkylamino(C 1 -C 6 ) alkyl, where each aryl is a group consisting of up to four C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, cyano, hydroxy, oxo, halogen, halo(C 1 -C 6 ) Alkyl, Hydroxy C 1 -C 6 Alkyl, amino, or mono- or di-(C 1 -C 6 alkyl)amino, independently optionally substituted; R 14 is a 5-8 membered heteroaryl (C 1 -C 6 ) alkoxy, 5-8 membered heteroaryl (C 1 -C 6 )Alkoxy(C 1 -C 6 ) alkyl, 5-8 membered heteroaryl (C 1 -C 6 ) alkylamino or 5-8 membered heteroaryl (C 1 -C 6 ) Alkylamino(C 1 -C 6 ) alkyl, wherein each of up to four heteroaryls is C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, cyano, hydroxy, oxo, halogen, halo(C 1 -C 6 ) Alkyl, Hydroxy C 1 -C 6 Alkyl, amino, or mono- or di-(C 1 -C 6 alkyl)amino, independently optionally substituted; R 15 is (C 1 -C 6 ) cycloalkyl or (C 1 -C 6 ) Cycloalkyl(C 1 -C 6 ) alkyl, where each cycloalkyl is a group having up to four C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, cyano, hydroxy, oxo, halogen, halo(C 1 -C 6 ) Alkyl, Hydroxy C 1 -C 6 Alkyl, amino, or mono- or di-(C 1 -C 6 alkyl)amino, independently optionally substituted; and R 16 is (C 1 -C 6 ) Cycloalkyl(C 1 -C 6 ) alkoxy, (C 1 -C 6 ) Cycloalkyl(C 1 -C 6 )Alkoxy(C 1 -C 6 ) alkyl, (C 1 -C 6 ) Cycloalkyl(C 1 -C 6 ) alkylamino or (C 1 -C 6 ) Cycloalkyl(C 1 -C 6 ) Alkylamino(C 1 -C 6 ) alkyl, where each cycloalkyl is a group having up to four C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, cyano, hydroxy, oxo, halogen, halo(C 1 -C 6 ) Alkyl, Hydroxy C 1 -C 6 Alkyl, amino, or mono- or di-(C 1 -C 6 (alkyl)amino, independently optionally substituted) or a pharmaceutically acceptable salt thereof, or a deuterated version thereof.

2. The compound of claim 1 , wherein formula (Z) represents formula (D):

3. The compound of claim 1 , wherein formula (Z) represents formula (G):

4. The compound of claim 1 , wherein formula (Z) represents formula (J):

5. The compound of claim 1 , wherein formula (Z) represents formula (K):

6. The compound according to any one of claims 1 to 5, wherein ring A is a 5-7 membered carbocyclic ring.

7. The compound according to any one of claims 1 to 5, wherein ring A is a 5-7 membered heterocyclic ring.

8. The compound according to any one of claims 1 to 5, wherein ring A is cyclohexyl, cyclopentyl, pyranyl or azetidinyl.

9. R 1 is H or CH 3 The compound according to any one of claims 1 to 6,

10. R 2 is phenyl, pyridinyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyrazinyl, pyridazinyl, or pyrimidinyl, each of which is selected from 1 to 5 R 7 10. The compound of any one of claims 1 to 9, optionally substituted with

11. R 2 is phenyl or pyridinyl, each of which has 1-5 R 7 10. The compound of any one of claims 1 to 9, optionally substituted with

12. R 2 is phenyl or 5-7 membered heteroaryl, each of which is 1, 2, or 3 R 7 The compound of any one of claims 1 to 9, substituted with a group.

13. R 2 is phenyl or 5-7 membered heteroaryl, each of which is 1, 2, or 3 R 7 group and at least one R 7 The group is -C(O)OR A The compound according to any one of claims 1 to 9,

14. The compound of any one of claims 1 to 13, wherein the alkyl group is unsubstituted, substituted with 1-5 halo groups, or perfluorinated.

15. m is 1 or 2, and each R 5 is a halogen, C 3 -C 6 cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein each cycloalkyl, phenyl, and heteroaryl is selected from the group consisting of 1-3 halogen, hydroxy, C 1 -C 2 Alkyl, C 1 -C 2 Alkoxy, cyano, amino, or mono- or di-(C 1 -C 2 14. The compound of any one of claims 1 to 13, optionally substituted with alkylamino.

16. m is 1 or 2, and each R 5 is a halogen, C 3 -C 6 cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein each cycloalkyl, phenyl, and heteroaryl is selected from the group consisting of 1 or 2 halogen atoms, hydroxy, C 1 -C 2 Alkyl, C 1 -C 2 Alkoxy, cyano, amino, or mono- or di-(C 1 -C 2 14. The compound of any one of claims 1 to 13, optionally substituted with alkylamino.

17. m is 0, 1, or 2, and each R 5 The compound of any one of claims 1 to 14, wherein is halogen, hydroxy, cyano or amino.

18. R 2 The compound of any one of claims 1 to 16, wherein is optionally substituted with phenyl.

19. R 2 The compound of any one of claims 1 to 16, wherein is optionally substituted with pyridinyl.

20. R 4 is hydrogen, methyl, methoxy, ethyl, ethoxy, fluoro, bromo, chloro, cyclopropyl, trifluoromethyl or cyano.

21. R 8 is hydrogen or C 1 -C 6 The compound of any one of claims 1 to 20, which is alkyl.

22. The compound may be represented by the following formula (IIa-1), (IIa-2), (IIa-3), (IIb-1), (IIb-2), (IIb-3), (IIc-1), (IIc-2), (IIc-3), (IId-1), (IId-2), or (IId-3): 【Transformation 7】 【Transformation 8】 [In the formula, R 1 is H, C 1 -C 3 Alkyl, or C 3 -C 6 is cycloalkyl; R 2 is phenyl or pyridinyl, where each phenyl and pyridinyl is selected from 1-5 R 7 optionally substituted with; Each R 7 independently, C 1 -C 4 Alkyl; -OR A , -C(O)OR A , (C 1 -C 3 alkyl)-OR A , -C(O)N(R B ) 2 , cyano, halogen or tetrazolyl; Each R A are independently H, C 1 -C 6 Alkyl, or C 3 -C 6 is cycloalkyl; Each R B are independently H, -OH, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or C 3 -C 6 is cycloalkyl; and R 3 is C 1 -C 3 Alkyl or C 3 -C 6 is cycloalkyl; R 4 is H, C 1 -C 3 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 6 cycloalkyl, cyano, or halo, where each C 1 -C 3 The alkyl is optionally substituted with 1-5 halo groups; m is 0, 1, 2, 3, 4 or 5; Each R 5 independently, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen, cyano, hydroxy, hydroxy C 1 -C 6 Alkyl, amino, or mono- or di-(C 1 -C 6 Alkyl)amino, C 3 -C 6 cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein each cycloalkyl, phenyl, and heteroaryl is selected from the group consisting of 1-3 halogen, hydroxy, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, cyano, amino, or mono- or di-(C 1 -C 3 ) optionally substituted with alkyl amino; where R 5 Each non-spiro carbon in the ring having the formula: may be replaced with a heteroatom which is nitrogen, oxygen, or sulfur; n is 0, 1 or 2; and Each R 8 independently, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, cyano, hydroxy, halogen, oxo, hydroxyC 1 -C 6 Alkyl, amino, or mono- or di-(C 1 -C 6 alkyl)amino] 2. The compound of claim 1, which is: or a pharmaceutically acceptable salt thereof.

23. m is 0, 1, or 2, and each R 5 is independently halogen, hydroxy, cyano, or amino.

24. n is 0 or 1, and each R 8 is halogen, hydroxy, cyano or amino.

25. R 3 is C 1 -C 3 The compound according to any one of claims 22 to 24, which is alkyl.

26. R 3 The compound according to any one of claims 22 to 24, wherein is methyl.

27. R 4 is H, C 1 -C 3 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 4 The compound of any one of claims 22 to 26, which is cycloalkyl, halo, trifluoromethyl or cyano.

28. The compound may be represented by the following formula (IIb-1A), (IIb-1B), (IIc-1A), (IIc-1B), (IId-1A) or (IId-1B): 【Chemistry 9】 【Chemistry 10】 [In the formula, R 1 is H, C 1 -C 3 Alkyl, or C 3 -C 6 is cycloalkyl; R 2 is phenyl or pyridinyl, where phenyl and pyridinyl each have 1-5 R 7 optionally substituted with; Each R 7 independently, C 1 -C 4 Alkyl; -OR A , -C(O)OR A , (C 1 -C 3 alkyl)-OR A , -C(O)N(R B ) 2 , cyano, halogen or tetrazolyl; Each R A are independently H, C 1 -C 6 Alkyl, or C 3 -C 6 is cycloalkyl; Each R B are independently H, -OH, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or C 3 -C 6 is cycloalkyl; and R 3 is C 1 -C 3 Alkyl or C 3 -C 6 is cycloalkyl; R 4 is H, C 1 -C 3 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 6 cycloalkyl, cyano, or halo, where each C 1 -C 3 The alkyl is optionally substituted with 1-5 halo groups; m is 0 or 1; Each R 5 independently, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen, cyano, hydroxy, hydroxy C 1 -C 6 Alkyl, amino, or mono- or di-(C 1 -C 6 Alkyl)amino, C 3 -C 6 cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein each cycloalkyl, phenyl, and heteroaryl is selected from the group consisting of 1-3 halogen, hydroxy, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, cyano, amino, or mono- or di-(C 1 -C 3 ) optionally substituted with alkyl amino; R 9 is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen, cyano, hydroxy, hydroxy C 1 -C 6 Alkyl, amino, or mono- or di-(C 1 -C 6 Alkyl)amino, C 3 -C 6 cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein each cycloalkyl, phenyl, and heteroaryl is selected from the group consisting of 1-3 halogen, hydroxy, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, cyano, amino, or mono- or di-(C 1 -C 3 ) optionally substituted with alkylamino; n is 0, 1 or 2; and Each R 8 independently, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, cyano, hydroxy, halogen, oxo, hydroxyC 1 -C 6 Alkyl, amino, or mono- or di-(C 1 -C 6 alkyl)amino.

2. The compound of claim 1, which is: or a pharmaceutically acceptable salt thereof.

29. m is 0, 1, or 2, and each R 5 independently, C 1 -C 6 Alkyl or hydroxy C 1 -C 6 29. The compound of claim 28, wherein the compound is alkyl.

30. n is 0 or 1, and each R 8 30. The compound of claim 28 or claim 29, wherein is halogen, hydroxy, cyano or amino.

31. R 3 is C 1 -C 3 The compound according to any one of claims 28 to 30, which is alkyl.

32. R 3 The compound according to any one of claims 28 to 31, wherein is methyl.

33. R 4 is H, C 1 -C 3 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 4 The compound of any one of claims 28 to 32, which is cycloalkyl, halo, trifluoromethyl or cyano.

34. The compound has the following formula (IIIa) or (IIIb): 【Chemistry 11】 [In the formula, R 1 is H, C 1 -C 3 Alkyl, or C 3 -C 6 is cycloalkyl; R 2 is phenyl or pyridinyl, where phenyl and pyridinyl each have 1-5 R 7 optionally substituted with; Each R 7 independently, C 1 -C 4 Alkyl; -OR A , -C(O)OR A , (C 1 -C 3 alkyl)-OR A , -C(O)N(R B ) 2 , cyano, halogen or tetrazolyl; Each R A are independently H, C 1 -C 6 Alkyl, or C 3 -C 6 is cycloalkyl; Each R B are independently H, -OH, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or C 3 -C 6 is cycloalkyl; and R 3 is C 1 -C 3 Alkyl or C 3 -C 6 is cycloalkyl; and R 4 is H, C 1 -C 3 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 6 cycloalkyl, cyano, or halo, where each C 1 -C 3 The alkyl is optionally substituted with 1 to 5 halo groups.

2. The compound of claim 1, which is: or a pharmaceutically acceptable salt thereof.

35. Each R 10 independently, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, cyano, hydroxy, oxo, halogen, halo(C 1 -C 6 ) Alkyl, Hydroxy C 1 -C 6 Alkyl, amino, or mono- or di-(C 1 -C 6 35. The compound of claim 1 or claim 34, wherein:

36. 35. The compound of claim 34, wherein t is 1.

37. t is 2 and both R 10 35. The compound of claim 34, wherein the groups are attached to the same carbon atom.

38. t is 2 and R 10 35. The compound of claim 34, wherein the groups are attached to different carbon atoms.

39. Each R 10 independently, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, cyano, hydroxy, oxo, halogen, halo(C 1 -C 3 ) Alkyl, Hydroxy C 1 -C 3 Alkyl, amino, or mono- or di-(C 1 -C 3 The compound of any one of claims 34 to 38, which is (alkyl)amino.

40. Each R 10 independently, C 1 -C 2 Alkyl, C 1 -C 2 Alkoxy, cyano, hydroxy, halogen, or halo(C 1 -C 2 39. The compound according to any one of claims 34 to 38, wherein:

41. Each R 10 independently, C 1 -C 2 39. The compound of any one of claims 34 to 38, which is alkyl, chloro, fluoro, fluoromethyl, difluoromethyl, or trifluoromethyl.

42. R 10 is C 1 -C 2 37. The compound of claim 36, which is alkyl, chloro, fluoro, fluoromethyl, difluoromethyl, or trifluoromethyl.

43. Both R 10 The groups are identical and C 1 -C 2 38. The compound of claim 37, which is alkyl, chloro, fluoro, or fluoromethyl.

44. t is 1 and R 10 is R 11 , R 12 , R 13 , R 14 , R 15 , or R 16 35. The compound of claim 1 or claim 34, wherein:

45. t is 2, while R 10 is C 1 -C 6 Alkyl, halogen or halo(C 1 -C 2 ) alkyl, and the other is R 11 , R 12 , R 13 , R 14 , R 15 , or R 16 35. The compound of claim 1 or claim 34, wherein:

46. t is 1 and R 10 is R 11 35. The compound of claim 1 or claim 34, wherein:

47. t is 1 and R 10 is R 12 35. The compound of claim 1 or claim 34, wherein:

48. t is 1 and R 10 is R 13 35. The compound of claim 1 or claim 34, wherein:

49. t is 1 and R 10 is R 14 35. The compound of claim 1 or claim 34, wherein:

50. t is 1 and R 10 is R 15 35. The compound of claim 1 or claim 34, wherein:

51. t is 1 and R 10 is R 16 35. The compound of claim 1 or claim 34, wherein:

52. R 10 is R 11 or R 12 The compound according to any one of claims 46 to 51,

53. R 11 and R 12 is unsubstituted.

54. R 11 and R 12 is C 1 -C 2 53. The compound of claim 52, substituted with alkyl, bromo, chloro, fluoro, fluoromethyl, difluoromethyl, or trifluoromethyl.

55. t is 2, while R 10 is C 1 -C 6 Alkyl, halogen or halo(C 1 -C 2 ) alkyl, and the other is R 11 where R 11 is phenyl (C 1 -C 6 ) alkyl, wherein the phenyl is selected from the group consisting of 1, 2 or 3 C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, cyano, hydroxy, oxo, halogen, halo(C 1 -C 6 ) Alkyl, Hydroxy C 1 -C 6 Alkyl, amino, or mono- or di-(C 1 -C 6 35. The compound of claim 1 or claim 34, optionally substituted with (alkyl)amino.

56. t is 2, while R 10 is C 1 -C 6 Alkyl, halogen or halo(C 1 -C 2 ) alkyl, and the other is R 11 where R 11 is a 5- or 6-membered heteroaryl (C 1 -C 6 ) alkyl, wherein the heteroaryl is selected from 1, 2, or 3 C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, cyano, hydroxy, oxo, halogen, halo(C 1 -C 6 ) Alkyl, Hydroxy C 1 -C 6 Alkyl, amino, or mono- or di-(C 1 -C 6 35. The compound of claim 1 or claim 34, optionally substituted with (alkyl)amino.

57. 57. The compound of claim 56, wherein the heteroaryl is optionally substituted with pyridyl, thiazolyl, imidazolyl, oxazolyl, or isoxazolyl.

58. The following compounds: (R)-2-((1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; 2-((1-(9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; 2-((1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; 2-((1-(7'-bromo-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; (R)-2-((1-(7'-cyclopropyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; (R)-2-((1-(4,4-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; (R)-2-((1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; (R)-2-((1-(7'-cyano-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; (R)-2-((1-(7'-methyl-9'-oxo-1',2,2',3,5,6-hexahydro-9'H-spiro[pyran-4,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; or (R)-5-fluoro-2-((1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; (R)-2-((1-(4,4-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)-5-fluorobenzoic acid; (R)-4-((1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)pyrazine-3-carboxylic acid; (R)-6-chloro-3-((1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(4,4-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; (R)-3-((1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)pyrazine-2-carboxylic acid; (R)-4-((1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)thiazole-5-carboxylic acid; (R)-4-((1-(4,4-difluoro-7'-methyl-5'-oxo-2',3'-dihydro-5'H-spiro[cyclohexane-1,1'-pyrrolo[1,2-b]isoquinoline]-9'-yl)ethyl)amino)thiazole-5-carboxylic acid; (R)-4-((1-(4,4-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)pyrazine-3-carboxylic acid; (R)-5-((1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)thiazole-4-carboxylic acid; (R)-5-((1-(4,4-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)thiazole-4-carboxylic acid; (R)-3-((1-(4,4-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)pyrazine-2-carboxylic acid; (R)-6-chloro-3-((1-(7'-methyl-9'-oxo-1',2,2',3,5,6-hexahydro-9'H-spiro[pyran-4,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; (R)-2-((1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; (R)-2-((1-(7'-methyl-9'-oxo-3',9'-dihydro-1'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; (R)-2-((1-(7'-methyl-9'-oxo-1-phenyl-1',2'-dihydro-9'H-spiro[azetidine-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; (R)-2-((1-(1-(4-cyanophenyl)-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[azetidine-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; (R)-2-((1-(1-(4-cyano-2-methylphenyl)-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[azetidine-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2'-methyl-10'-oxo-7',8'-dihydro-10'H-spiro[cyclopentane-1,6'-pyrido[3,2-d]pyrrolo[1,2-a]pyrimidin]-4'-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2'-methyl-11'-oxo-8',9'-dihydro-7'H,11'H-spiro[cyclopentane-1,6'-pyrido[2,1-b]quinazoline]-4'-yl)ethyl)amino)benzoic acid; (R)-2-((1-(4,4-difluoro-2'-methyl-10'-oxo-7',8'-dihydro-10'H-spiro[cyclohexane-1,6'-pyrido[3,2-d]pyrrolo[1,2-a]pyrimidin]-4'-yl)ethyl)amino)benzoic acid; 2-((1-(7-methyl-9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-5-yl)ethyl)amino)benzoic acid; 2-((1-(3,3-difluoro-7-methyl-9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-5-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,3-diethyl-7-methyl-9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-5-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,3,7-trimethyl-9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-5-yl)ethyl)amino)benzoic acid; (R)-6-chloro-3-((1-(3,3,7-trimethyl-9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-5-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; (R)-6-chloro-4-((1-(4,4-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)pyrazine-3-carboxylic acid; (R)-2-((1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopropane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; (R)-3-((1-(3,3,7-trimethyl-9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-5-yl)ethyl)amino)pyrazine-2-carboxylic acid; (R)-5-((1-(7'-methyl-9'-oxo-1',2,2',3,5,6-hexahydro-9'H-spiro[pyran-4,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)thiazole-4-carboxylic acid; (R)-3-((1-(7'-methyl-9'-oxo-1',2,2',3,5,6-hexahydro-9'H-spiro[pyran-4,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)pyrazine-2-carboxylic acid; (R)-2-((1-(7'-cyclopropyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; (R)-6-chloro-3-((1-(7'-cyclopropyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 2-(((R)-1-((S)-3-benzyl-3,7-dimethyl-9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-5-yl)ethyl)amino)benzoic acid; 2-(((R)-1-((R)-3-benzyl-3,7-dimethyl-9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-5-yl)ethyl)amino)benzoic acid; (R)-6-chloro-3-((1-(10'-oxo-7',8'-dihydro-10'H-spiro[cyclobutane-1,6'-pyrido[4,3-d]pyrrolo[1,2-a]pyrimidin]-4'-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(7'-cyclopropyl-4,4-difluoro-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(7'-fluoro-9'-oxo-1',2,2',3,5,6-hexahydro-9'H-spiro[pyran-4,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; (R)-3-((1-(7'-fluoro-9'-oxo-1',2,2',3,5,6-hexahydro-9'H-spiro[pyran-4,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)-6-methylpicolinic acid; (R)-2-((1-(7'-fluoro-9'-oxo-1',2,2',3,5,6-hexahydro-9'H-spiro[pyran-4,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; (R)-2-((1-(7'-chloro-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; (R)-6-chloro-3-((1-(7'-chloro-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(7'-cyclopropyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; (R)-2-((1-(3,3-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; (R)-6-chloro-3-((1-(3,3-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; (R)-2-((1-(7'-chloro-3,3-difluoro-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,3-difluoro-9'-oxo-7'-(trifluoromethyl)-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; (R)-6-chloro-3-((1-(3,3-difluoro-9'-oxo-7'-(trifluoromethyl)-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 2-(((R)-1-((S)-2,2-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; 2-(((R)-1-((R)-2,2-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; (R)-2-((1-(7'-ethyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; (R)-2-((1-(7'-ethyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; (R)-6-chloro-3-((1-(7'-ethyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 2-(((R)-1-((S)-3,3-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; 2-(((R)-1-((R)-3,3-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; 6-chloro-3-(((R)-1-((S)-2,2-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((R)-1-((R)-2,2-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 2-(((1R)-1-(3,7-dimethyl-9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-5-yl)ethyl)amino)benzoic acid; (R)-2-((1-(7'-methoxy-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(3,7-dimethyl-9-oxo-3-(4-(trifluoromethyl)benzyl)-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-5-yl)ethyl)amino)benzoic acid; (R)-6-chloro-3-((1-(7'-methoxy-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; (R)-2-((1-(3,3-difluoro-7'-methoxy-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,3,7'-trifluoro-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; (R)-2-((1-(7'-ethyl-3,3-difluoro-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; (R)-6-chloro-3-((1-(3,3-difluoro-7'-methoxy-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(3,3,7'-trifluoro-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(7'-ethyl-3,3-difluoro-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 2-(((R)-1-((R)-1',7'-dimethyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; 2-(((R)-1-((S)-1',7'-dimethyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; 2-(((R)-1-((R)-1',7'-dimethyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; 2-(((R)-1-((S)-1',7'-dimethyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; 6-chloro-3-(((R)-1-((R)-1',7'-dimethyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((R)-1-((S)-1',7'-dimethyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; (R)-2-((1-(7-methyl-9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-5-yl)ethyl)amino)benzoic acid; (R)-6-chloro-3-((1-(7'-methoxy-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((1R)-1-(7-methyl-9-oxo-3-(4-(trifluoromethyl)benzyl)-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-5-yl)ethyl)amino)picolinic acid; 3-(((R)-1-((R)-3,3-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 3-(((R)-1-((S)-3,3-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((R)-1-((R)-7'-ethyl-3,3-difluoro-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((R)-1-((S)-7'-ethyl-3,3-difluoro-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 2-((1-(3,3-difluoro-7-methyl-9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-5-yl)ethyl)amino)benzoic acid; (R)-3-((1-(4,4-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)thiophene-2-carboxylic acid; (R)-2-((1-(4,4-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclohexane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)thiophene-3-carboxylic acid; (R)-3-((1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)pyrazine-2-carboxylic acid; (R)-5-((1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)thiazole-4-carboxylic acid; 3-(((R)-1-((R)-3-benzyl-3,7-dimethyl-9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-5-yl)ethyl)amino)-6-chloropicolinic acid; 3-(((R)-1-((S)-3-benzyl-3,7-dimethyl-9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-5-yl)ethyl)amino)-6-chloropicolinic acid; (R)-2-((1-(10'-oxo-7',8'-dihydro-10'H-spiro[cyclobutane-1,6'-pyrido[4,3-d]pyrrolo[1,2-a]pyrimidin]-4'-yl)ethyl)amino)benzoic acid; (R)-7'-Fluoro-5'-(1-((3-(hydroxymethyl)phenyl)amino)ethyl)-1',2,2',3,5,6-hexahydro-9'H-spiro[pyran-4,3'-pyrrolo[2,1-b]quinazolin]-9'-one (R)-6-methyl-3-((1-(7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(7'-chloro-3,3-difluoro-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((R)-1-((R)-3,3-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((R)-1-((S)-3,3-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((R)-1-((R)-1',7'-dimethyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((R)-1-((S)-1',7'-dimethyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((1R)-1-(2,2-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((R)-1-((R)-2,2-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((R)-1-((S)-7'-methyl-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((R)-1-((R)-7'-methyl-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((R)-1-((S)-3,3,7'-trifluoro-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((R)-1-((R)-3,3,7'-trifluoro-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((R)-1-((S)-7'-chloro-3,3-difluoro-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((R)-1-((R)-7'-chloro-3,3-difluoro-9'-oxo-1',2'-dihydro-9'H-spiro[cyclopentane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 2-(((R)-1-((R)-3,3-difluoro-1',7'-dimethyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; 2-(((R)-1-((S)-3,3-difluoro-1',7'-dimethyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; 6-chloro-3-(((R)-1-((R)-3,3-difluoro-1',7'-dimethyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((R)-1-((S)-3,3-difluoro-1',7'-dimethyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 2-(((R)-1-((R)-1'-ethyl-3,3-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; 2-(((R)-1-((S)-1'-ethyl-3,3-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; 6-chloro-3-(((R)-1-((R)-1'-ethyl-3,3-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((R)-1-((S)-1'-ethyl-3,3-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 2-(((R)-1-((S)-3,3-difluoro-7'-methyl-9'-oxo-1'-(trifluoromethyl)-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; 2-(((R)-1-((R)-3,3-difluoro-7'-methyl-9'-oxo-1'-(trifluoromethyl)-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; 6-chloro-3-(((R)-1-((S)-3,3-difluoro-7'-methyl-9'-oxo-1'-(trifluoromethyl)-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((R)-1-((R)-3,3-difluoro-7'-methyl-9'-oxo-1'-(trifluoromethyl)-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 2-(((R)-1-((R)-7'-chloro-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; 2-(((R)-1-((S)-7'-chloro-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; 6-chloro-3-(((R)-1-((R)-7'-chloro-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((R)-1-((S)-7'-chloro-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 2-(((R)-1-((R)-7'-fluoro-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; 2-(((R)-1-((S)-7'-fluoro-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; 6-chloro-3-(((R)-1-((R)-7'-fluoro-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((R)-1-((S)-7'-fluoro-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 2-(((R)-1-((1'R,3R)-1',7'-dimethyl-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; 2-(((R)-1-((1'S,3R)-1',7'-dimethyl-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; 2-(((R)-1-((1'R,3S)-1',7'-dimethyl-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; 2-(((R)-1-((1'S,3S)-1',7'-dimethyl-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; 6-chloro-3-(((R)-1-((1'R,3R)-1',7'-dimethyl-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((R)-1-((1'S,3R)-1',7'-dimethyl-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((R)-1-((1'R,3S)-1',7'-dimethyl-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((R)-1-((1'S,3S)-1',7'-dimethyl-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 2-(((R)-1-((1'R,3R)-1'-ethyl-7'-methyl-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; 2-(((R)-1-((1'S,3R)-1'-ethyl-7'-methyl-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; 2-(((R)-1-((1'R,3S)-1'-ethyl-7'-methyl-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; 2-(((R)-1-((1'S,3S)-1'-ethyl-7'-methyl-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; 6-chloro-3-(((R)-1-((1'R,3R)-1'-ethyl-7'-methyl-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((R)-1-((1'S,3R)-1'-ethyl-7'-methyl-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((R)-1-((1'R,3S)-1'-ethyl-7'-methyl-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((R)-1-((1'S,3S)-1'-ethyl-7'-methyl-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 2-(((R)-1-((1'S,3R)-7'-methyl-9'-oxo-1'-(trifluoromethyl)-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; 2-(((R)-1-((1'R,3R)-7'-methyl-9'-oxo-1'-(trifluoromethyl)-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; 2-(((R)-1-((1'S,3S)-7'-methyl-9'-oxo-1'-(trifluoromethyl)-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; 2-(((R)-1-((1'R,3S)-7'-methyl-9'-oxo-1'-(trifluoromethyl)-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoic acid; 6-chloro-3-(((R)-1-((1'S,3R)-7'-methyl-9'-oxo-1'-(trifluoromethyl)-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((R)-1-((1'R,3R)-7'-methyl-9'-oxo-1'-(trifluoromethyl)-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((R)-1-((1'S,3S)-7'-methyl-9'-oxo-1'-(trifluoromethyl)-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((R)-1-((1'R,3S)-7'-methyl-9'-oxo-1'-(trifluoromethyl)-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinic acid; (R)-4-((1-(3,3-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)thiophene-3-carboxylic acid; (R)-4-((1-(3,3-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)isothiazole-3-carboxylic acid; 4-(((R)-1-((R)-7'-methyl-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)thiophene-3-carboxylic acid; 4-(((R)-1-((S)-7'-methyl-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)thiophene-3-carboxylic acid; 4-(((R)-1-((R)-7'-methyl-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)isothiazole-3-carboxylic acid; 4-(((R)-1-((S)-7'-methyl-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)isothiazole-3-carboxylic acid; (R)-2-((1-(3,3-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)-N-methylbenzamide; (R)-6-chloro-3-((1-(3,3-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)-N-methylpicolinamide; N-methyl-2-(((R)-1-((R)-7'-methyl-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzamide; N-methyl-2-(((R)-1-((S)-7'-methyl-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzamide; 6-chloro-N-methyl-3-(((R)-1-((R)-7'-methyl-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinamide; 6-chloro-N-methyl-3-(((R)-1-((S)-7'-methyl-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinamide; (R)-2-((1-(3,3-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzonitrile; (R)-6-chloro-3-((1-(3,3-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)picolinonitrile; (R)-5'-(1-((2-(1H-tetrazol-5-yl)phenyl)amino)ethyl)-3,3-difluoro-7'-methyl-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one; (R)-5'-(1-((6-chloro-2-(1H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3,3-difluoro-7'-methyl-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazolin]-9'-one; (R)-2-((1-(3,3-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoate; (R)-6-chloro-3-((1-(3,3-difluoro-7'-methyl-9'-oxo-1',2'-dihydro-9'H-spiro[cyclobutane-1,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)ethyl picolinate; 2-(((R)-1-((R)-7'-methyl-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoate ethyl; 2-(((R)-1-((S)-7'-methyl-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)benzoate ethyl; 6-chloro-3-(((R)-1-((R)-7'-methyl-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)ethyl picolinate; 6-chloro-3-(((R)-1-((S)-7'-methyl-9'-oxo-1',2',4,5-tetrahydro-2H,9'H-spiro[furan-3,3'-pyrrolo[2,1-b]quinazoline]-5'-yl)ethyl)amino)ethyl picolinate; and pharmaceutically acceptable salts thereof.

59. 59. A pharmaceutical composition comprising a compound or salt according to any one of claims 1 to 58, together with a pharmaceutically acceptable carrier, excipient or diluent.

60. 60. A method for treating a disease or disorder associated with the regulation of phosphoinositide 3 kinase (PI3K), comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 58 or a pharmaceutical composition of claim 59.

61. The method of claim 60, wherein the PI3K is PI3Kα.

62. 62. The method of claim 60 or claim 61, wherein the PI3K associated with the disease or disorder has an H1047R mutation.

63. 63. The method of any one of claims 60 to 62, wherein the disease or disorder is cancer.

64. 64. The method of claim 63, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colon cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer.

65. 63. The method of any one of claims 60 to 62, wherein the disease or disorder is CLOVES syndrome (congenital lipomatous overgrowth syndrome, vascular malformations, epidermal nevi, scoliosis / skeletal and spinal syndrome), or PIK3Cα-associated overgrowth syndrome (PROS).

66. A method for inhibiting phosphoinositide 3-kinase (PI3K), comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of any one of claims 1 to 58 or a pharmaceutical composition of claim 59.

67. 60. 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 of claims 1 to 58 or a pharmaceutical composition of claim 59.

68. 68. The method of claim 67, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colon cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer.

69. 66. The method of claim 65, wherein the disorder is CLOVES syndrome (congenital lipomatous overgrowth syndrome, vascular malformations, epidermal nevus, scoliosis / skeletal and spinal syndrome), or PIK3Cα-associated overgrowth syndrome (PROS).

70. 60. A method for treating cancer, comprising administering a compound of any one of claims 1 to 58 or a pharmaceutical composition of claim 59 and a KRAS inhibitor to a patient in need of treatment, wherein the cancer is breast cancer, uterine carcinosarcoma, endometrial cancer, colorectal adenocarcinoma, gastric adenocarcinoma, head and neck squamous cell carcinoma, bile duct carcinoma, esophageal adenocarcinoma, bladder cancer, lung squamous cell carcinoma, brain glioma, adrenocortical carcinoma, liver hepatocellular carcinoma, sarcoma, prostate adenocarcinoma, kidney renal cell carcinoma, lung adenocarcinoma, ovarian cystadenocarcinoma, glioblastoma multiforme, or melanoma.

71. 60. A method for treating cancer, comprising administering a compound according to any one of claims 1 to 58 or a pharmaceutical composition according to claim 59 and a mutation-selective KRAS inhibitor to a patient in need of treatment, wherein the cancer is breast cancer, uterine carcinosarcoma, endometrial cancer, colorectal adenocarcinoma, gastric adenocarcinoma, head and neck squamous cell carcinoma, bile duct carcinoma, esophageal adenocarcinoma, bladder cancer, lung squamous cell carcinoma, brain glioma, adrenocortical carcinoma, liver hepatocellular carcinoma, sarcoma, prostate adenocarcinoma, kidney renal cell carcinoma, lung adenocarcinoma, ovarian cystadenocarcinoma, glioblastoma multiforme, or melanoma.

72. 60. A compound according to any one of claims 1 to 58 or a pharmaceutical composition according to claim 59 for use in treatment of cancer, in combination with a KRAS inhibitor, characterized in that the cancer is breast cancer, uterine carcinosarcoma, endometrial cancer, colorectal adenocarcinoma, gastric adenocarcinoma, head and neck squamous cell carcinoma, bile duct carcinoma, esophageal adenocarcinoma, bladder cancer, lung squamous cell carcinoma, brain glioma, adrenocortical carcinoma, liver hepatocellular carcinoma, sarcoma, prostate adenocarcinoma, kidney renal cell carcinoma, lung adenocarcinoma, ovarian cystadenocarcinoma, glioblastoma multiforme, or melanoma.

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