KRAS (G12D) inhibitors

Abstract

The present invention provides small molecule inhibitors of KRAS (G12D) mutant oncoproteins having the structural formula R00F2C-L-R0, as well as pharmaceutically acceptable salts and compositions thereof, which are useful for the treatment of cancer and related conditions.

Description

[0001] Related Applications

[0002] This application claims the priority of International Application No. PCT / CN2022 / 092880 filed on May 13, 2022 and International Application No. PCT / CN2022 / 102534 filed on June 29, 2022, the entire contents of each of which are incorporated herein by reference. Background Art

[0003] The Kirsten rat sarcoma virus homolog (KRAS) gene was discovered as a human cancer gene in the early 1980s. The gene encodes a small monomeric 21kDa GTPase that has long been a difficult-to-study cancer drug target (Chang et al., PNAS, 1982, 79: 4848-52; McCoy et al., Nature, 1983, 302: 79-8). KRAS acts as a molecular switch that promotes cell growth by cycling between a GTP-bound state and a GDP-bound state. In the GTP-bound state, KRAS sends growth signals through the RAF-MAPK and PI3K-AKT-MTOR pathways. KRAS then hydrolyzes GTP to GDP with the help of GTPase activating proteins (GAPs). This GDP-bound state switches to "off" KRAS growth-promoting signaling. KRAS can then be switched back “on” by the exchange of GDP for GTP with the help of guanine nucleotide exchange factors such as SOS1 (Cox and Der, Small GTPases, 2010, 1: 2-27; Kerk et al., Nat Rev Cancer, 2021, 21: 510-525). Preventing this exchange by locking KRAS in the GDP-bound state is a practical approach to inhibit its growth-promoting activity.

[0004] The human KRAS gene is encoded on chromosome 12p12.1 and is one of the most frequently mutated genes in human cancer (Pylayeva-Gupta et al., Nat Rev Cancer, 2011, 11: 761-774). Mutations that prevent GTP hydrolysis lock KRAS in an active GTP-bound state and reprogram cells to proliferate forever. Mutation of glycine (G) to aspartic acid (D) at the 12th codon of KRAS produces a long-term active KRAS (G12D) cancer protein, which was observed in 6.8% of cancer cases by next-generation sequencing analysis (Zhou et al., Pathol Oncol Res, 2020, 26: 2835-2837). In tumor type-specific studies, KRAS(G12D) was associated with adverse clinical outcomes and was observed in 17% of lung cancer, 14.3% of colorectal cancer, and 48% of pancreatic tumors (Aredo et al., Lung Cancer, 2019, 133:144-150; Olmedillas-López et al., World J Gastroenterol, 2017, 23(39):7087-709; Miglio et al., Pathol Res Pract, 2014, 210:307-11; Gou et al., Br J Cancer, 2020, 22:857-867), as well as in other cancers. Historically, oncogenic KRAS mutants were considered undruggable (McCormick F, Biochem J, 2019, 476: 356-74), however, the discovery of an allosteric pocket in GDP-bound KRAS has made it possible to find small molecule inhibitors (Ostrem et al., Nature, 2013, 503: 548-51). In addition, the G12D mutation also provides a unique chemical molecular binding space because the encoded acidic amino acid residue (D) replaces the small flexible amino acid residue (G) with only a hydrogen side chain. This change in the structure of the KRAS protein provides a unique space that can be used to specifically inhibit the oncogenic activity of KRAS (G12D) with small molecule drugs. Therefore, it is expected to design and develop small molecule drugs targeting KRAS (G12D) with sufficient bioavailability to treat diseases such as cancer. Summary of the invention

[0005] The present invention provides small molecule inhibitors of KRAS (G12D) mutant tumor proteins. KRAS (G12D) inhibitors include those having the following structural formula I*:

[0006] R 00 F2C-LR 0 (I*)

[0007] and pharmaceutically acceptable salts and compositions comprising the same, wherein L, R 0 and R 00 As defined herein. Also disclosed are the uses of these compounds, salts and compositions for treating diseases responsive to inhibition of KRAS (G12D), such as cancer.

[0008] In one aspect, due to the trifluoroacetyl group on the nitrogen atom of the diazabisoctanoyl group, the disclosed compounds show improved bioavailability compared to non-trifluoroacetylated counterparts and / or derivatives. For example, Table 2 shows that the introduction of a trifluoroacetyl group on the nitrogen atom of the diazabisoctanoyl group results in an increase of at least 15 times in the %F of the compounds of the invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Figure 1 Results from an in vivo xenograft tumor model using 75 mg / kg of Compound 3 administered orally over 3 weeks are shown. Specific implementation plan

[0010] 1. Description of compound formula

[0011] As part of a first embodiment, the present invention provides a compound of the following structural formula I*:

[0012] R 00 F2C-LR 0 (I*);

[0013] or a pharmaceutically acceptable salt thereof, wherein L is selected from -C(=O), -S(=O) and -S(O)2; R 0 Is related to KRAS G12D The chemical entity to which R 00 Selected from hydrogen, F, Cl and CF3.

[0014] 2. Definition

[0015] As used herein, the articles "a" and "an" refer to one or more than one of the grammatical objects of the article, for example, to at least one of the grammatical objects of the article. When used in conjunction with the term "comprising" herein, the use of the word "a" or "an" can mean "one", but is also consistent with the meaning of "one or more", "at least one" and "one or more than one".

[0016] As used herein, the terms "comprising" or "including" are intended to refer to compositions, methods, and their respective components, which are present in a given embodiment, but are also open to including unspecified elements.

[0017] As used herein, unless otherwise specified, the term "alkyl" means a saturated straight or branched non-cyclic hydrocarbon having 1 to 10 carbon atoms, such as (C1-C6) alkyl or (C1-C4) alkyl. Representative straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl , 2,2-dimethylpentyl, 2,2-dimethylhexyl, 3,3-dimethylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl, etc.

[0018] As used herein, unless otherwise specified, the term "alkenyl" means a saturated straight or branched chain non-cyclic hydrocarbon having 2 to 10 carbon atoms (e.g., (C2-C6)alkenyl or (C2-C4)alkenyl) and having at least one carbon-carbon double bond. Representative straight and branched (C2-C 10 )Alkenyl includes vinyl, allyl, 1-butenyl, 2-butenyl, isobutenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, etc.

[0019] As used herein, unless otherwise indicated, the term "alkynyl" means a saturated straight or branched non-cyclic hydrocarbon having 2 to 10 carbon atoms (e.g., (C2-C6) alkynyl or (C2-C4) alkynyl), and having at least one carbon-carbon triple bond. Representative straight and branched alkynyl groups include ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl, 6-heptynyl, 1-octynyl, 2-octynyl, 7-octynyl, 1-nonynyl, 2-nonynyl, 8-nonynyl, 1-decynyl, 2-decynyl, 9-decynyl, etc.

[0020] The term "aryl", used alone or as part of a larger molecule, such as "-(C1-C4)alkylaryl", refers to a monocyclic or bicyclic carbon ring system having a total of six to ten ring members, wherein at least one ring in the system is aromatic. Examples include, but are not limited to, phenyl, naphthyl, anthracenyl, and the like. It will be understood that, when specified, optional substituents on the aryl group may be present in any substitutable position.

[0021] As used herein, the term "cycloalkyl" means a saturated monocyclic alkyl group having 3 to 10 carbon atoms, such as 3 to 6 carbon atoms. Representative cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl.

[0022] The term "oxo" refers to the group =0.

[0023] As used herein, the term "haloalkyl" means that one or more (including all) hydrogen atoms in an alkyl group are substituted with a halo group, wherein each halo group is independently selected from -F, -Cl, -Br and -I. Representative haloalkyl groups include trifluoromethyl, bromomethyl, 1,2-dichloroethyl, 4-iodobutyl, 2-fluoropentyl, and the like.

[0024] "Alkoxy" means an alkyl group attached through an oxygen linking atom, represented by -O-alkyl. For example, "(C1-C4)alkoxy" includes methoxy, ethoxy, propoxy and butoxy.

[0025] "Haloalkoxy" is a haloalkyl group attached to another molecule through an oxygen atom, for example, -OCHF2 or -OCF3.

[0026] As used herein, the term "halogen" or "halo" means F, Cl, Br or I.

[0027] As used herein, the term "heterocyclyl" means a 4- to 12-membered monocyclic or polycyclic saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O and S. Where valence permits, the heterocyclic ring may be attached via any heteroatom or carbon atom. Representative heterocyclic rings include morpholinyl, thiomorpholinyl, pyrrolidonyl, pyrrolidinyl, piperidinyl, piperazinyl, glycidyl, dioxanyl, oxetanyl, dihydrofuranyl, dihydropyranyl, isoindolyl, dihydropyridyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, diazabicyclooctyl, hexahydropyrrolidinyl, 2- Azaspiro[3.3]heptynyl, 2,7-diazaspiro[3.5]nonyl, 2-azaspiro[3.5]nonyl, 3-azabicyclo[3.1.0]hexyl, 8-azabicyclo[3.2.1]octyl, 3,8-diazabicyclo[3.2.1]octyl, 3,6-diazabicyclo[3.1.1]heptyl, octahydro-1H-pyrrolo[2,3-c]pyridinyl, etc. Optional substituents on the heterocyclyl may be present at any substitutable position, and for example include positions where the heterocyclyl is attached where valence permits.

[0028] As used herein, the term "heteroaryl" means a 5 to 12 membered aromatic group containing 1 to 4 heteroatoms selected from N, O and S. Where valence permits, the heteroaryl group may be attached via any heteroatom or carbon atom. Representative heterocyclic groups include pyridyl, furyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, thiadiazolyl, isoquinolyl, indazolyl, benzoxazolyl, benzofuranyl, indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl, quinazolinyl, purinyl, benzothienyl, etc. Optional substituents on a heteroaryl group may be present at any substitutable position and, for example, include the position at which the heteroaryl group is attached where valency permits.

[0029] When used to describe a chemical group that may have multiple points of attachment, the hyphen (-) indicates the point of attachment of the group to the variable it defines. For example, -(C1-C4)alkylaryl means that the point of attachment of these groups is on the alkyl group.

[0030] like The wavy line in the represents the point of attachment of the depicted group to the defined variable.

[0031] The term "KRAS" refers to the protein product of the KRAS proto-oncogene GTPase gene.

[0032] The term "KRAS(G12D)" refers to the protein product of the KRAS gene carrying a mutation resulting in a substitution of glycine at position 12 of KRAS with aspartic acid.

[0033] “With KRAS G12D "Binding chemical entity" refers to a chemical entity that binds to KRAS G12D In some aspects, the KRAS G12D The chemical entity that binds is a small molecule. In some aspects, the KRAS G12D The chemical entity that binds is a small molecule with a molecular weight of less than 2000 g / mol. G12D The bound chemical entity induces KRAS G12D conformational changes.

[0034] The term "SOS1" refers to the protein product of the SOS1 gene, which functions as a guanine nucleotide exchange factor for RAS proteins.

[0035] The compounds described herein may have chiral centers and / or geometric centers (E- and Z-isomers). It will be understood that the present disclosure encompasses all stereoisomers and geometric isomers. Tautomeric forms of the compounds described herein are also part of the present disclosure.

[0036] When the stereochemistry of a disclosed compound is named or depicted in a structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight relative to all other stereoisomers. The percent purity by weight relative to all other stereoisomers refers to the ratio of the weight of one stereoisomer to the weight of that stereoisomer plus the weight of the other stereoisomers.

[0037] When used in medicine, the pharmaceutically acceptable salts of the disclosed compounds refer to non-toxic "pharmaceutically acceptable salts". Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic / anionic salts or basic / cationic salts. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include, for example, salts of inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid and sulfuric acid) and organic acids (such as acetic acid, benzenesulfonic acid, benzoic acid, methanesulfonic acid and p-toluenesulfonic acid). The compounds of the present invention having acidic groups (such as carboxylic acids) can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. Suitable pharmaceutically acceptable alkali salts include, for example, ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts). Compounds having quaternary ammonium groups also contain counter anions, such as chloride ions, bromide ions, iodide ions, acetate ions, perchlorate ions, etc. Other examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, benzoates, and salts formed with amino acids (such as glutamic acid).

[0038] The term "pharmaceutically acceptable carrier" refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound formulated therewith. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates, glycine, sorbic acid, potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as ammonium sulfate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and lanolin.

[0039] As used herein, the term "subject" refers to humans and non-human animals, including veterinary subjects. The term "non-human animal" includes all vertebrates, such as mammals and non-mammals, such as non-human primates, mice, rabbits, sheep, dogs, cats, horses, cows, chickens, amphibians and reptiles. In a preferred embodiment, the subject is a human, which can be referred to as a patient.

[0040] As used herein, the terms "treat," "treating," or "treatment" preferably refer to actions that achieve a benefit or desired clinical outcome, including but not limited to alleviating or ameliorating one or more signs or symptoms of a disease or condition, reducing the extent of the disease, stabilizing (i.e., not worsening) the disease state, improving or alleviating the disease state, reducing the rate or time of disease progression, and alleviating (whether partial or complete). "Treatment" may also refer to prolonging survival compared to the expected survival without treatment. Treatment is not necessarily curative.

[0041] "Therapeutically effective amount" refers to an amount sufficient to treat a subject's disease. A therapeutically effective amount can be administered once or multiple times. In one aspect, a therapeutically effective amount refers to a dosage of about 0.01 to 100 mg / kg body weight / day.

[0042] The terms "administer", "adeministering" or "administration" include any method of delivering a pharmaceutical composition or agent to a specific area in a subject or on the surface of a subject's body. In certain embodiments, the agent is administered intravenously, intramuscularly, subcutaneously, intradermally, intranasally, orally, transdermally or mucosally. In certain embodiments, the agent is administered intravenously. In certain embodiments, the agent is administered orally. The administration of the agent can be accomplished by multiple people in collaboration. The administration of the agent includes, for example, issuing a prescription for the agent to be administered to the subject and / or providing instructions for taking a specific preparation directly or through another person, and can also be self-delivered, such as oral delivery, subcutaneous delivery, intravenous delivery through a central catheter, etc.; or delivered by a trained professional, such as intravenous delivery, intramuscular delivery, intratumoral delivery, etc.

[0043] 3. Compounds

[0044] As part of the second embodiment, the compound of formula I* has the following formula I

[0045]

[0046] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined above in formula I*.

[0047] As part of a third embodiment, the compound of formula I* or I has the following compound of formula Ia or Ib:

[0048]

[0049] or a pharmaceutically acceptable salt thereof, wherein

[0050] R 1 Selected from -(C1-C4)alkylO(C1-C4)alkyl, -(C1-C4)alkylNH(C1-C4)alkyl, -(C1-C4)alkylN[(C1-C4)alkyl]2, heterocyclyl and cycloalkyl, wherein the heterocyclyl and cycloalkyl are each optionally and independently substituted;

[0051] R 2 is selected from hydrogen, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, (C1-C4) alkynyl, (C1-C4) alkenyl, halogen, (C3-C6) cycloalkyl, -O(C3-C6) cycloalkyl, cyano, NH 2、 -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -P(O)[(C1-C4)alkyl]2 and -S(C1-C4)alkyl;

[0052] R 3 Selected from

[0053] a 1 N or CHZ 1 ;

[0054] Z 1 is selected from hydrogen, halogen, (C1-C4)alkyl, (C2-C4)alkenyl, cyano, cyano(C1-C4)alkyl, -S[halo(C1-C4)alkyl] and (C3-C6)cycloalkyl (e.g., such as hydrogen, methyl, ethyl, isopropyl, cyano, -SCF3, cyanoethyl, cyclopropyl and 2-methylpropenyl;

[0055] R 8 , R 9 , R 10 , R 11 , R 12 and R 13 each independently selected from hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)cyanoalkyl, (C1-C4)hydroxyalkyl, -(C1-C4)alkylNR a R b 、(C1-C4)alkylC(O)NR a R b 、(C1-C4)alkylO(C1-C4)alkyl、-(C1-C4)alkyl-C(O)OR a 、-(C1-C4)alkylNR a C(O)OR b 、-(C1-C4)alkylC(O)R a , -(C1-C4) alkylheterocyclyl, -(C1-C4) alkylaryl, -(C1-C4) alkylheteroaryl, (C2-C4) alkenyl, (C2-C4) haloalkenyl, (C2-C4) cyanoalkenyl, (C2-C4) hydroxyalkenyl, -(C2-C4) alkenyl NR a R b , (C2-C4)alkynyl, (C2-C4)haloalkynyl, (C2-C4)cyanoalkynyl, (C2-C4)hydroxyalkynyl, -(C2-C4)alkynylNR a R b , (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, cyano, oxo, hydroxy, -S(C1-C4) alkyl, -S(C1-C4) haloalkyl, -NR a R b 、-NR a C(O)R b 、-C(O)R a 、-C(O)ORa 、-SO2R a 、-S(O)R a 、-SO2NR a R b 、-NR a S02R b , (C3-C6)cycloalkyl, 5- or 6-membered heteroaryl and 4- to 6-membered heterocyclyl, wherein the heterocyclyl, aryl and heteroaryl of -(C1-C4)alkylheterocyclyl, -(C1-C4)alkylaryl and -(C1-C4)alkylheteroaryl, and the (C3-C6)cycloalkyl, 5- or 6-membered heteroaryl and 4- to 6-membered heterocyclyl are each optionally and independently replaced by 1 to 3 selected from R c The group substitution;

[0056] m is 0, 1 or 2;

[0057] R a and R b are each independently selected from hydrogen, (C1-C4)alkyl and (C1-C4)haloalkyl, or when R a and R b When on the same nitrogen atom, they may together form a heterocyclic group; and

[0058] R c is selected from halogen, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, cyano, hydroxy, oxo, -C(O)OR a 、-C(O)R a 、-SO2R a 、-S(O)R a 、-SO2NR a R b 、-NR a C(O)R b 、-NR a S02R b 、-NR a R b and -NO2, wherein the remaining variables are as described above for Formula I* or I.

[0059] As part of a fourth embodiment, the compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof wherein R 1 is selected from optionally substituted heterocyclyl and optionally substituted cycloalkyl, wherein the remaining variables are as described above for Formula I*, I, Ia or Ib. Alternatively, as part of the fourth embodiment, R in the compound of Formula Ia or Ib or a pharmaceutically acceptable salt thereof is 1is selected from optionally substituted fused bicyclic heterocyclyl and optionally substituted (C3-C6) cycloalkyl, wherein the remaining variables are as described above for Formula I*, I, Ia or Ib. In another alternative, as part of the fourth embodiment, R in the compound of Formula Ia or Ib or a pharmaceutically acceptable salt thereof is 1 Selected from

[0060] R 4 , R 6 and R 7 each independently selected from hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)cyanoalkyl, (C1-C4)hydroxyalkyl, -(C1-C4)alkylNR a R b 、-(C1-C4)alkylC(O)NR a R b 、(C1-C4)alkylO(C1-C4)alkyl、-(C1-C4)alkylC(O)OR a 、-(C1-C4)alkylNR a C(O)OR b 、-(C1-C4)alkylC(O)R a , (C1-C4) alkyl heterocyclic group, -(C1-C4) alkyl aryl group, -(C1-C4) alkyl heteroaryl group, (C2-C4) alkenyl group, (C2-C4) haloalkenyl group, (C2-C4) cyanoalkenyl group, (C2-C4) hydroxyalkenyl group, -(C2-C4) alkenyl NR a R b , (C2-C4)alkynyl, (C2-C4)haloalkynyl, (C2-C4)cyanoalkynyl, (C2-C4)hydroxyalkynyl, -(C2-C4)alkynylNR a R b , (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, cyano, oxo, hydroxy, -S(C1-C4) alkyl, -S(C1-C4) haloalkyl, -NR a R b 、-NR a C(O)R b 、-C(O)R a 、-C(O)OR a 、-SO2R a 、-S(O)R a 、-SO2NR a R b 、-NR a S02R b, (C3-C6)cycloalkyl, 5- or 6-membered heteroaryl and 4- to 6-membered heterocyclyl, wherein the heterocyclyl, aryl and heteroaryl of -(C1-C4)alkylheterocyclyl, -(C1-C4)alkylaryl and -(C1-C4)alkylheteroaryl, and the (C3-C6)cycloalkyl, 5- or 6-membered heteroaryl and 4- to 6-membered heterocyclyl are each optionally and independently replaced by 1 to 3 selected from R c The group substitution;

[0061] R 5 is (C1-C4)alkyl or halogen; and

[0062]

[0063] n, x and z are each independently 0, 1 or 2, wherein the remaining variables are as described above for Formula I*, I, Ia or Ib. In another alternative, as part of the fourth embodiment, R in the compound of Formula Ia or Ib or a pharmaceutically acceptable salt thereof is 1 Selected from The remaining variables are as described in the above structural formula I*, I, Ia or Ib.

[0064] As part of a fifth embodiment, the compound of formula I*, I, Ia or Ib is of formula Ia':

[0065]

[0066] or a pharmaceutically acceptable salt thereof, wherein the remaining variables are as described above in Structural Formula I*, I, Ia or Ib or in the fourth embodiment.

[0067] As part of the sixth embodiment, the compound of formula Ia or Ia' or a pharmaceutically acceptable salt thereof wherein a 1 is N, wherein the remaining variables are as described above for Structural Formula Ia or Ia' or the fourth embodiment.

[0068] As part of the seventh embodiment, the compound of formula I*, I, Ia, Ia' or Ib or a pharmaceutically acceptable salt thereof wherein R 00 is F, wherein the remaining variables are as described above for Structural Formula I*, I, Ia, Ia' or Ib or the fourth or sixth embodiment.

[0069] As part of an eighth embodiment, the compound of formula Ia, Ia' or Ib or a pharmaceutically acceptable salt thereof wherein R 3 for wherein the remaining variables are as described above for Structural Formula Ia, Ia' or Ib or the fourth, sixth or seventh embodiment.

[0070] As part of the ninth embodiment, the compound of formula Ia, Ia' or Ib or a pharmaceutically acceptable salt thereof wherein R 8 , R 9 , R 10 and R 11 Each is independently selected from hydrogen, halogen, hydroxyl and (C2-C4) alkynyl, wherein the remaining variables are as described above for Formula Ia, Ia' or Ib or any one of the fourth or sixth to eighth embodiments. Alternatively, as part of the ninth embodiment, R in the compound of Formula Ia, Ia' or Ib or a pharmaceutically acceptable salt thereof is 8 , R 9 , R 10 and R 11 each is hydrogen; or R 9 , R 10 and R 11 are each hydrogen, and R 8 is selected from halogen, hydroxy and (C2-C4)alkynyl; or R 10 and R 11 are each hydrogen, and R 8 and R 9 are each independently selected from halogen, hydroxyl and (C2-C4)alkynyl; or R 11 is hydrogen, and R 8 , R 9 and R 10 wherein the remaining variables are as described above for Formula Ia, Ia' or Ib or any one of the fourth or sixth to eighth embodiments. In another alternative, as part of the ninth embodiment, R in the compound of Formula Ia, Ia' or Ib or a pharmaceutically acceptable salt thereof is 8 , R 9 , R 10 and R 11 each is hydrogen; or R 9 , R 10 and R 11 are each hydrogen, and R 8 is (C2-C4)alkynyl; or R 10 and R 11 Each is hydrogen, R 8 is (C2-C4)alkynyl, and R 9 is a halogen, or R 11 is hydrogen, R 8 is (C2-C4) alkynyl, R 9 is a halogen, and R 10 is hydroxyl, wherein the remainder of the variables are as described above for Formula Ia, Ia', Ib, or any of the fourth or sixth through eighth embodiments.

[0071] As part of the tenth embodiment, the compound of formula Ia, Ia' or Ib or a pharmaceutically acceptable salt thereof wherein R 3 for wherein the remaining variables are as described above for Formula Ia, Ia' or Ib or any one of the fourth or sixth to ninth embodiments. Alternatively, as part of the tenth embodiment, R in the compound of Formula Ia, Ia' or Ib or a pharmaceutically acceptable salt thereof is 3 for wherein the remaining variables are as described above in Formula Ia, Ia' or Ib or any one of the fourth or sixth to ninth embodiments.

[0072] As part of the eleventh embodiment, the compound of formula Ia, Ia' or Ib or a pharmaceutically acceptable salt thereof wherein R 3 Selected from

[0073] wherein the remaining variables are as described above for Structural Formula Ia, Ia' or Ib or any one of the fourth, sixth or seventh embodiments.

[0074] As part of the twelfth embodiment, the compound of formula Ia' or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1, wherein the remaining variables are as described above for formula Ia, Ia' or Ib, or any one of the fourth or sixth to eleventh embodiments. Alternatively, as part of the twelfth embodiment, the compound of formula Ia' or a pharmaceutically acceptable salt thereof, wherein m is 1, wherein the remaining variables are as described above for formula Ia, Ia' or Ib, or any one of the fourth or sixth to eleventh embodiments.

[0075] As part of the thirteenth embodiment, the compound of formula Ia' or a pharmaceutically acceptable salt thereof wherein R 5 is halogen, wherein the remaining variables are as described above in Formula Ia, Ia' or Ib or any one of the fourth or sixth through twelfth embodiments.

[0076] As part of the fourteenth embodiment, the compound of formula Ia' or a pharmaceutically acceptable salt thereof, wherein z is 0 or 2, wherein the remaining variables are as described above for formula Ia, Ia' or Ib, or any one of the fourth or sixth to thirteenth embodiments. Alternatively, as part of the fourteenth embodiment, the compound of formula Ia' or a pharmaceutically acceptable salt thereof, wherein z is 0, wherein the remaining variables are as described above for formula Ia, Ia' or Ib, or any one of the fourth or sixth to thirteenth embodiments.

[0077] As part of the fifteenth embodiment, the compound of formula Ia', Ia' or Ib or a pharmaceutically acceptable salt thereof wherein R 1for wherein the remaining variables are as described above for Formula Ia, Ia' or Ib or any one of the fourth or sixth to fourteenth embodiments. Alternatively, as part of the fifteenth embodiment, R in the compound of Formula Ia', Ia' or Ib or a pharmaceutically acceptable salt thereof is 1 Selected from

[0078]

[0079] wherein the remaining variables are as described above in Formula Ia, Ia' or Ib or any one of the fourth or sixth through fourteenth embodiments.

[0080] As part of a sixteenth embodiment, the compounds described herein or pharmaceutically acceptable salts thereof wherein R 4 is optionally 1 to 3 selected from R c -(C1-C4)alkylheterocyclyl substituted with a group, wherein the remaining variables are as described above for Formula Ia, Ia' or Ib or any one of the fourth or sixth to fifteenth embodiments. In addition, as part of the sixteenth embodiment, R 4 are each optionally substituted by 1 to 3 selected from R c Substituted wherein the remaining variables are as described above in Formula Ia, Ia' or Ib or any one of the fourth or sixth to fifteenth embodiments.

[0081] As part of the seventeenth embodiment, the compound of formula Ia, Ia' or Ib or a pharmaceutically acceptable salt thereof wherein R c is selected from (C1-C4)alkyl, (C1-C4)haloalkyl and halogen, wherein the remaining variables are as described above for Formula Ia, Ia' or Ib or any one of the fourth or sixth to sixteenth embodiments. Alternatively, as part of the seventeenth embodiment, R in the compound of Formula Ia, Ia' or Ib or a pharmaceutically acceptable salt thereof is c is selected from (C1-C4)haloalkyl and halogen, wherein the remaining variables are as described above in Formula Ia, Ia' or Ib or any one of the fourth or sixth through sixteenth embodiments.

[0082] As part of the eighteenth embodiment, the compound of formula Ia or Ia' or a pharmaceutically acceptable salt thereof wherein R 2is selected from hydrogen, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, (C1-C4) alkynyl, (C1-C4) alkenyl, halogen, (C3-C6) cycloalkyl, cyano, NH2, -NH(C1-C4) alkyl, -N[(C1-C4) alkyl]2, -P(O)[(C1-C4) alkyl]2 and -S(C1-C4) alkyl, wherein the remaining variables are as described above for Formula Ia, Ia' or Ib or any one of the fourth or sixth to seventeenth embodiments. In addition, as part of the eighteenth embodiment, R in the compound of Formula Ia or Ia' or a pharmaceutically acceptable salt thereof is 2 wherein the remaining variables are as described above for Formula Ia, Ia' or Ib or any one of the fourth or sixth to seventeenth embodiments. Alternatively, as part of the eighteenth embodiment, R in the compound of Formula Ia or Ia' or a pharmaceutically acceptable salt thereof is 2 Selected from hydrogen, chlorine, cyano, methoxy, ethoxy, CF3, OCF3 and wherein the remaining variables are as described above in Formula Ia, Ia' or Ib or any one of the fourth or sixth to seventeenth embodiments.

[0083] The examples further disclose other compounds, which are also included in the present disclosure. Also included are pharmaceutically acceptable salts and neutral forms thereof.

[0084] 4. Use, preparation and administration

[0085] The compounds and compositions described herein are generally useful for anti-cancer therapy. In one aspect, the disclosed compounds and compositions can be used as inhibitors of KRAS(G12D). Their mechanism of action includes, but is not limited to, inhibiting KRAS(G12D), thereby preventing downstream signals that may lead to inhibition of cancer cell growth and / or induction of cancer cell apoptosis or other KRAS or KRAS(G12D) functions. In one aspect, the disclosed compounds can effectively inhibit KRAS(G12D).

[0086] Therefore, provided herein is a method for treating a disease responsive to inhibition of KRAS (G12D), comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds or compositions described herein. Also provided is the use of one or more compounds or compositions described herein in the preparation of a medicament for treating a disease responsive to inhibition of KRAS (G12D). Further provided is the use of a compound or composition described herein for treating a disease responsive to inhibition of KRAS (G12D).

[0087] In one aspect, the condition treated by the present compounds and compositions is cancer. The term "cancer" or "tumor" is well known in the art and refers to cells with typical oncogenic characteristics as present in a subject, such as uncontrolled proliferation, immortality, potential metastasis, rapid growth and proliferation rate, reduced cell death / apoptosis, and certain characteristic morphological features. Cancer cells usually exist in the form of solid tumors. However, cancer also includes non-solid tumors, such as blood tumors, such as leukemia, in which cancer cells are derived from the bone marrow. As used herein, the term "cancer" includes pre-malignant cancers as well as malignant cancers. Cancers include, but are not limited to, acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytoma, medulloblastoma, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytoma and myeloblastic leukemia), acute T-cell leukemia, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, Bowel cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, Burkitt lymphoma, proliferative disorders (dysplasia and variants), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythrocytic leukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, smooth muscle Sarcoma, liposarcoma, lung cancer, lymphoendothelial sarcoma, lymphangiosarcoma, lymphocytic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, sarcoma, neuroblastoma, non-small cell Lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinomas and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer, and Weil's tumor.Other cancers include primary cancer, metastatic cancer, oropharyngeal cancer, hypopharyngeal cancer, liver cancer, gallbladder cancer, bile duct cancer, small intestine cancer, urinary tract cancer, kidney cancer, urethral cancer, female genital tract cancer, uterine cancer, gestational trophoblastic disease, male genital tract cancer, seminal vesicle cancer, testicular cancer, germ cell tumors, endocrine gland tumors, thyroid cancer, adrenal cancer, pituitary cancer, hemangioma, bone and soft tissue sarcoma, Kaposi sarcoma, nerve cancer, eye cancer, meningeal cancer, glioblastoma, neuroma, neuroblastoma, Schwann tumor, solid tumors caused by leukemia and other hematopoietic malignancies, metastatic melanoma, recurrent or refractory ovarian epithelial cancer, fallopian tube cancer, primary peritoneal cancer, gastrointestinal stromal tumors, colorectal cancer, gastric cancer, melanoma, glioblastoma multiforme, non-squamous non-small cell lung cancer, malignant glioma, epithelial ovarian cancer, primary peritoneal serous carcinoma, metastatic liver cancer, neuroendocrine cancer, refractory malignancies, triple-negative breast cancer, HER2-amplified breast cancer, nasopharyngeal cancer, oral cancer, bile duct cancer, hepatocellular carcinoma, squamous cell carcinoma of the head and neck (SCCHN), non-medullary thyroid cancer, recurrent glioblastoma multiforme, neurofibromatosis type 1, central nervous system cancer, liposarcoma, myometrial sarcoma, salivary gland cancer, mucosal melanoma, condyloma acuminatum / lichen planus melanoma, paraganglioma, pheochromocytoma, advanced metastatic cancer, solid tumors, triple-negative breast cancer, colorectal cancer, sarcoma, melanoma, renal cancer, endometrial cancer, thyroid cancer, rhabdomyosarcoma, multiple myeloma, ovarian cancer, glioblastoma, gastrointestinal stromal tumor, mantle cell lymphoma, and refractory malignancies.

[0088] As used herein, "solid tumor" refers to any pathogenic tumor that can be palpated or detected using imaging methods as having three-dimensional abnormal growth. Solid tumors are different from blood tumors such as leukemia. However, the cells of blood tumors are derived from the bone marrow; therefore, the tissue that produces cancer cells is likely to be hypoxic solid tissue.

[0089] "Tumor tissue" or "tumor-like tissue" may be understood as cells, extracellular matrix and other naturally occurring components associated with solid tumors.

[0090] The specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the attending physician, and the severity of the specific disease being treated. The amount of the compound described herein in the composition also depends on the specific compound in the composition.

[0091] Example

[0092] Chemical synthesis

[0093] The following representative examples are intended to help illustrate the present disclosure and are not intended to limit the scope of the present invention, nor should they be construed as limiting the scope of the present invention. Unless otherwise stated, general starting materials used were obtained from commercial sources or prepared in other examples.

[0094] Compound preparation

[0095] The compounds described herein were prepared according to the procedures outlined in the following schemes.

[0096]

[0097] Intermediate 2:

[0098]

[0099] 2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine. Batch 2: To a mixture of intermediate 1 (50.0 g, 232 mmol, 1.00 eq) in toluene (150 mL) was added POCl3 (178 g, 1.16 mol, 108 mL, 5.00 eq) at 25 °C. Then DIEA (65.9 g, 510 mmol, 88.9 mL, 2.20 eq) was added at less than 40 °C. The mixture was stirred at 110 °C for 12 hours. LC-MS showed that the expected MS was detected. The reaction mixture was distilled under reduced pressure at 90 °C to remove POCl3. The residue was slowly poured into a saturated NaHCO3 solution (maintaining pH = 8). A yellow precipitate was formed in the process. The yellow precipitate was collected after filtration and washed with water. The solid was used directly in the next step of the reaction. Intermediate 2 was obtained as a brown solid (101 g, 400 mmol, 86.2% yield). HNMR(DMSO-d6,400MHz): δ8.92-8.86(m,1H). LC-MS:m / z 253.9[M+H] + .

[0100] Intermediate 3:

[0101]

[0102] Tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. Batch 2: To a mixture of intermediate 2 (48.5 g, 192 mmol, 1.00 eq) in DCM (485 mL) was added a mixture of compound 2a (38.7 g, 183 mmol, 0.950 eq) in DCM (120 mL). DIEA (49.7 g, 384 mmol, 66.9 mL, 2.00 eq) was then added to the mixture at -40°C and stirred at -40°C under nitrogen atmosphere for 0.5 h. LCMS showed that compound 2 had been consumed and the target MS was detected. The mixture was quenched with HCl (0.5 M) and the aqueous phase was acidified to pH 6-7, then separated and the organic phase dried over Na2SO4. The residue was purified by column chromatography (SiO2, TLC: petroleum ether: ethyl acetate = 3:1, R f =0.4, petroleum ether:ethyl acetate = 10:1 to 1:1, R f =0.4). The obtained intermediate 3 (120 g, 280 mmol, 72.9% yield) was a white solid. HNMR (DMSO-d6, 400 MHz): δ9.13-8.98 (m, 1H), 4.67-4.36 (m, 2H), 4.35-4.21 (m, 2H), 3.87-3.50 (m, 2H), 1.85-1.71 (m, 2H), 1.66-1.56 (m, 2H), 1.46 (s, 9H). LC-MS: m / z 428.0 [M+H] + .

[0103] Intermediate 4:

[0104]

[0105] 3-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester. To a stirred mixture of [1-(hydroxymethyl)cyclopropyl]methanol (14.31 g, 140 mmol, 3 eq) and t-BuONa (13.46 g, 140 mmol, 3 eq) in THF was added portionwise 3-{2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (20 g, 46.697 mmol, 1 eq) at 0°C under nitrogen atmosphere. The resulting mixture was stirred under nitrogen atmosphere for 1 hour. The reaction was quenched with water at 0°C. The resulting mixture was extracted with CH2Cl2 (3x10mL). The organic phases were combined, washed with saturated aqueous NaCl solution (2x5mL), and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the intermediate 4 (14.5g, 62.86%) was obtained by elution with PE / EA (1:1) as a white solid. LCMS (ES, m / z): 494 [M+H] + .

[0106] Intermediate 5:

[0107]

[0108] Tert-butyl 3-(8-fluoro-7-(7-fluoro-2-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. To a solution of intermediate 4 (3 g, 6.073 mmol, 1.0 eq) and ((3-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl)ethynyl)triisopropylsilane (2.63 g, 9.110 mmol, 1.5 eq) in 1,4-dioxane (40 mL) was treated with Pd(PPh3)4 (1.40 g, 1.215 mmol, 0.2 eq) and K3PO4 (3.87 g, 18.219 mmol, 3.0 eq) under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere overnight. The reaction was quenched with water at room temperature. The resulting mixture was extracted with CH2Cl2 (3x10 mL). The combined organic phases were washed with saturated aqueous NaCl solution (2x5 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10:1) to obtain Intermediate 5 (2.5 g, 66.38%) as a yellow solid. LCMS (ES, m / z): 620 [M+H] + .

[0109] Intermediate 6:

[0110]

[0111] tert-Butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilane)ethynyl)naphthalen-1-yl)-2-((1-formylcyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. To a stirred mixture of intermediate 5 (200 mg, 0.323 mmol, 1 eq) in DCM was added Dess-Martin (410.38 mg, 0.969 mmol, 3 eq) in portions at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated NaHCO3(aq) at 0°C and the resulting mixture was extracted with CH2Cl2(3x10 mL). The combined organic phases were washed with saturated NaCl(aq) (3x5 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS (ES, m / z): 618 [M+H] + .

[0112] Intermediate 7

[0113]

[0114] tert-Butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-((4-fluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. STAB (102.87 mg, 0.486 mmol, 3 eq) was added in portions to a stirred solution of intermediate 6 (100 mg, 0.162 mmol, 1 eq) and 4-fluoropiperidine hydrochloride (45.17 mg, 0.324 mmol, 2 eq) in DMF at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3x10 mL). The combined organic phase was washed with saturated aqueous NaCl solution (2 x 5 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS (ES, m / z): 605 [M+H] + .

[0115] Intermediate 8

[0116]

[0117] 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-((4-fluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. TFA (1 mL, 13.463 mmol, 101.84 eq) was added dropwise to a stirred solution of intermediate 7 (80 mg, 0.132 mmol, 1.0 eq) in DCM at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC with the following conditions: (column, XBridge Prep OBD C18 column, 30x150mm, 5μm; mobile phase, water (10mmol / L NH4HCO3) and ACN (30% ACN to 80%, 10min); detector, uv 220nm). Intermediate 8 (38.15mg, 47.69%) was obtained as a white solid. 1H NMR (DMSO-d6, 400MHz): δ10.15(s,1H),9.03(s,1H),7.97(dd,J=9.2,6.0Hz,1H),7.46(t,J=9.2Hz,1H) ,7.39(d,J=2.4Hz,1H),7.17(d,J=2.4Hz,1H),4.69(dt,J=7.6,3.6Hz,1H),4.48(d,J=12.0Hz,1H),4.3 4–4.22(m,3H),3.93(d,J=1.2Hz,1H),3.67–3.59(m,1H),3.54(t,J=5.6Hz,3H),2.74(s,1H),2.56(s,2 H), 2.30 (t, J = 7.6Hz, 4H), 1.88–1.76 (m, 2H), 1.66 (s, 6H), 0.64 (q, J = 3.2Hz, 2H), 0.40 (t, J = 3.2Hz, 2H). LC-MS:m / z 628.9[M+H] + .

[0118] Compound 1

[0119]

[0120] 1-(3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-((4-fluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one. After adding Py (5.00 eq) and TFAA (1.50 eq) to a DCM (2 mL) solution of compound 3 (1.00 eq) at 0°C, the mixture was stirred at 25°C for 2 hours. LC-MS showed that reactant 1 was completely consumed, and a main peak of the expected mass was detected. The reaction mixture was quenched by adding water (5 mL) at 10°C and extracted with DCM (5 mL*2). The combined organic phase was washed with saturated brine (5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (FA conditions; column: Phenomenex lunaC18 150*25mm*10μm; mobile phase: [water (FA)-ACN]; B%: 18%-48%, 10min). The obtained compound 1 (20.0 mg, 25.4μmol, 47.1% yield, 93.4% purity, HCl) was a yellow solid. 1H NMR (DMSO-d6, 400MHz): δ10.16(s,1H),9.05(d,J=1.2Hz,1H),7.98(dd,J=9.2,6.0Hz,1H),7.47(t,J=9.0Hz ,1H),7.40(d,J=2.4Hz,1H),7.18(t,J=2.4Hz,1H),4.80(s,1H),4.73(d,J=12.4Hz,1H),4.65(s,2H),4.59– 4.48(m,1H),4.35–4.24(m,2H),3.94(dd,J=6.4,1.2Hz,1H),3.76(d,J=12.4Hz,1H),3.68(d,J=12.4Hz,1H) ,2.48(s,1H),2.31-2.29(m,4H),1.90–1.75(m,6H),1.65(s,2H),0.65(d,J=4.8Hz,2H),0.45–0.40(m,2H). LC-MS:m / z 724.9[M+H] + .

[0121] The following compounds were prepared according to the general procedure described above using appropriate starting materials.

[0122] Compound 2

[0123]

[0124] 1-(3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one. 1 H NMR (400MHz, DMSO-d6) δ11.03-10.79(s,1H),10.24(s,1H),9.12(s,1H),8.00(dd,J=5.9,9.3Hz,1H),7.48(t,J=9.0Hz,1H),7.42(d,J=2.6Hz,1H ),7.20(s,1H),5.72-5.38(m,1H),4.84-4.57(m,6H),3.92(dd,J=3.5,5. 3Hz,1H),3.86-3.67(m,4H),3.54(s,2H),2.20-1.84(m,10H), LC-MS:m / z 697.3[M+H] + .

[0125] Compound 3

[0126]

[0127] 1-(3-{2-[(1-{3-azabicyclo[3.1.0]hexan-3-ylmethyl}cyclopropyl)methoxy]-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethanone. 1 H NMR (DMSO-d6, 400MHz): δ10.15(s,1H),9.05(s,1H),7.98(dd,J=9.2,6.0Hz,1H),7.47(t,J=9.2Hz,1H),7.40(d,J=2.4Hz,1H) ,7.18(t,J=2.4Hz,1H),4.80(s,1H),4.72(d,J=13.6Hz,1H),4.65(s,1H),4.52(d,J=12.8Hz,1H),4.33–4.18(m,2H),3.92(dd, J=6.8,1.2Hz,1H),3.76(d,J=12.8Hz,1H),3.68(d,J=12.8Hz,1H),2.96(dd,J=8.4,6.2Hz,2H),2.46–2.30(m,2H),2.23(d,J=8 .4Hz,2H),2.05–1.88(m,4H),1.32(dd,J=9.6,5.2Hz,2H),0.59(s,2H),0.55–0.50(m,1H),0.40(s,2H),0.25(p,J=3.6Hz,1H). LC-MS:m / z 705.0[M+H] + .

[0128] Compound 4

[0129]

[0130] 1-(3-(2-((1-((3-azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methoxy)-7-(8-ethynyl-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one. 1H NMR (DMSO-d6, 400MHz): δ10.14(s,1H),9.04(s,1H),7.89(dd,J=8.0,1.6Hz,1H),7.46–7.38(m,2H),7.35(d,J=2.4Hz, 1H),7.12(t,J=2.4Hz,1H),4.80(s,1H),4.73(dd,J=12.4,5.6Hz,1H),4.64(s,1H),4.52(d,J=12.8Hz,1H),4.27–4.17( m,2H),3.76(d,J=12.8Hz,1H),3.68(d,J=12.8Hz,1H),3.58(d,J=6.4Hz,1H),3.00–2.91(m,2H),2.42-2.35(m,2H),2.2 3(d,J=8.4Hz,2H),2.00–1.86(m,3H),1.31(s,2H),0.56-0.52(m,1H),0.46(d,J=4.0Hz,3H),0.40(s,2H),0.25(s,1H). LC-MS:m / z 687.1[M+H] + .

[0131] Predictive compounds

[0132] Compound 5

[0133]

[0134] 1-(3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one

[0135] Compound 6

[0136]

[0137] 1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methoxy-2-((1-((4-(trifluoromethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one 1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methoxy-2-((1-((4-(trifluoromethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one

[0138] Compound 7

[0139]

[0140] 1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methoxy-2-((1-(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one

[0141] Compound 8

[0142]

[0143] 1-(3-(2-((1-((3-azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one

[0144] Compound 9

[0145]

[0146] 1-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methoxy-4-((1R,5S)-8-(2,2,2-trifluoroacetyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-4-carbonitrile

[0147] Compound 10

[0148]

[0149] 1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-((4-(trifluoromethyl)

[0150] (piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one

[0151] Compound 11

[0152]

[0153] 1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-((4-fluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)-5-(trifluoromethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one

[0154] Compound 12

[0155]

[0156] 1-((1R,5S)-3-(5-ethoxy-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-((4-fluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one

[0157] Compound 13

[0158]

[0159] 1-((1R,5S)-3-(5-chloro-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-((4-fluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one

[0160] Compound 14

[0161]

[0162] 1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-((4-fluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)-5-(trifluoromethyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one

[0163] Compound 15

[0164]

[0165] 1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-((4-fluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one

[0166] Compound 16

[0167]

[0168] 1-(3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one

[0169] Compound 17

[0170]

[0171] 1-(3-(5-ethoxy-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one

[0172] Compound 18

[0173]

[0174] 1-(3-(5-chloro-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one

[0175] Compound 19

[0176]

[0177] 1-(3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-(trifluoromethyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one

[0178] Compound 20

[0179]

[0180] 1-(3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-(trifluoromethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one

[0181] Compound 21

[0182]

[0183] 1-((1R,5S)-3-(5-ethynyl-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-((4-fluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one

[0184] Compound 22

[0185]

[0186] 1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-((4-fluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)-5-(2-methylpropyl-1-en-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one

[0187] Compound 23

[0188]

[0189] 1-((1R,5S)-3-(5-cyclopropyl-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-((4-fluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one

[0190] Compound 24

[0191]

[0192] 1-((1R,5S)-3-(5-bromo-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-((4-fluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one

[0193] Compound 25

[0194]

[0195] 1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5,8-difluoro-2-((1-((4-fluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one

[0196] Compound 26

[0197]

[0198] 1-(3-(5-ethynyl-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one

[0199] Compound 27

[0200]

[0201] 1-(3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-(2-methylpropyl-1-en-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one

[0202] Compound 28

[0203]

[0204] 1-(3-(5-cyclopropyl-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one

[0205] Compound 29

[0206]

[0207] 1-(3-(5-bromo-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one

[0208] Compound 30

[0209]

[0210] 1-(3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5,8-difluoro-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one

[0211] Compound 31

[0212]

[0213] 1-((1R,5S)-3-(5-amino-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-((4-fluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one

[0214] Compound 32

[0215]

[0216] 1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-((4-fluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)-5-(methylamino)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one

[0217] Compound 33

[0218]

[0219] 1-((1R,5S)-3-(5-(dimethylamino)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-((4-fluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one

[0220] Compound 34

[0221]

[0222] 1-((1R,5S)-3-(5-(dimethylphosphoryl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-((4-fluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one

[0223] Compound 35

[0224]

[0225] 1-(3-(5-amino-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one

[0226] Compound 36

[0227]

[0228] 1-(3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-(methylamino)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one

[0229] Compound 37

[0230]

[0231] 1-(3-(5-(dimethylamino)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one

[0232] Compound 38

[0233]

[0234] 1-(3-(5-(dimethylphosphoryl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one

[0235] Compound 39

[0236]

[0237] 1-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((1R,5S)-8-(2,2,2-trifluoroacetyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-4-carbonitrile

[0238] Compound 39

[0239]

[0240] 1-((1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((1R,5S)-8-(2,2,2-trifluoroacetyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-4-carbonitrile. 1 H NMR(DMSO-d6,400MHz)δ10.15(s,1H),9.05(d,J=1.1Hz,1H),8.00-7.96(m,1H),7.47(t,J=9.0Hz,1H), 7.40(d,J=2.6Hz,1H),7.18(t,J=2.6Hz,1H),4.80(s,1H),4.73-4.71(m,1H),4.65(s,1H),4.53-4.50( m,1H),4.35–4.21(m,2H),3.93(dd,J=6.5,1.1Hz,1H),3.76-3.74(m,1H),3.69-3.67(m,1H),2.82(s,1 H),2.55(s,2H),2.32-2.27(m,4H),2.05-1.72(m,6H),1.65(d,J=8.8Hz,2H),0.65(s,2H),0.43(s,2H). LC-MS:m / z 731.90[M+H] + .

[0241] Compound 40

[0242]

[0243] 1-((1R,5S)-3-(2-((1-((6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one. 1 H NMR (400MHz, DMSO-d6) δ10.15(s,1H),9.05(d,J=1.1Hz,1H),7.98(dd,J=9.2,5.9Hz,1H),7.47(t,J=9.0Hz,1H),7.40(d,J=2.6Hz ,1H),7.18(t,J=2.4Hz,1H),4.80(s,1H),4.73(dd,J=13.0,5.2Hz,1H),4.64(s,1H),4.52(d,J=12.9Hz,1H),4.31–4.19(m,2H),4 .09(s,1H),3.92(dd,J=6.4,1.1Hz,1H),3.76(d,J=12.9Hz,2H),3.01(dd,J=9.7,2.7Hz,2H),2.77(d,J=9.7Hz,2H),2.42(dd,J=1 3.2, 10.3Hz, 2H), 2.28 (dd, J = 13.6, 2.6Hz, 2H), 1.95 (ddd, J = 30.3, 14.9, 7.2Hz, 4H), 0.61 (q, J = 3.2Hz, 2H), 0.43 (t, J = 2.9Hz, 2H). LC-MS:m / z 740.80[M+H] + .

[0244] Compound 41

[0245]

[0246] 3-((1-(((7-(8-ethynyl-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(8-(2,2,2-trifluoro-acetyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-3-azabicyclo[3.1.0]hexane-1-carbonitrile. 1H NMR(DMSO-d6,400MHz)δ10.13(s,1H),9.04(s,1H),7.89(dd,J=8.0,1.7Hz,1H),7.48–7.37(m,2H),7.35(d,J=2.6Hz,1H) ,7.12(t,J=2.4Hz,1H),4.80(s,1H),4.73-4.70(m,1H),4.64(s,1H),4.54-4.51(m,1H),4.24(d,J=2.3Hz,2H),3.75-3.6 6(m,2H),3.57(dd,J=6.5,1.3Hz,1H),3.22(dd,J=8.5,1.5Hz,1H),2.98(dd,J=9.3,3.1Hz,1H),2.47–2.34(m,4H),2.18( qd,J=4.7,2.2Hz,1H),2.08–1.77(m,4H),1.35–1.25(m,1H),1.09(dt,J=8.0,3.8Hz,1H),0.60(s,2H),0.43-0.41(m,2H). LC-MS:m / z711.90[M+H] + .

[0247] Compound 42

[0248]

[0249] 1-(3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-((4-fluoro-piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one. 1 H NMR (400MHz, DMSO-d6) δ10.17(s,1H),8.05-7.90(m,1H),7.55-7.35(m,2H),7.22(s,1H),4.87-4.53(m,2H),4.40-4.08(m,3H),4. 01-3.81(m,4H),3.54-3.40(m,3H),3.18-2.91(m,2H),2.40-2.27(m,1H),2.03-1.61(m,8H),1.55-1.28(m,2H),0.80-0.34(m,4H). LC-MS:m / z 755.5[M+H] + .

[0250] Compound 43

[0251]

[0252] 1-((1R,5S)-3-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-((1-((4-fluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one. 1 H NMR (400MHz, DMSO-d6) δ9.07 (d, J = 1.1Hz, 1H), 8.20–8.11 (m, 2H), 7.77–7.67 (m, 2H), 7.63–7. 54(m,2H),4.80(d,J=5.9Hz,1H),4.73(d,J=13.5Hz,1H),4.66(s,2H),4.53(d,J=13.0Hz,1H) ,4.36–4.24(m,2H),3.77(d,J=12.8Hz,1H),3.73–3.65(m,2H),2.57(s,2H),2.38–2.25(m,4H ),2.11–1.75(m,6H),1.65(t,J=9.5Hz,2H),0.66(q,J=3.5,3.0Hz,2H),0.43(t,J=2.9Hz,2H). LC-MS:m / z 690.90[M+H] + .

[0253] Compound 44

[0254]

[0255] 5-Ethynyl-6-fluoro-4-(8-fluoro-2-((1-((4-fluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S)-8-(2,2,2-trifluoroacetyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl isobutyrate. 1H NMR(DMSO-d6,400MHz)δ9.07(d,J=1.8Hz,1H),8.22(dd,J=9.2,5.8Hz,1H),8.01(d,J=2.6Hz,1H),7.66( t,J=9.0Hz,1H),7.49(t,J=2.8Hz,1H),4.80(s,1H),4.74-4.69(m,1H),4.67-4.62(m,1H),4.59-4.51(m ,2H),4.36–4.25(m,2H),4.06(d,J=7.2Hz,1H),3.78-3.68(m,2H),2.89(p,J=7.0Hz,1H),2.56(s,2H),2 .41–2.22(m,4H),2.07–1.74(m,6H),1.65(s,2H),1.27(dd,J=6.8,0.8Hz,6H),0.65(s,2H),0.43(s,2H). LC-MS:m / z 794.90[M+H] + .

[0256] Compound 45

[0257]

[0258] 1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-azabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one. 1 H NMR (400MHz, DMSO-d6) δ10.18(s,1H),9.08–9.01(m,1H),7.98(dd,J=9.2,5.9Hz,1H),7.47(t,J=9.0Hz,1H) ,7.40(d,J=2.6Hz,1H),7.18(t,J=2.5Hz,1H),4.80(s,1H),4.72(d,J=13.0Hz,1H),4.65(s,1H),4.52(d,J= 12.8Hz,1H),4.36–4.25(m,2H),3.94(d,J=6.4Hz,1H),3.76(d,J=12.8Hz,1H),3.68(d,J=13.1Hz,1H),3.53 (t,J=4.6Hz,4H),2.39(s,4H),2.31(s,2H),2.00–1.86(m,4H),0.65(q,J=3.1Hz,2H),0.43(q,J=4.0Hz,2H). LC-MS:m / z 708.80[M+H]+ .

[0259] Compound 46

[0260]

[0261] ((5-ethynyl-6-fluoro-4-(8-fluoro-4-((1R,5S)-8-(2,2,2-trifluoroacetyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((1-((4-(trifluoromethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)oxy)methyl dihydrogen phosphate. 1 H NMR (400MHz, DMSO-d6) δ9.07(s,1H),8.07(dd,J=9.2,5.9Hz,1H),7.80(d,J=2.7Hz,1H),7.54(t,J=9.0Hz,1H),7.36(t,J=2. 3Hz,1H),5.64(d,J=11.1Hz,2H),4.79(s,1H),4.72(d,J=12.9Hz,1H),4.62(s,1H),4.54(d,J=12.9Hz,1H),4.32(q,J=11.2H z,2H),3.96(d,J=6.3Hz,1H),3.75(dd,J=22.9,12.8Hz,2H),3.72(dd,J=22.9,12.8Hz,2H),3.19(dd,J=22.9,12.8Hz,1H),3 .05(dd,J=22.9,12.8Hz,2H),2.6(dd,J=22.9,12.8Hz,2H)1.88(s,6H),1.55(s,2H),0.74(s,1H),0.70(s,2H),0.55(s,2H). LC-MS:m / z 884.75[M+H] + .

[0262] Compound 47

[0263]

[0264] 5-Ethynyl-6-fluoro-4-(8-fluoro-2-((1-((4-fluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)-4-(8-(2,2,2-trifluoroacetyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl(tert-butoxycarbonyl)glycinate. 1H NMR (400MHz, DMSO-d6): δ9.07(d,J=1.7Hz,1H),8.25(dd,J=9.2,5.9Hz,1H),8.01(d,J=2.5Hz,1H),7.67(t,J =9.0Hz,1H),7.48(d,J=4.5Hz,2H),4.80(s,1H),4.76-4.68(m,1H),4.65(s,1H),4.58-4.51(m,1H),4.46(d,J =4.8Hz,1H),4.38(t,J=5.6Hz,1H),4.35–4.24(m,2H),4.09–3.98(m,2H),3.80–3.66(m,2H),3.30(s,3H),2.5 2(d,J=2.6Hz,2H),2.39–2.21(m,1H),2.07–1.71(m,6H),1.65(s,2H),1.40(s,9H),0.66(s,2H),0.43(s,2H). LC-MS:m / z 881.90[M+H] + .

[0265] Compound 48

[0266]

[0267] 1-(3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-((6-fluoro-3-azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methoxy)-5-(methoxy-d3)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one. 1 H NMR (400MHz, DMSO-d6) δ10.16(s,1H),7.98(dd,J=9.2,5.9Hz,1H),7.47(t,J=9.0H z,1H),7.42–7.32(m,1H),7.22(s,1H),4.75(s,1H),4.70–4.47(m,2H),4.24(q,J= 10.6Hz,4H),3.96(s,1H),3.56–3.38(m,2H),3.05(t,J=9.4Hz,2H),2.40–2.21(m, 5H),1.97(s,1H),1.92–1.83(m,2H),1.82–1.68(m,2H),0.58(s,2H),0.39(s,2H). LC-MS:m / z 756.10[M+H] + .

[0268] Compound 49

[0269]

[0270] 1-(3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((2-((6-fluoro-3-azabicyclo[3.1.0]hexan-3-yl)methyl)allyl)oxy)-5-(methoxy-d3)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one. 1 H NMR (400MHz, DMSO-d6) δ10.17(s,1H),7.98(dd,J=9.2,5.9Hz,1H),7.47(t,J=9.0Hz,1H),7. 39(d,J=2.6Hz,1H),7.26–7.20(m,1H),5.11(d,J=10.9Hz,2H),4.87(s,2H),4.80–4.50(m,3 H),4.45–4.07(m,2H),3.96(d,J=2.5Hz,1H),3.57–3.43(m,2H),3.05(s,2H),3.00(dd,J=9. 0,2.9Hz,2H),2.30(d,J=8.8Hz,2H),1.95(s,1H),1.86(d,J=12.7Hz,2H),1.82–1.75(m,3H). LC-MS:m / z742.1[M+H] + .

[0271] Compound 50

[0272]

[0273] 1-((1R,5S)-3-(2-((1-((3-azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-6-en-8-yl)-2,2,2-trifluoroethane-1-one. 1HNMR(DMSO-d6,400MHz)δ10.15(s,1H),7.97(dd,J=9.2,5.9Hz,1H),7.47(t,J=9.0Hz,1H),7.39(d,J=2.6Hz,1H),7.21( d,J=2.5Hz,1H),6.37–6.15(m,2H),5.04(d,J=18.0Hz,2H),4.42–4.32(m,1H),4.26–4.12(m,2H),4.05–4.02(m,1H),3. 94(dd,J=5.9,1.0Hz,1H),3.89(d,J=1.3Hz,3H),3.67-3.54(m,2H),2.96(t,J=8.0Hz,2H),2.44–2.29(m,2H),2.24(d,J =8.6Hz, 2H), 1.32 (dt, J = 6.7, 2.6Hz, 2H), 0.57 (q, J = 4.4, 3.3Hz, 3H), 0.39 (q, J = 4.2Hz, 2H), 0.26 (td, J = 7.7, 3.7Hz, 1H). LC-MS:m / z 733.00[M+H] + .

[0274] Compound 51

[0275]

[0276] 1-(3-(2-((1-((3-azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-6,6-difluoro-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one. 1H NMR (400MHz, DMSO-d6): δ10.19(d,J=13.0Hz,1H),7.99(dd,J=9.4,5.5Hz,1H),7.48(t,J=9.0Hz,1H), 7.40(t,J=3.3Hz,1H),7.28(s,1H),5.08–4.88(m,2H),4.86–4.63(m,1H),4.34–4.18(m,2H),4.17–4.0 1(m,1H),3.95–3.89(m,3H),3.82–3.61(m,2H),2.94(d,J=7.8Hz,2H),2.71–2.63(m,2H),2.41(d,J=11 .5Hz,1H),2.35(s,1H),2.23(s,2H),1.31(s,2H),1.23(s,1H),0.57(s,3H),0.39(s,2H),0.24(s,1H). LC-MS:m / z 771.30[M+H] + .

[0277] Compound 52

[0278]

[0279] 1-(3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-(methoxy-d3)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one. 1 H NMR (400MHz, DMSO-d6) δ10.16(s,1H),7.97(dd,J=6.0,8.9Hz,1H),7.47(t,J=9.0Hz,1H),7.39(d,J=2. 6Hz,1H),7.22(s,1H),5.37-5.19(m,1H),4.82-4.71(m,1H),4.68-4.57(m,1H),4.29-4.19(m,1H),4.1 3(d,J=9.8Hz,1H),4.06-4.00(m,1H),3.97(d,J=2.8Hz,1H),3.52-3.37(m,3H),3.12-3.06(m,2H),3.0 1(s,1H),2.86-2.78(m,1H),2.13(d,J=3.0Hz,1H),2.05(s,1H),2.01-1.95(m,2H),1.89-1.75(m,6H). LC-MS:m / z 730.6[M+H]+ .

[0280] Compound 53

[0281]

[0282] 1-(3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-(methoxy-d3)-2-((1-((4-(trifluoromethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one. 1 H NMR (DMSO-d 6, 400MHz) δ10.25-10.13(m,1H),8.01-7.95(m,1H),7.51-7.44(m,1H),7.41-7.37( m,1H),7.24-7.19(m,1H),4.79-4.71(m,1H),4.67-4.56(m,1H),4.30(s,2H),3.9 6(s,1H),3.47-3.40(m,2H),3.07-2.97(m,3H),2.34(m,2H),2.05-1.93(m,2H),1 .92-1.82(m,4H),1.77-1.70(m,3H),1.43-1.20(m,3H),0.64(s,2H),0.48(s,2H). LC-MS:m / z 808.5[M+H] + .

[0283] Compound 54

[0284]

[0285] 1-(3-(5-cyclopropyloxy-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-((4-(trifluoromethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one. 1H NMR (400MHz, DMSO-d6) δ10.20 (s, 1H), 7.98 (dd, J = 6.2, 9.2Hz, 1H), 7.52-7.36 (m,2H),7.26-7.17(m,1H),4.76-4.68(m,1H),4.59-4.49(m,1H),4.29(s,3H), 3.94(d,J=8.4Hz,1H),3.85-3.75(m,2H),3.54-3.45(m,4H),3.28-3.21(m,2H ),3.03-2.94(m,2H),2.18-2.05(m,2H),1.97-1.66(m,8H),0.91-0.65(m,8H). LC-MS: m / z 831.7[M+H] + .

[0286] Compound 55

[0287]

[0288] 1-(3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-isopropoxy-2-((1-((4-(trifluoromethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one. 1 H NMR(DMSO-d6,400MHz)δ10.22(s,1H),7.97(dd,J=6.0,9.2Hz,1H),7.50-7.43(m,1H),7.38(d,J=2.4H z,1H),7.19(dd,J=2.4,8.8Hz,1H),5.39-5.30(m,1H),4.75(s,1H),4.65-4.53(m,1H),4.34-4.28(m,2 H),3.95(d,J=3.4Hz,1H),3.50-3.26(m,4H),3.03-2.97(m,2H),2.38-2.31(m,1H),2.30-2.24(m,1H), 2.23-2.13(m,1H),1.97-1.65(m,8H),1.40-1.34(m,1H),1.33-1.26(m,6H),0.64(s,2H),0.41(s,2H). LC-MS:m / z 833.7[M+H] + .

[0289] Compound 56

[0290]

[0291] 1-(3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-(2,2,2-trifluoroethoxy)-2-((1-((4-(trifluoromethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethane-1-one. 1 H NMR (400MHz, DMSO-d6) δ10.29-10.12(m,1H),8.04-7.96(m,1H),7.48(t,J=9.0Hz,1H),7 .41(d,J=2.6Hz,1H),7.23(dd,J=2.4,7.1Hz,1H),5.17-4.91(m,2H),4.81-4.70(m,1H), 4.63-4.52(m,1H),4.33(s,2H),4.00(d,J=7.8Hz,1H),3.60-3.41(m,2H),3.05-2.93(m, 2H),2.39-2.15(m,4H),1.93-1.68(m,8H),1.42-1.21(m,3H),0.65(s,2H),0.43(s,2H). LC-MS:m / z 873.7[M+H] + .

[0292] Other compounds that are contemplated and are part of this disclosure include the following.

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301] Biological activity assays / tests

[0302] Cell lines

[0303] The following cancer cell lines were used: A427 human lung cancer cells [KRAS (G12D) 1 copy] (ATCC, #HTB-53); AGS human gastric adenocarcinoma cells [KRAS (G12D) 1 copy] (ATCC, #CRL-1739) and AsPC-1 human adenocarcinoma cells [KRAS (G12D) 2 copies] (ATCC, CRL-1682). Cell lines were cultured essentially according to the recommendations of the American Type Culture Collection (ATCC).

[0304] Cytotoxicity

[0305] A427 and AGS cells were seeded at 4,000 cells / well in 96-well tissue culture plates and incubated at 37°C / 5% CO2 for 72 hours with 100 μl of culture medium. Three-fold serial dilutions of each test compound were prepared, ranging from 20 μM to 1.02 nM. Each cell line was then treated with different concentrations of the test compound at a final concentration of 0.5% DMSO / well and then incubated at 37°C / 5% CO2 for 24 hours. 100 μl of CellTiter- Reagents (Promega Corporation, Madison, WI) were added to each well and treated according to the manufacturer's protocol. Results were analyzed using GraphPad 7 software and IC 50 The results are listed in Table 1.

[0306] KRAS(G12D) / SOS1 Homogeneous Time-Resolved Fluorescence (HTRF) Assay

[0307] Unless otherwise stated, the KRAS-G12D / SOS1 binding assay kit (Cisbio, #63ADK000CB16PEG) was used according to the manufacturer's instructions to measure the binding of test compounds to the KRAS (G12D) target protein in the absence of GTP by homogeneous time-resolved fluorescence, thereby blocking the interaction of KRAS (G12D) with the SOS1 protein. A 3-fold serial dilution of each test compound was prepared, ranging from 20 μM to 1.02 nM. The test compound was mixed and incubated with the reaction components, incubated at 4 ° C for 3 hours in a sealed plate, and the fluorescence was measured using a PerkinElmer Envision plate reader. The IC of KRAS (G12D) -SOS1 was calculated using GraphPad Prism 7 software. 50 The results are listed in Table 1.

[0308] Table 1 - Cytotoxicity and target binding assays

[0309]

[0310]

[0311]

[0312]

[0313] 1 CellTiter-Glo cytotoxicity assay of A427 and AGS cells: A: 1-100nM, B: 101-1000nM, C: 1001-10000nM, D: >10000nM; 2 KRAS(G12D)-SOS1HTRF binding. A: 1-100 nM, B: 101-1000 nM, C: 1001-10000 nM, D: >10000 nM.

[0314] Oral availability

[0315] CD-1 mice were randomly divided into 6 groups, 3 male mice in each group. The control group included compound 1 (50 mg / kg), compound 3 (25 mg / kg) and compound 5 (25 mg / kg). The trifluoroacetate (COCF3) group included compound 2 (50 mg / kg), compound 4 (50 mg / kg) and compound 6 (50 mg / kg). The compounds were orally administered (PO) to each mouse in their group in a single dose. Blood samples were collected within 72 hours. Bioavailability (F%) was determined by liquid chromatography-mass spectrometry (LC-MS / MS). The average oral F% is provided in Table 2.

[0316] Table 2

[0317]

[0318]

[0319]

[0320] In vivo xenograft tumor models

[0321] 8-9 week old BALB / c nude mice were raised in a pathogen-free environment. AsPC-1 cells (5×10 6 ) were implanted subcutaneously into female mice. 3) were randomly divided into 4 treatment groups. Mice were administered 5% sulfobutyl ether-β-cyclodextrin (SBECD) vehicle control intravenously (iv) once a week (QW), or 75 mg / kg compound 3 orally (PO) twice a day (BID) for more than 3 weeks. Tumors were measured twice a week with calipers. Tumor volume (TV) was calculated as TV = (L×W2) / 2, where L is the tumor length and W is the tumor width. Results are plotted as + / - standard error (SEM). The Student's T test with Bonferroni post hoc adjustment was used to measure the statistical significance of the final (24 day) tumor measurements (P = 0.036). Results are in Figure 1 Displayed in.

[0322] Although the present disclosure has been described in conjunction with specific embodiments, it should be understood that the claimed disclosure should not be unduly limited to such specific embodiments. Indeed, it is intended and understood by those skilled in the art to which the present disclosure belongs that various modifications to the described manner of implementing the present disclosure fall within the scope of the present disclosure as represented by the following claims.

[0323] All patents and publications mentioned in this specification are herein incorporated by reference to the same extent as if each independent patent and publication was specifically and individually indicated to be incorporated by reference.

Claims

1. A compound of the following structural formula I*: R 00 F2C-L-R 0 (I*); or a pharmaceutically acceptable salt thereof, wherein: L is selected from -C(=O), -S(=O) and -S(O)2; R 0 Is related to KRAS G12D The bound chemical entity; and R 00 Selected from hydrogen, F, Cl and CF3.

2. The compound of claim 1, wherein the compound has the following structural formula I: or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 or 2, wherein the compound has the following structural formula Ia or Ib: or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from (C1-C4)alkylO(C1-C4)alkyl, -(C1-C4)alkylNH(C1-C4)alkyl, -(C1-C4)alkylN[(C1-C4)alkyl]2, heterocyclyl and cycloalkyl, wherein the heterocyclyl and cycloalkyl are each optionally and independently substituted; R 2 is selected from hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C1-C4)alkynyl, (C1-C4)alkenyl, halogen, (C3-C6)cycloalkyl, -O(C3-C6)cycloalkyl, cyano, -NH2, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -P(O)[(C1-C4)alkyl]2 and -S(C1-C4)alkyl; R 3 Selected from a 1 N or CHZ 1 ; Z 1 is selected from hydrogen, halogen, (C1-C4)alkyl, (C2-C4)alkenyl, cyano, cyano(C1-C4)alkyl, -S[halo(C1-C4)alkyl] and (C3-C6)cycloalkyl; R 8 , R 9 , R 10 , R 11 , R 12 and R 13 each independently selected from hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)cyanoalkyl, (C1-C4)hydroxyalkyl, -(C1-C4)alkylNR a R b 、-(C1-C4)alkylC(O)NR a R b 、(C1-C4)alkylO(C1-C4)alkyl、-(C1-C4)alkylC(O)OR a 、-(C1-C4)alkylNR a C(O)OR b 、-(C1-C4)alkylC(O)R a , -(C1-C4)alkylheterocycloalkyl, -(C1-C4)alkylaryl, -(C1-C4)alkylheteroaryl, (C2-C4)alkenyl, (C2-C4)haloalkenyl, (C2-C4)cyanoalkenyl, (C2-C4)hydroxyalkenyl, -(C2-C4)alkenylNR a R b , (C2-C4) alkynyl, (C2-C4) haloalkynyl, -(C2-C4) cyanoalkynyl, (C2-C4) hydroxyalkynyl, -(C2-C4) alkynylNR a R b , (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, cyano, oxo, hydroxy, -S(C1-C4) alkyl, -S(C1-C4) haloalkyl, -NR a R b 、-NR a C(O)R b 、-C(O)R a 、-C(O)OR a 、-SO2R a 、-S(O)R a 、-SO2NR a R b 、-NR a S02R b , (C3-C6)cycloalkyl, 5- or 6-membered heteroaryl and 4- to 6-membered heterocyclyl, wherein the heterocyclyl, aryl and heteroaryl of -(C1-C4)alkylheterocyclyl, -(C1-C4)alkylaryl and -(C1-C4)alkylheteroaryl, and the (C3-C6)cycloalkyl, 5- or 6-membered heteroaryl and 4- to 6-membered heterocyclyl are each optionally and independently replaced by 1 to 3 selected from R c The group substitution; m is 0, 1 or 2; R a and R b are each independently selected from hydrogen, (C1-C4)alkyl and (C1-C4)haloalkyl, or when R a and R b When on the same nitrogen atom, they may together form a heterocyclic group; and R c is selected from halogen, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, cyano, hydroxy, oxo, -C(O)OR a 、-C(O)R a 、-SO2R a 、-S(O)R a 、-SO2NR a R b 、-NR a C(O)R b 、-NR a S02R b 、-NR a R b and NO2.

4. The compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3, wherein Z is selected from hydrogen, methyl, ethyl, isopropyl, cyano, -SCF3, cyanoethyl, cyclopropyl and 2-methylpropenyl.

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from optionally substituted heterocyclyl and optionally substituted cycloalkyl.

6. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from optionally substituted fused bicyclic heterocyclyl and optionally substituted (C3-C6)cycloalkyl.

7. The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein: R 1 Selected from R 4 , R 6 and R 7 each independently selected from hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)cyanoalkyl, (C1-C4)hydroxyalkyl, -(C1-C4)alkylNR a R b 、-(C1-C4)alkyl-C(O)NR a R b , -(C1-C4)alkylO(C1-C4)alkyl, -(C1-C4)alkylC(O)OR a 、-(C1-C4)alkylNR a C(O)OR b 、-(C1-C4)alkylC(O)R a , -(C1-C4)alkylheterocycloalkyl, -(C1-C4)alkylaryl, -(C1-C4)alkylheteroaryl, (C2-C4)alkenyl, (C2-C4)haloalkenyl, (C2-C4)cyanoalkenyl, (C2-C4)hydroxyalkenyl, -(C2-C4)alkenylNR a R b , (C2-C4)alkynyl, (C2-C4)haloalkynyl, (C2-C4)cyanoalkynyl, -(C2-C4)hydroxyalkynyl, -(C2-C4)alkynylNR a R b , (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, cyano, oxo, hydroxy, -S(C1-C4) alkyl, -S(C1-C4) haloalkyl, -NR a R b 、-NR a C(O)R b 、-C(O)R a 、-C(O)OR a 、-SO2R a 、-S(O)R a 、-SO2NR a R b 、-NR a S02R b , (C3-C6)cycloalkyl, 5- or 6-membered heteroaryl and 4- to 6-membered heterocyclyl, wherein the heterocyclyl, aryl and heteroaryl of (C1-C4)alkylheterocyclyl, (C1-C4)alkylaryl and (C1-C4)alkylheteroaryl, and the (C3-C6)cycloalkyl, 5- or 6-membered heteroaryl and 4- to 6-membered heterocyclyl are each optionally and independently replaced by 1 to 3 selected from R c The group substitution; R 5 is (C1-C4)alkyl or halogen; and n, x and z are each independently 0, 1 or 2.

8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 1 Selected from 9. The compound according to any one of claims 1 to 8, wherein the compound has the following structural formula Ia': or a pharmaceutically acceptable salt thereof.

10. A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein a 1 is N.

11. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein R 00 For F.

12. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein R 3 for 13. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein R 8 , R 9 , R 10 and R 11 Each is independently selected from hydrogen, halogen, hydroxy and (C2-C4)alkynyl.

14. The compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, wherein R 8 , R 9 , R 10 and R 11 Each is H; or R 9 , R 10 and R 11 are each hydrogen, and R 8 is selected from halogen, hydroxy and (C2-C4)alkynyl; or R 10 and R 11 are each hydrogen, and R 8 and R 9 are each independently selected from halogen, hydroxy and (C2-C4)alkynyl; or R 11 is hydrogen, and R 8 , R 9 and R 10 Each is independently selected from halogen, hydroxy and (C2-C4)alkynyl.

15. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein R 8 , R 9 , R 10 and R 11 are each hydrogen; or R 9 , R 10 and R 11 are each hydrogen, and R 8 is (C2-C4)alkynyl; or R 10 and R 11 Each is hydrogen, R 8 is (C2-C4)alkynyl, and R 9 is a halogen; or R 11 is hydrogen, R 8 is (C2-C4) alkynyl, R 9 is a halogen, and R 10 It is hydroxyl.

16. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, wherein R 3 for or a pharmaceutically acceptable salt thereof.

17. A compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, wherein R 3 for or a pharmaceutically acceptable salt thereof.

18. A compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from 19. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, wherein m is 0 or 1.

20. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 19, wherein m is 1.

21. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R 5 It is a halogen.

22. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 21, wherein z is 0 or 2.

23. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 22, wherein z is 0.

24. A compound as described in any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R 1 for 25. A compound as described in any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein R 4 is -(C1-C4)alkylheterocyclic group, which is optionally substituted by 1 to 3 selected from R c The group is substituted.

26. A compound as described in any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein R 4 for Each is optionally 1 to 3 selected from R c The group is substituted.

27. A compound as described in any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein R c Selected from (C1-C4)alkyl, (C1-C4)haloalkyl and halogen.

28. A compound as described in any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein R c Selected from (C1-C4)haloalkyl and halogen.

29. A compound as described in any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from 30. A compound as described in any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C1-C4)alkynyl, (C1-C4)alkenyl, halogen, (C3-C6)cycloalkyl, cyano, NH2, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -P(O)[(C1-C4)alkyl]2 and -S(C1-C4)alkyl.

31. A compound as described in any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from hydrogen and (C1-C4)alkoxy.

32. A compound as described in any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from hydrogen, chlorine, cyano, methoxy, ethoxy, CF3 and 33. The compound of claim 1, wherein the compound is selected from or a pharmaceutically acceptable salt thereof.

34. A pharmaceutical composition comprising a compound according to any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

35. A method for treating cancer in a subject, comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 33, or a pharmaceutically acceptable composition as claimed in claim 34.

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