WO2022258057A1

WO2022258057A1 - Compounds as anticancer agents

Info

Publication number: WO2022258057A1
Application number: PCT/CN2022/098201
Authority: WO
Inventors: Ying Han; Dapeng Li; Huajun LONG; Zhiyu Yin; Jinghan WANG
Original assignee: Jingrui Biopharma Co Ltd
Current assignee: Jingrui Biopharma Co Ltd
Priority date: 2021-06-11
Filing date: 2022-06-10
Publication date: 2022-12-15
Anticipated expiration: 2023-12-11

Abstract

Disclosed are the compounds of formula I, their use as inhibitors of pan KRAS :: SOS1, their pharmaceutical compositions and their use as medicaments uses, especially as agents for the treatment of oncological diseases including cancer.

Description

COMPOUNDS AS ANTICANCER AGENTS

FIELD OF THE INVENTION

The present invention is directed to novel compounds which are used as inhibitors of pan KRAS :: SOS1, their synthesis and their use for treating diseases or conditions, such as cancer.

BACKGROUND OF THE INVENTION

RAS is one of the most well-known oncogenes. In human beings, three RAS genes (HRAS, KRAS and NRAS) encode four highly homologous RAS proteins (HRAS, KRAS-4A, KRAS-4B and NRAS) . RAS proteins are small GTPases, they function as binary molecular switches that involved in transduction of extracellular growth and differentiation signaling.

RAS generally cycles between a GDP-bound “off” state and a GTP-bound “on” state. This cycle is regulated by several factors. Guanine nucleotide exchange factors (GEFs) , including SOS1 and SOS2 facilitate the exchange and formation of GTP-bound RAS. While, GTPase-activating proteins (GAPs) , for example, NF-1 promote the hydrolysis of GTP and therefore turn RAS back to GDP-bound inactivate state (Kessler et al, PNAS, 2019, 116 (32) : 15823–15829) . Once bound to GTP, RAS initiates conformational changes in two specific regions Switch 1 and Switch 2, which allows engagement and activation of downstream effector proteins to initiate a cascade of intracellular signaling pathways. These effectors include RAF–MEK–ERK and PI3K-AKT–mTOR pathways, both of which have crucial roles in regulating cell proliferation, differentiation, and survival (Cox et al., Nature Reviews Drug Discovery, 2014, 13: 828-851) .

RAS mutations have been identified in around 30%of human tumors. These mutations occur frequently as single-base missense mutations in codons 12, 13 or 61, resulting in stabilization of the activated GTP-bound RAS form and constitutive activation of RAS downstream signaling pathways. KRAS is the most frequently mutated RAS in cancer, account for 85%of all RAS-driven cancers, followed by NRAS (12%) and HRAS (3%) . KRAS mutation has been detected in around 95%of pancreatic ductal adenocarcinoma, 50%of colorectal adenocarcinoma and 30%of lung adenocarcinoma. The majority of KRAS mutations occur at residue 12, and the mutation type varied in different cancers.

Son of Sevenless 1 (SOS1) is a human homologue of the originally identified Drosophila protein Son of Sevenless (Pierre et al., Biochem. Pharmacol., 2011, 82 (9) : 1049-56; Chardin et al., Cytogenet. Cell. Genet., 1994, 66 (1) : 68-9) . The SOS1 protein consists of 1333 amino acids (150 kDa) . SOS1 is a multi-domain protein with two tandem N-terminal histone domains (HD) followed by the Dbl homology domain (DH) , a Pleckstrin homology domain (PH) , a helical linker (HL) , RAS exchanger motif (REM) , CDC25 homology domain and a C-terminal proline rich domain (PR) . SOS1 has two binding sites for RAS-family proteins; a catalytic site that binds GDP-bound RAS-family proteins to promote guanine nucleotide exchange and an allosteric site that binds GTP-bound RAS-family proteins which causes a further increase in the catalytic GEF function of SOS1 (Freedman et al., Proc. Natl. Acad. Sci. U S A., 2006, 103 (45) : 16692-7; Pierre et al., Biochem. Pharmacol., 2011, 82 (9) : 1049-56) . Published data indicate a critical involvement of SOS1 in mutant KRAS activation and oncogenic signaling in cancer (Jeng et al., Nat. Commun., 2012, 3: 1168) . Depleting SOS1 levels decreased the proliferation rate and survival of tumor cells carrying a KRAS mutation whereas no effect was observed in KRAS wild type cell lines. The effect of loss of SOS1 could not be rescued by introduction of a catalytic site mutated SOS1, demonstrating the essential role of SOS1 GEF activity in KRAS mutant cancer cells.

SOS1 is critically involved in the activation of RAS-family protein signaling in cancer via mechanisms other than mutations in RAS-family proteins. SOS1 interacts with the adaptor protein Grb2 and the resulting SOS1/Grb2 complex binds to activated/phosphorylated Receptor Tyrosine Kinases (e.g. EGFR, ErbB2, ErbB3, ErbB4, PDGFR-A/B, FGFR1/2/3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1/2/3, AXL) (Pierre et al., Biochem. Pharmacol., 2011, 82 (9) : 1049-56) . SOS1 is also recruited to other phosphorylated cell surface receptors such as the T cell Receptor (TCR) , B cell Receptor (BCR) and monocyte colony-stimulating factor receptor (Salojin et al., J. Biol. Chem. 2000, 275 (8) : 5966-75) . This localization of SOS1 to the plasma membrane, proximal to RAS-family proteins, enables SOS1 to promote RAS-family protein activation. SOS1-activation of RAS-family proteins can also be mediated by the interaction of SOS1/Grb2 with the BCR-ABL oncoprotein commonly found in chronic myelogenous leukemia (Kardinal et al., 2001, Blood, 98:1773–81; Sini et al., Nat. Cell Biol., 2004, 6 (3) : 268-74) .

Furthermore, alterations in SOS1 have been implicated in cancer. SOS1 mutations are found in embryonal rhabdomyosarcomas, sertoli cell testis tumors, granular cell tumors of the skin (Denayer et al., Genes Chromosomes Cancer, 2010, 49 (3) : 242-52) and lung adenocarcinoma (Cancer Genome Atlas Research Network., Nature. 2014, 511 (7511) : 543-50) . Meanwhile over-expression of SOS1 has been described in bladder cancer (Watanabe et al., IUBMB Life., 2000, 49 (4) : 317-20) and prostate cancer (Timofeeva et al., Int. J. Oncol., 2009, ; 35 (4) : 751-60) . In addition to cancer, hereditary SOS1 mutations are implicated in the pathogenesis of RASopathies like e.g. Noonan syndrome (NS) , cardio-facio-cutaneous syndrome (CFC) and hereditary gingival fibromatosis type 1 (Pierre et al., Biochem. Pharmacol., 2011, 82 (9) : 1049-56) .

Selective pharmacological inhibition of the binding of the catalytic site of SOS1 to RAS-family proteins is expected to prevent SOS1-mediated activation of RAS-family proteins to the GTP-bound form. Such SOS1 inhibitor compounds are be expected to consequently inhibit signaling in cells downstream of RAS-family proteins (e.g. ERK phosphorylation) . In cancer cells associated with dependence on RAS-family proteins (e.g. KRAS mutant cancer cell lines) , SOS1 inhibitor compounds are be expected to deliver anti-cancer efficacy (e.g. inhibition of proliferation, survival, metastasis etc. ) . High potency towards inhibition of SOS1: RAS-family protein binding (nanomolar level IC ₅₀ values) and ERK phosphorylation in cells (nanomolar level IC ₅₀ values) are desirable characteristics for a SOS1 inhibitor compound.

These characteristics have not been achieved in previously described SOS1 inhibitor compounds. In the last decades the RAS family proteins-SOS1 protein interaction has gained increasing recognition. Until today several efforts to identify and optimize binders, which target either the effector binding site of RAS or the catalytic binding site of SOS1 (for a selected review see: Lu et al., ChemMedChem. 2016, 11 (8) : 814-21) , have been made with limited success.

Therefore, there remains a need to provide novel compounds which are used as inhibitors of pan KRAS : : SOS1. The compounds of the invention help meet this need.

SUMMARY OF THE INVENTION

The present invention provides novel compounds, their analogues including stereoisomers, or pharmaceutically acceptable salts, which are useful as pan KRAS : : SOS1 inhibitors.

The present invention also provides processes and intermediates for making the compounds of the present invention.

The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable excipient and at least one of the compounds of the present invention or stereoisomers thereof, or pharmaceutically acceptable salts thereof.

The compounds of the invention may be used in the treatment of diseases or conditions associated with KRAS activating mutations, or associated with or modulated by SOS1.

The compounds of the present invention may be used for the manufacture of a medicament for the treatment of diseases or conditions associated with KRAS activating mutations, or associated with or modulated by SOS1.

In another aspect, the present invention is directed to a method of treating a cancer comprising administering to a patient in need of such treatment a compound of the present invention as described above. Examples of such cancer includes a lung cancer, a colorectal cancer and a pancreatic cancer.

These and other features of the invention will be set forth in expanded form as the disclosure continues.

DETAILED DESCRIPTION OF THE INVENTION

In the first aspect of the present invention, the present application provides a compound of the formula I:

a pharmaceutically acceptable salt thereof or a stereoisomer thereof,

wherein R ₁ and R ₂ are independently selected from C _1-6 alkyl, tetrahydrofuranyl, tetrahydropyranyl and C _3-6 cycloalkyl, wherein the tetrahydrofuranyl, tetrahydropyranyl and C _3-6 cycloalkyl are optionally substituted with a C _1-6 alkyl or a halogen; or R ₁ and R ₂ together form a C _3-12 alkylene group,

wherein the C _3-12 alkylene group is optionally replaced by 1-3 heteroatoms selected from O, S and N, wherein the group replaced by 1-3 heteroatoms is optionally substituted by a C _1-3 alkyl, p-methoxybenzyl, acetyl or bivalent substitution =O;

R ₃ is selected from H, C _1-6 alkyl, phenyl, pyridyl, pyrazolyl, CN, amino, C _3-6 cycloalkyl and C _1-6 alkoxy, in which the C _1-6 alkyl is optionally substituted with -OH, -NR ₇R ₇ or halogen, each of the phenyl, the pyridyl, the amino and the pyrazolyl is optionally substituted with one or two C _1-6 alkyls or one or two halogens, R ₇ is independently selected from H and C _1-6 alkyl;

R ₄ is selected from H and C _1-6 alkyl;

X is selected from C, N and S;

Y is selected from a bivalent substituent =O or R ₅;

R ₅ is selected from H, C _1-6 alkyl, optionally substituted amino, C _1-6 alkoxy, SOR ₆, SO ₂R ₆, optionally substituted phenyl and optionally substituted pyridyl, in which R ₆ is independently selected from H and C _1-6 alkyl;

Z ₁ and Z ₂ are independently selected from C and N;

is selected from

R ₈ is selected from the group consisting of halogen, C _1-6 alkyl, halogen substituted C _1- ₆ alkyl and NH ₂;

n denotes 1 or 2, and

denotes a connection site.

In some embodiments of the first aspect, R ₁ and R ₂ are independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, isopentyl, sec-pentyl, n-pentyl, neopentyl, n-hexyl, sec hexyl, tetrahydrofuranyl, tetrahydropyranyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In some embodiments of the first aspect, R ₁ and R ₂ are independently selected from methyl, ethyl, n-propyl, isopropyl and tetrahydrofuranyl. In some embodiments of the first aspect, R ₁ and R ₂ are independently selected from methyl and tetrahydrofuranyl. In some embodiments of the first aspect, R ₁ is tetrahydrofuranyl, and R ₂ is C _1-6 alkyl. In some embodiments of the first aspect, R ₁ is tetrahydrofuranyl, and R ₂ is selected from methyl, ethyl, n-propyl and isopropyl. In some embodiments of the first aspect, R ₁ is tetrahydrofuranyl, and R ₂ is methyl.

In some embodiments of the first aspect, R ₁ and R ₂ together form a C _3-12 alkylene group, wherein the C _3-12 alkylene group is optionally replaced by 1 heteroatom selected from O and N, wherein the group replaced by 1 heteroatom is optionally substituted by C _1-3 alkyl, p-methoxybenzyl, acetyl or bivalent substitution =O. In some embodiments of the first aspect, R ₁ and R ₂ together form a C _3-12 alkylene group, wherein the C _3-12 alkylene group is optionally replaced by 1 oxygen atom. In some embodiments of the first aspect, R ₁ and R ₂ together form a C _3-8 alkylene group, wherein the C _3-8 alkylene group is optionally replaced by 1 oxygen atom. In some embodiments of the first aspect, R ₁ and R ₂ together form a C _3-6 alkylene group, wherein the C _3-6 alkylene group is optionally replaced by 1 oxygen atom. In some embodiments of the first aspect, R ₁ and R ₂ together form a C _3-5 alkylene group, wherein the C _3-5 alkylene group is optionally replaced by 1 oxygen atom. In some embodiments of the first aspect, R ₁ and R ₂ together form a C _5-12 alkylene group, wherein the C _5-12 alkylene group is replaced by 2 heteroatoms selected from O and N, wherein the group replaced by 2 heteroatoms is optionally substituted by C _1-3 alkyl, p-methoxybenzyl, acetyl or bivalent substitution =O. In some embodiments of the first aspect, R ₁ and R ₂ together form a C _5-12 alkylene group, wherein the C _5-12 alkylene group is replaced by 2 oxygen atoms. In some embodiments of the first aspect, R ₁ and R ₂ together form a C _5-8 alkylene group, wherein the C _5-8 alkylene group is replaced by 2 oxygen atoms. In some embodiments of the first aspect, R ₁ and R ₂ together form a C _5-6 alkylene group, wherein the C _5-6 alkylene group is replaced by 2 oxygen atoms. In some embodiments of the first aspect, R ₁ and R ₂ together form a C _8-12 alkylene group, wherein the C _8-12 alkylene group is replaced by 3 heteroatoms selected from O and N, wherein the group replaced by 3 heteroatoms is optionally substituted by C _1-3 alkyl, p-methoxybenzyl, acetyl or bivalent substitution =O. In some embodiments of the first aspect, R ₁ and R ₂ together form a C _8-12 alkylene group, wherein the C _8-12 alkylene group is replaced by 3 oxygen atoms. In some embodiments of the first aspect, R ₁ and R ₂ together form a C _3-8 alkylene group. In some embodiments of the first aspect, R ₁ and R ₂ together form a C _3-6 alkylene group. In some embodiments of the first aspect, R ₁ and R ₂ together form a C _3-4 alkylene group. In some embodiments of the first aspect, R ₁ and R ₂ together form a C ₃ alkylene group. In some embodiments of the first aspect, R ₁ and R ₂ together form a C _3-12 alkylene group, wherein the C _3-12 alkylene group is replaced by one oxygen atom. In some embodiments of the first aspect, R ₁ and R ₂ together form a C _3-8 alkylene group, wherein the C _3-8 alkylene group is replaced by one oxygen atom. In some embodiments of the first aspect, R ₁ and R ₂ together form a C _3-6 alkylene group, wherein the C _3-6 alkylene group is replaced by one oxygen atom. In some embodiments of the first aspect, R ₁ and R ₂ together form a C ₅ alkylene group, wherein the C ₅ alkylene group is replaced by one oxygen atom. In some embodiments of the first aspect, R ₁ and R ₂ together form a

In some embodiments of the first aspect, R ₁ and R ₂ together form a C _5- ₁₂ alkylene group, wherein the C _5-12 alkylene group is replaced by two oxygen atoms, wherein the two oxygen atoms are not adjacent to each other. In some embodiments of the first aspect, R ₁ and R ₂ together form a C _5-8 alkylene group, wherein the C _5-8 alkylene group is replaced by two oxygen atoms, wherein the two oxygen atoms are not adjacent to each other. In some embodiments of the first aspect, R ₁ and R ₂ together form a C ₈ alkylene group, wherein the C ₈ alkylene group is replaced by two oxygen atoms, wherein the two oxygen atoms are not adjacent to each other. In some embodiments of the first aspect, R ₁ and R ₂ together form a

In some embodiments of the first aspect, R ₁ and R ₂ together form a C _7-12 alkylene group, wherein the C _7-12 alkylene group is replaced by three oxygen atoms, wherein the three oxygen atoms are not adjacent to each other. In some embodiments of the first aspect, R ₁ and R ₂ together form a C _9-12 alkylene group, wherein the C _9-12 alkylene group is replaced by three oxygen atoms, wherein the three oxygen atoms are not adjacent to each other. In some embodiments of the first aspect, R ₁ and R ₂ together form a C _10-12 alkylene group, wherein the C _10-12 alkylene group is replaced by three oxygen atoms, wherein the three oxygen atoms are not adjacent to each other. In some embodiments of the first aspect, R ₁ and R ₂ together form a C ₁₂ alkylene group, wherein the C ₁₂ alkylene group is replaced by three oxygen atoms, wherein the three oxygen atoms are not adjacent to each other. In some embodiments of the first aspect, R ₁ and R ₂ together form a

In some embodiments of the first aspect, R ₁ and R ₂ together form a C _3-8 alkylene group, wherein the C _3-8 alkylene group is replaced by one nitrogen atom, wherein the group replaced by one nitrogen atom is optionally substituted by C _1-3 alkyl, p-methoxybenzyl, acetyl or bivalent substitution =O. In some embodiments of the first aspect, R ₁ and R ₂ together form a C _3-8 alkylene group, wherein the C _3-8 alkylene group is optionally replaced by two nitrogen atoms, the two nitrogen atoms are not adjacent to each other, wherein the group replaced by two nitrogen atoms is optionally substituted by C _1-3 alkyl, p-methoxybenzyl, acetyl or bivalent substitution =O. In some embodiments of the first aspect, R ₁ and R ₂ together form

In some embodiments of the first aspect, R ₁ and R ₂ together form

In some embodiments of the first aspect, R ₃ is selected from H, C _1-6 alkyl, phenyl, pyridyl, pyrazolyl, C _3-6 cycloalkyl and C _1-6 alkoxy, in which the C _1-6 alkyl is optionally substituted with -OH, -NR ₇R ₇ or halogen, each of the phenyl, the pyridyl, the amino and the pyrazolyl is optionally substituted with one or two C _1-6 alkyls or one or two halogens, R ₇ is independently selected from H and C _1-6 alkyl. In some embodiments of the first aspect, R ₃ is selected from H, C _1-6 alkyl, phenyl, pyridyl, pyrazolyl, and C _3- ₆ cycloalkyl, in which the C _1-6 alkyl is optionally substituted with –OH, -NR ₇R ₇ or halogen, the phenyl is optionally substituted with one or two C _1-6 alkyls or one or two halogens, the pyridyl is optionally substituted with one or two C _1-6 alkyl, the pyrazolyl is optionally substituted with a C _1-6 alkyl, and R ₇ is selected from H and C _1-6 alkyl. In some embodiments of the first aspect, R ₃ is H. In some embodiments of the first aspect, R ₃ is selected from C _1-6 alkyl, wherein the C _1-6 alkyl is optionally substituted with -OH, -NR ₇R ₇ or halogen, and R ₇ is independently selected from H and C _1-6 alkyl. In some embodiments of the first aspect, R ₃ is selected from methyl, ethyl and isopropyl, wherein the C _1-6 alkyl is optionally substituted with -OH, -NR ₇R ₇ or halogen, and R ₇ is independently selected from H and C _1-6 alkyl. In some embodiments of the first aspect, R ₃ is methyl. In some embodiments of the first aspect, R ₃ is selected from a phenyl, wherein the phenyl is optionally substituted with a C _1-6 alkyl or one or two halogens selected from F, Cl and Br. In some embodiments of the first aspect, R ₃ is selected from phenyl, wherein the phenyl is optionally substituted with a C _1-6 alkyl or one or two halogens selected from F and Cl. In some embodiments of the first aspect, R ₃ is selected from a pyridyl, wherein the pyridyl is optionally substituted with one or two C _1-6 alkyls. In some embodiments of the first aspect, R ₃ is selected from a pyridyl, wherein the pyridyl is optionally substituted with two C _1-6 alkyls. In some embodiments of the first aspect, R ₃ is selected from a pyridyl, wherein the pyridyl is optionally substituted with two C _1-3 alkyls. In some embodiments of the first aspect, R ₃ is selected from a pyrazolyl, wherein the pyrazolyl is optionally substituted with a C _1-6 alkyl. In some embodiments of the first aspect, R ₃ is selected from a pyrazolyl, wherein the pyrazolyl is optionally substituted with a C _1-3 alkyl. In some embodiments of the first aspect, R ₃ is cyclopropyl. In some embodiments of the first aspect, R ₃ is selected from H and methyl.

In some embodiments of the first aspect, R ₄ is selected from C _1-6 alkyl. In some embodiments of the first aspect, R ₄ is selected from methyl, ethyl, n-propyl and isopropyl. In some embodiments of the first aspect, R ₄ is methyl.

In some embodiments of the first aspect, X is selected from C and S. In some embodiments of the first aspect, X is C. In some embodiments of the first aspect, X is S.

In some embodiments of the first aspect, Y is selected from a bivalent substitution =O or R ₅; and R ₅ is selected from H and C _1-6 alkyl. In some embodiments of the first aspect, R ₅ is a bivalent substitution =O. In some embodiments of the first aspect, R ₅ is selected from methyl, ethyl, n-propyl and isopropyl. In some embodiments of the first aspect, R ₅ is methyl. In some embodiments of the first aspect, R ₅ is selected from C _1-3 alkoxy. In some embodiments of the first aspect, R ₅ is selected from SOR ₆, wherein R ₆ is independently selected from H and C _1-6 alkyl. In some embodiments of the first aspect, R ₅ is selected from SO ₂R ₆, wherein R ₆ is independently selected from H and C _1-6 alkyl.

In some embodiments of the first aspect, Z ₁ is independently selected from C and N, and Z ₂ is N. In some embodiments of the first aspect, Z ₁ is C, and Z ₂ is N. In some embodiments of the first aspect, Z ₁ is N, and Z ₂ is N.

In some embodiments of the first aspect,

is selected from

In some embodiments of the first aspect,

is

In some embodiments of the first aspect, R ₈ is selected from the group consisting of halogen, C _1-6 alkyl, halogen substituted C _1-6 alkyl, NH ₂. In some embodiments of the first aspect, R ₈ is selected from the group consisting of halogen, C _1-6 alkyl, halogen substituted C _1-6 alkyl, NH ₂. In some embodiments of the first aspect, R ₈ is selected from the group consisting of F, Cl, Br, C _1-3 alkyl, halogen substituted C _1-3 alkyl, NH ₂. In some embodiments of the first aspect, R ₈ is selected from the group consisting of F, CHF ₂, NH ₂, CF ₃ and CF ₂CH ₃. In some embodiments of the first aspect, R ₈ is NH ₂.

In some embodiments of the first aspect, n denotes 1. In some embodiments of the first aspect, n denotes 2.

In some embodiments of the first aspect, n denotes 2, one of R ₈ is NH ₂, and the other R ₈ is selected from the group consisting of F, CHF ₂, CF ₃ and CF ₂CH ₃.

In some embodiments of the first aspect,

is selected from

In some embodiments of the first aspect,

is selected from

In some embodiments of the first aspect,

is

In some embodiments of the first aspect, when X is C, Y is selected from a C _1-6 alkyl, and a bivalence substitution =O. In some embodiments of the first aspect, when X is S, Y is a bivalence substitution =O. In some embodiments of the first aspect, X and Y together form C-CH ₃, or C=O. In some embodiments of the first aspect, X and Y together form SO ₂ or SO.

In some embodiments of the first aspect, the compound is represented by formula I-1:

wherein R ₁ and R ₂ together form a C _3-12 alkylene group,

wherein the C _3-12 alkylene group is optionally replaced by 1-3 heteroatoms selected from O, S and N, wherein the group replaced by 1-3 heteroatoms is optionally substituted by a C _1-3 alkyl, p-methoxybenzyl, acetyl and oxygen. In some embodiments of the first aspect, R ₁ and R ₂ together form a C _3-8 alkylene group, wherein the C _3-8 alkylene group is optionally replaced by 1 heteroatom selected from O and S, or a C _5-12 alkylene group, wherein the C _5-12 alkylene group is replaced by 2 heteroatoms selected from O and S, wherein said 2 heteroatoms are not adjacent to each other. In some embodiments of the first aspect, R ₁ and R ₂ together form a C _3-5 alkylene group, wherein the C _3-5 alkylene group is optionally replaced by 1 heteroatom selected from O and S, or a C _5-8 alkylene group, wherein the C _5-8 alkylene group is replaced by 2 heteroatoms selected from O and S, wherein said 2 heteroatoms are not adjacent to each other. In some embodiments of the first aspect, R ₁ and R ₂ together form a C _3-5 alkylene group, wherein the C _3-5 alkylene group is optionally replaced by 1 oxygen atom, or a C _5-8 alkylene group, wherein the C _5-8 alkylene group is replaced by 2 oxygen atoms, wherein said 2 oxygen atoms are not adjacent to each other. In some embodiments of the first aspect, R ₁ and R ₂ together form a C _3-8 alkylene group. In some embodiments of the first aspect, R ₁ and R ₂ together form a C _3-6 alkylene group. In some embodiments of the first aspect, R ₁ and R ₂ together form a C _3-4 alkylene group. In some embodiments of the first aspect, R ₁ and R ₂ together form a C ₃ alkylene group. In some embodiments of the first aspect, R ₁ and R ₂ together form a C _3-12 alkylene group, wherein the C _3-12 alkylene group is replaced by one oxygen atom. In some embodiments of the first aspect, R ₁ and R ₂ together form a C _3-8 alkylene group, wherein the C _3-8 alkylene group is replaced by one oxygen atom. In some embodiments of the first aspect, R ₁ and R ₂ together form a C _3-6 alkylene group, wherein the C _3-6 alkylene group is replaced by one oxygen atom. In some embodiments of the first aspect, R ₁ and R ₂ together form a C ₅ alkylene group, wherein the C ₅ alkylene group is replaced by one oxygen atom. In some embodiments of the first aspect, R ₁ and R ₂ together form a

In some embodiments of the first aspect, R ₁ and R ₂ together form a C _5-12 alkylene group, wherein the C _5-12 alkylene group is replaced by two oxygen atoms, wherein the two oxygen atoms are not adjacent to each other. In some embodiments of the first aspect, R ₁ and R ₂ together form a C _5-8 alkylene group, wherein the C _5-8 alkylene group is replaced by two oxygen atoms, wherein the two oxygen atoms are not adjacent to each other. In some embodiments of the first aspect, R ₁ and R ₂ together form a C ₈ alkylene group, wherein the C ₈ alkylene group is replaced by two oxygen atoms, wherein the two oxygen atoms are not adjacent to each other. In some embodiments of the first aspect, R ₁ and R ₂ together form a

In some embodiments of the first aspect, R ₁ and R ₂ together form

In some embodiments of the first aspect, the compound is represented by formula I-2:

is selected from

R ₈ is selected from the group consisting of halogen, C _1-6 alkyl, halogen substituted C _1- ₆ alkyl and optionally substituted NH ₂; and n denotes 1 or 2. In some embodiments of the first aspect, R ₈ is selected from the group consisting of halogen, C _1-6 alkyl, halogen substituted C _1-6 alkyl, NH ₂. In some embodiments of the first aspect, R ₈ is selected from the group consisting of halogen, C _1-6 alkyl, halogen substituted C _1-6 alkyl, NH ₂. In some embodiments of the first aspect, R ₈ is selected from the group consisting of F, Cl, Br, C _1-3 alkyl, halogen substituted C _1-3 alkyl, NH ₂. In some embodiments of the first aspect, R ₈ is selected from the group consisting of F, CHF ₂, NH ₂, CF ₃ and CF ₂CH ₃. In some embodiments of the first aspect, R ₈ is NH ₂.

In some embodiments of the first aspect,

is selected from

In some embodiments of the first aspect,

is selected from

In some embodiments of the first aspect,

is

In some embodiments of the first aspect, the compound is represented by the following formula I-3:

wherein R ₃ is selected from H, C _1-6 alkyl, phenyl, pyridyl, pyrazolyl, CN, amino, C _3-6 cycloalkyl and C _1-6 alkoxy, in which the C _1-6 alkyl is optionally substituted with -OH, -NR ₇R ₇ or halogen, each of the phenyl, the pyridyl, the amino and the pyrazolyl is optionally substituted with one or two C _1-6 alkyls or one or two halogens, R ₇ is independently selected from H and C _1-6 alkyl.

In some embodiments of the first aspect, the compound is represented by the following formula I-4:

wherein R ₃ is selected from H, C _1-6 alkyl, phenyl, pyridyl, pyrazolyl, CN, amino, C _3-6 cycloalkyl and C _1-6 alkoxy, in which the C _1- ₆ alkyl is optionally substituted with -OH, -NR ₇R ₇ or halogen, each of the phenyl, the pyridyl, the amino and the pyrazolyl is optionally substituted with one or two C _1-6 alkyls or one or two halogens, R ₇ is independently selected from H and C _1-6 alkyl.

In some embodiments of the first aspect,

denotes a connection site.

The invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention also encompasses all combinations of alternative aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment to describe additional embodiments of the present invention. Furthermore, any elements (including individual variable definitions) of an embodiment are meant to be combined with any and all other elements from any of the embodiments to describe additional embodiments.

In some embodiments of the first aspect, the compound is selected from:

In the second aspect of the present invention, there is provided a pharmaceutical composition comprising the compound of the present invention, a pharmaceutically acceptable salt thereof or stereoisomer thereof and a pharmaceutically acceptable excipient.

In the third aspect of the present invention, there is provided the use of a compound of the present invention, a pharmaceutically acceptable salt thereof or stereoisomer thereof, in the manufacture of a medicament for the treatment of a disease or condition associated with KRAS activating mutations. In some embodiments of the third aspect, the disease or condition is a cancer. In some embodiments of the third aspect, the cancer is a lung cancer, a colorectal cancer or a pancreatic cancer.

In the fourth aspect of the present invention, there is provided a method of inhibiting a disease or condition associated with KRAS activating mutations, which comprises administering to an individual the compound of the present invention, a pharmaceutically acceptable salt thereof or stereoisomer thereof.

In the fifth aspect of the present invention, there is provided a method for treating a disease or condition in a patient, comprising administering a therapeutically effective amount of the compound of the present invention as a pan KRAS : : SOS1 inhibitor, a pharmaceutically acceptable salt thereof or stereoisomer thereof to the patient. In some embodiments of the fifth aspect, the disease or condition is associated with KRAS activating mutations. Preferably, the disease or condition is a cancer. More preferably, the disease or condition is a lung cancer, a colorectal cancer or a pancreatic cancer.

In one aspect, the method disclosed here can be used to treat or delay progression of a cancer that has a KRAS mutation. KRAS is a GTPase and KRAS mutations have been found in various human cancers, including but not limited to, pancreatic carcinomas, colon carcinomas, lung carcinomas, biliary tract malignancies, endometrial cancer, cervical cancer, bladder cancer, liver cancer, myeloid leukemia and breast cancer. Oncogenic forms of the KRAS gene are particularly prevalent in pancreatic cancer, colorectal cancer and lung cancer. KRAS has been reported to be mutated at several sites, but the vast majority of mutations occur at the Gly residue of codon 12 and codon 13. Common mutations include G12C, G12D, G12V, G12A, G12S, G12R and G13D. See Jia et al. (2017) Oncol. Lett. 14, 6525. Detection of these mutations can be performed using conventional methods, such as the non-limiting example reported in Lasota et al. (2015) Am. J. Surg. Pathol. 38, 1235. In some embodiments, KRAS mutation is detected in tissue or cell samples containing cancer cells from a subject. In some embodiments, the KRAS mutation is a somatic mutation. In some embodiments, the method is used to treat or delay progression of a cancer that has a KRAS G12C mutation. In some embodiments, the method is used to treat or delay progression of a cancer that has a KRAS G12V mutation. In some embodiments, the method is used to treat or delay progression of a cancer that has a KRAS G12D mutation.

DEFINITIONS

Unless specifically stated otherwise herein, references made in the singular may also include the plural. For example, “a” and “an” may refer to either one, or one or more. Herein, PMB refers to 4-methoxybenzyl.

Unless otherwise indicated, any heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences. Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to.

The indication of the number of members in groups that contain one or more heteroatom (s) (e.g. heteroaryl, heteroarylalkyl, heterocyclyl, heterocycylalkyl) relates to the total number of atoms of all the ring members or the total of all the ring and carbon chain members.

The indication of the number of carbon atoms in groups that consist of a combination of carbon chain and carbon ring structure (e.g. cycloalkylalkyl, arylalkyl) relates to the total number of carbon atoms of all the carbon ring and carbon chain members. Obviously, a ring structure has at least three members.

In general, for groups comprising two or more subgroups (e.g. heteroarylalkyl, heterocycylalkyl, cycloalkylalkyl, arylalkyl) the last named subgroup is the radical attachment point, for example, the substituent aryl-C _1-6alkyl means an aryl group which is bound to a C _1-6alkyl group, the latter of which is bound to the core or to the group to which the substituent is attached.

In groups like HO, H ₂N, (O) S, (O) ₂S, NC (cyano) , HOOC, F ₃C or the like, the skilled artisan can see the radical attachment point (s) to the molecule from the free valences of the group itself.

Alkyl denotes monovalent, saturated hydrocarbon chains, which may be present in both straight-chain (unbranched) and branched form. If an alkyl is substituted, the substitution may take place independently of one another, by mono-or polysubstitution in each case, on all the hydrogen-carrying carbon atoms.

As used herein, the term “alkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, “C ₁-C ₆ alkyl” denotes alkyl having 1 to 6 carbon atoms. Example alkyl groups include, but are not limited to, methyl (Me) , ethyl (Et) , propyl (e.g., n-propyl and isopropyl) , butyl (e.g., n-butyl, isobutyl, t-butyl) , and pentyl (e.g., n-pentyl, isopentyl, neopentyl) .

By the terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl etc. without any further definition are meant saturated hydrocarbon groups with the corresponding number of carbon atoms, wherein all isomeric forms are included.

The above definition for alkyl also applies if alkyl is a part of another (combined) group such as for example C _x-yalkylamino or C _x-yalkyloxy.

The term alkylene can also be derived from alkyl. Alkylene is bivalent, unlike alkyl, and requires two binding partners. Formally, the second valency is produced by removing a hydrogen atom in an alkyl. Corresponding groups are for example -CH ₃ and -CH ₂-, -CH ₂CH ₃ and -CH ₂CH ₂-or >CHCH ₃ etc.

The term “C _1-4alkylene” includes for example - (CH ₂) -, - (CH ₂-CH ₂) -, - (CH(CH ₃) ) -, - (CH ₂-CH ₂-CH ₂) -, - (C (CH ₃) ₂) -, - (CH (CH ₂CH ₃) ) -, - (CH (CH ₃) -CH ₂) -, - (CH ₂-CH (CH ₃) ) -, - (CH ₂-CH ₂-CH ₂-CH ₂) -, - (CH ₂-CH ₂-CH (CH ₃) ) -, - (CH (CH ₃) -CH ₂-CH ₂) -, - (CH ₂-CH (CH ₃) -CH ₂) -, - (CH ₂-C (CH ₃) ₂) -, - (C (CH ₃) ₂-CH ₂) -, - (CH (CH ₃) -CH(CH ₃) ) -, - (CH ₂-CH (CH ₂CH ₃) ) -, - (CH (CH ₂CH ₃) -CH ₂) -, - (CH (CH ₂CH ₂CH ₃) ) -, - (CH(CH (CH ₃) ) ₂) -and -C (CH ₃) (CH ₂CH ₃) -.

Other examples of alkylene are methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1, 1-dimethylethylene, 1, 2-dimethylethylene, pentylene, 1, 1-dimethylpropylene, 2, 2-dimethylpropylene, 1, 2-dimethylpropylene, 1, 3-dimethylpropylene, hexylene etc.

By the generic terms propylene, butylene, pentylene, hexylene etc. without any further definition are meant all the conceivable isomeric forms with the corresponding number of carbon atoms, i.e. propylene includes 1-methylethylene and butylene includes 1-methylpropylene, 2-methylpropylene, 1, 1-dimethylethylene and 1, 2-dimethylethylene.

The above definition for alkylene also applies if alkylene is part of another (combined) group such as for example in HO-C _x-yalkyleneamino or H ₂N-C _x-yalkyleneoxy.

Haloalkyl is derived from the previously defined alkyl by replacing one or more hydrogen atoms of the hydrocarbon chain independently of one another by halogen atoms, which may be identical or different. If a haloalkyl is to be further substituted, the substitutions may take place independently of one another, in the form of mono-or polysubstitutions in each case, on all the hydrogen-carrying carbon atoms.

Examples of haloalkyl are -CF ₃, -CHF ₂, -CH ₂F, -CF ₂CF ₃, -CHFCF ₃, -CH ₂CF ₃, -CF ₂CH ₃, -CHFCH ₃, -CF ₂CF ₂CF ₃, -CF ₂CH ₂CH ₃, -CF=CF ₂, -CCl=CH ₂, -CBr=CH ₂, -C≡C-CF ₃, -CHFCH ₂CH ₃, -CHFCH ₂CF ₃ etc.

From the previously defined haloalkyl are also derived the terms haloalkylene. Haloalkylene, unlike haloalkyl, is bivalent and requires two binding partners. Formally, the second valency is formed by removing a hydrogen atom from a haloalkyl.

Corresponding groups are for example -CH ₂F and -CHF-, -CHFCH ₂F and -CHFCHF-or >CFCH ₂F etc.

The above definitions also apply if the corresponding halogen-containing groups are part of another (combined) group.

Halogen relates to fluorine, chlorine, bromine and/or iodine atoms.

Cycloalkyl is made up of the subgroups monocyclic hydrocarbon rings, bicyclic hydrocarbon rings and spiro-hydrocarbon rings. The systems are saturated. In bicyclic hydrocarbon rings two rings are joined together so that they have at least two carbon atoms in common. In spiro-hydrocarbon rings one carbon atom (spiroatom) belongs to two rings together.

If a cycloalkyl is to be substituted, the substitutions may take place independently of one another, in the form of mono-or polysubstitutions in each case, on all the hydrogen-carrying carbon atoms. Cycloalkyl itself may be linked as a substituent to the molecule via every suitable position of the ring system.

Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo [2.2.0] hexyl, bicyclo [3.2.0] heptyl, bicyclo [3.2.1] octyl, bicyclo [2.2.2] octyl, bicyclo [4.3.0] nonyl (octahydroindenyl) , bicyclo [4.4.0] decyl (decahydronaphthyl) , bicyclo [2.2.1] heptyl (norbornyl) , bicyclo [4.1.0] heptyl (norcaranyl) , bicyclo [3.1.1] heptyl (pinanyl) , spiro [2.5] octyl, spiro [3.3] heptyl etc.

The above definition for cycloalkyl also applies if cycloalkyl is part of another (combined) group as for example in C _x-ycycloalkylamino, C _x-ycycloalkyloxy or C _x-ycycloalkylalkyl.

If the free valency of a cycloalkyl is saturated, then an alicyclic group is obtained.

The term cycloalkylene can thus be derived from the previously defined cycloalkyl. Cycloalkylene, unlike cycloalkyl, is bivalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from a cycloalkyl. Corresponding groups are for example:

cyclohexyl and

(cyclohexylene) .

The above definition for cycloalkylene also applies if cycloalkylene is part of another (combined) group as for example in HO-C _x-ycycloalkyleneamino or H ₂N-C _x-ycycloalkyleneoxy.

The term “alkoxy” or “alkyloxy” refers to an –O-alkyl group. “C _1-6 alkoxy” (or alkyloxy) , is intended to include C ₁, C ₂, C ₃, C ₄, C ₅, and C ₆ alkoxy groups. Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy) , and t-butoxy.

As referred to herein, the term “substituted” means that at least one hydrogen atom is replaced with a non-hydrogen group, provided that normal valencies are maintained and that the substitution results in a stable compound. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N) .

When the total number of C and N atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In some embodiments, the total number of C and N atoms in the heteroaryl group is not more than 2. In some embodiments, the total number of C and N atoms in the aromatic heterocycle is not more than 1. When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. The nitrogen atoms in the ring (s) of the heteroaryl group can be oxidized to form N-oxides.

When any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R, then said group may optionally be substituted with up to three R groups, and at each occurrence R is selected independently from the definition of R. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom in which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

When a substituent is noted as “optionally substituted” , the substituents are selected from, for example, substituents such as alkyl, cycloalkyl, aryl, heterocyclo, halo, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or arylalkyl; alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, arylalkylthio, alkylthiono, arylthiono, arylalkylthiono, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, sulfonamido, e.g. -SO ₂NH ₂, substituted sulfonamido, nitro, cyano, carboxy, carbamyl, e.g. -CONH ₂, substituted carbamyl e.g. -CONHalkyl, -CONHaryl, -CONHarylalkyl or cases where there are two substituents on the nitrogen selected from alkyl, aryl or arylalkyl; alkoxycarbonyl, aryl, substituted aryl, guanidino, heterocyclyl, e.g., indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl and the like, and substituted heterocyclyl, unless otherwise defined.

For purposes of clarity, where a substituent has a dash (-) that is not between two letters or symbols; this is used to indicate a point of attachment for a substituent. For example, -CONH ₂ is attached through the carbon atom.

Additionally, for purposes of clarity, when there is no substituent shown at the end of a solid line, this indicates that there is a methyl (CH ₃) group connected to the bond.

Throughout the specification and the appended claims, a given chemical formula or name shall encompass all stereo and optical isomers and racemates thereof where such isomers exist. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are within the scope of the invention. Many geometric isomers of C=C double bonds, C=N double bonds, ring systems, and the like can also be present in the compounds, and all such stable isomers are contemplated in the present invention. Cis-and trans- (or E-and Z-) geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. The present compounds can be isolated in optically active or racemic forms. Optically active forms may be prepared by resolution of racemic forms or by synthesis from optically active starting materials. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention. When enantiomeric or diastereomeric products are prepared, they may be separated by conventional methods, for example, by chromatography or fractional crystallization. Depending on the process conditions the end products of the present invention are obtained either in free (neutral) or salt form. Both the free form and the salts of these end products are within the scope of the invention. If so desired, one form of a compound may be converted into another form. A free base or acid may be converted into a salt; a salt may be converted into the free compound or another salt; a mixture of isomeric compounds of the present invention may be separated into the individual isomers. Compounds of the present invention, free form and salts thereof, may exist in multiple tautomeric forms, in which hydrogen atoms are transposed to other parts of the molecules and the chemical bonds between the atoms of the molecules are consequently rearranged. It should be understood that all tautomeric forms, insofar as they may exist, are included within the invention.

The present invention includes compounds described can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.

The present invention includes all stereoisomers of the compound and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.

The term “stereoisomer” as used in the present invention refers to an isomer in which atoms or groups of atoms in the molecule are connected to each other in the same order but differ in spatial arrangement, including conformational isomers and configuration isomers. The configuration isomers include geometric isomers and optical isomers, and optical isomers mainly include enantiomers and diastereomers.

As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington: The Science and Practice of Pharmacy, ²²nd Edition, Allen, L.V. Jr., Ed.; Pharmaceutical Press, London, UK (2012) , the disclosure of which is hereby incorporated by reference.

For therapeutic use, salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

"Treating" , "treat" or "treatment" or "alleviation" refers to administering at least one compound and /or at least one stereoisomer thereof, and /or at least one pharmaceutically acceptable salt thereof disclosed herein to a subject in recognized need thereof that has, for example, cancer.

The term "therapeutically effective amount" refers to an amount of at least one compound and /or at least one stereoisomer thereof, and /or at least one pharmaceutically acceptable salt thereof disclosed herein effective to "treat" as defined above, a disease or disorder in a subject.

As used herein, “cancer” refers to or describes the physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia. More particular examples of such cancers include but are not limited to squamous cell cancer, lung cancer (including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous carcinoma of the lung) , cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer (including gastrointestinal cancer) , pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, liver cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma and various types of head and neck cancer, as well as B-cell lymphoma (including low grade/follicular non-Hodgkin's lymphoma (NHL) ; small lymphocytic (SL) NHL; intermediate grade/follicular NHL; intermediate grade diffuse NHL; high grade immunoblastic NHL; high grade lymphoblastic NHL; high grade small non-cleaved cell NHL; bulky disease NHL; mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom's Macroglobulinemia) ; chronic lymphocytic leukemia (CLL) ; acute lymphoblastic leukemia (ALL) ; Hairy cell leukemia; chronic myeloblastic leukemia; and post-transplant lymphoproliferative disorder (PTLD) , as well as abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors) , and Meigs' syndrome. Examples of cancer may include primary tumors of any of the above types of cancer or metastatic tumors at a second site derived from any of the above types of cancer. Included in this definition are benign and malignant cancers as well as dormant tumors or micrometastases.

As used herein, the term “inhibitor” refers to biological or chemical substance that interferes with or otherwise reduces the physiological and/or biochemical action of another biological or chemical molecule. In some embodiments, the inhibitor or antagonist specifically binds to the other molecule.

A “subject, ” “patient” or “individual” includes a mammal, such as a human or other animal, and typically is human. In some embodiments, the subject, e.g., patient, to whom the therapeutic agents and compositions are administered, is a mammal, typically a primate, such as a human. In some embodiments, the primate is a monkey or an ape. The subject can be male or female and can be any suitable age, including infant, juvenile, adolescent, adult, and geriatric subjects. In some embodiments, the subject is a non-primate mammal, such as a rodent, a dog, a cat, a farm animal, such as a cow or a horse, etc.

METHODS OF PREPARATION

The compounds in the present invention can be synthesized in a number of ways well to one skilled in the art of organic synthesis described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods are not limited as those described below. The references cited here are incorporated by reference in their entirety.

The methods of synthesis described hereinafter are intended as an illustration of the invention, without restricting its subject matter and the scope of the compounds claimed to these examples. Where the preparation of starting compounds is not described, they are commercially obtainable or may be prepared analogously to known compounds or methods described herein. Substances described in the literature are prepared according to the published methods of synthesis. Compounds of formula I may be synthesized by reference to methods illustrated in the following schemes. As shown herein, the end compound is a product having the same structural formula depicted as formula I. It will be understood that any compound of formula I may be prepared by the selection of reagents with appropriate substitution. Solvents, temperature, pressures, and other reaction conditions may be readily selected by one of ordinary skill in the art. Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Green and P.G.M. Wuts (1999) Protective Groups in Organic Synthesis, 3 ^rd edition, John Wiley &Sons) . These groups are removed at certain stage of the compound synthesis using the methods that are apparent to those skilled in the art.

Compounds of Formula I (including Formula I-1 to I-4) may be prepared by reference to the methods illustrated in the following Schemes. As shown therein the end product is a compound having the same structural formula as Formula I. It will be understood that any compound of Formula I may be produced by the schemes by the suitable selection of reagents with appropriate substitution. Solvents, temperatures, pressures, and other reaction conditions may readily be selected by one of ordinary skill in the art.

Starting materials are commercially available or readily prepared by one of ordinary skill in the art. Constituents of compounds are as defined herein or elsewhere in the specification.

Scheme I

Scheme II

Scheme III

EXAMPLES

The invention is further defined in the following Examples. It should be understood that the Examples are given by way of illustration only. From the above discussion and the Examples, one skilled in the art can ascertain the essential characteristics of the invention, and without departing from the spirit and scope thereof, can make various changes and modifications to adapt the invention to various uses and conditions. As a result, the invention is not limited by the illustrative examples set forth herein below, but rather is defined by the claims appended hereto.

The following table shows the part abbreviation of the present invention:

Intermediate preparation

Unless otherwise stated, starting materials for the preparation of intermediates and Examples are commercially available.

Intermediate-1

(S) -7-Methoxy-2-methyl-6- ( (tetrahydrofuran-3-yl) oxy) quinazolin-4-ol

Step 1: (S) -3- (5-Bromo-2-methoxy-4-nitrophenoxy) tetrahydrofuran

To a solution of (S) -tetrahydrofuran-3-ol (4.2 g, 48 mmol) in DMF (80 mL) was added NaH (1.9 g, 48 mmol, 60 w%) at 0 ℃. After stirred for 30 min, 1-bromo-5-fluoro-4-methoxy-2-nitrobenzene (10 g, 40 mmol) was added at 0 ℃, then the resulting mixture was stirred at 0～20 ℃ for 2 h. The mixture was poured into sat. aq. NH ₄Cl (100 mL) , extracted with EtOAc (200 mL x 3) . The combined organic layer was washed with brine (50 mL) , dried over Na ₂SO ₄, filtered and concentrated. The residue was purified by column chromatography to give the title product (8.8 g, 69.2%yield) as a yellow solid. ¹H NMR (400 MHz, CDCl ₃) δ 7.56 (s, 1H) , 7.05 (s, 1H) , 5.01 (qd, J = 4.3, 2.3 Hz, 1H) , 4.07-3.98 (m, 3H) , 3.94 (dd, J = 8.3, 4.4 Hz, 1H) , 3.91 (s, 3H) , 2.39-2.11 (m, 2H) .

Step 2: Methyl (S) -4-methoxy-2-nitro-5- ( (tetrahydrofuran-3-yl) oxy) benzoate

To a solution of (S) -3- (5-bromo-2-methoxy-4-nitrophenoxy) tetrahydrofuran (1.0 g, 3.14 mmol) in MeOH (20 mL) was added Et ₃N (7 mL, 69.3 mmol) and Pd (dppf) Cl ₂ (115 mg, 0.16 mmol) , the mixture was stirred at 80 ℃ for 4 h under Ar. The mixture was concentrated. The residue was purified by column chromatography to give the title product (650 mg, 69.6%yield) as a yellow oil. ¹H NMR (400 MHz, CDCl ₃) δ7.44 (s, 1H) , 7.02 (s, 1H) , 5.04 (d, J = 2.6 Hz, 1H) , 4.07-3.98 (m, 3H) , 3.96-3.86 (m, 7H) , 2.43-2.09 (m, 2H) .

Step 3: (S) -4-Methoxy-2-nitro-5- ( (tetrahydrofuran-3-yl) oxy) benzamide

A solution of methyl (S) -4-methoxy-2-nitro-5- ( (tetrahydrofuran-3-yl) oxy) benzoate (1.0 g, 2.36 mmol) in NH ₃H ₂O (20 mL) was stirred at 100 ℃ for 12 h in a sealed tube. The mixture was concentrated. The residue was purified by column chromatography to give the title product (680 mg, 71.7%yield) . LCMS: m/z (ESI) = 283.4 [M+H] ⁺. ¹H NMR (400 MHz, CDCl ₃) δ 7.68 (s, 1H) , 6.94 (s, 1H) , 5.82 (s, 2H) , 5.10 (d, J = 3.2 Hz, 1H) , 4.17-3.83 (m, 7H) , 2.31 –2.25 (m, 2H) .

Step 4: (S) -2-Amino-4-methoxy-5- ( (tetrahydrofuran-3-yl) oxy) benzamide

To a solution of (S) -4-methoxy-2-nitro-5- ( (tetrahydrofuran-3-yl) oxy) benzamide (680 mg, 2.41 mmol) in MeOH (10 mL) was added Pd/C (100 mg, 10 w%) , the mixture was stirred at 20 ℃ for 4 h under H ₂. The mixture was filtered and washed with MeOH (5 mL x 2) . The filtrates were concentrated to give the title product (480 mg, 78.9%yield) . LCMS: m/z (ESI) = 253.0 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d ₆) δ7.53 (s, 1H) , 7.14 (s, 1H) , 6.83 (s, 1H) , 6.50 (s, 2H) , 6.29 (s, 1H) , 4.78-4.81 (m, 1H) , 3.71-3.73 (m, 7H) , 1.94-2.04 (m, 2H) .

Step 5: (S) -7-Methoxy-2-methyl-6- ( (tetrahydrofuran-3-yl) oxy) quinazolin-4-ol

To a solution of (S) -2-amino-4-methoxy-5- ( (tetrahydrofuran-3-yl) oxy) benzamide (480 mg, 1.9 mmol) and triethyl orthoacetate (923.4 mg, 5.7 mmol) in EtOH (10 mL) was added CH ₃COOH (342 mg, 5.7 mmol) , the mixture was stirred at 110 ℃ for 40 min. The mixture was concentrated. To the residue PE (15 mL) was added, the mixture was stirred at r.t. for 1 h, filtered and dried to give the title product (390 mg, 74.3%yield) as a gray solid. LCMS: m/z (ESI) = 277.1 [M+H] ⁺. ¹H NMR (400 MHz, CDCl ₃) δ 12.08 (s, 1H) , 7.35 (s, 1H) , 7.07 (s, 1H) , 5.09 -5.11 (m, 1H) , 3.82-3.89 (m, 7H) , 2.98 (s, 3H) , 2.19 -2.23 (m, 1H) , 1.96 -2.03 (m, 1H) .

Example 2

4- ( ( (R) -1- (3-Amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-1-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) quinazolin-2 (1H) -one

Step 1: Methyl (S) -4-methoxy-2-nitro-5- ( (tetrahydrofuran-3-yl) oxy) benzoate

To a solution of methyl (S) -4-methoxy-2-nitro-5- ( (tetrahydrofuran-3-yl) oxy) benzoate (2.0 g, 8.4 mmol) in EtOH (20 mL) and H ₂O (4 mL) was added Fe power (2.4 g, 42.1 mmol) and NH ₄Cl (2.3 g, 42.1 mmol) , the mixture was stirred at 85 ℃ for 2 h. The mixture was extracted with EtOAc (50 mL x 3) . The combined organic layers were concentrated. The residue was purified by column chromatography to give title product (1.3 g, 76.7%yield) as a yellow solid. LCMS: m/z (ESI) : 268.1 [M+H] ⁺.

Step 2: Methyl (S) -4-methoxy-2- (methylamino) -5- ( (tetrahydrofuran-3-yl) oxy) benzoate

To a solution of methyl (S) -4-methoxy-2-nitro-5- ( (tetrahydrofuran-3-yl) oxy) benzoate (700 mg, 2.62 mmol) , MeB (OH) ₂ (393 mg, 6.55 mmol) and Cu (acac) ₂ (1.31 g, 6.55 mmol) in dioxane (20 mL) was added Pyridine (515 mg, 6.55 mmol) , the resulting mixture was stirred at 105 ℃ for 12 h under O ₂ atmosphere. The mixture was extracted with EtOAc (30 mL x 3) . The combined organic layer was washed with brine and dried over Na ₂SO ₄. The organic layer was concentrated. The residue was purified by column chromatography to give the title product (460 mg, 62.5%yield) as a yellow solid. LCMS: m/z (ESI) : 282.1 [M+H] ⁺.

Step 3: (S) -4-methoxy-2- (methylamino) -5- ( (tetrahydrofuran-3-yl) oxy) benzamide

A solution of methyl (S) -4-methoxy-2- (methylamino) -5- ( (tetrahydrofuran-3-yl) oxy) benzoate (460 mg, 1.64 mmol) in NH ₃. H ₂O (10 mL) was stirred at 100 ℃ for 12 h under nitrogen atmosphere. The mixture was cooled to room temperature and the precipitate was filtered off. The residue was purified by column chromatography to give the title product (100 mg, 22%yield) . LCMS: m/z (ESI) : 267.1 [M+H] ⁺.

Step 4: (S) -4-Methoxy-2- (methylamino) -5- ( (tetrahydrofuran-3-yl) oxy) benzamide

To a solution of (S) -4-methoxy-2- (methylamino) -5- ( (tetrahydrofuran-3-yl) oxy) benzamide (250 mg, 0.56 mmol) in DMF (10 mL) was added NH ₄Cl (60 mg, 1.12 mmol) , HATU (426 mg, 1.12 mmol) and DIEA (218 mg, 1.68 mmol) , the resulting mixture was stirred at 20 ℃ for 2 h. The mixture was extracted with EtOAc (30 mL x 3) . The combined organic layer was concentrated. The residue was purified by column chromatography to give the title product (100 mg, 35.4%yield) as a white solid. LCMS: m/z (ESI) : 267.0 [M+H] ⁺.

Step 5: (S) -4-hydroxy-7-methoxy-1-methyl-6- ( (tetrahydrofuran-3-yl) oxy) quinazolin-2 (1H) -one

A solution of (S) -4-methoxy-2- (methylamino) -5- ( (tetrahydrofuran-3-yl) oxy) benzamide (50 mg, 0.018 mmol) and oxalyl chloride (70 mg, 0.018 mmol) in toluene (5 mL) was stirred at 100 ℃ for 2 h under nitrogen atmosphere. The mixture was diluted with H ₂O (5 mL) and extracted with EtOAc (10 mL x 2) . The combined organic layer was concentrated. The residue was purified by column chromatography to give the title product (30 mg, 55.5%yield) as a white solid. LCMS: m/z (ESI) : 293.1 [M+H] ⁺.

Step 6: 4- ( ( (R) -1- (3-Amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-1-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) quinazolin-2 (1H) -one

To a solution of (R) -3- (1-aminoethyl) -5- (trifluoromethyl) aniline (22 mg, 0.103 mmol) and (S) -4-hydroxy-7-methoxy-1-methyl-6- ( (tetrahydrofuran-3-yl) oxy) quinazolin-2 (1H) -one (20 mg, 0.068 mmol) in DMF (2 mL) was added BOP (61 mg, 0.136 mmol) and DBU (22 mg, 0.136 mmol) , the resulting mixture was stirred at 20 ℃ for 2 h. The mixture was diluted with H ₂O (5 mL) and extracted with EtOAc (10 mL) . The combined organic layers were concentrated. The residue was purified by prep-HPLC to afford the title product (2.4 mg, 99.1%purity) as a white solid. LCMS: m/z (ESI) : 479.2 [M+H] ⁺. ¹H NMR: (400 MHz, MeOD) δ 7.70 (s, 1H) , 6.95 (d, J = 5.6 Hz, 2H) , 6.89 (s, 1H) , 6.79 (s, 1H) , 5.63 (d, J = 7.1 Hz, 1H) , 5.10 (s, 1H) , 4.09-3.83 (m, 7H) , 3.60 (s, 3H) , 2.28-2.14 (m, 2H) , 1.60 (d, J = 7.1 Hz, 3H) .

Example 3

4- ( ( (R) -1- (3-Amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-1-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) -1H-pyrido [2, 3-c] [1, 2, 6] thiadiazine 2, 2-dioxide

Step 1: 2-Chloro-6-methoxynicotinic acid

To a solution of 2, 6-dichloronicotinic acid (5.0 g, 26.1 mmol) in MeOH (30 mL) was added t-BuOK (9.6 g, 85.7 mmol) , and the mixture was stirred at 70 ℃ for 18 h. The mixture was diluted with H ₂O (30 mL) , and the resulting mixture was filtered. The filtrates were concentrated to give the title product (7.0 g, 98%yield) as a white solid. LCMS: m/z (ESI) = 188.1 [M+H] ⁺.

Step 2: Methyl 2-chloro-6-methoxynicotinate

A solution of 2-chloro-6-methoxynicotinic acid (7.0 g, 37.4 mmol) in SOCl ₂ (50 mL) was stirred at 80 ℃ for 2 h. The mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (30 mL) , and the mixture was stirred at 70 ℃ for 10 min. The mixture was diluted with H ₂O (50 mL) and extracted with DCM (50 mL x 3) . The combined organic layers were concentrated under reduced pressure. The residue was purified by column to afford the title product (4.9 g, 65.3%yield) as a yellow solid. ¹H NMR (400 MHz, CDCl ₃) δ 8.12 (d, J = 8.5 Hz, 1H) , 6.69 (d, J = 8.5 Hz, 1H) , 3.99 (s, 3H) , 3.90 (s, 3H) .

Step 3: Methyl 6-methoxy-2- (methylamino) nicotinate

A solution of methyl 2-chloro-6-methoxynicotinate (3.8 g, 18.9 mmol) and MeNH ₂ (8.0 g, 258 mmol) in EtOH (20 mL) was stirred at 80 ℃ for 2 h. The mixture was diluted with H ₂O (30 mL) and extracted with DCM (30 mL x 3) . The combined organic layers were concentrated under reduced pressure. The residue was purified by column to afford the title product (3.0 g, 81.1%yield) as a yellow oil. ¹H NMR (400 MHz, CDCl ₃) δ 7.99 (s, 1H) , 7.96 (d, J = 8.5 Hz, 1H) , 5.92 (d, J = 8.5 Hz, 1H) , 3.93 (s, 3H) , 3.80 (s, 3H) , 3.04 (d, J = 4.6 Hz, 3H) .

Step 4: Methyl 5-bromo-6-methoxy-2- (methylamino) nicotinate

A solution of methyl 6-methoxy-2- (methylamino) nicotinate (1.5 g, 7.65 mmol) in DMF (10 mL) was stirred at 20 ℃ for 8 h. Then H ₂O (50 mL) was added and the mixture was filtered. The filter cake was dried to give the title product (1.7 g, 80.9%yield) as a yellow solid. LCMS: m/z (ESI) = 277.1 [M+1] ⁺.

Step 5: Methyl 6-methoxy-2- (methylamino) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan -2-yl) nicotinate

A solution of methyl 5-bromo-6-methoxy-2- (methylamino) nicotinate (1.0 g, 3.64 mmol) , 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (1.38 g, 5.43 mmol) , Pd (dppf) Cl ₂ (266 mg, 0.36 mmol) and AcOK (712 mg, 7.26 mmol) in 1, 4-dioxane (15 mL) was stirred at 100 ℃ for 2 h under N ₂ atmosphere. The mixture was diluted with H ₂O (30 mL) and extracted with EtOAc (20 mL x 3) . The combined organic layer was concentrated. The residue was purified by column to afford the title product (900 mg, 76.5%yield) as a white solid. LCMS: m/z (ESI) = 323.3 [M+1] ⁺.

Step 6: Methyl 5-hydroxy-6-methoxy-2- (methylamino) nicotinate

To a solution of methyl 6-methoxy-2- (methylamino) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) nicotinate (900 mg, 2.79 mmol) and NaOH (220 mg, 5.5 mmol) in DCM (10 mL) was added H ₂O ₂ (2 mL) . The mixture was stirred at 20 ℃ for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by column to afford the title product (200 mg, 33.7%yield) as a white solid. ¹H NMR (400 MHz, CDCl ₃) δ 7.58 (s, 1H) , 4.03 (s, 3H) , 3.81 (s, 3H) , 3.02 (s, 3H) .

Step 7: Methyl 2- ( (tert-butoxycarbonyl) (methyl) amino) -5-hydroxy-6-methoxy nicotinate

To a solution of methyl 5-hydroxy-6-methoxy-2- (methylamino) nicotinate (900 mg, 4.24 mmol) in THF (10 mL) was added di-tert-butyl dicarbonate (987 mg, 4.5 mmol) and TEA (762 mg, 7.54 mmol) , DMAP (46 mg, 0.37 mmol) , and the mixture was stirred at r.t. for 2 h. The mixture was diluted with H ₂O (50 mL) , extracted with EtOAc (50 mL x 3) . The combined organic layer was concentrated. The residue was purified by column to give the title product (1.2 g, 92%yield) as a white solid. LCMS: m/z (ESI) = 313.1 [M+H] ⁺.

Step 8: Methyl (S) -6-methoxy-2- (methylamino) -5- ( (tetrahydrofuran-3-yl) oxy) nicotinate

To a solution of methyl 2- ( (tert-butoxycarbonyl) (methyl) amino) -5-hydroxy-6-methoxynicotinate (1.2 g, 3.5 mmol) in DMF (20 mL) was added (R) -tetrahydrofuran-3-ylmethanesulfonate (1.75 g, 10.5 mmol) and Cs ₂CO ₃ (3.4 g, 10.5 mmol) , and the mixture was stirred at 100 ℃ for 18 h. The mixture was diluted with H ₂O (100 mL) , extracted with EtOAc (50 mL x 3) . The organic layer was concentrated. The residue was purified by column to give the title product (1.0 g, 92%yield) as a white solid. LCMS: m/z (ESI) = 283.0 [M+H] ⁺.

Step 9: Methyl (S) -2- ( (N- ( (benzyloxy) carbonyl) sulfamoyl) (methyl) amino) -6-methoxy-5 - ( (tetrahydrofuran-3-yl) oxy) nicotinate

To a solution of methyl (S) -6-methoxy-2- (methylamino) -5- ( (tetrahydrofuran-3-yl) oxy) nicotinate (1.0 g, 3.54 mmol) in dioxane (20 mL) was added benzyl (chlorosulfonyl) carbamate (4.3 g, 17.7 mmol) and TEA (17.8 g, 177 mmol) , and the mixture was stirred at 0～r.t. for 18 h. The mixture was diluted with H ₂O (50 mL) , extracted with EtOAc (50 mL x 3) . The mixture was concentrated and purified by column to give the title product (700 mg, 40%yield) as a colorless oil. LCMS: m/z (ESI) = 496.4 [M+H] ⁺.

Step 10: Methyl (S) -6-methoxy-2- (methyl (sulfamoyl) amino) -5- ( (tetrahydro furan-3-yl) oxy) nicotinate

To a solution of methyl (S) -2- ( (N- ( (benzyloxy) carbonyl) sulfamoyl) (methyl) amino) -6-methoxy-5- ( (tetrahydrofuran-3-yl) oxy) nicotinate (700 mg, 0.28 mmol) in EtOAc (10 mL) was added Pd/C (350 mg) , and the mixture was stirred at r.t. for 1 h. The mixture was filtered, and the filtrates was concentrated to give the title product (400 mg, 78%yield) , which was used in next step without purification.

Step 11: (S) -4-Hydroxy-7-methoxy-1-methyl-6- ( (tetrahydrofuran-3-yl) oxy) -1H-pyrido [2, 3-c] [1, 2, 6] thiadiazine 2, 2-dioxide

To a solution of methyl (S) -6-methoxy-2- (methyl (sulfamoyl) amino) -5- ( (tetrahydro furan-3-yl) oxy) nicotinate (400 mg, 1.1 mmol) in EtOH (20 mL) was added NaOH (88 mg, 2.2 mmol) , and the mixture was stirred at r.t. for 2 h. Then the mixture was concentrated and purified by column to give the title product (250 mg, 68%yield) as a white solid. ¹H NMR (400 MHz, DMSO-d ₆) δ 7.57 (s, 1H) , 4.94 (dd, J = 4.0, 1.9 Hz, 1H) , 3.93 (s, 3H) , 3.83 –3.79 (m, 2H) , 3.76 –3.70 (m, 2H) , 3.23 (s, 3H) , 2.17 –2.08 (m, 1H) , 2.00 –1.94 (m, 1H) .

Step 12: 4- ( ( (R) -1- (3-Amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-1-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) -1H-pyrido [2, 3-c] [1, 2, 6] thiadiazine 2, 2-dioxide

To a solution of (S) -4-hydroxy-7-methoxy-1-methyl-6- ( (tetrahydrofuran-3-yl) oxy) -1H-pyrido [2, 3-c] [1, 2, 6] thiadiazine 2, 2-dioxide (50 mg, 0.15 mmol) in dioxane (2 mL) was added Et ₃N (45 mg, 0.45 mmol) then TsCl (42 mg, 0.22 mmol) , and the mixture was stirred at r.t. for 2 h. Then (R) -3- (1-aminoethyl) -5- (trifluoromethyl) aniline (61 mg, 0.3 mmol) in DMF (2 mL) was added, and the mixture was stirred at 80 ℃ for 4 h.The mixture was diluted with H ₂O (20 mL) and extracted with EtOAc (30 mL x 2) . The combined organic layers were concentrated. The residue was purified by prep-HPLC to afford the title product (5 mg, 6%yield) as a white solid. LCMS: m/z (ESI) = 516.2 [M+1] ⁺. ¹H NMR (400 MHz, DMSO-d ₆) δ 8.03 (s, 1H) , 6.80 (d, J = 13.7 Hz, 2H) , 6.74 (s, 1H) , 5.61 (s, 2H) , 5.20 (s, 1H) , 5.07 (s, 1H) , 4.01 (d, J = 2.2 Hz, 3H) , 3.85 (s, 3H) , 3.78 (s, 1H) , 3.34 (s, 3H) , 2.19 (s, 1H) , 2.04 (s, 1H) , 1.53 (d, J = 6.9 Hz, 3H) .

Example 4

4- ( ( (R) -1- (3-Amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-1-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) -1H-benzo [c] [1, 2, 6] thiadiazine 2, 2-dioxide

Step 1: (S) -3- (5-Bromo-2-methoxy-4-nitrophenoxy) tetrahydrofuran

To a solution of 1-bromo-5-fluoro-4-methoxy-2-nitrobenzene (3.0 g, 12.0 mmol) and (S) -tetrahydrofuran-3-ol (3.2 g, 36 mmol) in DMF (30 mL) was added Cs ₂CO ₃ (7.9 g, 24 mmol) , the resulting mixture was stirred at 60 ℃ for 2 h. The mixture was diluted with H ₂O (30 mL) and extracted with EtOAc (200 mL x 3) . The combined organic layers were washed with brine, dried over Na ₂SO ₄ and concentrated. The residue was purified by column chromatography to give the title product (3.1 g, 81.5%yield) as a yellow oil. LCMS: m/z (ESI) : 318.0 [M+H] ⁺.

Step 2: (S) -2-Bromo-5-methoxy-4- ( (tetrahydrofuran-3-yl) oxy) aniline

To a solution of (S) -3- (5-bromo-2-methoxy-4-nitrophenoxy) tetrahydrofuran (2.2 g, 6.94 mmol) in EtOH (20 mL) and H ₂O (4 mL) was added Fe power (1.94 g, 34.7 mmol) and NH ₄Cl (1.87 g, 34.7 mmol) , the resulting mixture was stirred at 85 ℃ for 2 h. The mixture was extracted with EtOAc (100 mL x 3) , the combined organic layer was washed with Brine, dried over Na ₂SO ₄ and concentrated. The residue was purified by column chromatography to give the title product (1.1 g, 57.9%yield) as a black solid. LCMS: m/z (ESI) : 289.0 [M+H] ⁺.

Step 3: Methyl (S) -2-amino-4-methoxy-5- ( (tetrahydrofuran-3-yl) oxy) benzoate

To a solution of (S) -2-bromo-5-methoxy-4- ( (tetrahydrofuran-3-yl) oxy) aniline (1.0 g, 3.4 mmol) in MeOH (10 mL) was added TEA (1.0 g, 10.4 mmol) and Pd (dppf) Cl ₂ (382 mg, 0.52 mmol) , the resulting mixture was stirred at 80 ℃ for 12 h under nitrogen atmosphere. The mixture was cooled to room temperature and the precipitate was filtered off. The residue was purified by column chromatography to provide the title product (900 mg, 96%yield) . LCMS: m/z (ESI) : 268.1 [M+H] ⁺.

Step 4: Methyl (S) -4-methoxy-2- (sulfamoylamino) -5- ( (tetrahydrofuran-3-yl) oxy) benzoate

To a solution of methyl (S) -2-amino-4-methoxy-5- ( (tetrahydrofuran-3-yl) oxy) benzoate (500 mg, 1.85 mmol) and sulfamoyl chloride (216 mg, 9.35 mmol) in THF (20 mL) was added LDA (200 mg, 9.35 mmol) dropwise at 0 ℃, the resulting mixture was stirred at 20 ℃ for 12 h under nitrogen atmosphere. The mixture was diluted with H ₂O (10 mL) and extracted with EtOAc (30 mL x 3) . The organic layer was concentrated. The residue was purified by column chromatography to give the title product (360 mg, 56.2%yield) as a yellow solid. LCMS: m/z (ESI) : 347.1 [M+H] ⁺.

Step 5: (S) -4-Hydroxy-7-methoxy-6- ( (tetrahydrofuran-3-yl) oxy) -1H-benzo [c] [1, 2, 6] thiadiazine 2, 2-dioxide

To a solution of methyl (S) -4-methoxy-2- (sulfamoylamino) -5- ( (tetrahydrofuran-3-yl) oxy) benzoate (100 mg, 0.29 mmol) in EtOH (5 mL) was added NaOH (60 mg, 1.45 mmol) , the resulting mixture was stirred at 20 ℃ for 12 h. The mixture was diluted with H ₂O (5 mL) and extracted with EtOAc (10 mL x 2) . The combined organic layers were washed with brine and dried over Na ₂SO ₄. The organic layer was concentrated to give the crude title product (1.0 g, 90%yield) . LCMS: m/z (ESI) : 315.0 [M+H] ⁺.

Step 6: (S) -4-Hydroxy-7-methoxy-1-methyl-6- ( (tetrahydrofuran-3-yl) oxy) -1H-benzo [c] [1, 2, 6] thiadiazine 2, 2-dioxide

To a solution of (S) -4-hydroxy-7-methoxy-6- ( (tetrahydrofuran-3-yl) oxy) -1H-benzo [c] [1, 2, 6] thiadiazine 2, 2-dioxide (100 mg, 0.32 mmol) in EtOH (5 mL) was added NaOH (25 mg, 0.63 mmol) , the mixture was stirred at 20 ℃ for 0.5 h, then MeI (45 mg, 0.32 mmol) was added. The resulting mixture was stirred at 20 ℃ for 12 h. The mixture was diluted with H ₂O (10 mL) and extracted with EtOAc (40 mL x 3) , the combined organic layers were washed with brine, dried over Na ₂SO ₄ and concentrated. The residue was purified by column chromatography to give the title product (50 mg, 50.1%yield) as a white solid. LCMS: m/z (ESI) : 329.1 [M+H] ⁺.

Step 7: 4- ( ( (R) -1- (3-Amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-1-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) -1H-benzo [c] [1, 2, 6] thiadiazine-2, 2-dioxide

To a solution of (R) -3- (1-aminoethyl) -5- (trifluoromethyl) aniline (50 mg, 0.23 mmol) and (S) -4-hydroxy-7-methoxy-1-methyl-6- ( (tetrahydrofuran-3-yl) oxy) -1H-benzo [c] [1, 2, 6] thiadiazine-2, 2-dioxide (50 mg, 0.15 mmol) in DMF (5 mL) was added BOP (135 mg, 0.3 mmol) and DBU (50 mg, 0.3 mmol) , the resulting mixture was stirred at 20 ℃ for 2 h. The mixture was diluted with H ₂O (5 mL) and extracted with EtOAc (10 mL) . The combined organic layer was concentrated and the residue was purified by prep-HPLC to afford the title product (5.5 mg, 99.4%purity) as a white solid. LCMS: m/z (ESI) : 515.2 [M+H] ⁺. ¹H NMR (400 MHz, MeOD) δ 7.53 (s, 1H) , 6.93 (s, 2H) , 6.82 (s, 1H) , 6.73 (s, 1H) , 5.33 (t, J = 6.9 Hz, 1H) , 5.06 (d, J = 3.6 Hz, 1H) , 4.08-3.94 (m, 5H) , 3.91-3.82 (m, 2H) , 3.37 (s, 3H) , 2.15 (td, J = 7.7, 4.2 Hz, 2H) , 1.59 (d, J = 7.0 Hz, 3H) .

Example 8

4- ( ( (R) -1- (3-Amino-5- (trifluoromethyl) phenyl) ethyl) amino) -1-isopropyl-7-methoxy-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) -1H-benzo [c] [1, 2, 6] thiadiazine 2, 2-dioxide

Step 1: (S) -2-Bromo-N-isopropyl-5-methoxy-4- ( (tetrahydrofuran-3-yl) oxy) aniline

A mixture of (S) -2-bromo-5-methoxy-4- ( (tetrahydrofuran-3-yl) oxy) aniline (300 mg, 1.0 mmol) , acetone (300 mg, 5.2 mmol) and TFA (0.1 mL) in DCE (5 mL) was stirred at r.t. for 1 h, then NaBH (OAc) ₃ (1.1 g, 5.2 mmol) was added. The resulting mixture was stirred at 20 ℃ for 12 h. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography to afford the title product (310 mg, 90%) as a white solid. ¹H NMR (400 MHz, CDCl ₃) δ 6.99 (s, 1H) , 6.27 (s, 1H) , 4.81 -4.77 (m, 1H) , 4.05 -3.97 (m, 2H) , 3.91 -3.86 (m, 2H) , 3.82 (s, 3H) , 3.60 (dt, J = 12.4, 6.4 Hz, 1H) , 2.21 -1.99 (m, 2H) , 1.25 (d, J = 6.4 Hz, 6H) .

Step 2: Methyl (S) -2- (isopropylamino) -4-methoxy-5- ( (tetrahydrofuran-3-yl) oxy) benzoate

To a solution of (S) -2-bromo-N-isopropyl-5-methoxy-4- ( (tetrahydrofuran-3-yl) oxy) aniline (310 mg, 0.94 mmol) in MeOH (10 mL) , then TEA (285 mg, 2.8 mmol, 3.0 eq) and Pd (dppf) Cl ₂ (105 mg, 0.14 mmol) was added. The resulting mixture was heated at 80 ℃ for 12 h under CO atmosphere. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography column to provide the title product (260 mg, 89%yield) . ¹H NMR (400 MHz, CDCl ₃) δ 7.66 (s, 1H) , 7.41 (s, 1H) , 6.16 (s, 1H) , 5.00 -4.59 (m, 1H) , 4.09 -3.79 (m, 9H) , 3.68 (dq, J = 12.8, 6.4 Hz, 1H) , 2.23 -2.00 (m, 2H) , 1.28 (d, J = 6.3 Hz, 6H) .

Step 3: Methyl (S) -2- ( (N- ( (benzyloxy) carbonyl) sulfamoyl) (isopropyl) amino) -4-methoxy-5- ( (tetrahydrofuran-3-yl) oxy) benzoate

To a solution of methyl (S) -2- (isopropylamino) -4-methoxy-5- ( (tetrahydrofuran-3-yl) oxy) benzoate (260 mg, 0.84 mmol) and TEA (4.4 g, 40 mmol) in dioxane (10 mL) was added benzyl (chlorosulfonyl) carbamate (629 mg, 2.5 mmol) at 0 ℃, and the mixture was stirred at 0 ～ r.t. for 18 h. The mixture was diluted with H ₂O (30 mL) and extracted with EtOAc (30 mL x 3) . The combined organic layers were concentrated under reduced pressure. The residue was purified by column to afford the title product (350 mg, 80%yield) as a white solid. LCMS: m/z (ESI) = 523.3 [M-H] .

Step 4: Methyl (S) -2- (isopropyl (sulfamoyl) amino) -4-methoxy-5- ( (tetrahydro furan-3 -yl) oxy) benzoate

To a solution of methyl (S) -2- ( (N- ( (benzyloxy) carbonyl) sulfamoyl) (isopropyl) amino) -4-methoxy-5- ( (tetrahydrofuran-3-yl) oxy) benzoate (300 mg, 0.57 mmol) in EtOAc (10 mL) was added Pd/C (50 mg) , and the mixture was stirred at r.t. for 1 h. The mixture was filtered and concentrated to give the title product (300 mg, crude) as a yellow solid. LCMS: m/z (ESI) = 389.2 [M+H] ⁺.

Step 5: 4- (4-Bromo-2- (2- (methylamino) ethoxy) -5-nitrophenoxy) butanoic acid

To a solution of methyl (S) -2- (isopropyl (sulfamoyl) amino) -4-methoxy-5- ( (tetrahydrofuran-3-yl) oxy) benzoate (300 mg, 0.77 mmol) in EtOH (15 mL) was added NaOH (362 mg, 1.5 mmol) , and the mixture was stirred at r.t. for 2 h. The reaction mixture was concentrated. The residue was purified by chromatography column to afford the title product (150 mg, 54%yield) as a white solid. LCMS: m/z (ESI) = 357.0 [M+H] ⁺. ¹H NMR (400 MHz, CDCl ₃) δ 12.85 (s, 1H) , 7.37 (s, 1H) , 7.01 (s, 1H) , 5.12 -5.09 (m, 1H) , 4.40 -4.26 (m, 1H) , 3.93 -3.72 (m, 7H) , 2.22 (td, J = 14.2, 8.2 Hz, 1H) , 2.04 -1.93 (m, 1H) , 1.23 (d, J = 6.4 Hz, 6H) .

Step 6: 4- ( ( (R) -1- (3-Amino-5- (trifluoromethyl) phenyl) ethyl) amino) -1-isopropyl -7-methoxy-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) -1H-benzo [c] [1, 2, 6] thiadiazine 2, 2-dioxide

To a solution of 4- (4-bromo-2- (2- (methylamino) ethoxy) -5-nitrophenoxy) butanoic acid (35 mg, 0.1 mmol) , (R) -3- (1-aminoethyl) -5- (trifluoromethyl) aniline (30 mg, 0.15 mmol) and DBU (71 mg, 0.45 mmol) in DMF (2 mL) was added BOP (60 mg, 1.5 mmol) , and the mixture was stirred at 20 ℃ for 12 h. The mixture was purified by pre-HPLC to afford the title product (5.8 mg, 11%yield) as a white solid. LCMS: m/z (ESI) = 543.3 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d ₆) δ 8.69 (s, 1H) , 7.46 (s, 1H) , 6.91 (s, 1H) , 6.78 (s, 2H) , 6.72 (s, 1H) , 5.59 (s, 2H) , 5.14 (s, 2H) , 4.31 (dt, J = 13.8, 6.8 Hz, 1H) , 3.96 -3.75 (m, 7H) , 2.31 -2.00 (m, 2H) , 1.52 (d, J = 6.9 Hz, 3H) , 1.20 (dd, J = 19.9, 6.8 Hz, 6H) .

Example 18-1 and 18-2

N- ( (S) -1- (8-aminoquinolin-6-yl) ethyl) -7-methoxy-2-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) quinazolin-4-amine

N- ( (R) -1- (8-aminoquinolin-6-yl) ethyl) -7-methoxy-2-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) quinazolin-4-amine

Step 1: 6-Bromo-8-nitroquinoline

Glycerol (4.7 mL, 62.0 mmol) was stirred at 160 ℃ for 30 min, then cooled down to 110 ℃, 4-bromo-2-nitroaniline (5.0 g, 23.0 mmol) and NaI (0.07 g, 0.48 mmol) were added. The resulting mixture was heated to 150 ℃, con. H ₂SO ₄ (2.8 mL, 53.0 mmol) was added, the mixture was stirred at 150 ℃ for 45 min. The mixture was poured into water (100 mL) , extracted with DCM (50 mL x 3) . The organic layer was washed with water (30 mL) and Brine (30 mL) , dried over Na ₂SO ₄, filtered and concentrated. The residue was purified by column chromatography to give the title product (2.4 g, 41.2%yield) . LCMS: m/z (ESI) = 253 [M+1] ⁺. ¹H NMR (300 MHz, DMSO-d ₆) : δ9.06 (d, J = 4.3Hz, 1H) , 8.52-8.66 (m, 3H) , 7.79 (dd, J = 8.4.2Hz, 1H) .

Step 2: 1- (8-Nitroquinolin-6-yl) ethan-1-one

A solution of tributyl (1-ethoxyvinyl) stannane (3.2 g, 8.9 mmol) , 6-bromo-8-nitroquinoline (1.5 g, 5.9 mmol) ) and Pd (PPh ₃) Cl ₂ (125 mg, 0.18 mmol) in toluene (75 mL) was stirred at 120 ℃ for 4 h under N ₂. The mixture was filtered through silica gel, the filtrates was poured into aq. HCl (4 M, 50 mL) and stirred at r.t. for 1 h. Then the mixture was extracted with EtOAc (100 mL × 2) , the organic layer was dried over Na ₂SO ₄, filtered and concentrated. The residue was purified by column chromatography to give the title product (920 mg, 71.8%yield) . LCMS: m/z (ESI) =217.0 [M+H] ⁺.

Step 3: (Z) -1- (8-Nitroquinolin-6-yl) ethan-1-one oxime

To a solution of 1- (8-nitroquinolin-6-yl) ethan-1-one (400 mg, 1.85 mmol) in EtOH (10 mL) was added NH ₂OH (193 mg, 2.8 mmol) and NaOH (80 mg, 2.0 mmol) , the mixture was stirred at 80 ℃ for 16 h. The mixture was poured into water (20 mL) , extracted with EtOAc (20 mL x 3) . The organic layer was dried over Na ₂SO ₄, filtered and concentrated to give the title product (405 mg, yield 94.7%) . LCMS: m/z (ESI) =232.0 [M+H] ⁺.

Step 4: 6- (1-Aminoethyl) quinolin-8-amine

To a solution of (Z) -1- (8-nitroquinolin-6-yl) ethan-1-one oxime (405 mg, 1.75 mmol) in MeOH (20 mL) was added Raney Ni (100 mg) , the mixture was stirred at 20 ℃ for 16 h under H ₂. The mixture was filtered and washed with MeOH (5 mL x 2) . The filtrates were concentrated to give the title product (270 mg, 82.5%yield) . LCMS: m/z (ESI) = 188.0 [M+H] ⁺.

Step 5: N- ( (R) -1- (8-aminoquinolin-6-yl) ethyl) -7-methoxy-2-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) quinazolin-4-amine

A solution of (S) -7-methoxy-2-methyl-6- ( (tetrahydrofuran-3-yl) oxy) quinazolin-4-ol (100 mg, 0.36 mmol) , BOP (208 mg, 0.47 mmol) and DBU (274 mg, 1.8 mmol) in DMF (10 mL) was stirred at 20 ℃ for 1 h, then 6- (1-aminoethyl) quinolin-8-amine (135 mg, 0.72 mmol) was added, the resulting mixture was stirred at 20 ℃ for 2 h. The mixture was poured into water (20 mL) , extracted with EtOAc (10 mL x 3) . The organic layer was dried over Na ₂SO ₄, filtered and concentrated. The residue was purified by column chromatography and SFC to give the title product (9.0 mg, 0.02 mmol) and the isomer (7.8 mg, 0.018 mmol) . LCMS: (m/z) (ESI) = 446.4 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d ₆) δ 8.66 (s, 1H) , 8.15 (d, J = 8.3 Hz, 1H) , 8.03 (s, 1H) , 7.74 (s, 1H) , 7.42 (s, 1H) , 7.08 (d, J = 24.8 Hz, 2H) , 6.95 (s, 1H) , 5.88 (s, 2H) , 5.18 (s, 1H) , 4.01-3.77 (m, 8H) , 2.35 (s, 3H) , 2.02 (s, 2H) , 1.64 (d, J = 5.9 Hz, 3H) .

Example 21-1 and 21-2

N- ( (R) -1- (4-amino-1-methyl-1H-indol-3-yl) ethyl) -7-methoxy-2-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) quinazolin-4-amine

N- ( (S) -1- (4-amino-1-methyl-1H-indol-3-yl) ethyl) -7-methoxy-2-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) quinazolin-4-amine

Step 1: 1- (4-Nitro-1H-indol-3-yl) ethan-1-one

To a solution of 4-nitro-1H-indole (1.0 g, 6.2 mmol) and acetyl chloride (581 mg, 7.4 mmol) in DCM (20 mL) was added SnCl ₄ (1.77 g, 6.8 mmol) drop-wise at 0 ℃, then the mixture was stirred at 20 ℃ for 4 h. The mixture was poured into water (50 mL) , extract with EtOAc (50 mL) . The organic layer was washed with Brine (50 mL) , dried over Na ₂SO ₄, filtered and concentrated. The residue was purified by column chromatography to give the title product (1.1 g, 87%yield) as a light green solid. LCMS: m/z (ESI) = 205.0 [M+H] ⁺.

Step 2: 1- (4-Nitro-1H-indol-3-yl) ethan-1-one

To a solution of 1- (4-nitro-1H-indol-3-yl) ethan-1-one (1.0 g, 4.9 mmol) in THF (25 mL) was added Cs ₂CO ₃ (4.8 g, 14.7 mmol) and MeI (1.0 g, 7.3 mmol) , the resulting mixture was stirred at 20 ℃ for 2 h. The mixture was poured into water (30 mL) , extracted with EtOAc (50 mL x 3) . The organic layer was washed with Brine (50 mL) . The combined organic layer was dried over Na ₂SO ₄ and filtered. The filtrates were concentrated to give the title product (0.98 g, 91.7%yield) as a brown solid. LCMS: m/z (ESI) = 219.0 [M+H] ⁺.

Step 3: Tert-butyl (3-acetyl-1-methyl-1H-indol-4-yl) carbamate

To a solution of 1- (4-nitro-1H-indol-3-yl) ethan-1-one (1.0 g, 4.5 mmol) and Boc ₂O (1.0 g, 4.5 mmol) in MeOH (50 mL) was added Pd/C (200 mg) , the mixture was stirred at 20 ℃ for 16 h under H ₂. The mixture was filtered, and washed with MeOH (10 mL x 2) . The filtrates were concentrated to give the title product (1.0 g, 77.7%yield) as a white solid. LCMS: m/z (ESI) = 189.1 [M+H] ⁺.

Step 4: Tert-butyl (Z) - (3- (1- (hydroxyimino) ethyl) -1-methyl-1H-indol-4-yl) carbamate

To a solution of tert-butyl (3-acetyl-1-methyl-1H-indol-4-yl) carbamate (385 mg, 1.34 mmol) in EtOH (10 mL) was added NH ₂OH (186 mg, 2.67 mmol) and NaOH (70 mg, 1.74 mmol) , the mixture was stirred at 80 ℃ for 16 h. The mixture was poured into water (20 mL) , extracted with EtOAc (20 mL x 3) . The organic layer was dried over Na ₂SO ₄ and filtered. The filtrates were concentrated to give the title product (390 mg, 96.4%yield) as a white solid. LCMS: m/z (ESI) = 304.3 [M+H] ⁺.

Step 5: Tert-butyl (3- (1-aminoethyl) -1-methyl-1H-indol-4-yl) carbamate

To a solution of tert-butyl (Z) - (3- (1- (hydroxyimino) ethyl) -1-methyl-1H-indol-4-yl) carbamate (390 mg, 1.3 mmol) in MeOH (10 mL) was added Raney Ni (100 mg) , the mixture was stirred at 20 ℃ for 16 h under H ₂. The mixture was filtrated, and the filtrates was concentrated to give the title product (273 mg, 73.3%yield) . LCMS: m/z (ESI) = 273.2 [M+H] ⁺.

Step 6: 3- (1-Aminoethyl) -1-methyl-1H-indol-4-amine

To a solution of tert-butyl (3- (1-aminoethyl) -1-methyl-1H-indol-4-yl) carbamate (273 mg, 0.94 mmol) in DCM (10 mL) was added HCl in dioxane (4.0 M, 3 mL) , the resulting mixture was stirred at 20 ℃ for 16 h. The mixture was concentrated to give the title product (170 mg, 95.2%yield) . LCMS: m/z (ESI) = 173.2 [M+H] ⁺.

Step 7: N- ( (R) -1- (4-amino-1-methyl-1H-indol-3-yl) ethyl) -7-methoxy-2-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) quinazolin-4-amine

A solution of (S) -7-methoxy-2-methyl-6- ( (tetrahydrofuran-3-yl) oxy) quinazolin-4-ol (40 mg, 0.15 mmol) , BOP (83 mg, 0.18 mmol) and DBU (110 mg, 0.72 mmol) in DMF (2 mL) was stirred at 20 ℃ for 1 h, then 3- (1-aminoethyl) -1-methyl-1H-indol-4-amine (55 mg, 0.29 mmol) was added, the resulting mixture was stirred at 20 ℃ overnight. The mixture was poured into water (20 mL) , extracted with EtOAc (10 mL x 3) . The organic layer was dried over Na ₂SO ₄, filtered and concentrated. The residue was purified by column chromatography and SFC to give the title product (7.49 mg, 11.5%yield, and the isomer 4.72 mg) . LCMS: m/z (ESI) = 448.3 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d ₆) δ 7.90-7.92 (m, 1H) , 7.62 (s, 1H) , 7.24 (s, 1H) , 7.04 (s, 1H) , 6.79-6.83 (m, 1H) , 6.58-6.60 (m, 1H) , 6.13-6.20 (m, 2H) , 5.29 (s, 2H) , 5.11 (s, 1H) , 3.90-3.97 (m, 2H) , 3.85 (s, 3H) , 3.79-3.83 (m, 2H) , 3.70 (s, 3H) , 2.45 (s, 3H) , 2.14-2.25 (m, 1H) , 1.85-2.20 (m, 1H) , 1.65 (d, J = 8 Hz, 3H) .

Example 22-1 and 22-2

5- ( (R) -1- ( (7-methoxy-2-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) quinazolin-4-yl) amino) ethyl) -4-methylthiazol-2-amine

5- ( (S) -1- ( (7-methoxy-2-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) quinazolin-4-yl) amino) ethyl) -4-methylthiazol-2-amine

Step 1: Tert-butyl (5-acetyl-4-methylthiazol-2-yl) carbamate

To a solution of 1- (2-amino-4-methylthiazol-5-yl) ethan-1-one (487 mg, 3.1 mmol) in DCM (10 mL) was added Boc ₂O (1.02 g, 4.6 mmol) and TEA (632 mg, 6.2 mmol) , the mixture was stirred at 20 ℃ for 2 h. The mixture was poured into water (20 mL) , extracted with EtOAc (20 mL x 3) . The organic layer was dried over Na ₂SO ₄, filtered and concentrated. The residue was purified by column chromatography to give the title product (713 mg, 89.2%yield) .

Step 2: Tert-butyl (Z) - (5- (1- (hydroxyimino) ethyl) -4-methylthiazol-2-yl) carbamate

To a solution of tert-butyl (5-acetyl-4-methylthiazol-2-yl) carbamate (713 mg, 2.7 mmol) in EtOH (10 mL) was added NH ₂OH (386 mg, 5.6 mmol) and NaOH (144 mg, 3.6 mmol) , the resulting mixture was stirred at 80 ℃ for 16 h. The mixture was poured into water (20 mL) , extracted with EtOAc (20 mL x 3) . The organic layer was dried over Na ₂SO ₄ and filtered. The filtrates were concentrated to give the title product (575 mg, 76.3%yield) . LCMS: m/z (ESI) = 272.2 [M+H] ⁺.

Step 3: Tert-butyl (5- (1-aminoethyl) -4-methylthiazol-2-yl) carbamate

To a solution of tert-butyl (Z) - (5- (1- (hydroxyimino) ethyl) -4-methylthiazol-2-yl) carbamate (575 mg, 2.1 mmol) in MeOH (10 mL) was added Raney Ni (100 mg) , the resulting mixture was stirred at 20 ℃ for 16 h under H ₂. The mixture was filtered and washed with MeOH (5 mL x 2) , the filtrates was concentrated to give the title product (436 mg, 80.0%yield) . LCMS: m/z (ESI) = 241.3 [M+H] ⁺.

Step 4: Tert-butyl (5- ( (R) -1- ( (7-methoxy-2-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) quinazolin-4-yl) amino) ethyl) -4-methylthiazol-2-yl) carbamate

A solution of (S) -7-methoxy-2-methyl-6- ( (tetrahydrofuran-3-yl) oxy) quinazolin-4-ol (50 mg, 0.18 mmol) , BOP (104 mg, 0.24 mmol) and DBU (138 mg, 0.91 mmol) in DMF (2 mL) was stirred at 20 ℃ for 1 h, then tert-butyl (5- (1-aminoethyl) -4-methylthiazol-2-yl) carbamate (93 mg, 0.36 mmol) was added, the resulting mixture was stirred at 20 ℃ overnight. The mixture was poured into water (20 mL) , extracted with EtOAc (10 mL x 3) . The organic layer was dried over Na ₂SO ₄, filtered and concentrated. The residue was purified by column chromatography to give the title product (45 mg, 48.2%yield) . LCMS: m/z (ESI) = 516.2 M+H] ⁺.

Step 5: 5- ( (R) -1- ( (7-Methoxy-2-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) quinazolin-4-yl) amino) ethyl) -4-methylthiazol-2-amine

To a solution of tert-butyl (5- ( (R) -1- ( (7-methoxy-2-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) quinazolin-4-yl) amino) ethyl) -4-methylthiazol-2-yl) carbamate (45 mg, 0.087 mmol) in DCM (10 mL) was added HCl in dioxane (3 mL, 4 M) , the mixture was stirred at 20 ℃ for 4 h. The mixture was concentrated and purified by Pre-HPLC and SFC to give the title product (7.2 mg, 19.7%yield) and the isomer (7.5 mg, 20.6%yield) . LCMS: m/z (ESI) = 416.3 [M+H] ⁺.

Example 23

Step 1: N- ( (R) -1- (6-aminopyridin-2-yl) ethyl) -7-methoxy-2-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) quinazolin-4-amine

A solution of (S) -7-methoxy-2-methyl-6- ( (tetrahydrofuran-3-yl) oxy) quinazolin-4-ol (20 mg, 0.07 mmol) , BOP (41.6 mg, 0.09 mmol) , DBU (55.1 mg, 0.36 mmol) in DMF (2 mL) was stirred at 20 ℃ for 1 h, then (R) -6- (1-aminoethyl) pyridin-2-amine (19.8 mg, 0.14 mmol) was added. The resulting mixture was stirred at 20 ℃ overnight. The mixture was poured into water (20 mL) , extracted with EtOAc (10 mL x 3) , dried over Na ₂SO ₄, filtered and concentrated. The residue was purified by column chromatography to give the title product (1.0 mg, 3.61%yield) . LCMS: m/z (ESI) =396.1 [M+H] ⁺. ¹H NMR (400 MHz, MeOD) δ 8.43 (s, 1H) , 7.82 (s, 1H) , 7.50 -7.41 (m, 1H) , 7.08 (s, 1H) , 6.69 (d, J = 7.3 Hz, 1H) , 6.50 (d, J = 8.3 Hz, 1H) , 5.61 (q, J =6.9 Hz, 1H) , 5.22 (s, 1H) , 4.08-3.90 (m, 7H) , 2.58 (s, 3H) , 2.42-2.15 (m, 2H) , 1.68 (d, J = 7.0 Hz, 3H) .

Example 28

4- ( ( (R) -1- (3-Amino-5- (trifluoromethyl) phenyl) ethyl) amino) -1-cyclopropyl-7-methoxy-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) -1H-benzo [c] [1, 2, 6] thiadiazine 2, 2-dioxide

Step 1: Methyl (S) -2- (cyclopropylamino) -4-methoxy-5- ( (tetrahydrofuran-3-yl) oxy) benzoate

A solution of methyl (S) -2-amino-4-methoxy-5- ( (tetrahydrofuran-3-yl) oxy) benzoate (0.5 g, 1.87 mmol) , cyclopropylboronic acid (0.96 g, 11.2 mmol) , Cu (OAc) ₂ (2.0 g, 11.2 mmol) , bipyridine (1.7 g. 11.2 mmol) and Na ₂CO ₃ (1.1 g, 11.2 mmol) in DME (10 mL) was stirred at 60 ℃ for 12 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by column to give the title product (190 mg, 33%yield) as a yellow solid. ¹H NMR (400 MHz, CDCl ₃) δ 7.79 (s, 1H) , 7.39 (s, 1H) , 6.62 (s, 1H) , 4.82 (t, J = 5.2 Hz, 1H) , 4.03 (dd, J = 16.2, 9.1 Hz, 2H) , 3.94 -3.87 (m, 5H) , 3.80 (s, 3H) , 2.51 -2.40 (m, 1H) , 2.21 -2.15 (m, 1H) , 0.84 -0.76 (m, 2H) , 0.63 -0.52 (m, 2H) .

Step 2: Methyl (S) -2- ( (N- ( (benzyloxy) carbonyl) sulfamoyl) (cyclopropyl) amino) -4-methoxy-5- ( (tetrahydrofuran-3-yl) oxy) benzoate

To a solution of methyl (S) -2- (cyclopropylamino) -4-methoxy-5- ( (tetrahydrofuran-3-yl) oxy) benzoate (150 mg, 0.48 mmol) in 1, 4-dioxane (5 mL) was added benzyl (chlorosulfonyl) carbamate (1.2 g, 4.8 mmol) and TEA (2.4 g, 24 mmol) , and the mixture was stirred at 0～r.t. for 18 h. The mixture was diluted with H ₂O (20 mL) , extracted with EtOAc (20 mL x 2) . The organic layer was concentrated under reduced pressure. The residue was purified by column to give the title product (150 mg, 60%yield) as a white solid. LCMS: m/z (ESI) = 521.3 [M+H] ⁺.

Step 3: Methyl (S) -2- (cyclopropyl (sulfamoyl) amino) -4-methoxy-5- ( (tetra hydrofuran-3-yl) oxy) benzoate

To a solution of methyl (S) -2- ( (N- ( (benzyloxy) carbonyl) sulfamoyl) (cyclopropyl) amino) -4-methoxy-5- ( (tetrahydrofuran-3-yl) oxy) benzoate (150 mg, 0.28 mmol) in EtOAc (3 mL) was added Pd/C (50 mg) , and the mixture was stirred at r.t. for 1 h. The mixture was filtered, and the filtrates were concentrated to give the title product (100 mg, 90 %yield) . LCMS m/z (ESI) = 387 [M+1] ⁺.

Step 4: (S) -1-cyclopropyl-4-hydroxy-7-methoxy-6- ( (tetrahydrofuran-3-yl) oxy) -1H-benzo [c] [1, 2, 6] thiadiazine 2, 2-dioxide

To a solution of methyl (S) -2- (cyclopropyl (sulfamoyl) amino) -4-methoxy-5- ( (tetra hydrofuran-3-yl) oxy) benzoate (100 mg, 0.26 mmol) in EtOH (4 mL) was added NaOH (12 mg, 0.52 mmol) , and the mixture was stirred at r.t. for 2 h. The mixture was concentrated. The residue was purified by column to give the title product (30 mg, 32%yield) as a white solid. ¹H NMR (400 MHz, DMSO) δ 7.33 (s, 1H) , 6.97 (s, 1H) , 4.90 (d, J = 1.7 Hz, 1H) , 3.91 -3.73 (m, 7H) , 2.49 -2.44 (m, 1H) , 2.12 (td, J =14.2, 8.3 Hz, 1H) , 2.03 -1.92 (m, 1H) , 1.00 (d, J = 4.7 Hz, 2H) , 0.83 (dd, J = 6.6, 3.6 Hz, 2H) .

Step 5: N- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6a, 7, 9, 9a-tetrahydrofuro [3', 4': 5, 6] [1, 4] dioxino [2, 3-g] quinazolin-4-amine

A solution of (S) -1-cyclopropyl-4-hydroxy-7-methoxy-6- ( (tetrahydrofuran-3-yl) oxy) -1H-benzo [c] [1, 2, 6] thiadiazine 2, 2-dioxide (30 mg, 0.084 mmol) , (R) -3- (1-amino-ethyl) -5- (trifluoromethyl) aniline (34.6 mg, 0.16 mmol) in DMF (3 mL) was stirred at r.t. for 12 h. The mixture was diluted with H ₂O (15 mL) and extracted with EtOAc (30 mL x 2) . The combined organic layers were concentrated and the residue was purified by prep-HPLC to afford the title product (0.6 mg, 95%purity) as a white solid. LCMS: m/z (ESI) = 541.6 [M+1] ⁺. ¹H NMR (400 MHz, MeOD) δ 7.50 (s, 1H) , 7.19 (s, 1H) , 6.93 (s, 2H) , 6.82 (s, 1H) , 5.32 (s, 1H) , 5.06 (s, 1H) , 4.01 (d, J = 7.9 Hz, 2H) , 3.98 (s, 3H) , 3.91 (d, J = 4.3 Hz, 2H) , 2.78 (s, 1H) , 2.16 (s, 2H) , 1.59 (d, J = 7.0 Hz, 3H) , 1.13 (d, J = 6.4 Hz, 2H) , 0.91 (d, J = 13.2 Hz, 2H) .

Example 38

(R) -4- ( (1- (3-Amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2, 9-dimethyl-8, 9, 12, 13-tetrahydro-7H- [1, 4] dioxa [7] azacycloundecino [3, 2-g] quinazolin-10 (11H) -one

Step 1: Methyl 4- (4-bromo-2-fluorophenoxy) butanoate

To a solution of 4-bromo-2-fluorophenol (50 g, 261 mmol) and methyl 4-bromobutanoate (71 g, 392 mmol) in THF (500 mL) was added K ₂CO ₃ (72 g, 523 mmol) . The mixture was stirred at 70 ℃ for 3 h. The mixture was concentrated under reduced pressure. The residue was purified by chromatography column to afford the title product (72 g, 94%yield) as a yellow oil. LCMS: m/z (ESI) = 292.8 [M+H] ⁺. ¹H NMR (400 MHz, CDCl ₃) δ 7.25 -7.13 (m, 2H) , 6.82 (t, J = 8.7 Hz, 1H) , 4.05 (t, J =6.1 Hz, 2H) , 3.69 (s, 3H) , 2.52 (dt, J = 11.2, 7.2 Hz, 2H) , 2.22 -2.07 (m, 2H) .

Step 2: Methyl 4- (4-bromo-2-fluoro-5-nitrophenoxy) butanoate

To a solution of methyl 4- (4-bromo-2-fluorophenoxy) butanoate (70 g, 240 mmol) in H ₂SO ₄ (500 mL) was added KNO ₃ (24 g, 240 mmol) at 0 ℃, and the mixture was stirred at 0 ℃ for 2 h. The mixture was diluted with H ₂O (800 mL) and extracted with EtOAc (500 mL x 3) . The combined organic layers were concentrated. The residue was purified by column to afford the title product (27 g, 33%yield) as a yellow solid. ¹H NMR (400 MHz, CDCl ₃) δ 7.57 (d, J = 7.7 Hz, 1H) , 7.43 (t, J = 8.9 Hz, 1H) , 4.14 (t, J = 6.1 Hz, 2H) , 3.70 (s, 3H) , 2.55 (t, J = 7.0 Hz, 2H) , 2.22 -2.14 (m, 2H) .

Step 3: Methyl 4- (4-bromo-2- (2- ( (tert-butoxycarbonyl) (methyl) amino) ethoxy) -5-nitrophenoxy) butanoate

To a solution of tert-butyl (2-hydroxyethyl) (methyl) carbamate (4.7 g, 26.8 mmol) in THF (50 mL) was added NaH (1.1 g, 26.8 mmol) at 0 ℃ , then methyl 4- (4-bromo-2-fluoro-5-nitrophenoxy) butanoate (6.0 g, 17.8 mmol) was added, and the mixture was stirred at 0 ℃ for 1 h. The mixture was diluted with H ₂O (50 mL) and extracted with EtOAc (50 mL x 3) . The combined organic layers were concentrated. The residue was purified by column to afford the title product (4.0 g, 46%yield) as a yellow solid. ¹H NMR (400 MHz, CDCl ₃) δ 7.55 (s, 1H) , 7.09 (d, J = 12.6 Hz, 1H) , 4.14 (dd, J = 18.0, 10.9 Hz, 2H) , 4.07 (t, J = 6.2 Hz, 2H) , 3.69 (s, 3H) , 3.66 (s, 2H) , 3.01 (s, 3H) , 2.62 -2.48 (m, 2H) , 2.22 -2.09 (m, 2H) , 1.45 (d, J = 5.6 Hz, 9H) .

Step 4: 4- (4-Bromo-2- (2- ( (tert-butoxycarbonyl) (methyl) amino) ethoxy) -5-nitro phenoxy) butanoic acid

A solution of methyl 4- (4-bromo-2- (2- ( (tert-butoxycarbonyl) (methyl) amino) ethoxy) -5-nitrophenoxy) butanoate (4.0 g, 8.1 mmol) and LiOH ^. H ₂O (1.3 g, 32.6 mmol) in H ₂O (4 mL) , THF (20 mL) and MeOH (12 mL) was stirred at r.t. for 2 h. The mixture was adjusted to pH = 3 with 1 M aq. HCl, and extracted with (DCM/MeOH = 10/1, 30 mL x 5) . The combined organic layer was dried over Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography column to give the title product (3.5 g, 90%yield) as a yellow solid. LCMS: m/z (ESI) = 377.0 [M-100] ⁺.

Step 5: 4- (4-Bromo-2- (2- (methylamino) ethoxy) -5-nitrophenoxy) butanoic acid

To a solution of 4- (4-bromo-2- (2- ( (tert-butoxycarbonyl) (methyl) amino) ethoxy) -5-nitrophenoxy) butanoic acid (3.5 g, 7.3 mmol) in HCl/dioxane (1 M, 25 mL) . The mixture was stirred at 20 ℃ for 2 h. EtOAc (20 mL) was added, and the mixture was filtered. The filter cake was dried to give the title product (3.9 g, HCl salt) as a yellow solid. LCMS: m/z (ESI) = 376.9 [M+H] ⁺.

Step 6: 12-Bromo-4-methyl-11-nitro-3, 4, 7, 8-tetrahydro-2H-benzo [b] [1, 4] dioxa [7] azacycloundecin-5 (6H) -one

To a solution of 4- (4-bromo-2- (2- (methylamino) ethoxy) -5-nitrophenoxy) butanoic acid (3.9 g, 10.3 mmol) and DIPEA (8.0 g, 62 mmol) in DMF (500 mL) was added HATU (5.2 g, 15 mmol) . The mixture was stirred at 20 ℃ for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by chromatography column to afford the title product (750 mg, 20%yield) as a yellow solid. ¹H NMR (400 MHz, CDCl ₃) δ 7.72 (s, 1H) , 7.09 (s, 1H) , 4.67 -4.49 (m, 1H) , 4.46 -4.29 (m, 1H) , 4.25 –3.95 (m, 4H) , 3.02 (s, 3H) , 2.64 -2.32 (m, 2H) , 2.28 -2.11 (m, 2H) .

Step 7: Methyl 4-methyl-11-nitro-5-oxo-3, 4, 5, 6, 7, 8-hexahydro-2H-benzo [b] [1, 4] dioxa [7] azacycloundecine-12-carboxylate

A solution of 12-bromo-4-methyl-11-nitro-3, 4, 7, 8-tetrahydro-2H-benzo [b] [1, 4] dioxa [7] azacycloundecin-5 (6H) -one (750 mg, 2.1 mmol) , Pd (dppf) Cl ₂ (140 mg, 0.2 mmol) , TEA (633 mg, 6.3 mmol) in MeOH (10 mL) was stirred at 80 ℃ for 8 h under CO atmosphere. The mixture was diluted with H ₂O (10 mL) and extracted with EtOAc (20 mL x 3) . The mixture was concentrated under reduced pressure. The residue was purified by column to afford the title product (420 mg, 59%yield) as a yellow solid. LCMS: m/z (ESI) = 339.0 [M+H] ⁺.

Step 8: Methyl 11-amino-4-methyl-5-oxo-3, 4, 5, 6, 7, 8-hexahydro-2H-benzo [b] [1, 4] dioxa [7] azacycloundecine-12-carboxylate

To a solution of methyl4-methyl-11-nitro-5-oxo-3, 4, 5, 6, 7, 8-hexahydro-2H-benzo [b] [1, 4] dioxa [7] azacycloundecine-12-carboxylate (420 mg, 1.2 mmol) in MeOH (10 mL) was added Pd/C (132 mg, 0.12 mmol) , and the mixture was stirred at 20 ℃ for 8 h under H ₂ atmosphere. The mixture was filtered. The filtrates were concentrated to afford the title product (290 mg, 76%yield) as a yellow solid. LCMS: m/z (ESI) =339.0 [M+H] ⁺.

Step 9: 4-Hydroxy-2, 9-dimethyl-8, 9, 12, 13-tetrahydro-7H- [1, 4] dioxa [7] aza cycloundecino [3, 2-g] quinazolin-10 (11H) -one

A solution of methyl11-amino-4-methyl-5-oxo-3, 4, 5, 6, 7, 8-hexahydro-2H-benzo [b] [1, 4] dioxa [7] azacycloundecine-12-carboxylate (290 mg, 0.94 mmol) in CH ₃CN (10 mL) and HCl/dioxane (4 M, 2.9 mL) was stirred at 100 ℃ for 6 h under N ₂ atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by pre-TLC to afford the title product (180 mg, 60%yield) as a white solid. ¹H NMR (400 MHz, DMSO) δ 12.08 (s, 1H) , 7.58 -7.47 (m, 1H) , 7.15 -7.02 (m, 1H) 4.43 -4.06 (m, 4H) , 3.70 -3.25 (m, 2H) , 2.90 (s, 3H) , 2.75 -2.60 (m, 2H) , 2.30 (s, 3H) , 2.07 (d, J = 12.4, 2H) .

Step 10: (R) -4- ( (1- (3-Amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2, 9-dimethyl-8, 9, 12, 13-tetrahydro-7H- [1, 4] dioxa [7] azacycloundecino [3, 2-g] quinazolin-10 (11H) -one

To a solution of 4-hydroxy-2, 9-dimethyl-8, 9, 12, 13-tetrahydro-7H- [1, 4] dioxa [7] azacycloundecino [3, 2-g] quinazolin-10 (11H) -one (30 mg, 0.09 mmol) , DBU (71 mg, 0.45 mmol) and (R) -3- (1-aminoethyl) -5- (trifluoromethyl) aniline (29 mg, 0.14 mmol) in DMF (2 mL) was added BOP (60 mg, 1.5 mmol) , and the mixture was stirred at 20 ℃ for 12 h. The mixture was purified by pre-HPLC to afford the title product (9.8 mg, 20%yield) as a white solid. LCMS: m/z (ESI) = 504.3 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d ₆) δ 8.01 (d, J = 5.0 Hz, 1H) , 7.95 -7.77 (m, 1H) , 7.06 (d, J = 60.5 Hz, 1H) , 6.86 (d, J = 11.9 Hz, 2H) , 6.69 (s, 1H) , 5.53 (s, 3H) , 4.50 -4.05 (m, 4H) , 3.22 -3.10 (m, 1H) , 2.82 (s, 3H) , 2.34 (s, 3H) , 2.15 –1.90 (m, 2H) , 1.80 -1.70 (m, 1H) , 1.64 -1.48 (m, 5H) .

Example 40

N- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -7- (methoxymethyl) -2-methyl-7, 8-dihydro- [1, 4] dioxino [2, 3-g] quinazolin-4-amine

Step 1: Methyl 3- (hydroxymethyl) -2, 3-dihydrobenzo [b] [1, 4] dioxine-6-carboxylate

A solution of methyl 3, 4-dihydroxybenzoate (10.0 g, 59.5 mmol) in DMF (100 mL) was added K ₂CO ₃ (16.4 g, 119 mmol) , and the mixture was stirred at 100 ℃ for 30 min, then 2, 3-dibromopropan-1-ol (12.8 g, 59.5 mmol) was added, and the mixture was stirred at 100 ℃ for 18 h. The mixture was diluted with H ₂O (150 mL) and extracted with EtOAc (150 mL x 3) . The combined organic layers were concentrated. The residue was purified by chromatography column to afford the title product (3.0 g, 30%yield) as a white solid. LCMS: m/z (ESI) = 225.0 [M+H] ⁺.

Step 2: Methyl 3- (methoxymethyl) -2, 3-dihydrobenzo [b] [1, 4] dioxine-6-carboxylate

To a solution of methyl 3- (hydroxymethyl) -2, 3-dihydrobenzo [b] [1, 4] dioxine-6-carboxylate (3.0 g, 13.3 mmol) in THF (30 mL) was added NaH (0.8 g, 20.0 mmol) , CH ₃I (2.9 g, 17.4 mmol) at 0 ℃, and the mixture was stirred at 0 ～ r.t. for 2 h. The mixture was diluted with H ₂O (15 mL) and extracted with EtOAc (50 mL x 3) . The combined organic layers were concentrated. The residue was purified by chromatography column to afford the title product (0.8 g, 25%yield) as a white solid. ¹H NMR (400 MHz, CDCl ₃) δ 7.66 -7.50 (m, 2H) , 6.90 (dd, J = 12.1, 8.5 Hz, 1H) , 4.40 -4.22 (m, 2H) , 4.16 -4.02 (m, 1H) , 3.86 (s, 3H) , 3.69 -3.58 (m, 2H) , 3.43 (s, 3H) .

Step 3: Methyl 3- (methoxymethyl) -7-nitro-2, 3-dihydrobenzo [b] [1, 4] dioxine-6-carboxylate

To a solution of methyl 3- (methoxymethyl) -2, 3-dihydrobenzo [b] [1, 4] dioxine-6-carboxylate (0.8 g, 3.3 mmol) in H ₂SO ₄ (15 mL) was added KNO ₃ (0.34 g, 3.3 mmol) at 0 ℃, and the mixture was stirred at 0～r.t. for 2 h. The mixture was diluted with H ₂O (15 mL) and extracted with EtOAc (50 mL x 3) . The combined organic layers were concentrated. The residue was purified by chromatography column to afford the title product (500 mg, 52 %yield) as a white solid. LCMS: m/z (ESI) = 283.0 [M+H] ⁺.

Step 4: Methyl 7-amino-3- (methoxymethyl) -2, 3-dihydrobenzo [b] [1, 4] dioxine-6-carboxylate

To a solution of methyl 3- (methoxymethyl) -7-nitro-2, 3-dihydrobenzo [b] [1, 4] dioxine-6-carboxylate (0.45 g, 1.6 mmol) in MeOH (5 mL) was added Pd/C (45 mg, 10 w%) , and the mixture was stirred at r.t. for 2 h under H ₂ atmosphere . The mixture was filtered and concentrated to give the title product (400 mg, 89%yield) as a yellow solid. LCMS: m/z (ESI) = 254.0 [M+H] ⁺.

Step 5: 7- (Methoxymethyl) -2-methyl-7, 8-dihydro- [1, 4] dioxino [2, 3-g] quinazolin-4-ol

To a solution of methyl 7-amino-3- (methoxymethyl) -2, 3-dihydrobenzo [b] [1, 4] dioxine-6-carboxylate (400 mg, 1.5 mmol) in CH ₃CN (1 mL) and HCl/dioxane (4 M, 2 mL) was stirred at 100 ℃ for 3 h. The mixture was concentrated under reduced pressure. The residue was purified by chromatography column to afford the title product (120 mg, 29%yield) . ¹H NMR (400 MHz, DMSO) δ 11.97 (s, 1H) , 7.42 (d, J = 3.3 Hz, 1H) , 7.01 (s, 1H) , 4.45 -4.39 (m, 2H) , 4.15 -4.10 (m, 1H) , 3.68 -3.58 (m, 2H) , 3.33 (s, 3H) , 2.28 (s, 3H) .

Step 6: N- ( (R) -1- (3-Amino-5- (trifluoromethyl) phenyl) ethyl) -7- (methoxymethyl) -2-methyl-7, 8-dihydro- [1, 4] dioxino [2, 3-g] quinazolin-4-amine

A solution of 7- (methoxymethyl) -2-methyl-7, 8-dihydro- [1, 4] dioxino [2, 3-g] quinazolin-4-ol (50 mg, 0.19 mmol) , (R) -3- (1-aminoethyl) -5- (trifluoromethyl) aniline (58 mg, 0.28 mmol) , BOP (170 mg, 0.38 mmol, DBU (176 mg , 1.15 mmol) in DMF (3 mL) was stirred at r.t. for 12 h. The mixture was diluted with H ₂O (15 mL) and extracted with EtOAc (30 mL x 3) . The combined organic layers were concentrated. The residue was purified by prep-HPLC to afford the title product (19 mg, 22%yield) as a white solid. LCMS: m/z (ESI) = 449.2 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H) , 7.96 (dd, J = 24.6, 12.8 Hz, 2H) , 6.99 (s, 1H) , 6.85 (d, J = 20.6 Hz, 2H) , 6.68 (s, 1H) , 5.49 (dd, J = 14.7, 7.1 Hz, 4H) , 4.45 (dd, J = 11.2, 8.8 Hz, 2H) , 4.13 (dd, J = 10.3, 6.3 Hz, 1H) , 3.62 (d, J = 4.2 Hz, 2H) , 3.33 (s, 3H) , 2.33 (s, 3H) , 1.50 (d, J = 7.0 Hz, 3H) .

Example 42

N- ( (R) -1- (3-Amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6a, 7, 9, 9a-tetrahydrofuro [3', 4': 5, 6] [1, 4] dioxino [2, 3-g] quinazolin-4-amine

Step 1: Tetrahydrofuran-3, 4-diyl dimethanesulfonate

To a solution of methyl tetrahydrofuran-3, 4-diol (2.0 g, 19.2 mmol) and Et ₃N (9.7 g, 96 mmol) in DCM (30 mL) was added MsCl (5.5 g, 48 mmol) at 0 ℃, and the mixture was stirred at 0 ℃ for 2 h. Then the mixture was diluted with H ₂O (50 mL) and extracted with EtOAc (50 mL x 3) . The combined organic layers were concentrated to afford the title product (5 g, crude) as a yellow oil, which was used in next step without purification. LCMS: m/z (ESI) = 260.9 [M+H] ⁺. ¹H NMR (400 MHz, DMSO) δ 5.40 -5.28 (m, 2H) , 4.07 -4.01 (m, 2H) , 3.82 (dd, J = 10.0, 3.8 Hz, 2H) , 3.29 (s, 6H) .

Step 2: Methyl 1, 3, 3a, 9a-tetrahydrobenzo [b] furo [3, 4-e] [1, 4] dioxine-6-carboxylate

To a solution of methyl 3, 4-dihydroxybenzoate (3.0 g, 17.8 mmol) in DMF (30 mL) was added Cs ₂CO ₃ (11.6 g, 35.7 mmol) , and the mixture was stirred at 100 ℃ for 30 min. Then tetrahydrofuran-3, 4-diyl dimethanesulfonate (4.6 g, 17.8 mmol) was added, and the mixture was stirred at 100 ℃ for 18 h. The mixture was diluted with H ₂O (50 mL) and extracted with EtOAc (50 mL x 3) . The combined organic layers were concentrated. The residue was purified by chromatography column to afford the title product (1.3 g, 30%yield) as a white solid. ¹H NMR (400 MHz, CDCl3) δ 7.60 (q, J = 1.7 Hz, 2H) , 6.94 (dd, J = 8.0, 0.7 Hz, 1H) , 4.69 (dtd, J = 9.2, 5.1, 4.1 Hz, 2H) , 4.14 (dt, J = 11.2, 5.6 Hz, 2H) , 3.93 (dt, J = 9.5, 4.8 Hz, 2H) , 3.88 (s, 3H) .

Step 3: Methyl 7-nitro-1, 3, 3a, 9a-tetrahydrobenzo [b] furo [3, 4-e] [1, 4] dioxine-6-carboxylate

To a solution of methyl 1, 3, 3a, 9a-tetrahydrobenzo [b] furo [3, 4-e] [1, 4] dioxine-6-carboxylate (1.3 g, 5.5 mmol) in H ₂SO ₄ (30 mL) was added KNO ₃ (0.56 g, 5.5 mmol) at 0 ℃, and the mixture was stirred at 0 ～ r.t. for 2 h. The mixture was diluted with H ₂O (15 mL) and extracted with EtOAc (50 mL x 3) . The combined organic layers were concentrated. The residue was purified by chromatography column to afford the title product (450 mg, 30 %yield) as a white solid. ¹H NMR (400 MHZ, DMSO-d ₆) δ7.55 (s, 1H) , 7.23 (s, 1H) , 4.80 -4.73 (m, 2H) , 4.20 -4.16 (m, 2H) , 3.94 -3.89 (m, 2H) , 3.88 (s, 3H) .

Step 4: Methyl 7-amino-1, 3, 3a, 9a-tetrahydrobenzo [b] furo [3, 4-e] [1, 4] dioxine-6-carboxylate

To a solution of methyl 7-nitro-1, 3, 3a, 9a-tetrahydrobenzo [b] furo [3, 4-e] [1, 4] dioxine-6-carboxylate (200 mg, 0.8 mmol) in MeOH (5 mL) was added Pd /C (20 mg) , and the mixture was stirred at r.t. for 12 h under H ₂ atmosphere. The mixture was filtered and concentrated to give the title product (160 mg, 89%yield) as a yellow solid. LCMS: m/z (ESI) : 251.9 [M+H] ⁺.

Step 5: 2-Methyl-6a, 7, 9, 9a-tetrahydrofuro [3', 4': 5, 6] [1, 4] dioxino [2, 3-g] quinazolin-4-ol

A solution of methyl 7-amino-1, 3, 3a, 9a-tetrahydrobenzo [b] furo [3, 4-e] [1, 4] dioxine-6-carboxylate (160 mg, 0.637 mmol) in CH ₃CN (1 mL) and HCl/dioxane (4 M, 2 mL) was stirred at 100 ℃ for 3 h. The mixture was concentrated under reduced pressure. The residue was purified by chromatography column to afford the title product (100 mg, 60%yield) . LCMS: m/z (ESI) = 261.0 [M+H] ⁺.

Step 6: N- ( (R) -1- (3-Amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6a, 7, 9, 9a -tetrahydrofuro [3', 4': 5, 6] [1, 4] dioxino [2, 3-g] quinazolin-4-amine

A solution of (R) -3- (1-aminoethyl) -5- (trifluoromethyl) aniline (114 mg, 0.58 mmol) , 2-methyl-6a, 7, 9, 9a-tetrahydrofuro [3', 4': 5, 6] [1, 4] dioxino [2, 3-g] quinazolin-4-ol (100 mg, 0.38 mmol) , BOP (340 mg, 0.77 mmol, DBU (176 mg , 1.15 mmol ) in DMF (3 mL) was stirred at r.t. for 12 h. The mixture was diluted with H ₂O (15 mL) and extracted with EtOAc (30 mL x 2) . The combined organic layers were concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product (17 mg, 11%yield) as a white solid. LCMS: m/z (ESI) = 447.0 [M+H] ⁺. ¹HNMR (400 MHz, DMSO-d ₆) 8.00 (d, J = 10.5 Hz, 2H) , 7.04 (s, 1H) , 6.86 (d, J = 18.2 Hz, 2H) , 6.68 (s, 1H) , 5.51 (s, 2H) , 4.99 -4.88 (m, 2H) , 4.07 (ddd, J = 9.5, 5.3, 1.7 Hz, 2H) , 3.84 -3.76 (m, 2H) , 2.34 (s, 3H) , 1.51 (d, J = 7.0 Hz, 3H) , 0.59 -0.37 (m, 1H) .

Example 45

(R) -4- ( (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2, 9-dimethyl-8, 9, 12, 13-tetrahydro-7H- [1, 4] dioxa [7] azacycloundecino [3, 2-g] quinazolin-10 (11H) -one

Step 1: (R) -4- ( (1- (3- (Difluoromethyl) -2-fluorophenyl) ethyl) amino) -2, 9-dimethyl-8, 9, 12, 13-tetrahydro-7H- [1, 4] dioxa [7] azacycloundecino [3, 2-g] quinazolin-10 (11H) -one

To a solution of 4-hydroxy-2, 9-dimethyl-8, 9, 12, 13-tetrahydro-7H- [1, 4] dioxa [7] aza cycloundecino [3, 2-g] quinazolin-10 (11H) -one (30 mg, 0.09 mmol) , (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethan-1-amine (27 mg, 0.14 mmol) and DBU (71 mg, 0.45 mmol) in DMF (2 mL) was added BOP (60 mg, 1.5 mmol) , and the mixture was stirred at 20 ℃ for 12 h. The mixture was purified by pre-HPLC to afford the title product (3.8 mg, 8.2%yield) as a white solid. LCMS: m/z (ESI) = 489.2 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d ₆) δ 8.18 -7.82 (m, 2H) , 7.71 -7.35 (m, 2H) , 7.31 -6.93 (m, 2H) , 5.89 -5.56 (m, 1H) , 4.65 -4.24 (m, 3H) , 4.17 –3.97 (m, 2H) , 3.16 (d, J =7.6 Hz, 1H) , 3.02 -2.87 (m, 3H) , 2.76 (d, J = 11.9 Hz, 1H) , 2.29 (s, 3H) , 2.14 -1.90 (m, 2H) , 1.83 -1.38 (m, 5H) .

Pharmacological testing

1. KRAS G12D-SOS1 binding assay:

The KRAS G12D-SOS1 biochemical binding assay was carried out by Pharmaron Beijing Co., Ltd. (China) .

a) Reagents, Consumables and Instruments

b) General assay procedure:

1) Dilute compounds in DMSO by hand for 11 points, 3 folds dilution, then transfer 0.1 μL compounds to 384 assay plate by ECHO.

2) Add 5 μL specified concentration of Tag2-KRAS G12D&GTP to 384 assay plate, centrifuge 1000 RPM for 1 min.

3) Add 5 μL specified concentration of Tag1-SOS1 to the assay plate, centrifuge 1000 RPM for 1 min.

4) incubate at 25℃ for 15 min.

5) Add 10 μL anti-Tag1-Tb3+ and anti-Tag2-XL665 mixture to the assay plates.

6) Centrifuge 1000 RPM for 1 min, incubate at 4℃ for 3h.

7) Read the 665 /615 nm Ratio on Envision

8) Analyze the raw data using the equation (V. Data analysis)

c) Data analysis

Fit the cpd IC50 from non-linear regression equation by Graph-pad Prism 8:

Y=Bottom + (Top-Bottom) / (1+10^ ( (LogIC50-X) *HillSlope) )

X: Log of cpd concentration

Y: 665/615 ratio

Top and Bottom: Plateaus in same units as Y

logIC50: same log units as X

HillSlope: Slope factor or Hill slope

The results of KRAS G12D-SOS1 binding assay are in the following Table 1.

Table 1: The result of KRAS G12D-SOS1 binding assay

Example #	IC ₅₀	Example #	IC ₅₀
Example 2	A	Example 22-1	C
Example 4	A	Example 22-2	C
Example 18-1	C	Example 23	C
Example 18-2	A
Example 21-1	C
Example 21-2	B

A means < 100 nM, B means >100 nM and < 1000 nM, C means >1000 nM

2. pERK in-cell WB assay:

The pERK in-cell WB assay was tested in GP2D cell lines and carried out by Pharmaron Beijing Co., Ltd. (China) .

Protocol

1) Day 1, seed 6000 cells/well/40 μL in 384 well plate, and incubate at 37℃ under 5%CO ₂ overnight.

2) Day 2, add 200 nL serial diluted compound (final 0.5%DMSO) by Echo 550, incubate cells at 37℃ under 5%CO ₂ for 1 h, and then add 0.1ng/mL hEGF and incubate for 10min.

3) Fixed cells with 40 μL/well 8%fixative solution by Apricot, incubate for 20 min at RT.

4) Wash with 40 μL PBS once and permeate cells with 40 μL/well cold 100%methanol, incubate for 10 min at RT.

5) Wash once with 40 μL/well PBS once.

6) Add 20 μL/well Li-Cor blocking buffer, incubate at RT for 1 hr.

7) Remove blocking buffer and add 20 μL /well primary antibody mixture, rabbit anti pERK (1: 1000) , mouse anti GAPDH (1: 2000) , incubate at 4℃ overnight.

8) Day 3, wash with 40 μL/well PBST (0.05%Tween-20 in PBS) , soak 2 min each round, total 3 times.

9) Add 20 μL/well secondary antibody mixture, goat anti rabbit 800CW (1: 2000) and goat anti mouse 680RD (1: 2000) , incubate for 45 min at RT away from light.

10) Wash with 40 μL /well PBST, soak 2 min each round, total 3 times.

11) Centrifuge plate up-side-down at 1000 rpm, 1 min and scan the plate with Odyssey CLx.

Table 2: The result of pERK in-cell assay

Example #	IC ₅₀
Example 2	C
Example 4	A
Example 18-2	B
Example 21-1	C

A means < 1 uM, B means >1 uM and < 2 uM, C means >2 uM

3. Cell proliferation:

The cell proliferation was carried out in H358 and GP2D cell lines by Pharmaron.

a) Protocol

1) Day 1. Add 200 nl diluted compound into each well with Echo. Seed cells into 384-well plate, 40 μl medium per well.

2) Day 8. Add 3D CTG reagent to each well.

3) Record signal using Envision.

Table 3: The result of cell proliferation

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is apparent to those skilled in the art that certain minor changes and modifications will be practiced. Therefore, the description and examples should not be construed as limiting the scope of the invention.

The disclosures of all publications, patents, patent applications and published patent applications referred to herein are hereby incorporated herein by reference in their entirety.

Claims

The compound of formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein the compound is represented by formula I-1:

wherein R ₁ and R ₂ together form a C _3-12 alkylene group,
wherein the C _3-12 alkylene group is optionally replaced by 1-3 heteroatoms selected from O, S and N, wherein the group replaced by 1-3 heteroatoms is optionally substituted by a C _1-3 alkyl, p-methoxybenzyl, acetyl or bivalent substitution =O,

wherein
denotes a connection site.
The compound of formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 1, wherein R ₁ and R ₂ together form a C _3-8 alkylene group, wherein the C _3-8 alkylene group is optionally replaced by 1 heteroatom selected from O and S, or a C _5-12 alkylene group, wherein the C _5-12 alkylene group is replaced by 2 heteroatoms selected from O and S, wherein said 2 heteroatoms are not adjacent to each other.
The compound of formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 1 or 2, wherein R ₁ and R ₂ together form a C _3-5 alkylene group, wherein the C _3-5 alkylene group is optionally replaced by 1 heteroatom selected from O and S, or a C _5-8 alkylene group, wherein the C _5-8 alkylene group is replaced by 2 heteroatoms selected from O and S, wherein said 2 heteroatoms are not adjacent to each other.
The compound of formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claim 1-3, wherein R ₁ and R ₂ together form a C _3-5 alkylene group, wherein the C _3-5 alkylene group is optionally replaced by 1 oxygen atom, or a C _5-8 alkylene group, wherein the C _5-8 alkylene group is replaced by 2 oxygen atoms, wherein said 2 oxygen atoms are not adjacent to each other.
The compound of formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any of claims 1-4, wherein R ₁ and R ₂ together form
The compound of formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein the compound is represented by formula I-2:

is selected from

R ₈ is selected from the group consisting of halogen, C _1-6 alkyl, halogen substituted C _1- ₆ alkyl and NH ₂; and

n denotes 1 or 2.
The compound of formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 6, wherein R ₈ is selected from the group consisting of halogen, C _1-6 alkyl, halogen substituted C _1-3 alkyl and NH ₂.
The compound of formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any of claim 6-7, wherein R ₈ is selected from the group consisting of F, CHF ₂, NH ₂, CF ₃ and CF ₂CH ₃.
The compound of formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any of claims 6-8, wherein n denotes 2, one of R ₈ is NH ₂, and the other R ₈ is selected from the group consisting of F, CHF ₂, CF ₃ and CF ₂CH ₃.
The compound of formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein the compound is represented by the following formula I-3:

or formula I-4:
wherein R ₃ is selected from H, C _1-6 alkyl, phenyl, pyridyl, pyrazolyl, CN, amino, C _3-6 cycloalkyl and C _1-6 alkoxy, in which the C _1-6 alkyl is optionally substituted with -OH, -NR ₇R ₇ or halogen, each of the phenyl, the pyridyl, the amino and the pyrazolyl is optionally substituted with one or two C _1-6 alkyls or one or two halogens, R ₇ is independently selected from H and C _1-6 alkyl.
The compound of formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 10, wherein R ₃ is selected from H, C _1-6 alkyl, phenyl, pyridyl, pyrazolyl, CN, amino, C _3-6 cycloalkyl and C _1-6 alkoxy, in which the C _1- ₆ alkyl is optionally substituted with –OH, -NHR ₇ or halogen, the phenyl is optionally substituted with one or two halogens, the pyridyl is optionally substituted with one or two C _1-6 alkyl, the pyrazolyl is optionally substituted with C _1-6 alkyl, and the amino is optionally substituted with one or two C _1-6 alkyl, R ₇ is selected from H and C _1-6 alkyl.
The compound of formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 10 or 11, wherein R ₃ is selected from H, C _1-6 alkyl, phenyl, pyridyl, pyrazolyl, and C _3-6 cycloalkyl, in which the C _1-6 alkyl is optionally substituted with –OH or halogen, the phenyl is optionally substituted with one or two halogens, the pyridyl is optionally substituted with one or two C _1-6 alkyl, and the pyrazolyl is optionally substituted with C _1-6 alkyl.
The compound of formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claims 10-12, wherein R ₃ is selected from H, C _1-6 alkyl and C _3-6 cycloalkyl.
The compound of formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claims 10-13, wherein R ₃ is selected from H and C _1-6 alkyl.
The compound of formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claims 10-14, wherein R ₃ is methyl.
The compound of formula I, a pharmaceutically acceptable salt thereof or stereoisomer thereof according to any one of claims 1-15, wherein the compound is selected from:
A pharmaceutical composition comprising the compound of any one of claims 1-16, a pharmaceutically acceptable salt thereof or stereoisomer thereof and a pharmaceutically acceptable excipient.
Use of the compound of any one of claims 1-16, a pharmaceutically acceptable salt thereof or stereoisomer thereof in the manufacture of a medicament for the treatment of a disease or condition associated with KRAS activating mutations.
The use according to claim 18, wherein the disease or condition is a cancer.
The use according to claim 19, wherein the cancer is a lung cancer, a colorectal cancer or a pancreatic cancer.
A method for treating a disease or condition associated with KRAS activating mutations in a patient, comprising administering a therapeutically effective amount of the compound of any one of claims 1-16, a pharmaceutically acceptable salt thereof or stereoisomer thereof to the patient.
The method according to claim 21, wherein the disease or condition is a cancer.
The method according to claim 22, wherein the cancer is a lung cancer, a colorectal cancer or a pancreatic cancer.