Inhibitors of KRAS G12C protein and uses thereof

Abstract

The present disclosure relates to novel compounds useful as inhibitors of KRAS protein, as well as pharmaceutical compositions comprising these compounds, and methods of treatment by administration of these compounds or the pharmaceutical compositions.

Description

Field of the Invention

[0001] The present disclosure generally relates to novel compounds useful as inhibitors of the KRAS protein, as well as pharmaceutical compositions comprising these compounds, and methods of treatment by administering these compounds or the pharmaceutical compositions. Background Art

[0002] The KRAS oncoprotein is a GTPase and a fundamental mediator of intracellular signaling pathways involved in tumor cell growth and survival. In normal cells, KRAS acts as a molecular switch, switching between an inactive GDP-bound state and an active GTP-bound state. The transition between these states is promoted by a guanine nucleotide exchange factor that loads GTP and activates KRAS and GTP hydrolysis, which is catalyzed by GTPase-activated proteins to inactivate KRAS. GTP bound to KRAS promotes the binding of effectors to trigger signal transduction pathways including the RAF-MEK-ERK (MAPK) pathway.

[0003] Activating mutations in KRAS are a hallmark of cancer and prevent the association of GTPase-activated proteins, thereby stabilizing effector binding and enhancing KRAS signaling. KRAS G12C is present in approximately 13% of lung adenocarcinomas, 3% of colorectal cancers, and 2% of other solid tumors. Therefore, KRAS, and KRAS G12C in particular, is widely considered a particularly important oncology target.

[0004] Although progress has been made in targeting KRAS G12C, targeting this gene with small molecules remains a challenge. Therefore, there is a need in the art to develop improved small molecule compounds that inhibit KRAS, particularly KRAS G12C. Summary of the Invention

[0005] The present disclosure provides compounds capable of modulating KRAS G12C protein, including stereoisomers, pharmaceutically acceptable salts, tautomers, and prodrugs thereof, and methods of using such compounds to treat various diseases or conditions, such as cancer, are also provided.

[0006] In one aspect, the present disclosure provides a compound having formula (I):

[0007]

[0008] or a pharmaceutically acceptable salt thereof,

[0009] in

[0010] Ring A is selected from the group consisting of a saturated or partially unsaturated cycloalkyl group, a saturated or partially unsaturated heterocyclyl group, and a heteroaryl group;

[0011] L1 is a bond, O, S or N(R a );

[0012] L 2 selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl;

[0013] R 1 is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with one or more R b replace;

[0014] R 2 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl and heteroaryl, wherein each of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted by one or more R c replace,

[0015] R 3 Selected from the group consisting of: hydrogen, oxo, halogen, cyano, hydroxyl, -NR d R e 、-C(O)NR d R e , alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl and heteroaryl, wherein each of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with one or more R f replace; or

[0016] R 4 and R 5 、R 4 and R 6 、R 4 and R 7 Together with the atoms to which they are attached, they form a saturated or partially unsaturated cycloalkyl, or a saturated or partially unsaturated heterocyclyl, wherein each of the cycloalkyl and heterocyclyl groups is optionally substituted by cyano, halogen, hydroxy, -NR c R d , carboxyl, carbamoyl, aryl or heteroaryl substituted;

[0017] W is a saturated or partially unsaturated cycloalkyl group, or a saturated or partially unsaturated heterocyclyl group, wherein each of the cycloalkyl group and the heterocyclyl group is optionally substituted by one or more Rg replace,

[0018] L 3 is a bond, an alkyl group or -NR d -;

[0019] B is an electrophilic moiety that is capable of forming a covalent bond with the cysteine ​​residue at position 12 of the K-Ras G12C mutant protein;

[0020] R a are independently hydrogen or alkyl;

[0021] Each R b are independently selected from the group consisting of: oxo, cyano, halogen, hydroxy, acyl, -NR d R e , carbamoyl, carboxyl, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkylalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0022] Each R c are independently selected from the group consisting of: oxo, halogen, cyano, hydroxyl, -NR d R e 、-C(O)OR a 、-C(O)N(R d )(R e ), alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, alkoxy, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl;

[0023] R d and R e each of is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, and heteroaryl, wherein each of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, and heteroaryl is optionally substituted with cyano, halogen, hydroxyl, or amino;

[0024] Each R f are independently selected from the group consisting of: oxo, halogen, cyano, hydroxyl, -NR c R d , alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0025] Each R g are independently selected from the group consisting of: oxo, cyano, halogen, hydroxyl, -NR d R e, carbamoyl, carboxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl and saturated or partially unsaturated heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl and heterocyclyl is optionally substituted by cyano, halogen, hydroxyl, -NR d R e , carboxyl, carbamoyl, haloalkyl, aryl or heteroaryl;

[0026] n is 0, 1, 2, 3 or 4.

[0027] In some embodiments, the present disclosure provides compounds having a formula selected from the group consisting of:

[0028]

[0029]

[0030] or a pharmaceutically acceptable salt thereof,

[0031] in

[0032] J 1 Does not exist, CH(R 4 ),NR 4 , SO2 or P(O)CH3;

[0033] J 2 Does not exist, CR 5 , N, SO2 or P(O)CH3;

[0034] J 3 Does not exist, CH(R 6 ),NR 6 , SO2 or P(O)CH3;

[0035] J 4 Does not exist, CR 7 , N, SO2 or P(O)CH3;

[0036] J 5 Does not exist, CH(R 8 ),NR 8 , SO2 or P(O)CH3;

[0037] R 4 、R 5 、R 6 、R 7 and R 8 are each independently selected from the group consisting of hydrogen, oxo, halogen, cyano, hydroxyl, -NR d R e, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl and heteroaryl, wherein each of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with one or more R f replace; or

[0038] R 2 and R 4 、R 5 、R 6 、R 7 and R 8 Any of them together with the atoms to which they are attached form a saturated or partially unsaturated cycloalkyl, or a saturated or partially unsaturated heterocyclyl, wherein each of the cycloalkyl and heterocyclyl is optionally substituted by cyano, halogen, hydroxyl, -NR c R d , carboxyl, carbamoyl, aryl or heteroaryl; or

[0039] R 3 and R 4 、R 5 、R 6 and R 8 Any of them together with the atoms to which they are attached form a saturated or partially unsaturated cycloalkyl, or a saturated or partially unsaturated heterocyclyl, wherein each of the cycloalkyl and heterocyclyl is optionally substituted by cyano, halogen, hydroxyl, -NR c R d , carboxyl, carbamoyl, aryl or heteroaryl; or

[0040] R 4 and R 6 and R 8 Any of them together with the atoms to which they are attached form a saturated or partially unsaturated cycloalkyl, or a saturated or partially unsaturated heterocyclyl, wherein each of the cycloalkyl and heterocyclyl is optionally substituted by cyano, halogen, hydroxyl, -NR c R d , carboxyl, carbamoyl, aryl or heteroaryl; or

[0041] R 6 and R 8 Together with the atoms to which they are attached, they form a saturated or partially unsaturated cycloalkyl, or a saturated or partially unsaturated heterocyclyl, wherein each of the cycloalkyl and heterocyclyl groups is optionally substituted by cyano, halogen, hydroxy, -NR c R d , carboxyl, carbamoyl, aryl or heteroaryl.

[0042] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0043] In another aspect, the present disclosure provides a method for treating cancer, comprising administering an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure to a subject in need thereof.

[0044] In another aspect, the present disclosure provides a method for treating cancer in an individual in need thereof, the method comprising:

[0045] (a) determining that the cancer is associated with a KRAS G12C mutation; and

[0046] (b) administering to the individual an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0047] In another aspect, the present disclosure provides a method for inhibiting tumor metastasis, comprising administering an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure to a subject in need thereof.

[0048] In another aspect, the present disclosure provides a method for modulating the activity of a KRAS G12C mutant protein, comprising reacting the KRAS G12C mutant protein with a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0049] In another aspect, the present disclosure provides a method for preparing a labeled KRAS G12C mutant protein, comprising reacting the KRAS G12C mutant protein with a compound of the present disclosure or a pharmaceutically acceptable salt thereof to obtain the labeled KRAS G12C mutant protein.

[0050] In another aspect, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating cancer.

[0051] In another aspect, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure in the manufacture of a medicament for inhibiting tumor metastasis.

[0052] In another aspect, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, for use in treating cancer.

[0053] In another aspect, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, for use in inhibiting tumor metastasis. DETAILED DESCRIPTION

[0054] Reference will now be made in detail to certain embodiments of the present disclosure, examples of which are illustrated in the accompanying structures and formulas. While the present disclosure will be described in conjunction with the enumerated embodiments, it will be understood that the present disclosure is not limited to these embodiments. Rather, the present disclosure is intended to cover all alternatives, modifications, and equivalents that can be included within the scope of the present disclosure, as defined by the claims. One skilled in the art will recognize many methods and materials as being suitable for use in the present disclosure. The present disclosure is in no way limited to the methods and materials described. In the event that one or more of the incorporated references and similar materials (including but not limited to defined terms, term usage, described techniques, and the like) differ from or contradict the present application, the present disclosure controls. All references cited in the present disclosure, patents, patent applications, are hereby incorporated by reference in their entirety.

[0055] It should be understood that certain features of the present disclosure, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the present disclosure, which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable

[0056] definition

[0057] Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition, inside cover, and specific functional groups are generally defined as described therein. In addition, general principles of organic chemistry as well as specific functional moieties and reactivities are described in Organic Chemistry, Thomas Sorrell, 2nd edition, University Science Books, Sausalito, 2006; Smith and March March's Advanced Organic Chemistry, 6th edition, John Wiley & Sons, Inc., New York, 2007; Larock, Comprehensive Organic Transformations, 3rd edition, VCH Publishers, Inc., New York, 2018; Carruthers, Some Modern Methods of Organic Synthesis, 4th edition, Cambridge University Press, Cambridge, 2004; the entire contents of each of which are incorporated herein by reference.

[0058] At various locations in this disclosure, a linking substituent is described. It is specifically intended that each linking substituent include both the forward and backward forms of the linking substituent. For example, -NR(CR'R")- includes both -NR(CR'R")- and -(CR'R")NR-. In cases where the structure explicitly requires a linking group, the Markush variables listed for that group are to be understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition of the variable lists "alkyl", it is to be understood that the "alkyl" means a linking alkylene group.

[0059] 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 in the ring. If a substituent is listed without indicating that such substituent is bonded to an atom in the rest of the compound of a specified formula, then such substituent may be bonded via any atom in such formula. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0060] When any variable (e.g., R i) occurs more than once in any component or formula of a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown with 0 to 2 R i Partially substituted, then the group may optionally be substituted with up to two R i Partially substituted, and R i independently selected at each occurrence from R i Again, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0061] As used herein, the term "C i-j " indicates a carbon atom numerical range, wherein i and j are integers and the carbon atom numerical range includes the endpoints (i.e., i and j) and each integer point between the two, and wherein j is greater than i. For example, C 1-6 Indicates a range of one to six carbon atoms, including one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms, and six carbon atoms. In some embodiments, the term "C 1-12 ” indicates 1 to 12, especially 1 to 10, especially 1 to 8, especially 1 to 6, especially 1 to 5, especially 1 to 4, especially 1 to 3 or especially 1 to 2 carbon atoms.

[0062] As used herein, the term "acyl" refers to -C(=O)-R, wherein R is a substituent such as hydrogen, alkyl, cycloalkyl, aryl, or heterocyclyl, wherein the alkyl, cycloalkyl, aryl, and heterocyclyl are as defined herein.

[0063] As used herein, the term "alkyl", whether used as part of another term or independently, refers to a saturated straight or branched chain hydrocarbon group, which may be optionally substituted independently with one or more substituents as described below. i-j "Alkyl" refers to an alkyl group having i to j carbon atoms. In some embodiments, the alkyl group contains 1 to 10 carbon atoms. In some embodiments, the alkyl group contains 1 to 9 carbon atoms. In some embodiments, the alkyl group contains 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. "C 1-10 Examples of "alkyl" include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. 1-6Examples of "alkyl" groups are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-l-butyl, 2-methyl-l-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, and the like.

[0064] As used herein, the term "alkenyl," whether used alone or as part of another term, refers to straight or branched chain hydrocarbon groups having at least one carbon-carbon double bond, which can be optionally substituted independently with one or more substituents described herein, and includes groups having "cis" and "trans" orientations, or "E" and "Z" orientations. In some embodiments, the alkenyl group contains 2 to 12 carbon atoms. In some embodiments, the alkenyl group contains 2 to 11 carbon atoms. In some embodiments, the alkenyl group contains 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, the alkenyl group contains 2 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethylene (or vinyl), propylene (allyl), butenylene, pentenylene, 1 -methyl-2but-l-yl, 5-hexenyl, and the like.

[0065] As used herein, the term "alkynyl," whether used alone or as part of another term, refers to straight or branched chain hydrocarbon groups having at least one carbon-carbon triple bond, which can be optionally substituted independently with one or more substituents described herein. In some embodiments, the alkenyl group contains 2 to 12 carbon atoms. In some embodiments, the alkynyl group contains 2 to 11 carbon atoms. In some embodiments, the alkynyl group contains 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, the alkynyl group contains 2 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, 1 -propynyl, 2-propynyl, and the like.

[0066] As used herein, the term "alkoxy," whether used alone or as part of another term, refers to an alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom. The term "C i-j"Alkoxy" means an alkyl moiety having i to j carbon atoms of an alkoxy group. In some embodiments, an alkoxy group contains 1 to 10 carbon atoms. In some embodiments, an alkoxy group contains 1 to 9 carbon atoms. In some embodiments, an alkoxy group contains 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. "C 1-6 Examples of "alkoxy" groups include, but are not limited to, methoxy, ethoxy, propyloxy (e.g., n- propyloxy and isopropyloxy), t-butyloxy, neopentyloxy, n-hexyloxy, and the like.

[0067] As used herein, the term "alkoxyalkyl" refers to a group of the formula -R"OR', wherein R' and R" are independently alkyl as defined above.

[0068] As used herein, the term "amino" refers to a -NH2group. An amino group can also be substituted with one or more groups of, for example, alkyl, aryl, carbonyl, or other amino groups.

[0069] As used herein, the term "aryl" whether used alone or as part of another term, refers to monocyclic and polycyclic ring systems having from 5 to 20 ring members in total, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains from 3 to 12 ring members. Examples of "aryl" groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthryl, and the like, which can carry one or more substituents. Also included within the scope of the term "aryl" when used herein are groups in which an aromatic ring is fused to one or more non-aromatic rings. While all rings can be aromatic (e.g., quinoline), in the case of polycyclic ring systems, only one of the rings need be aromatic (e.g., 2,3-dihydroindole). The second ring can also be fused or bridged. Examples of polycyclic aryl groups include, but are not limited to, benzofuryl, dihydroindenyl, phthalimidyl, naphthalimidyl, indolizinyl, or tetrahydronaphthyl, and the like. An aryl group can be substituted at one or more ring positions with the substituents described above.

[0070] As used herein, the term "carbamoyl" refers to -C(O)NH2.

[0071] As used herein, the term "carboxyl" refers to -COOH.

[0072] As used herein, the term "cycloalkyl", whether used as part of another term or independently, refers to a monovalent non-aromatic, saturated or partially unsaturated monocyclic and polycyclic ring system, wherein all ring atoms are carbon and it contains at least three ring-forming carbon atoms. In some embodiments, the cycloalkyl may contain 3 to 12 ring-forming carbon atoms, 3 to 10 ring-forming carbon atoms, 3 to 9 ring-forming carbon atoms, 3 to 8 ring-forming carbon atoms, 3 to 7 ring-forming carbon atoms, 3 to 6 ring-forming carbon atoms, 3 to 5 ring-forming carbon atoms, 4 to 12 ring-forming carbon atoms, 4 to 10 ring-forming carbon atoms, 4 to 9 ring-forming carbon atoms, 4 to 8 ring-forming carbon atoms, 4 to 7 ring-forming carbon atoms, 4 to 6 ring-forming carbon atoms, 4 to 5 ring-forming carbon atoms. Cycloalkyl can be saturated or partially unsaturated. Cycloalkyl can be substituted. In some embodiments, the cycloalkyl can be a saturated cycloalkyl. In some embodiments, a cycloalkyl group may be a partially unsaturated cycloalkyl group containing at least one double or triple bond in its ring system. In some embodiments, a cycloalkyl group may be monocyclic or polycyclic. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Examples of polycyclic cycloalkyl groups include, but are not limited to, adamantyl, norbornyl, fluorenyl, spiro-pentadienyl, spiro[3.6]-decyl, bicyclo[1,1,1]pentenyl, bicyclo[2,2,1]heptenyl, and the like.

[0073] As used herein, the term "cycloalkylalkyl" refers to a group of the formula -R'R", wherein R' is alkyl as defined above, and R" is cycloalkyl as defined above.

[0074] As used herein, the term "cyano" refers to -CN.

[0075] As used herein, the term "halogen" refers to an atom selected from fluorine (or a fluoro group), chlorine (or a chloro group), bromine (or a bromo group), and iodine (or an iodo group).

[0076] As used herein, the term "haloalkyl" refers to an alkyl group as defined above that is substituted with one or more halogen groups as defined above. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0077] As used herein, the term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur and any quaternized form (including N-oxides) of a basic nitrogen.

[0078] As used herein, the term "heteroaryl," whether used alone or as part of another term, refers to an aryl group having one or more heteroatoms in addition to carbon atoms. The heteroaryl group can be monocyclic. Examples of monocyclic heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, benzofuranyl, and pteridinyl. Heteroaryl groups also include polycyclic groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the group or point of attachment is on the heteroaromatic ring. Examples of polycyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, benzothienyl, benzofuranyl, benzo[1,3]dioxolyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, dihydroquinolyl, dihydroisoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenoxazinyl, phenothiazinyl, phenoxzinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0079] As used herein, the term "heterocyclyl" refers to a saturated or partially unsaturated carbocyclic group in which one or more ring atoms are heteroatoms independently selected from oxygen, sulfur, nitrogen, phosphorus, and the like, with the remaining ring atoms being carbon, wherein one or more ring atoms can optionally be independently substituted with one or more substituents. In some embodiments, the heterocyclyl group is a saturated heterocyclyl group. In some embodiments, the heterocyclyl group is a partially unsaturated heterocyclyl group having one or more double bonds in its ring system. In some embodiments, the heterocyclyl group can contain any oxidized form of carbon, nitrogen or sulfur, and any quaternized form of basic nitrogen. "Heterocyclyl" also includes groups in which the heterocyclyl is fused to a saturated, partially unsaturated, or fully unsaturated (i.e., aromatic) carbocyclic or heterocyclic ring. Where possible, the heterocyclyl group can be carbon-attached or nitrogen-attached. In some embodiments, the heterocycle is carbon-attached. In some embodiments, the heterocycle is nitrogen-attached. For example, a group derived from pyrrole can be pyrrol-1-yl (nitrogen-attached) or pyrrol-3-yl (carbon-attached). In addition, a group derived from imidazole can be imidazol-1-yl (nitrogen-attached) or imidazol-3-yl (carbon-attached).

[0080] In some embodiments, the term "3- to 12-membered heterocyclyl" refers to a 3- to 12-membered saturated or partially unsaturated monocyclic or polycyclic heterocyclic ring system having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Fused, spirocyclic, and bridged ring systems are also included within the scope of this definition. Examples of monocyclic heterocyclyls include, but are not limited to, oxetanyl, 1,1-dioxathietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, piperidinyl, piperazinyl, piperidinyl, morpholinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyridonyl, pyrimidinyl, pyrazinonyl, pyrimidinyl, pyridazonyl, pyrrolidinyl, triazinonyl, and the like. Examples of fused heterocyclic groups include, but are not limited to, phenyl-fused rings or pyridyl-fused rings, such as quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, quinolizinyl, quinazolinyl, azaindolizinyl, pteridinyl, chromenyl, isochromenyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothiophenyl, benzothiazolyl, carbazolyl, phenanthrazinyl, phenanthiazinyl, phenanthidinyl, imidazo[1,2-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,3]triazolo[4,3-a]pyridinyl, etc. Examples of spiro heterocyclic groups include, but are not limited to, spiropyranyl, spirooxazinyl, etc. Examples of bridged heterocyclic groups include, but are not limited to, morphinyl, hexamethylenetetraamino, 3-aza-bicyclo[3.1.0]hexane, 8-aza-bicyclo[3.2.1]octane, 1-aza-bicyclo[2.2.2]octane, 1,4-diazabicyclo[2.2.2]octane (DABCO), and the like.

[0081] As used herein, the term "hydroxy" refers to -OH.

[0082] As used herein, the term "oxo" refers to a =0 substituent.

[0083] As used herein, the term "partially unsaturated" refers to a group that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (ie, fully unsaturated) moieties.

[0084] As used herein, the term "substituted," whether or not preceded by the term "optionally," means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. It should be understood that "substituted" or "substituted" includes implicit restrictions: such substitutions are according to the permitted valences of the substituted atom, and that the substitutions produce stable or chemically feasible compounds, e.g., compounds that do not spontaneously transform, e.g., by rearrangement, cyclization, elimination, etc. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a designated group, the substituents at each position may be the same or different. It will be understood by those skilled in the art that substituents themselves may be substituted, where appropriate. Unless specifically stated as "unsubstituted," references to chemical moieties herein should be understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants.

[0085] Compound

[0086] The present disclosure provides novel compounds of formula (I) and pharmaceutically acceptable salts thereof, synthetic methods for producing the compounds, pharmaceutical compositions containing the compounds, and various uses of the disclosed compounds.

[0087] In one aspect, the present disclosure provides a compound having formula (I):

[0088]

[0089] or a pharmaceutically acceptable salt thereof,

[0090] in

[0091] Ring A is selected from the group consisting of a saturated or partially unsaturated cycloalkyl group, a saturated or partially unsaturated heterocyclyl group, and a heteroaryl group;

[0092] L 1 is a bond, O, S or N(R a );

[0093] L 2 selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl;

[0094] R 1 is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally substituted with one or more R b replace;

[0095] R 2 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl and heteroaryl, wherein each of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted by one or more R c replace,

[0096] R 3 Selected from the group consisting of: hydrogen, oxo, halogen, cyano, hydroxyl, -NR d R e 、-C(O)NR d R e , alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl and heteroaryl, wherein each of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with one or more R f replace; or

[0097] R 4 and R 5 、R 4 and R 6 、R 4 and R 7 Together with the atoms to which they are attached, they form a saturated or partially unsaturated cycloalkyl, or a saturated or partially unsaturated heterocyclyl, wherein each of the cycloalkyl and heterocyclyl groups is optionally substituted by cyano, halogen, hydroxy, -NR c R d , carboxyl, carbamoyl, aryl or heteroaryl substituted;

[0098] W is a saturated or partially unsaturated cycloalkyl group, or a saturated or partially unsaturated heterocyclyl group, wherein each of the cycloalkyl group and the heterocyclyl group is optionally substituted by one or more R g replace,

[0099] L 3 is a bond, an alkyl group or -NR d -;

[0100] B is an electrophilic moiety that is capable of forming a covalent bond with the cysteine ​​residue at position 12 of the K-Ras G12C mutant protein;

[0101] R a are independently hydrogen or alkyl;

[0102] Each R b are independently selected from the group consisting of: oxo, cyano, halogen, hydroxy, acyl, -NR d Re , carbamoyl, carboxyl, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkylalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0103] Each R c are independently selected from the group consisting of: oxo, halogen, cyano, hydroxy, -NR d R e 、-C(O)OR a 、-C(O)N(R d )(R e ), alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, alkoxy, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl;

[0104] R d and R e each of is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, wherein each of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, and heteroaryl is optionally substituted with cyano, halogen, hydroxyl, or amino;

[0105] Each R f are independently selected from the group consisting of: oxo, halogen, cyano, hydroxy, -NR c R d , alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0106] Each R g are independently selected from the group consisting of: oxo, cyano, halogen, hydroxyl, -NR d R e , carbamoyl, carboxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl and saturated or partially unsaturated heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl and heterocyclyl is optionally substituted by cyano, halogen, hydroxyl, -NR d R e , carboxyl, carbamoyl, haloalkyl, aryl or heteroaryl;

[0107] n is 0, 1, 2, 3 or 4.

[0108] In some embodiments, Ring A is a saturated or partially unsaturated cycloalkyl group.

[0109] In some embodiments, Ring A is a saturated or partially unsaturated heterocyclic group.

[0110] In some embodiments, Ring A is heteroaryl.

[0111] In some embodiments, L 1 It is O.

[0112] In some embodiments, L 2 is the key.

[0113] In some embodiments, L 2 It is an alkyl group.

[0114] In some embodiments, L 2 is methyl, ethyl or propyl.

[0115] In some embodiments, R 1 is a saturated or partially unsaturated cycloalkyl group or a saturated or partially unsaturated heterocyclic group, wherein each cycloalkyl group and heterocyclic group is optionally substituted by one or more R b In certain embodiments, each R b Selected from the group consisting of: oxo, cyano, halogen, hydroxy, acyl, -NR d R e , alkyl, alkoxy, alkoxyalkyl and cycloalkylalkyl.

[0116] In some embodiments, R 1 is a saturated or partially unsaturated heterocyclic group selected from the group consisting of:

[0117]

[0118] Each of which is optionally treated with one or more R b replace.

[0119] In certain embodiments, each R b Selected from the group consisting of: oxo, halogen, acyl, -NR d R e , alkyl, alkoxy, alkoxyalkyl, and cycloalkylalkyl. In certain embodiments, each R b is halogen or alkyl. In certain embodiments, each R b is fluorine, chlorine or methyl.

[0120] In some embodiments, R 1 for

[0121] In some embodiments, -L 1 -L 2 -R 1 for

[0122] In some embodiments, R 1 for

[0123] In some embodiments, -L 1 -L 2 -R 1 for

[0124] In some embodiments, R 2 is optionally through one or more R c In certain embodiments, each R c Selected from the group consisting of halogen, cyano, hydroxy, alkyl, alkenyl, alkoxy and saturated or partially unsaturated cycloalkyl.

[0125] In some embodiments, R 2 is an aryl group selected from the group consisting of:

[0126]

[0127] Each of which is optionally treated with one or more R c replace.

[0128] In certain embodiments, each R c is selected from the group consisting of halogen, hydroxy, alkyl, alkenyl, alkoxy, and saturated or partially unsaturated cycloalkyl. c is selected from the group consisting of halogen, hydroxy, alkyl, alkenyl, alkoxy, and saturated cycloalkyl. c Selected from the group consisting of fluoro, chloro, hydroxy, methyl, ethyl, 2-methylpropenyl, methoxy and cyclopropyl.

[0129] In some embodiments, R 2 Selected from the group consisting of:

[0130]

[0131] In some embodiments, R 2 is optionally through one or more R c In certain embodiments, each R c Selected from the group consisting of: halogen, cyano, hydroxy, -NR d R e , alkyl, alkenyl, alkoxy and saturated or partially unsaturated cycloalkyl.

[0132] In some embodiments, R 2 is a heteroaryl group selected from the group consisting of:

[0133]

[0134] Each of which is optionally treated with one or more R creplace.

[0135] In certain embodiments, each R c Selected from the group consisting of: halogen, cyano, hydroxy, -NR d R e , alkyl, alkenyl, alkoxy and saturated or partially unsaturated cycloalkyl. In certain embodiments, each R c is halogen or alkyl. In certain embodiments, each R c Selected from the group consisting of fluoro, chloro, methyl and ethyl.

[0136] In some embodiments, R 2 Selected from the group consisting of:

[0137]

[0138] In some embodiments, R 3 Selected from the group consisting of: oxo, alkyl and aryl, wherein alkyl and aryl are optionally substituted by one or more R c In certain embodiments, R c Selected from the group consisting of: halogen, cyano, hydroxy, -NR c R d ,alkyl.

[0139] In some embodiments, R 3 Selected from the group consisting of oxo, methyl, ethyl, trifluoromethyl and phenyl.

[0140] In some embodiments, two R 3 Together with the atoms to which they are attached, they form a saturated or partially unsaturated cycloalkyl group optionally substituted with one or more substituents selected from the group consisting of cyano, halogen, hydroxyl and -NR c R d .

[0141] In some embodiments, W is optionally substituted with one or more R g In certain embodiments, R g is an alkyl group optionally substituted with one or more substituents selected from the group consisting of cyano, halogen and hydroxy.

[0142] In some embodiments, W is a heterocyclyl selected from the group consisting of:

[0143]

[0144]

[0145] Each of which is optionally treated with one or more R greplace.

[0146] In certain embodiments, each R g is an alkyl group optionally substituted with a cyano group. g is a methyl group optionally substituted by a cyano group.

[0147] In some embodiments, W is selected from the group consisting of:

[0148]

[0149] In some embodiments, L 3 is a bond or -NR d -.

[0150] In some embodiments, B is selected from the group consisting of:

[0151]

[0152]

[0153] In some embodiments, the present disclosure provides a compound having a formula selected from the group consisting of:

[0154]

[0155] or a pharmaceutically acceptable salt thereof,

[0156] in

[0157] J 1 Does not exist, CH(R 4 ),NR 4 , SO2 or P(O)CH3;

[0158] J 2 Does not exist, CR 5 , N, SO2 or P(O)CH3;

[0159] J 3 Does not exist, CH(R 6 ),NR 6 , SO2 or P(O)CH3;

[0160] J 4 Does not exist, CR 7 , N, SO2 or P(O)CH3;

[0161] J 5 Does not exist, CH(R 8 ),NR 8 , SO2 or P(O)CH3;

[0162] R4 、R 5 、R 6 、R 7 and R 8 are each independently selected from the group consisting of hydrogen, oxo, halogen, cyano, hydroxyl, -NR d R e , alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl and heteroaryl, wherein each of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with one or more R f replace; or

[0163] R 2 and R 4 、R 5 、R 6 、R 7 and R 8 Any of them together with the atoms to which they are attached form a saturated or partially unsaturated cycloalkyl, or a saturated or partially unsaturated heterocyclyl, wherein each of the cycloalkyl and heterocyclyl is optionally substituted by cyano, halogen, hydroxyl, -NR c R d , carboxyl, carbamoyl, aryl or heteroaryl; or

[0164] R 3 and R 4 、R 5 、R 6 and R 8 Any of them together with the atoms to which they are attached form a saturated or partially unsaturated cycloalkyl, or a saturated or partially unsaturated heterocyclyl, wherein each of the cycloalkyl and heterocyclyl is optionally substituted by cyano, halogen, hydroxyl, -NR c R d , carboxyl, carbamoyl, aryl or heteroaryl; or

[0165] R 4 and R 6 and R 8 Any of them together with the atoms to which they are attached form a saturated or partially unsaturated cycloalkyl, or a saturated or partially unsaturated heterocyclyl, wherein each of the cycloalkyl and heterocyclyl is optionally substituted by cyano, halogen, hydroxyl, -NR c R d , carboxyl, carbamoyl, aryl or heteroaryl; or

[0166] R 6 and R 8Together with the atoms to which they are attached, they form a saturated or partially unsaturated cycloalkyl or a saturated or partially unsaturated heterocyclyl, wherein each of the cycloalkyl and heterocyclyl groups is optionally substituted by cyano, halogen, hydroxy, -NR c R d , carboxyl, carbamoyl, aryl or heteroaryl.

[0167] In some embodiments, the present disclosure provides a compound having a formula selected from the group consisting of:

[0168]

[0169] or a pharmaceutically acceptable salt thereof.

[0170] In some embodiments, the present disclosure provides a compound having a formula selected from the group consisting of:

[0171]

[0172]

[0173] or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3 or 4.

[0174] In some embodiments, the present disclosure provides a compound having a formula selected from the group consisting of:

[0175]

[0176] or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3 or 4.

[0177] In some embodiments, the present disclosure provides a compound having a formula selected from the group consisting of:

[0178]

[0179] or a pharmaceutically acceptable salt thereof.

[0180] In some embodiments, the present disclosure provides a compound having the formula:

[0181]

[0182] or a pharmaceutically acceptable salt thereof.

[0183] In some embodiments, the present disclosure provides a compound having the formula:

[0184]

[0185] or a pharmaceutically acceptable salt thereof.

[0186] In some embodiments, the present disclosure provides a compound having the formula:

[0187]

[0188] or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3 or 4.

[0189] In some embodiments, the present disclosure provides a compound having the formula:

[0190]

[0191] or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3 or 4.

[0192] In some embodiments, the present disclosure provides a compound having the formula:

[0193]

[0194] or a pharmaceutically acceptable salt thereof.

[0195] In some embodiments, the present disclosure provides a compound having a formula selected from the group consisting of:

[0196]

[0197] In some embodiments, the present disclosure provides a compound having a formula selected from the group consisting of:

[0198]

[0199]

[0200] In some embodiments, L 2 For alkyl.

[0201] In some embodiments, R 1 for

[0202] In some embodiments, R 3 Selected from methyl, ethyl or trifluoromethyl.

[0203] In some embodiments, the present disclosure provides a compound having a formula selected from the group consisting of:

[0204]

[0205]

[0206]

[0207]

[0208]

[0209] or a pharmaceutically acceptable salt thereof.

[0210] The compounds provided herein are described with reference to both general formulae and specific compounds. Additionally, the compounds of the present disclosure may exist in a variety of different forms or derivatives, including but not limited to prodrugs, soft drugs, active metabolic derivatives (active metabolites), and pharmaceutically acceptable salts thereof, all of which are within the scope of the present disclosure.

[0211] As used herein, the term "prodrug" refers to a compound or a pharmaceutically acceptable salt thereof that, when metabolized under physiological conditions or converted by dissolution, produces the desired active compound. Prodrugs include, but are not limited to, esters, amides, carbamates, carbonates, urea, solvates, or hydrates of the active compound. Typically, a prodrug is inactive or less active than the active compound but may provide one or more advantageous handling, administration, and / or metabolic properties. For example, some prodrugs are esters of the active compound; during metabolic dissolution, the ester group is cleaved to yield the active drug. In addition, some prodrugs are enzymatically activated to produce the active compound or produce the active compound upon further chemical reaction. A prodrug may be converted from the prodrug form to the active form in a single step, or may have one or more intermediate forms that may themselves be active or inactive. The preparation and use of prodrugs are discussed in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems”, volume 14 of the ACSSymposium Series, in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987; in Prodrugs: Challenges and Rewards, ed. V. Stella, R. Borchardt, M. Hageman, R. Oliyai, H. Maag, J. Tilley, Springer-Verlag New York, 2007, all of which are hereby incorporated by reference in their entirety.

[0212] As used herein, the term "soft drug" refers to a compound that exerts a pharmacological effect but breaks down into inactive metabolite degradation products so that the activity is of limited duration. See, for example, "Soft drugs: Principles and methods for the design of safe drugs" Nicholas Bodor, Medicinal Research Reviews, Vol. 4, No. 4, 449-469, 1984, which is hereby incorporated by reference in its entirety.

[0213] As used herein, the term "metabolite", for example, an active metabolite overlaps with a prodrug as described above. Thus, such metabolites are pharmacologically active compounds or compounds that are further metabolized into pharmacologically active compounds (which are derivatives produced by metabolic processes in the body of an individual). For example, such metabolites can be produced by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound or salt or prodrug. Among them, active metabolites are such pharmacologically active derivative compounds. For prodrugs, the prodrug compound is generally inactive or less active than the metabolite. For active metabolites, the parent compound may be an active compound or may be an inactive prodrug.

[0214] Prodrugs and active metabolites can be identified using routine techniques known in the art. See, for example, Bertolini et al., 1997, J Med Chem 40:2011-2016; Shan et al., J Pharm Sci 86:756-757; Bagshawe, 1995, Drug Dev Res 34:220-230; Wermuth, supra.

[0215] As used herein, the term "pharmaceutically acceptable" indicates that the substance or composition is chemically and / or toxicologically compatible with the other ingredients comprising the formulation and / or the subject being treated therewith.

[0216] Unless otherwise indicated, as used herein, the term "pharmaceutically acceptable salt" includes salts that retain the biological effectiveness of the free acids and bases of the specified compound and are not biologically or otherwise undesirable. Pharmaceutically acceptable salt forms encompassed include, but are not limited to, mono-, di-, tri-, tetra-salts, and the like. Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations to which they are administered. The preparation of such salts can facilitate pharmacological use by altering their physical characteristics without hindering the compound from exerting its physiological effects. Applicable changes in physical properties include lowering the melting point for ease of transmucosal administration and increasing solubility for ease of administration of higher concentrations of the drug.

[0217] Pharmaceutically acceptable salts include acid addition salts, such as those containing the following acid addition salts: sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate. Pharmaceutically acceptable salts can be obtained, for example, from the following acids: hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamate, fumaric acid and quinic acid.

[0218] When an acidic functional group is present, such as a carboxylic acid or phenol, pharmaceutically acceptable salts also include base addition salts, such as those containing benzophenone, chloroprocaine, choline, diethanolamine, ethanolamine, tert-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamines, and zinc. For example, see Remington's Pharmaceutical Sciences, 19th edition, Mack Publishing Co., Easton, PA, Vol. 2, p. 1457, 1995; "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahland Wermuth, Wiley-VCH, Weinheim, Germany, 2002. Such salts can be prepared using the appropriate corresponding base.

[0219] Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the free base form of the compound can be dissolved in a suitable solvent (e.g., an aqueous or aqueous-alcoholic solution containing a suitable acid) and then isolated by evaporation of the solution. Thus, if the particular compound is a base, the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art, such as treating the free base with an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) or with an organic acid (e.g., acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranose acid (e.g., glucuronic acid or galacturonic acid), α-hydroxy acid (e.g., citric acid or tartaric acid), amino acid (e.g., aspartic acid or glutamic acid), aromatic acid (e.g., benzoic acid or cinnamic acid), sulfonic acid (e.g., p-toluenesulfonic acid or ethanesulfonic acid), etc.).

[0220] Similarly, if the particular compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, by treating the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or an alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include organic salts derived from amino acids such as L-glycine, L-lysine and L-arginine, ammonia, primary, secondary and tertiary amines, and cyclic amines such as hydroxyethylpyrrolidine, piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

[0221] It will also be understood that the compounds of the present disclosure may exist in unsolvated forms, solvated forms (eg, hydrated forms), and solid forms (eg, crystalline or polymorphic forms), and that the present disclosure is intended to encompass all such forms.

[0222] As used herein, the term "solvate" or "solvated form" refers to a solvent addition form containing either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thereby forming a solvate. If the solvent is water, the solvate formed is a hydrate; and if the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by combining one or more molecules of water with one molecule of a substance, wherein the water retains its molecular state as HO. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

[0223] As used herein, the terms "crystal form," "crystalline form," "polymorphic form," and "polymorph" are used interchangeably and refer to crystal structures in which a compound (or a salt or solvate thereof) can crystallize in different crystal packing configurations, all having the same elemental composition. Different crystal forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors can cause one crystal form to dominate. Crystal polymorphs of a compound can be prepared by crystallization under different conditions.

[0224] The present disclosure is also intended to include all isotopes of atoms in the compounds. Isotopes of atoms include atoms with the same atomic number but different mass numbers. For example, unless otherwise specified, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, or iodine in the compounds of the present disclosure are also intended to include their isotopes, such as (but not limited to) 1 H. 2 H. 3 H. 11 C. 12 C. 13 C.14 C. 14 N. 15 N. 16 O. 17 O. 18 O. 31 P. 32 P. 32 S. 33 S. 34 S. 36 S. 17 F. 18 F. 19 F. 35 Cl, 37 Cl, 79 Br, 81 Br, 124 I. 127 I and 131 1. In some embodiments, hydrogen includes protium, deuterium, and tritium. In some embodiments, carbon includes 12 C and 13 C.

[0225] Those skilled in the art will appreciate that the compounds of the present disclosure can exist in different tautomeric forms, and all such forms are encompassed within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be mutually converted via a low energy barrier. The presence and concentration of the isomeric forms will depend on the environment in which the compound exists, and may vary depending on, for example, whether the compound is solid or in an organic or aqueous solution form. By way of example, proton tautomers (also referred to as prototropic tautomers) include interconversions via migration of protons, such as keto-enol, amide-imidic acid, lactam-lactim, imine-enamine isomerization, and cyclic forms, wherein the proton can occupy two or more positions in the heterocyclic ring system. Valence tautomers include interconversions performed by the reorganization of some bonding electrons. Tautomers can be in equilibrium or stereo locked into one form by appropriate substitution. Unless otherwise stated, compounds of the present disclosure identified as a specific tautomeric form by name or structure are intended to include other tautomeric forms.

[0226] Synthesis of compounds

[0227] The compounds provided herein, including the synthesis of pharmaceutically acceptable salts thereof, are described in the synthesis processes in the examples. The compounds provided herein can be prepared using any known organic synthesis technique and can be synthesized according to any of a variety of possible synthetic pathways, and therefore these processes are merely exemplary and are not intended to limit other possible methods for preparing the compounds provided herein. In addition, the steps in the process are for preferred illustration and can be changed when appropriate. For the purpose of research and potentially submitting to regulatory agencies, embodiments of the compounds in the examples are synthesized.

[0228] The reaction for preparing the compound of the present disclosure can be carried out in a suitable solvent, and the solvent can be easily selected by a person skilled in the art. Suitable solvents can be generally not reacted with starting material (reactant), intermediate or product at a temperature within the range of solvent freezing temperature to solvent boiling temperature, for example. The specified reaction can be carried out in a solvent or a mixture of more than one solvent. Depending on the specific reaction step, the suitable solvent for the specific reaction step can be selected by a person skilled in the art.

[0229] The preparation of compounds of the present disclosure may involve the protection and deprotection of various chemical groups. The demand for protection and deprotection and the selection of appropriate protecting groups can be easily determined by those skilled in the art. The chemistry of protecting groups can be found in, for example, TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3rd edition, Wiley & Sons, Inc., New York (1999), in P. Kocienski, Protecting Groups, Georg Thieme Verlag, 2003, and in Peter G.M. Wuts, Greene's Protective Groups in Organic Synthesis, 5th edition, Wiley, 2014, all of which are incorporated herein by reference in their entirety.

[0230] The reaction can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g. 1 H or 13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry) or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS), or thin layer chromatography (TLC). Compounds can be purified by a variety of methods by those skilled in the art, including high performance liquid chromatography (HPLC) ("Preparative LC-MS Purification: Improved Compound Specific Method Optimization" Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs, J. Combi. Chem. 2004, 6(6), 874-883, which is incorporated herein by reference in its entirety) and normal phase silica chromatography.

[0231] The structures of the compounds in the examples were characterized by nuclear magnetic resonance (NMR). 1 H's 400MHz and for 13 NMR spectra were acquired on a Bruker AVANCE III HD 400 NMR spectrometer operating at 101 MHz with a 100 nm wavelength. The spectra were recorded at 400 MHz in CHCl3-d, (CH3)2SO-d6, and (CH3)2CO-d6 using residual CHCl3 (7.26 ppm), DMSO (2.50 ppm), and (CH3)2CO (2.05 ppm) as internal standards. 1 H NMR spectra were recorded at 101 MHz in CHCl3-d, (CH3)2SO-d6, and (CH3)2CO-d6 using residual CHCl3 (77.16 ppm), DMSO (39.52 ppm), and (CH3)2CO (29.84 ppm and 206.26 ppm) as internal standards. 13 C NMR spectroscopy.

[0232] Mass spectrometry analyses were performed on a Thermo Scientific QExactive mass spectrometer (ESI) at the Mass Spectrometry Facility of the School of Pharmaceutical Sciences at Tsinghua University.

[0233] On Merck Kieselgel eluted with the specified solvent Thin layer chromatography was performed on F254 plates, visualized by UV light at 254 nm and stained with 12-molybdophosphoric acid in ethanol. 230-400 mesh, Silicycle Inc.) purification.

[0234] Known starting materials of the present disclosure can be synthesized by using or according to methods known in the art, or can be purchased from commercial suppliers. Unless otherwise noted, analytical grade solvents and commercially available reagents were used without further purification.

[0235] Unless otherwise specified, the reactions of the present disclosure were performed under a positive pressure of nitrogen or argon or in anhydrous solvents using a drying tube, and the reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven-dried and / or heat-dried.

[0236] For the purpose of illustration, the following examples partially show the synthetic routes for preparing the compounds of the present disclosure and key intermediates. Those skilled in the art will appreciate that other synthetic routes can also be used to synthesize the disclosed compounds. Although specific starting materials and reagents are described, other starting materials and reagents can be easily substituted to provide a variety of derivatives and / or reaction conditions. In addition, many compounds prepared by the following methods can be further modified according to the present disclosure using conventional chemical methods known to those skilled in the art.

[0237] Uses of compounds

[0238] In one aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is capable of inhibiting KRAS protein, particularly KRAS G12C protein.

[0239] As used herein, the term "therapy" is intended to have the standard meaning of its treatment of a disease to fully or partially alleviate one, some or all of the symptoms of the disease or to correct or compensate for the underlying pathology, thereby achieving a beneficial or desired clinical result. For the purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, symptom relief, alleviation of the degree of disease, stabilization of the disease condition (i.e., no worsening), delay or slowing of the disease process, improvement or alleviation of the disease condition, and alleviation of symptoms (partial or complete), the results being detectable or undetectable. "Therapy" can also mean a prolonged survival period compared to the expected survival period without therapy. Individuals in need of therapy include individuals who have already suffered from a condition or illness and individuals who are prone to the condition or illness, or individuals who should prevent the condition or illness. Unless there is a specific contrary indication, the term "therapy" also includes prevention. The terms "therapeutic" and "therapeutically" should be interpreted in a corresponding manner.

[0240] As used herein, the term "prevention" is intended to have its standard meaning and includes primary prevention to prevent the development of a disease and secondary prevention, i.e., once a disease has developed and temporarily or permanently protecting the patient from exacerbation or worsening of the disease or the development of new symptoms associated with the disease.

[0241] The term "treat" is used synonymously with "therapy." Similarly, the term "treatment" can be viewed as "applying therapy," where "therapy" is as defined herein.

[0242] In another aspect, the present disclosure provides for use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, for use in therapy, for example, for therapy associated with the KRAS protein.

[0243] In another aspect, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating cancer.

[0244] In some embodiments, the cancer is mediated by the KRAS protein. In some embodiments, the cancer is mediated by the KRAS-G12C mutant protein.

[0245] In another aspect, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure in the manufacture of a medicament for inhibiting tumor metastasis.

[0246] In another aspect, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, for use in treating cancer.

[0247] In another aspect, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, for use in inhibiting tumor metastasis.

[0248] Pharmaceutical composition

[0249] In another aspect, pharmaceutical compositions comprising one or more molecules or compounds of the present disclosure, or pharmaceutically acceptable salts thereof, are provided.

[0250] In another aspect, pharmaceutical compositions are provided comprising one or more molecules or compounds of the present disclosure, or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient.

[0251] As used herein, the term "pharmaceutical composition" refers to a formulation containing a molecule or compound of the present disclosure in a form suitable for administration to a subject.

[0252] As used herein, the term "pharmaceutically acceptable excipient" means an excipient that is suitable for use in preparing a pharmaceutical composition that is generally safe, non-toxic, and not biologically or otherwise undesirable, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use. As used herein, a "pharmaceutically acceptable excipient" includes both one and more than one such excipient. The term "pharmaceutically acceptable excipient" also encompasses a "pharmaceutically acceptable carrier" and a "pharmaceutically acceptable diluent."

[0253] The specific excipient used will depend on the manner and purpose of applying the compounds of the present disclosure. The solvent is generally selected based on solvents generally considered safe by those skilled in the art for administration to mammals, including humans. In general, safe solvents are non-toxic aqueous solvents, such as water and other non-toxic solvents that are soluble in water or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG 400, PEG 300), and the like, and mixtures thereof.

[0254] In some embodiments, suitable excipients may include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (e.g., octadecyldimethylbenzyl ammonium chloride; hexahydroxyquaternium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl alcohol, or benzyl alcohol; alkyl parabens such as methyl paraben or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins The present invention also includes a chelating agent such as EDTA; a sugar such as sucrose, mannitol, trehalose or sorbitol; a salt-forming counterion such as sodium; a metal complex (e.g., a Zn-protein complex); and / or a nonionic surfactant such as TWEEN®. T M, PL U RONICS TM or polyethylene glycol (PEG).

[0255] In some embodiments, suitable excipients may include one or more stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, light-shielding agents, glidants, processing aids, colorants, sweeteners, fragrances, flavorings, and other known additives to provide a refined presentation of the drug (i.e., the compound of the present disclosure or its pharmaceutical composition) or to aid in the manufacture of a pharmaceutical product (i.e., a medicament). The active pharmaceutical ingredient may also be embedded in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, such as hydroxymethylcellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules in colloidal drug delivery systems (e.g., liposomes, albumin microparticles, microemulsions, nanoparticles, and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences, 16th edition, Osol, A., ed. (1980). "Liposomes" are small vesicles composed of various types of lipids, phospholipids, and / or surfactants that are suitable for delivering drugs (e.g., the compounds disclosed herein and optionally chemotherapeutic agents) to mammals, including humans. The components of liposomes are typically arranged in a bilayer formation, similar to the lipid configuration of biological membranes.

[0256] The pharmaceutical compositions provided herein may be in any form that permits administration of the compositions to a subject, including but not limited to, humans, and is formulated to be compatible with the intended route of administration.

[0257] Contain the multiple approaches about the pharmaceutical composition provided herein, and therefore the pharmaceutical composition provided herein can be supplied in bulk or unit dosage form depending on the expected route of administration. For example, for oral, buccal and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, capsules and capsules can be accepted in solid dosage form, and emulsions, syrups, elixirs, suspensions and solutions can be accepted in liquid dosage form. For injection, emulsions and suspensions can be accepted in liquid dosage form, and powders are suitable for reconstitution as solid dosage form with appropriate solution. For inhalation administration, solutions, sprays, dry powders and aerosols can be acceptable dosage forms. For local (including buccal and sublingual) or transdermal administration, powders, sprays, ointments, pastes, creams, emulsions, gels, solutions and patches can be acceptable dosage forms. For vaginal administration, pessaries, tampons, creams, gels, pastes, foams and sprays can be acceptable dosage forms.

[0258] The amount of active ingredient in a unit dosage form of the composition is a therapeutically effective amount and varies depending on the specific treatment involved. As used herein, the term "therapeutically effective amount" refers to the amount of a molecule, compound, or composition comprising the molecule or compound to treat, improve, or prevent the identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any analytical method known in the art. The precise effective amount for an individual will depend on the individual's weight, size, and health; the nature and extent of the condition; the rate of administration; the therapeutic agent or combination of therapeutic agents selected for administration; and the judgment of the prescribing physician. The therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician.

[0259] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of formulations for oral administration.

[0260] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of tablet formulations. Pharmaceutically acceptable excipients suitable for tablet formulations include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate, or calcium carbonate; granulating and disintegrants such as corn starch or alginic acid; binders such as starch; lubricants such as magnesium stearate, stearic acid, or talc; preservatives such as ethylparaben or propylparaben; and antioxidants such as ascorbic acid. The tablet formulations may be uncoated or coated using conventional coating agents and procedures well known in the art to modify their disintegration and subsequent absorption of the active ingredient in the gastrointestinal tract, or to improve their stability and / or appearance.

[0261] In certain embodiments, the pharmaceutical compositions of the present disclosure can be formulated in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin); or in the form of soft gelatin capsules in which the active ingredient is mixed with water or an oil (e.g., peanut oil, liquid paraffin, or olive oil).

[0262] In certain embodiments, the pharmaceutical compositions of the present disclosure can be in the form of aqueous suspensions, which typically contain the active ingredient in the form of a fine suspension. Suitable suspensions include those suspensions which contain one or more of the following: a suspending agent, such as sodium carboxymethylcellulose, methycellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth, and gum acacia; a dispersing agent, or wetting agent, such as a phospho lec tine, or a condensation product of partially hydrogenated quinone with a fatty acid (e.g., polyoxyethylene stearate), or a condensation product of partially hydrogenated quinone with a fatty acid and a hexitol (e.g., polyoxyethylene castor oil), or a condensation product of partially hydrogenated quinone with a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension can also contain one or more of the following: a preservative, such as ethyl or propyl p-hydroxybenzoate; an antioxidant, such as ascorbic acid; a coloring agent; a flavoring agent; and / or a sweetening agent, such as sucrose, saccharin, or aspartame.

[0263] In certain embodiments, the pharmaceutical compositions of the present disclosure can be in the form of oil suspensions. These suspensions can be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil, or coconut oil, or in a mineral oil, such as liquid paraffin. The oil suspensions can also contain a thickening agent, such as beeswax, hard paraffin, or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant, such as ascorbic acid.

[0264] In certain embodiments, the pharmaceutical compositions of the present disclosure can be in the form of oil suspensions. These suspensions can be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil, or coconut oil, or in a mineral oil, such as liquid paraffin. The oil suspensions can also contain a thickening agent, such as beeswax, hard paraffin, or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant, such as ascorbic acid.

[0265] In certain embodiments, the pharmaceutical compositions provided herein can be in the form of a syrup or elixir, which can contain a sweetening agent, such as glycerin, propylene glycol, sorbitol, aspartame, or sucrose, a flavoring agent, a preservative, a coloring agent, and / or a flavoring agent.

[0266] In some embodiments, the pharmaceutical compositions of the present disclosure can be in the form of formulations for injection administration.

[0267] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of sterile injectable preparations, such as sterile injectable aqueous or oily suspensions. Such suspensions can be formulated according to known techniques using suitable dispersants or wetting agents and suspending agents such as those mentioned above. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol; or prepared as lyophilized powders. Among the acceptable vehicles and solvents, water, Ringer's solution, and isotonic sodium chloride solution may be used. In addition, sterile fixed oils are commonly used as solvents or suspending media. For this purpose, any bland fixed oil may be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid may also be used to prepare injectable preparations.

[0268] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of formulations for inhaled administration.

[0269] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of aqueous and non-aqueous (e.g., in fluorocarbon propellants) aerosols containing any suitable solvent and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH adjusters, surfactants, bioavailable modifiers, and combinations thereof. Carriers and stabilizers vary depending on the requirements of the particular compound, but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol), harmless proteins (such as serum albumin), sorbitan esters, oleic acid, lecithin, amino acids (e.g., glycine), buffers, salts, sugars, or sugar alcohols.

[0270] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of formulations for topical or transdermal administration.

[0271] In certain embodiments, the pharmaceutical compositions provided herein may be in the form of creams, ointments, gels, and aqueous or oily solutions or suspensions, which are generally obtainable by formulating the active ingredient with conventional topically acceptable excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0272] In certain embodiments, the pharmaceutical compositions provided herein may be formulated in the form of transdermal skin patches well known to those of ordinary skill in the art.

[0273] In addition to those representative dosage forms described above, pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are therefore included in the present disclosure. Such excipients and carriers are described, for example, in "Remingtons Pharmaceutical Sciences" Mack Pub. Co., New Jersey (1991), in "Remington: The Science and Practice of Pharmacy", Ed. University of the Sciences in Philadelphia, 21st edition, LWW (2005), which is incorporated herein by reference.

[0274] In some embodiments, the pharmaceutical compositions of the present disclosure can be formulated as a single dosage form. The amount of a compound provided herein in a single dosage form will vary depending upon the individual being treated and the particular mode of administration.

[0275] In some embodiments, the pharmaceutical compositions of the present disclosure may be formulated so as to be administered at a dose of 0.001-1000 mg / kg body weight / day, for example, 0.01-800 mg / kg body weight / day, 0.01-700 mg / kg body weight / day, 0.01-600 mg / kg body weight / day, 0.01-500 mg / kg body weight / day, 0.01-400 mg / kg body weight / day, 0.01-300 mg / kg body weight / day, 0.1-200 mg / kg body weight / day, 0.1-150 mg / kg body weight In some cases, the dosage concentration below the lower limit of the aforementioned range may be completely sufficient, and in other cases, more significant dosage may be employed without causing any adverse side effects, provided that first such significant dosage is divided into several smaller dosages for use throughout the day. For further information on routes of administration and dosage regimens, see Chapter 25.3, Vol. 5, of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990, which is specifically incorporated herein by reference.

[0276] In some embodiments, the pharmaceutical compositions of the present disclosure can be formulated for short-acting, fast-releasing, long-acting, and sustained-releasing. Thus, the pharmaceutical formulations of the present disclosure can also be formulated for controlled-release or for slow-release.

[0277] In another aspect, veterinary compositions are also provided, comprising one or more molecules or compounds of the present disclosure, or pharmaceutically acceptable salts thereof, and a veterinary carrier. A veterinary carrier is a substance suitable for the purpose of administering the composition and can be a solid, liquid, or gaseous substance that is otherwise inert or acceptable in the veterinary art and compatible with the active ingredient. These veterinary compositions can be administered parenterally, orally, or by any other desired route.

[0278] Pharmaceutical compositions or veterinary compositions can be packaged in a variety of ways, depending on the method for administering the drug. For example, the article for distribution may include a container in which a composition of appropriate form is stored. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), medicine capsules, ampoules, plastic bags, metal cylinders, etc. The container may also include an anti-opening assembly to prevent easy access to the encapsulated contents. In addition, a label describing the container contents is attached to the container. The label may also include appropriate warnings. The composition may also be packaged in a unit dose or multidose container such as a sealed ampoule and bottle, and may be stored under freeze-dried (lyophilized) conditions, requiring only the addition of a sterile liquid carrier for injection such as water just before use. Ready-to-use injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the types described previously.

[0279] In another aspect, pharmaceutical compositions are also provided, comprising one or more compounds of the present disclosure or pharmaceutically acceptable salts thereof as a first active ingredient and a second active ingredient.

[0280] In some embodiments, the second active ingredient has complementary activities to the compound provided herein such that they do not adversely affect each other. Such ingredients are suitably present in combination in amounts that are effective for the intended purpose.

[0281] Disease treatment methods

[0282] In another aspect, the present disclosure provides a method for treating cancer, comprising administering to a subject in need thereof an effective amount of a compound provided herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0283] In some embodiments, the method is directed to the treatment of cancer, such as lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, large intestine cancer, breast cancer, uterine cancer, blood cancer, colorectal cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's Disease, esophageal cancer, small intestine cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, cancer of the kidney or ureter, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) neoplasm, primary CNS lymphoma, spinal axis tumor, brain stem glioma, MYH-associated polyposis, or pituitary adenoma.

[0284] In some embodiments, the cancer is associated with a KRAS G12C mutation. In certain embodiments, the cancer is a blood cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer.

[0285] In another aspect, the present disclosure also provides a method for treating cancer in an individual in need thereof, the method comprising:

[0286] (a) determining that the cancer is associated with a KRAS G12C mutation; and

[0287] (b) administering to the individual an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0288] In another aspect, the present disclosure provides a method for inhibiting tumor metastasis, comprising administering an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt or pharmaceutical composition thereof to a subject in need thereof.

[0289] In another aspect, the present disclosure provides a method for modulating the activity of a KRAS G12C mutant protein, comprising reacting the KRAS G12C mutant protein with a compound of the present disclosure or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0290] In another aspect, the present disclosure provides a method for preparing a labeled KRAS G12C mutant protein, comprising reacting the KRAS G12C mutant protein with a compound provided herein or a pharmaceutically acceptable salt thereof to obtain the labeled KRAS G12C mutant protein.

[0291] Examples

[0292] For illustrative purposes, the following examples are included. However, it should be understood that these examples do not limit the present disclosure and are only intended to suggest methods for implementing the present disclosure. Those skilled in the art will recognize that the chemical reactions described can be easily adapted to prepare a variety of other compounds of the present disclosure, and that alternative methods for preparing compounds of the present disclosure are considered to be within the scope of the present disclosure. For example, the synthesis of non-exemplary compounds according to the present disclosure can be successfully carried out by modifications that are obvious to those skilled in the art, such as by appropriately protecting interfering groups, by utilizing other suitable reagents and building blocks known in the art except those described, and / or by conventional modifications to reaction conditions. Alternatively, it will be considered that other reactions disclosed herein or known in the art are applicable to the preparation of other compounds of the present disclosure.

[0293] Example 1

[0294]

[0295] Step 1: Synthesis of compound 1-2

[0296]

[0297] To a mixture of 5-amino-6-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxylic acid (270 mg, 0.574 mmol, 1.0 equiv) and naphthalene-1-amine (82 mg, 0.574 mmol, 1.0 equiv) in anhydrous DMF (3.0 mL) was added DIEA (0.28 mL, 1.722 mmol, 3.0 equiv) followed by HATU (435 mg, 1.144 mmol, 2.0 equiv). The reaction mixture was stirred at 60 °C under Ar for 1 hour. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was cooled to room temperature, diluted with EtOAc (30 mL) and washed with brine (3 x 30 mL), dried over anhydrous NaSO, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with DCM / MeOH (1 / 0-10:1, v / v) to give (S)-benzyl 4-(5-amino-2-((1-methylpyrrolidin-2-yl)methoxy)-6-(naphthalen-1-ylcarbamoyl)pyrimidin-4-yl)piperazine-1-carboxylate (80 mg, 17%).

[0298] LCMS: Rt: 0.941min; MS m / z(ESI): 596.3[M+H] + .

[0299] Step 2: Synthesis of compounds 1-3

[0300]

[0301] To a mixture of (S)-benzyl 4-(5-amino-2-((1-methylpyrrolidin-2-yl)methoxy)-6-(naphthalen-1-ylcarbamoyl)pyrimidin-4-yl)piperazine-1-carboxylate (60 mg, 0.0504 mmol, 1.0 equiv) in EtOH (1 mL) was added 1,1,1-triethoxyethane (1 mL) and AcOH (6 drops). The mixture was stirred at 145 ° C in a sealed tube for 2 hours. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was adjusted to pH = 8-9 with aqueous NaHCO 3 solution and extracted with DCM (3×20 mL). The combined organic layers were dried over anhydrous Na 2 SO 4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC eluting with DCM / MeOH (10:1, v / v) to give (S)-benzyl 4-(6-methyl-2-((1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (15 mg, 18%).

[0302] LCMS: Rt: 0.966min; MS m / z(ESI): 620.3[M+H] + .

[0303] Step 3: Synthesis of compounds 1-4

[0304]

[0305] To a mixture of (S)-benzyl 4-(6-methyl-2-((1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (15 mg, 0.024 mmol) in MeOH (5.0 mL) was added Pd(OH) / C (10 mg, 20% wt) and the mixture was stirred at room temperature under H (50 psi) for 2 h. LCMS showed consumption of the starting material and formation of the desired product. The resulting mixture was filtered through celite. The filter cake was washed with MeOH (30 mL). The filtrate was concentrated under reduced pressure to give (S)-2-methyl-6-((1-methylpyrrolidin-2-yl)methoxy)-3-(naphthalen-1-yl)-8-(piperazin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one (12 mg, 100%) as a yellow solid, which was used directly in the next step without further purification.

[0306] LCMS: Rt: 0.557min; MS m / z(ESI): 486.2[M+H] + .

[0307] Step 4: Synthesis of Compound 1

[0308]

[0309] To a mixture of (S)-2-methyl-6-((1-methylpyrrolidin-2-yl)methoxy)-3-(naphthalen-1-yl)-8-(piperazin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one (12 mg, 0.024 mmol, 1.0 equiv) and EtN (7 mg, 0.072 mmol, 3.0 equiv) in DCM (1 mL) was added a solution of acryloyl chloride (2.2 mg, 0.024 mmol, 1.0 equiv) in DCM (0.2 mL) dropwise at -20 ° C. After the addition, the mixture was stirred at -20 ° C. under N 2 for 30 min. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was quenched with water (10 mL) and extracted with DCM (3×10 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was separated and purified by basic preparative HPLC to give (S)-8-(4-acryloylpiperazin-1-yl)-2-methyl-6-((1-methylpyrrolidin-2-yl)methoxy)-3-(naphthalen-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one (3.5 mg, 27%, 1).

[0310] LCMS: Rt: 0.839min; MS m / z(ESI): 540.3[M+H] + ;

[0311] 1 H NMR (400MHz, CDCl3) δ8.04(d,J=8.2Hz,1H),7.98(d,J=8.2Hz,1H),7.65-7.50(m,3H),7.47-7.40(m,2H),6.68-6.58(m,1H),6.42-6.34(m,1H),5 .83-5.73(m,1H),5.12-4.75(m,1H),4.70-4.22(m,4H),3.95-3.70m,6H ),3.17-2.82(m,4H),2.42-2.13(m,3H),2.11(s,3H),1.41-1.22(m,2H).

[0312] Example 2

[0313]

[0314] Step 1: Synthesis of compound 2-2

[0315]

[0316] To a solution of 5-amino-6-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxylic acid (300 mg, 0.589 mmol, 1.0 equiv) and naphthalene-1-amine (59 mg, 0.412 mmol, 0.7 equiv) in anhydrous DMF (4.0 mL) was added DIEA (0.29 mL, 1.77 mmol, 3.0 equiv) followed by HATU (224 mg, 0.589 mmol, 1.0 equiv). The reaction mixture was stirred at 60 ° C under Ar for 1 hour. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was cooled to room temperature, diluted with water (30 mL) and extracted with EtOAc (20 mL×2). The combined organic fractions were washed with brine (30 mL), dried over anhydrous NaSO and concentrated. The residue was purified by silica column chromatography eluting with DCM / MeOH (20:1, v / v) to give (S)-benzyl 4-(5-amino-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-(naphthalen-1-ylcarbamoyl)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (223 mg, 60%).

[0317] LCMS (ESI, m / z): [M+1] + =635; RT=1.242min.

[0318] Step 2: Synthesis of Compound 2-3

[0319]

[0320] To a mixture of (S)-4-(5-amino-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-(naphthalen-1-ylcarbamoyl)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (90 mg, 0.071 mmol, 1.0 equiv) and AcOH (1.0 mL) was added 1,1,1-triethoxyethane (346 mg, 1.06 mmol, 15.0 equiv). The mixture was stirred at 135 ° C in a sealed tube for 7 min. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was quenched with aqueous NaHCO 3 solution (saturated, 60 mL) to adjust the pH = 7-8 and extracted with DCM (20 mL×3). The combined organic fractions were dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by silica column chromatography eluting with DCM / MeOH (15:1, v / v) to give (S)-benzyl 2-(cyanomethyl)-4-(6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (43 mg, 46%).

[0321] LCMS (ESI, m / z): [M+1] + =659; RT=1.194min.

[0322] Step 3: Synthesis of Compounds 2-4

[0323]

[0324] To a solution of (S)-benzyl 2-(cyanomethyl)-4-(6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (43 mg, 0.065 mmol, 1.0 equiv) in i-PrOH (1.5 mL) and THF (1.5 mL) was added Pd / C (10% w / w, 7 mg, 0.0065 mmol, 0.1 equiv) and Pd(OH) / C (10% w / w, 9 mg, 0.0065 mmol, 0.1 equiv). The reaction mixture was stirred at room temperature under H (balloon) for 2 h. LCMS showed that most of the starting material was consumed and the desired product was formed. The mixture was filtered through celite and the filtrate was concentrated to dryness to give 2-((S)-4-(6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (18 mg, 53%) as a light yellow solid which was used directly in the next step.

[0325] LCMS (ESI, m / z): [M+1] + =525; RT=0.381min and 0.565min.

[0326] Step 4: Synthesis of Compound 2

[0327]

[0328] To a cooled (0 ° C) solution of 2-((S)-4-(6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (18 mg, 0.034 mmol, 1.0 equiv) and Et3N (10.4 mg, 0.103 mmol, 3.0 equiv) in DCM (1.5 mL) was added dropwise a solution of acryloyl chloride (3.1 mg, 0.034 mmol, 1.0 equiv) in DCM (0.3 mL). After the addition, the mixture was stirred at 0 ° C for 15 min. LCMS showed that most of the starting material was consumed and the desired product was formed. Water (10 mL) was added and the organic layer was separated. The aqueous layer was extracted with DCM (5 mL×3). The combined organic fractions were dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative HPLC (ACN-H2O + 0.1% HCOOH) to give 2-((S)-4-(6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (HCOOH salt, 2.1 mg, 9.9%, 2.063 HCOOH) (C 32 H 34 N8O3·0.63HCOOH).

[0329] LCMS (ESI, m / z): [M+1] + =579; RT=0.994min.

[0330] 1H NMR(400MHz,DMSO-d6)δ8.33(s,1H),8.32(s,0.63H),8.13(dd,J=13.4,8.2Hz,2H),7.76-7.50(m,4H),6 .95-6.81(m,1H),6.20(dd,J=16.8,2.0Hz,1H),5.79(d,J=10.8Hz,1H),5.59-5.36(m,1H),5.10-4.77(m, 2H),4.49(d,J=7.6Hz,1H),4.38-4.28(m,1H),4.18-4.10(m,1H),3.33-3.12(m,4H),3.02-2.92(m,2H),2 .65-2.52(m,1H),2.37-2.28(m,4H),2.18(dd,J=17.0,8.6Hz,1H),2.06-1.84(m,4H),1.73-1.55(m,3H).

[0331] Example 3

[0332]

[0333] Step 1: Synthesis of compound 3-2

[0334]

[0335] To a mixture of 5-amino-6-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxylic acid (120 mg, 0.255 mmol, 1.0 equiv) and 8-chloronaphthalen-1-amine (68 mg, 0.383 mmol, 1.5 equiv) in anhydrous DMF (3.0 mL) was added DIEA (99 mg, 0.765 mmol, 3.0 equiv) followed by HATU (194 mg, 0.51 mmol, 2.0 equiv). The reaction mixture was stirred at 60 °C under Ar for 1 hour. LCMS showed the reaction was complete. The reaction mixture was cooled to room temperature, diluted with EtOAc (30 mL) and washed with brine (3 x 30 mL), dried over anhydrous NaSO, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC with DCM / MeOH (10:1, v / v) to give (S)-benzyl 4-(5-amino-6-((8-chloronaphthalen-1-yl)carbamoyl)-2-((1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)piperazine-1-carboxylate (80 mg, 50%).

[0336] LCMS: Rt: 0.951min; MS m / z(ESI): 630.2[M+H] + .

[0337] Step 2: Synthesis of compound 3-3

[0338]

[0339] To a mixture of (S)-benzyl 4-(5-amino-6-((8-chloronaphthalen-1-yl)carbamoyl)-2-((1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)piperazine-1-carboxylate (30 mg, 0.0477 mmol, 1.0 equiv) in AcOH (0.5 mL) was added 1,1,1-triethoxyethane (116 mg, 0.715 mmol, 15.0 equiv). The mixture was stirred at 135 ° C in a sealed tube for 15 min. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was adjusted to pH = 8-9 with aqueous NaHCO 3 solution and extracted with DCM (3×15 mL). The combined organic layers were dried over anhydrous Na 2 SO 4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC eluting with DCM / MeOH (10:1, v / v) to give (S)-benzyl 4-(7-(8-chloronaphthalen-1-yl)-6-methyl-2-((1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (32 mg, 100%).

[0340] LCMS: Rt: 0.969min; MS m / z(ESI): 654.3[M+H] + .

[0341] Step 3: Synthesis of Compound 3-4

[0342]

[0343] To a mixture of (S)-benzyl 4-(7-(8-chloronaphthalen-1-yl)-6-methyl-2-((1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (63 mg, 0.0965 mmol) in DCM (2 mL) was added Et3SiH (45 mg, 0.386 mmol) and Et3N (39 mg, 0.386 mmol) followed by PdCl2 (2 mg, 0.00964 mmol). The mixture was stirred at room temperature under N2 for 0.5 h. LCMS showed that the starting material was not consumed. Et3SiH (45 mg, 0.386 mmol), Et3N (39 mg, 0.386 mmol) and PdCl2 (8 mg, 0.0386 mmol) were added to the mixture. The mixture was stirred at room temperature under N for 0.5 hours. LCMS showed that the reaction was complete. The reaction mixture was quenched with H2O (15 mL) and extracted with DCM / MeOH (10 / 1, 3 × 15 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a crude material (S) -3- (8- chloronaphthalene -1- bases) -2- methyl -6- ((1- methylpyrrolidin-2-yl) methoxy) -8- (piperazine -1- bases) pyrimido [5,4-d] pyrimidin -4 (3H) -one (50 mg, 100%) as a yellow oil, which was used directly in the next step without further purification.

[0344] LCMS: Rt: 0.549min; MS m / z(ESI): 520.2[M+H] + .

[0345] Step 4: Synthesis of compound 3

[0346]

[0347] To a mixture of (S)-3-(8-chloronaphthalen-1-yl)-2-methyl-6-((1-methylpyrrolidin-2-yl)methoxy)-8-(piperazin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one (50 mg, 0.0965 mmol, 1.0 equiv) and EtN (29 mg, 0.2895 mmol, 3.0 equiv) in DCM (2 mL) was added a solution of acryloyl chloride (8.8 mg, 0.0965 mmol, 1.0 equiv) in DCM (0.2 mL) dropwise at -20 ° C. After the addition, the mixture was stirred at -20 ° C. under N2 for 30 min. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was quenched with water (10 mL) and extracted with DCM (3×10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was separated and purified by HCOOH preparative HPLC to give (S)-8-(4-acryloylpiperazin-1-yl)-3-(8-chloronaphthalen-1-yl)-2-methyl-6-((1-methylpyrrolidin-2-yl)methoxy)pyrimido[5,4-d]pyrimidin-4(3H)-one (6 mg, 10.9%, 3).

[0348] LCMS: Rt: 0.825min; MS m / z(ESI): 574.3[M+H] + ;

[0349] 1 H NMR(400MHz,DMSO)δ8.27(s,0.89H),8.26-8.23(m,1H),8.18-8.10(m,1H),7.82-7.55(m,4H ),6.85(dd,J=16.6,10.4Hz,1H),6.17(dd,J=16.7,2.1Hz,1H),5.73(dd,J=10.4,2.2Hz,1H), 4.47-4.17(m,5H),4.15-4.09(m,1H),3.83-3.70(m,4H),2.98-2.93(m,1H),2.59-2.53(m,1 H),2.35(s,3H),2.22-2.13(m,1H),2.09-1.99(m,3H),1.97-1.86(m,1H),1.73-1.54(m,3H).

[0350] Example 4

[0351]

[0352] Step 1: Synthesis of compound 4-3

[0353]

[0354] To a mixture of 5-amino-6-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxylic acid (200 mg, 0.393 mmol, 1.0 equiv) and 8-chloronaphthalen-1-amine (49 mg, 0.275 mmol, 1.0 equiv) in anhydrous DMF (5.0 mL) was added DIEA (152 mg, 1.179 mmol, 3.0 equiv) followed by HATU (149 mg, 0.393 mmol, 1.0 equiv). The reaction mixture was stirred at 60 °C under Ar for 1 hour. LCMS showed consumption of the starting material and formation of the desired product. The reaction mixture was cooled to room temperature, diluted with EtOAc (30 mL) and washed with brine (3 x 30 mL), dried over anhydrous NaSO, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with DCM / MeOH (1 / 0-10:1, v / v) to give (S)-benzyl 4-(5-amino-6-((8-chloronaphthalen-1-yl)carbamoyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (200 mg, 51%).

[0355] LCMS: Rt: 0.955min; MS m / z(ESI): 669.3[M+H] + .

[0356] Step 2: Synthesis of Compounds 4-5

[0357]

[0358] To a mixture of (S)-4-(5-amino-6-((8-chloronaphthalen-1-yl)carbamoyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (90 mg, 0.1348 mmol, 1.0 equiv) and AcOH (0.8 mL) was added 1,1,1-triethoxyethane (332 mg, 2.020 mmol, 15.0 equiv). The mixture was stirred at 135 ° C in a sealed tube for 8 min. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was adjusted to pH = 8-9 with aqueous NaHCO 3 solution and extracted with DCM (3×20 mL). The combined organic layers were dried over anhydrous Na 2 SO 4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC eluting with DCM / MeOH (10:1, v / v) to give (S)-benzyl 4-(7-(8-chloronaphthalen-1-yl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (64 mg, 62%).

[0359] LCMS: Rt: 0.929min; MS m / z(ESI): 693.0[M+H] + .

[0360] Step 3: Synthesis of compounds 4-6

[0361]

[0362] To a mixture of (S)-benzyl 4-(7-(8-chloronaphthalen-1-yl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (64 mg, 0.0925 mmol, 1 eq) in CHCN (5.0 mL) was added TMSI (148 mg, 0.740 mmol, 8 eq), and the mixture was stirred at 35 °C under N for 1 hour. LCMS showed that the starting material was consumed. To the resulting mixture was added EtN (149 mg, 1.48 mmol, 16 eq), and stirred at room temperature for 15 min. The mixture was concentrated under reduced pressure. The residue was diluted with H0 (15 mL) and extracted with DCM / MeOH (10 / 1, 3 x 15 mL). The combined organic layers were dried over anhydrous NaSO, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC eluting with DCM / MeOH (8:1, v / v) to give 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (50 mg, 96%).

[0363] LCMS: Rt: 0.379min; MS m / z(ESI): 559.3[M+H] + .

[0364] Step 4: Synthesis of Compound 4

[0365]

[0366] To a mixture of 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (50 mg, 0.085 mmol, 1.0 equiv) and EtN (26 mg, 0.255 mmol, 3.0 equiv) in DCM (2 mL) was added dropwise a solution of acryloyl chloride (7.7 mg, 0.085 mmol, 1.0 equiv) in DCM (0.2 mL) at -20 °C. After the addition, the mixture was stirred at -20 °C under N for 30 min. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was quenched with water (10 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was separated and purified by HCOOH preparative HPLC to give 2-((S)-1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (20 mg, 38%, 4).

[0367] LCMS: Rt: 0.996min; MS m / z(ESI): 580.2[M+H] + ;

[0368] 1 H NMR (400MHz, DMSO) δ8.27(d,J=8.0Hz,1H),8.20(s,0.64H),8.16(d,J=8.1Hz,1H),7.86-7.67(m,3H) ,7.60(t,J=7.9Hz,1H),6.95-6.80(m,1H),6.21(d,J=16.5Hz,1H),5.79(d,J=10.2Hz,1H),5.65-4.70 (m,3H),4.53-4.31(m,1.5H),4.22-4.12(m,1.5H),3.76-3.41(m,2H),3.25-2.90(m,4H),2.75-2.65 (m,1H),2.41(s,3H),2.34-2.23(m,1H),2.10(d,J=1.3Hz,3H),2.00-1.92(m,1H),1.77-1.57(m,3H).

[0369] Example 5

[0370]

[0371] Step 1: Synthesis of compound 5-3

[0372]

[0373] To a mixture of 5-amino-6-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxylic acid (120 mg, 0.255 mmol, 1.0 equiv) and 8-chloronaphthalen-1-amine (68 mg, 0.383 mmol, 1.5 equiv) in anhydrous DMF (3.0 mL) was added DIEA (99 mg, 0.765 mmol, 3.0 equiv) followed by HATU (194 mg, 0.51 mmol, 2.0 equiv). The reaction mixture was stirred at 60 °C under Ar for 1 hour. LCMS showed the reaction was complete. The reaction mixture was cooled to room temperature, diluted with EtOAc (30 mL) and washed with brine (3 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC with DCM / MeOH (10:1, v / v) to give (S)-benzyl 4-(5-amino-6-((8-chloronaphthalen-1-yl)carbamoyl)-2-((1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)piperazine-1-carboxylate (80 mg, 50%).

[0374] LCMS: Rt: 0.951min; MS m / z(ESI): 630.2[M+H] + .

[0375] Step 2: Synthesis of compound 5-5

[0376]

[0377] To a mixture of (S)-benzyl 4-(5-amino-6-((8-chloronaphthalen-1-yl)carbamoyl)-2-((1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)piperazine-1-carboxylate (90 mg, 0.143 mmol, 1.0 equiv) in AcOH (0.8 mL) was added triethoxymethane (317 mg, 2.145 mmol, 15.0 equiv). The mixture was stirred at 135 ° C in a sealed tube for 8 min. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was adjusted to pH = 8-9 with aqueous NaHCO 3 solution and extracted with DCM (3×15 mL). The combined organic layers were dried over anhydrous Na 2 SO 4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC eluting with DCM / MeOH (10:1, v / v) to give (S)-benzyl 4-(7-(8-chloronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (50 mg, 55%).

[0378] LCMS: Rt: 0.951min; MS m / z(ESI): 640.2[M+H] + .

[0379] Step 3: Synthesis of compounds 5-6

[0380]

[0381] To a mixture of (S)-benzyl 4-(7-(8-chloronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (50 mg, 0.078 mmol) in DCM (3 mL) was added Et3SiH (73 mg, 0.626 mmol) and Et3N (63 mg, 0.626 mmol) followed by PdCl2 (4.1 mg, 0.0235 mmol). The mixture was stirred at room temperature under N2 for 1 hour. LCMS showed 30% desired MS was observed. Et3SiH (73 mg, 0.626 mmol) and Et3N (63 mg, 0.626 mmol) and PdCl2 (8 mg, 0.047 mmol) were added to the mixture. The mixture was stirred at room temperature under N2 for 1 hour. LCMS showed that de-Cl product was observed. The reaction mixture was quenched with H2O (15 mL) and extracted with DCM / MeOH (10 / 1, 3×15 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a crude material (S)-6-((1-methylpyrrolidin-2-yl)methoxy)-3-(naphthalene-1-yl)-8-(piperazine-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one (36.7 mg, 100%) as a yellow oil, which was used directly in the next step without further purification.

[0382] LCMS: Rt: 0.385min; MS m / z(ESI): 472.2[M+H] + .

[0383] Step 4: Synthesis of compound 5

[0384]

[0385] To a mixture of (S)-6-((1-methylpyrrolidin-2-yl)methoxy)-3-(naphthalen-1-yl)-8-(piperazin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one (36.7 mg, 0.078 mmol, 1.0 equiv) and EtN (24 mg, 0.234 mmol, 3.0 equiv) in DCM (2 mL) was added dropwise a solution of acryloyl chloride (5.7 mg, 0.0624 mmol, 0.8 equiv) in DCM (0.2 mL) at -20 ° C. After the addition, the mixture was stirred at -20 ° C under N for 30 min. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was quenched with water (10 mL) and extracted with DCM (3×10 mL). The combined organic layers were dried over anhydrous NaSO, filtered and concentrated under reduced pressure. The residue was separated and purified by HCOOH preparative HPLC to give (S)-8-(4-acryloylpiperazin-1-yl)-6-((1-methylpyrrolidin-2-yl)methoxy)-3-(naphthalen-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one (7 mg, 17%, 5).

[0386] LCMS: Rt: 0.819min; MS m / z(ESI): 526.2[M+H] + ;

[0387] 1 H NMR(400MHz,DMSO)δ8.29(s,0.93H),8.27(s,1H),8.19-8.06(m,2H),7.74-7.54(m,5H) ,6.87(dd,J=16.7,10.4Hz,1H),6.18(dd,J=16.7,2.3Hz,1H),5.74(dd,J=10.4,2.3Hz, 1H),4.38-4.25(m,4H),4.19-4.13(m,1H),3.84-3.69(m,5H),2.98-2.92(m,1H),2.64- 2.53(m,1H),2.36(s,3H),2.19(q,J=8.6Hz,1H),2.00-1.91(m,1H),1.74-1.59(m,3H).

[0388] Example 6

[0389]

[0390] Step 1: Synthesis of compound 6-2

[0391]

[0392] To a cooled (0 ° C) solution of naphthalene-1,8-diamine (20 g, 126.58 mmol, 1.0 equivalent) in EtOH (400 mL) and AcOH (40 mL) is added isoamyl nitrite (16.6 mL, 124.05 mmol, 0.98 equivalent) dropwise. After addition, the reaction mixture was stirred at room temperature overnight. LCMS analysis showed that the starting material was exhausted and the desired product was formed. The solid was collected by filtration, washed with EtOH (200 mL), and dried under vacuum to give 1H-naphtho[1,8-de][1,2,3]triazine (18 g, 86%), which was used directly in the next step.

[0393] LCMS (ESI, m / z): [M+1] + =170; RT=1.219min.

[0394] Step 2: Synthesis of compound 6-3

[0395]

[0396] To a cooled (0 ° C) mixture of copper shavings (0.5 g, 7.81 mmol, 0.07 equiv) in aqueous HBr solution (48%, 200 mL) was slowly added 1H-naphtho[1,8-de][1,2,3]triazine (18 g, 106.51 mmol, 1.0 equiv). After addition, the reaction mixture was stirred at room temperature overnight. LCMS analysis showed that the starting material was consumed and the desired product was formed. The reaction mixture was diluted with EtOAc (50 mL), followed by addition of aqueous KOH (45%, w / w) to adjust pH = 11-12. The organic layer of the filtrate was separated, and the aqueous layer was extracted with EtOAc (50 mL × 2). The combined organics were dried over anhydrous Na2SO4 and concentrated to give 8-bromonaphthalene-1-amine (15.8 g, 67%), which was used directly in the next step.

[0397] LCMS (ESI, m / z): [M+1] + =222; RT=1.575min.

[0398] Step 3: Synthesis of compound 6-4

[0399]

[0400] To 8-bromonaphthalene-1-amine (6 g, 27.15 mmol, 1.0 equiv) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxaborol To a solution of dtbpf (10.22 g, 81.45 mmol, 3.0 equiv) in dioxane (40 mL) and H2O (10 mL) was added PdCl2(dtbpf) (0.89 g, 1.36 mmol, 0.05 equiv) and K3PO4 (17.27 g, 81.45 mmol, 3.0 equiv). The mixture was stirred at 80 ° C under Ar overnight. LCMS analysis showed that the starting material was exhausted and the desired product was formed. The reaction mixture was filtered through celite, and the filtrate was concentrated to dryness. The residue was purified by silica column chromatography eluted with EtOAc / petroleum ether (10%, v / v) to give 8-methylnaphthalene-1-amine (1.2 g, 29%).

[0401] LCMS (ESI, m / z): [M+1] + =158; RT=1.253min.

[0402] Step 4: Synthesis of compound 6-5

[0403]

[0404] To a mixture of 5-amino-6-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxylic acid (150 mg, 0.319 mmol, 1.0 equiv) and 8-methylnaphthalen-1-amine HCl (62 mg, 0.319 mmol, 1.0 equiv) in anhydrous DMF (5.0 mL) was added DIEA (123 mL, 0.957 mmol, 3.0 equiv) followed by HATU (121 mg, 0.319 mmol, 1.0 equiv). The reaction mixture was stirred at 60 °C under Ar for 1 hour. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was cooled to room temperature, diluted with EtOAc (30 mL) and washed with brine (3 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC with DCM / MeOH (1 / 0-10:1, v / v) to give (S)-benzyl 4-(5-amino-6-((8-methylnaphthalen-1-yl)carbamoyl)-2-((1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)piperazine-1-carboxylate (56 mg, 29%).

[0405] LCMS (ESI, m / z): [M+1] + =610; RT=0.943min.

[0406] Step 5: Synthesis of compound 6-6

[0407]

[0408] To a solution of (S)-benzyl 4-(5-amino-6-((8-methylnaphthalen-1-yl)carbamoyl)-2-((1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)piperazine-1-carboxylate (20 mg, 0.033 mmol, 1.0 equiv) and AcOH (0.2 mL) was added 1,1,1-triethoxyethane (78 mg, 0.493 mmol, 15.0 equiv). The mixture was stirred at 135 ° C in a sealed tube for 2.5 min. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was quenched with aqueous NaHCO 3 solution (saturated, 20 mL) to adjust the pH = 7-8 and extracted with DCM (10 mL×3). The combined organic fractions were dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by preparative TLC eluting with DCM / MeOH (10:1, v / v) to give (S)-benzyl 4-(6-methyl-7-(8-methylnaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (13 mg, 64%).

[0409] LCMS (ESI, m / z): [M+1] + =634; RT=1.230min.

[0410] Step 6: Synthesis of Compounds 6-7

[0411]

[0412] To a solution of (S)-benzyl 4-(6-methyl-7-(8-methylnaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (43 mg, 0.118 mmol, 1.0 equiv) in MeOH (0.2 mL) was added Pd(OH) / C (20% on carbon, wet with approximately 50% water, 8.4 mg, 0.012 mmol, 0.1 equiv) and the mixture was stirred at room temperature under H for 1 h. LCMS showed consumption of the starting material and formation of the desired product. The reaction mixture was filtered, and the filtrate was concentrated to dryness to give (S)-2-methyl-3-(8-methylnaphthalen-1-yl)-6-((1-methylpyrrolidin-2-yl)methoxy)-8-(piperazin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one (33 mg, 99%), which was used directly in the next step.

[0413] LCMS (ESI, m / z): [M+1]+ =500; RT = 0.664min;

[0414] Step 7: Synthesis of Compound 6

[0415]

[0416] To a cooled (0 ° C) solution of (S)-2-methyl-3-(8-methylnaphthalen-1-yl)-6-((1-methylpyrrolidin-2-yl)methoxy)-8-(piperazin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one (33 mg, 0.067 mmol, 1.0 equiv) and Et3N (20.2 mg, 0.200 mmol, 3.0 equiv) in DCM (2 mL) was added a solution of acryloyl chloride (60 mg, 0.067 mmol, 1 equiv) in DCM (5.0 mL) dropwise. After the addition, the mixture was stirred at 0 ° C for 30 min. LCMS showed that the starting material was consumed and the desired product was formed. Water (20 mL) was added and the organic layer was separated. The aqueous layer was extracted with DCM (10 mL×3). The combined organic fractions were dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative HPLC (ACN-H2O + 0.1% HCOOH) to give (S)-8-(4-acryloylpiperazin-1-yl)-2-methyl-3-(8-methylnaphthalen-1-yl)-6-((1-methylpyrrolidin-2-yl)methoxy)pyrimido[5,4-d]pyrimidin-4(3H)-one (HCOOH salt, 5.6 mg, 15%, 6·HCOOH) (C 31 H 35 N7O3·HCOOH).

[0417] LCMS (ESI, m / z): [M+1] + =554; RT = 1.014min;

[0418] 1H NMR (400MHz, DMSO-d6) δ8.25(d,J=8.0Hz,1H),8.14(dd,J=8.4,1.2Hz,1H),7.98(d,J=8.0Hz,1H),7.71-7.62(m,1H),7 .59(d,J=7.6Hz,1H),7.54-7.45(m,1H),7.39(d,J=6.8Hz,1H),6.85(dd,J=16.8,10.8Hz,1H),6.17(dd,J=16.8,2.8Hz ,1H),5.73(dd,J=10.4,2.4Hz,1H),4.32(dd,J=10.4,4.8Hz,4H),4.17-4.10(m,1H),3.85-3.64(m,5H),2.96(d,J=4.8 Hz,1H),2.56(d,J=6.8Hz,1H),2.36(s,3H),2.19(d,J=5.6Hz,4H),2.02(s,3H),1.97-1.90(m,1H),1.73-1.57(m,3H).

[0419] Example 7

[0420]

[0421] Step 1: Synthesis of compound 7-2

[0422]

[0423] To a mixture of (S)-benzyl 4-(5-amino-6-((8-methylnaphthalen-1-yl)carbamoyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (1) (230 mg, 0.354 mmol, 1.0 equiv) and AcOH (2.5 mL) was added 1,1,1-triethoxyethane (863 mg, 5.32 mmol, 15.0 equiv). The mixture was stirred at 135 °C in a sealed tube for 4.5 min. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was quenched with aqueous NaHCO3 (saturated, 90 mL) to adjust pH = 7-8 and extracted with DCM (30 mL x 2). The combined organic fractions were dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica column chromatography eluting with DCM / MeOH (15:1, v / v) to give (S)-benzyl 2-(cyanomethyl)-4-(6-methyl-7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (52 mg, 22%).

[0424] LCMS (ESI, m / z): [M+1] + =673; RT=1.233min.

[0425] Step 2: Synthesis of compound 7-3

[0426]

[0427] To a solution of (S)-benzyl 2-(cyanomethyl)-4-(6-methyl-7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (2) (52 mg, 0.077 mmol, 1.0 equiv) in MeOH (5 mL) was added Pd / C (10% w / w, 8.2 mg, 0.0077 mmol, 0.1 equiv) and Pd(OH)2 / C (10% w / w, 11 mg, 0.0077 mmol, 0.1 equiv). The reaction mixture was stirred at room temperature under H2 (balloon) for 1 hour. LCMS showed consumption of the starting material and formation of the desired product. The mixture was filtered through celite and the filtrate was concentrated to dryness to give 2-((S)-4-(6-methyl-7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (39 mg, 94%) which was used directly in the next step.

[0428] LCMS (ESI, m / z): [M+1] + =539; RT=0.809min.

[0429] Step 3: Synthesis of compound 7

[0430]

[0431] To a cooled (0 ° C) solution of 2-((S)-4-(6-methyl-7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (3) (39 mg, 0.072 mmol, 1.0 equiv) and Et3N (36 mg, 0.360 mmol, 5.0 equiv) in DCM (3.0 mL) was added dropwise a solution of acryloyl chloride (8 mg, 0.086 mmol, 1.2 equiv) in DCM (1.5 mL). After the addition, the mixture was stirred at 0 ° C for 30 min. LCMS showed that most of the starting material was consumed and the desired product was formed. Water (10 mL) was added and the organic layer was separated. The aqueous layer was extracted with DCM (5 mL×3). The combined organic fractions were dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative HPLC (ACN-H2O + 0.1% HCOOH) to give 2-((S)-1-acryloyl-4-(6-methyl-7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (HCOOH salt, 5.94 mg, 13%, 7.06% HCOOH) (C 33 H 36 N8O3·0.6HCOOH).

[0432] LCMS (ESI, m / z): [M+1] + =593; RT=1.575min.

[0433] 1H NMR (400MHz, DMSO-d6) δ8.24(s,0.6H),8.14(d,J=8.0Hz,1H),7.98(d,J=8.0Hz,1H),7.70-7.63(m,1H),7.61-7.54( m,1H),7.50(t,J=7.6Hz,1H),7.40(d,J=7.2Hz,1H),6.93-6.81(m,1H),6.20(dd,J=16.6,2.2Hz,1H),5.79(d,J=11. 2Hz,1H),5.14-4.74(m,2H),4.47(s,1H),4.33(dd,J=10.8,4.8Hz,1H),4.19-4.12(m,1H),3.23-3.06(m,4H),3.04- 2.90(m,3H),2.66-2.52(m,1H),2.36(s,3H),2.24-2.12(m,4H),2.05(s,3H),1.99-1.90(m,1H),1.73-1.57(m,3H).

[0434] Example 8

[0435]

[0436] Step 1: Synthesis of compound 8-2

[0437]

[0438] To a cooled (0 ° C) solution of ethyl 2,6-dichloro-5-nitropyrimidine-4-carboxylate (1.00 g, 3.76 mmol, 1.0 equiv) (1) in anhydrous THF (15 mL) was added dropwise a solution of tert-butyl (2S,5S)-2,5-dimethylpiperazine-1-carboxylate (805 mg, 3.76 mmol, 1.0 equiv) and DIEA (0.93 mL, 5.64 mmol, 1.5 equiv) in anhydrous THF (15 mL). After addition, the reaction mixture was stirred at 0 ° C for 40 min. TLC showed that the starting material was consumed, and the desired product was detected by LCMS. The reaction mixture was concentrated in vacuo. The residue was purified by silica column chromatography eluting with petroleum ether / EtOAc (10:1 to 4:1, v / v) to give ethyl 6-((2S,5S)-4-(tert-butoxycarbonyl)-2,5-dimethylpiperazin-1-yl)-2-chloro-5-nitropyrimidine-4-carboxylate (1.51 g, 90%).

[0439] LCMS (ESI, m / z): [M+1] + =444; RT=2.029min.

[0440] Step 2: Synthesis of compound 8-3

[0441]

[0442] To a stirred mixture of ethyl 6-((2S,5S)-4-(tert-butoxycarbonyl)-2,5-dimethylpiperazin-1-yl)-2-chloro-5-nitropyrimidine-4-carboxylate (1.51 g, 3.40 mmol, 1.0 equiv) and DIEA (1.1 mL, 6.80 mmol, 2.0 equiv) in anhydrous DMF (10 mL) was added (S)-(1-methylpyrrolidin-2-yl)methanol (588 mg, 5.10 mmol, 1.5 equiv). The mixture was stirred at room temperature for 15 hours. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (30 mL×3). The combined organic portions were washed with brine (50 mL), dried over anhydrous NaSO and concentrated. The residue was purified by silica column chromatography eluting with DCM / MeOH (20:1, v / v) to give ethyl 6-((2S,5S)-4-(tert-butoxycarbonyl)-2,5-dimethylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5-nitropyrimidine-4-carboxylate (1.51 g, 85%).

[0443] LCMS (ESI, m / z): [M+1] + =523; RT=1.168min.

[0444] Step 3: Synthesis of compound 8-4

[0445]

[0446] To a solution of ethyl 6-((2S,5S)-4-(tert-butoxycarbonyl)-2,5-dimethylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5-nitropyrimidine-4-carboxylate (1.51 g, 2.89 mmol, 1.0 equiv) in anhydrous EtOH (48 mL) / DMF (16 mL) was added SnCl2 2H2O (3.26 g, 14.1 mmol, 5.0 equiv) and the mixture was stirred at room temperature under Ar for 15 hours. LCMS showed that most of the starting material was consumed and the desired product was formed. The reaction mixture was concentrated to remove EtOH and then diluted with EtOAc (80 mL), followed by the addition of aqueous NaHCO3 (saturated, 120 mL). The resulting mixture was filtered through celite. The organic layer of the filtrate was separated, and the aqueous layer was extracted with EtOAc (60 mL×2). The combined organic fractions were washed with brine (100 mL), dried over anhydrous NaSO and concentrated. The residue was purified by silica column chromatography eluting with DCM / MeOH (15:1, v / v) to give ethyl 5-amino-6-((2S,5S)-4-(tert-butoxycarbonyl)-2,5-dimethylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxylate (664 mg, 47%).

[0447] LCMS (ESI, m / z): [M+1] + =493; RT=1.090min.

[0448] Step 4: Synthesis of compound 8-5

[0449]

[0450] To a solution of ethyl 5-amino-6-((2S,5S)-4-(tert-butoxycarbonyl)-2,5-dimethylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxylate (664 mg, 1.35 mmol, 1.0 equiv) in MeOH (6.0 mL) / HO (1.0 mL) was added LiOH.HO (283 mg, 6.74 mmol, 5.0 equiv), and the mixture was stirred at room temperature for 2 h. LCMS showed consumption of the starting material and formation of the desired product. The reaction mixture was acidified with aqueous HCl (1 M) until pH = 2-3 and then concentrated to dryness to give 5-amino-6-((2S,5S)-4-(tert-butoxycarbonyl)-2,5-dimethylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxylic acid (918 mg), which was used directly in the next step.

[0451] LCMS (ESI, m / z): [M+1] + =465; RT=0.930min.

[0452] Step 5: Synthesis of compound 8-6

[0453]

[0454] To a solution of 5-amino-6-((2S,5S)-4-(tert-butoxycarbonyl)-2,5-dimethylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxylic acid (400 mg, 0.861 mmol, 1.0 equiv) and 8-chloronaphthalen-1-amine (92 mg, 0.517 mmol, 0.6 equiv) in anhydrous DMF (4.0 mL) was added DIEA (0.43 mL, 2.58 mmol, 3.0 equiv) followed by HATU (328 mg, 0.861 mmol, 1.0 equiv). The reaction mixture was stirred at 60 ° C under Ar for 1 hour. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was cooled to room temperature, diluted with water (30 mL) and extracted with EtOAc (15 mL×3). The combined organic fractions were washed with brine (20 ml), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica column chromatography eluting with DCM / MeOH (15:1, v / v) to give tert-butyl (2S, 5S)-4-(5-amino-6-((8-chloronaphthalen-1-yl)carbamoyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (110 mg, 20%).

[0455] LCMS (ESI, m / z): [M+1] + =624; RT=1.293min.

[0456] Step 6: Synthesis of compound 8-7

[0457]

[0458] To a mixture of (2S,5S)-tert-butyl 4-(5-amino-6-((8-chloronaphthalen-1-yl)carbamoyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (110 mg, 0.176 mmol, 1.0 equiv) and AcOH (1.0 mL) was added 1,1,1-triethoxyethane (428 mg, 2.64 mmol, 15.0 equiv). The mixture was stirred at 135 ° C in a sealed tube for 2.5 min. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was quenched with aqueous NaHCO3 (saturated, 40 mL) to adjust pH = 7-8 and extracted with DCM (20 mL×3). The combined organic fractions were dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative TLC eluting with DCM / MeOH (10:1, v / v) to give tert-butyl (2S,5S)-4-(7-(8-chloronaphthalen-1-yl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (35 mg, 31%).

[0459] LCMS (ESI, m / z): [M+1] + =648; RT=1.286min.

[0460] Step 7: Synthesis of Compound 8-8

[0461]

[0462] To a solution of tert-butyl (2S,5S)-4-(7-(8-chloronaphthalen-1-yl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (35 mg, 0.054 mmol) in DCM (1.0 mL) was added TFA (1.0 mL) and the mixture was stirred at room temperature for 1 hour. LCMS showed consumption of the starting material and formation of the desired product. The reaction mixture was concentrated to dryness to give 3-(8-chloronaphthalen-1-yl)-8-((2S,5S)-2,5-dimethylpiperazin-1-yl)-2-methyl-6-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimido[5,4-d]pyrimidin-4(3H)-one (TFA salt, 32 mg, 91%) which was used directly in the next step.

[0463] LCMS (ESI, m / z): [M+1] + =548; RT=0.709min.

[0464] Step 8: Synthesis of Compound 8

[0465]

[0466] To a cooled (0 ° C) solution of 3-(8-chloronaphthalen-1-yl)-8-((2S,5S)-2,5-dimethylpiperazin-1-yl)-2-methyl-6-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimido[5,4-d]pyrimidin-4(3H)-one (TFA salt, 32 mg, 0.048 mmol, 1.0 equiv) and Et3N (24 mg, 0.242 mmol, 5.0 equiv) in DCM (2.5 mL) was added a solution of acryloyl chloride (5.2 mg, 0.058 mmol, 1.2 equiv) in DCM (0.5 mL) dropwise. After the addition, the mixture was stirred at 0 ° C for 30 min. LCMS showed that the starting material was consumed and the desired product was formed. Water (15 mL) was added and the organic layer was separated. The aqueous layer was extracted with DCM (8 mL×3). The combined organic fractions were dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative HPLC (ACN-H2O + 0.1% HCOOH) to give 8-((2S,5S)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-3-(8-chloronaphthalen-1-yl)-2-methyl-6-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimido[5,4-d]pyrimidin-4(3H)-one (HCOOH salt, 2.37 mg, 7.6%, 8·HCOOH) (C 32 H 36 ClN7O3·HCOOH).

[0467] LCMS (ESI, m / z): [M+1] + =602; RT=1.709min.

[0468] 1H NMR (400MHz, DMSO-d6) δ8.26(d,J=8.8Hz,1H),8.30(s,1H),8.15(d,J=8.0Hz,1H),7.90-7.65(m ,3H),7.60(t,J=7.8Hz,1H),6.95-6.61(m,1H),6.13(d,J=15.6Hz,1H),5.69(d,J=9.6Hz,1H),4. 82(s,1H),4.57-4.05(m,4H),3.29(s,3H),2.98-2.92(m,1H),2.63-2.53(m,1H),2.35(d,J=1.2H z,3H),2.24-2.14(m,1H),2.12-1.87(m,4H),1.76-1.53(m,3H),1.48-1.27(m,3H),1.18(s,3H).

[0469] Example 9

[0470]

[0471] Step 1: Synthesis of compound 9-2-intermediate

[0472]

[0473] To a cooled (0 ° C) solution of naphthalene-1,8-diamine (20 g, 126.58 mmol, 1.0 equivalent) in EtOH (400 mL) and AcOH (40 mL) is added isoamyl nitrite (16.6 mL, 124.05 mmol, 0.98 equivalent) dropwise. After addition, the reaction mixture was stirred at room temperature overnight. LCMS analysis showed that the starting material was exhausted and the desired product was formed. The solid was collected by filtration, washed with EtOH (200 mL), and dried under vacuum to give 1H-naphtho[1,8-de][1,2,3]triazine (18 g, 86%), which was used directly in the next step.

[0474] LCMS (ESI, m / z): [M+1] + =170; RT=1.219min.

[0475] Synthesis of compound 9-3-intermediate

[0476]

[0477] To a cooled (0 ° C) mixture of copper shavings (0.5 g, 7.81 mmol, 0.07 equiv) in aqueous HBr solution (48%, 200 mL) was slowly added 1H-naphtho[1,8-de][1,2,3]triazine (18 g, 106.51 mmol, 1.0 equiv). After addition, the reaction mixture was stirred at room temperature overnight. LCMS analysis showed that the starting material was consumed and the desired product was formed. The reaction mixture was diluted with EtOAc (50 mL), followed by addition of aqueous KOH solution (45 w%) to adjust pH = 11-12. The organic layer of the filtrate was separated, and the aqueous layer was extracted with EtOAc (50 mL×2). The combined organics were dried over anhydrous Na2SO4 and concentrated to give 8-bromonaphthalene-1-amine (15.8 g, 67%), which was used directly in the next step.

[0478] LCMS (ESI, m / z): [M+1] + =222; RT=1.575min.

[0479] Step 3: Synthesis of compound 9-4-intermediate

[0480]

[0481] To 8-bromonaphthalene-1-amine (1 g, 4.52 mmol, 1.0 equiv) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborol To a solution of (1.39 g, 9.04 mmol, 2.0 equiv) in dioxane (20 mL) and H2O (5 mL) was added PdCl2(dtbpf) (0.296 g, 0.45 mmol, 0.1 equiv) and K3PO4 (2.88 g, 13.38 mmol, 3.0 equiv). The mixture was stirred at 80 ° C under Ar overnight. LCMS analysis showed that the starting material was exhausted and the desired product was formed. The reaction mixture was filtered through celite, and the filtrate was concentrated to dryness. The residue was purified by silica column chromatography eluted with EtOAc / petroleum ether (10%, v / v) to give 8-vinylnaphthalene-1-amine (500 mg, 65%, 9-4-intermediate).

[0482] LCMS (ESI, m / z): [M+1] + =170; RT=1.790min.

[0483] Step 4: Synthesis of compound 9-1

[0484]

[0485] To a solution of 5-amino-6-((S)-4-((phenylmethyloxy)carbonyl)-3- (cyanomethyl)piperazin-l-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)pyrimidine- 4-carboxylic acid (300 mg, 0.589 mmol, 1.0 equiv) and 8-vinyl naphthalen-l-amine (99 mg, 0.589 mmol, 1.0 equiv) in anhydrous DMF (4.0 mL) was added DIEA (0.29 mL, 1.768 mmol, 3.0 equiv) followed by HATU (223 mg, 0.589 mmol, 1.0 equiv). The reaction mixture was stirred at 60 °C under Ar for 1 h. LCMS showed the starting material was consumed and the desired product was formed. The reaction mixture was cooled to rt, diluted with water (30 mL) and extracted with EtOAc (15 mL x 3). The combined organic portion was washed with brine (20 ml), dried over anhydrous Na2S04and concentrated. The residue was purified by silica column chromatography eluting with DCM / MeOH (15: 1, v / v) to give (S)-4-(5-amino-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-6-((8- vinyl naphthalen-l-yl)carbamoyl)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-l- carboxylate (210 mg, 54%).

[0486] LCMS (ESI, m / z): [M+1] + = 661; RT = 1.213 min.

[0487] Step 5: Synthesis of compound 9-2

[0488]

[0489] To a mixture of (S)-benzyl 4-(5-amino-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-((8-vinylnaphthalen-1-yl)carbamoyl)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (200 mg, 0.303 mmol, 1.0 equiv) and AcOH (1.0 mL) was added 1,1,1-triethoxyethane (736 mg, 4.54 mmol, 15.0 equiv). The mixture was stirred at 135 ° C in a sealed tube for 2.5 min. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was quenched with aqueous NaHCO 3 solution (saturated, 40 mL) to adjust pH = 7-8 and extracted with DCM (20 mL×3). The combined organic fractions were dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by preparative TLC eluting with DCM / MeOH (10:1, v / v) to give (S)-benzyl 2-(cyanomethyl)-4-(6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7-(8-vinylnaphthalen-1-yl)-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (110 mg, 53%).

[0490] LCMS (ESI, m / z): [M+1] + =685; RT=1.190min.

[0491] Step 6: Synthesis of compound 9-3

[0492]

[0493] To a solution of (S)-benzyl 2-(cyanomethyl)-4-(6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7-(8-vinylnaphthalen-1-yl)-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (110 mg, 0.161 mmol) in MeOH (5.0 mL) was added Pd / C (50 mg), and the mixture was stirred at room temperature under H for 1 hour. LCMS showed that the starting material was consumed and the desired product was formed. The resulting mixture was filtered through celite. The organic layer of the filtrate was concentrated to give 2-((S)-4-(7-(8-ethylnaphth-1-yl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (73 mg, 82%), which was used directly in the next step.

[0494] Step 7: Synthesis of Compound 9

[0495]

[0496] To a cooled (0 ° C) solution of 2-((S)-4-(7-(8-ethylnaphth-1-yl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (73 mg, 0.13 mmol, 1.0 equiv) and Et3N (40 mg, 0.39 mmol, 3.0 equiv) in DCM (2.5 mL) was added dropwise a solution of acryloyl chloride (12 mg, 0.13 mmol, 1.0 equiv) in DCM (0.5 mL). After the addition, the mixture was stirred at 0 ° C for 30 min. LCMS showed that the starting material was consumed and the desired product was formed. Water (15 mL) was added and the organic layer was separated. The aqueous layer was extracted with DCM (8 mL×3). The combined organic fractions were dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative HPLC (ACN-H2O + 0.1% HCOOH) to give 2-((S)-1-acryloyl-4-(7-(8-ethylnaphth-1-yl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (HCOOH salt, 20.5 mg, 25.6%, 9.0% HCOOH) (C 34 H 38 N8O3·HCOOH).

[0497] LCMS (ESI, m / z): [M+1] + =607; RT = 1.020min;

[0498] 1 H NMR (400MHz, DMSO-d6) δ8.31(s,1H),8.15(d,J=8.0Hz,1H),7.98(d,J=8.0Hz,1H),7.66(t,J= 7.7Hz,1H),7.60-7.52(m,2H),7.45(d,J=7.1Hz,1H),6.95-6.79(m,1H),6.20(d,J=16.5Hz,1H ),5.78(d,J=10.5Hz,1H),4.35-4.13(m,6H),3.44-2.82(m,6H),2.63-2.51(m,3H),2.36(s,3 H),2.23-2.12(m,1H),2.04(s,3H),1.98-1.87(m,1H),1.74-1.54(m,3H),1.06(t,J=4Hz,3H).

[0499] Example 10

[0500]

[0501] Step 1: Synthesis of compound 10-2

[0502]

[0503] To a solution of 8-bromonaphthalene-1-amine (1) (1.00 g, 4.50 mmol, 1.0 equiv) and cyclopropylboronic acid (773 mg, 9.00 mmol, 2.0 equiv) in dioxane (40 mL) and H2O (10 mL) was added PdCl2(dtbpf) (293 mg, 0.45 mmol, 0.1 equiv) and K3PO4 (2.87 g, 13.5 mmol, 3.0 equiv). The mixture was stirred at 80 ° C under Ar for 15 hours. LCMS showed that the starting material was exhausted and the desired product was formed. The reaction mixture was filtered through celite, and the filtrate was concentrated to dryness. The residue was purified by silica column chromatography eluted with EtOAc / petroleum ether (10%, v / v) to give 8-cyclopropylnaphthalene-1-amine (380 mg, 46%).

[0504] LCMS (ESI, m / z): [M+1] + =184; RT=1.785min.

[0505] Step 2: Synthesis of compound 10-3

[0506]

[0507] To a solution of 5-amino-6-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxylic acid (300 mg, 0.589 mmol, 1.0 equiv) and 8-cyclopropylnaphthalen-1-amine (76 mg, 0.412 mmol, 0.7 equiv) in anhydrous DMF (4.0 mL) was added DIEA (0.29 mL, 1.77 mmol, 3.0 equiv) followed by HATU (224 mg, 0.589 mmol, 1.0 equiv). The reaction mixture was stirred at 60 °C under Ar for 1 hour. LCMS showed that most of the starting material was consumed and the desired product was formed. The reaction mixture was cooled to room temperature, diluted with water (30 mL) and extracted with EtOAc (15 mL x 3). The combined organic fractions were washed with brine (20 ml), dried over anhydrous NaSO and concentrated. The residue was purified by silica column chromatography eluting with DCM / MeOH (15:1, v / v) to give (S)-benzyl 4-(5-amino-6-((8-cyclopropylnaphthalen-1-yl)carbamoyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (94 mg, 24%).

[0508] LCMS (ESI, m / z): [M+1] + =675; RT=1.254min.

[0509] Step 3: Synthesis of compound 10-4

[0510]

[0511] To a mixture of (S)-benzyl 4-(5-amino-6-((8-cyclopropylnaphthalen-1-yl)carbamoyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (94 mg, 0.139 mmol, 1.0 equiv) and AcOH (1.0 mL) was added 1,1,1-triethoxyethane (372 mg, 2.09 mmol, 15.0 equiv). The mixture was stirred at 135 ° C in a sealed tube for 7 min. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was quenched with aqueous NaHCO 3 solution (saturated, 40 mL) to adjust pH = 7-8 and extracted with DCM (20 mL×3). The combined organic fractions were dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by preparative TLC eluting with DCM / MeOH (10:1, v / v) to give (S)-benzyl 2-(cyanomethyl)-4-(6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (56 mg, 57%).

[0512] LCMS (ESI, m / z): [M+1] + =699; RT=1.303min.

[0513] Step 4: Synthesis of compound 10-5

[0514]

[0515] To a solution of (S)-benzyl 2-(cyanomethyl)-4-(6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (56 mg, 0.080 mmol, 1.0 equiv) in MeOH (5.0 mL) was added Pd / C (10% w / w, 8.5 mg, 0.0080 mmol, 0.1 equiv) and Pd(OH) / C (10% w / w, 11 mg, 0.0080 mmol, 0.1 equiv). The reaction mixture was stirred at room temperature under H (balloon) for 1 hour. LCMS showed consumption of the starting material and formation of the desired product. The mixture was filtered through celite and the filtrate was concentrated to dryness to give 2-((S)-4-(7-(8-cyclopropylnaphthalen-1-yl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (40 mg, 89%) which was used directly in the next step.

[0516] LCMS (ESI, m / z): [M+1] + =565; RT=0.409min and 0.757min.

[0517] Step 5: Synthesis of compound 10

[0518]

[0519] To a cooled (0 ° C) solution of 2-((S)-4-(7-(8-cyclopropylnaphthalen-1-yl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (40 mg, 0.071 mmol, 1.0 equiv) and Et3N (36 mg, 0.354 mmol, 5.0 equiv) in DCM (3.0 mL) was added dropwise a solution of acryloyl chloride (7.7 mg, 0.085 mmol, 1.2 equiv) in DCM (0.5 mL). After the addition, the mixture was stirred at 0 ° C for 30 min. LCMS showed that the starting material was consumed and the desired product was formed. Water (10 mL) was added and the organic layer was separated. The aqueous layer was extracted with DCM (5 mL×3). The combined organic fractions were dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative HPLC (ACN-H2O + 0.1% HCOOH) to give 2-((S)-1-acryloyl-4-(7-(8-cyclopropylnaphthalen-1-yl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (HCOOH salt, 18.64 mg, 39%, 10% HCOOH) (C 35 H 38 N8O3·HCOOH).

[0520] LCMS (ESI, m / z): [M+1] + =619; RT=1.623min.

[0521] 1H NMR (400MHz, DMSO-d6) δ8.26(s,1H),8.15(d,J=8.0Hz,1H),7.99(d,J=8.0Hz,1H),7.68(t,J=7.6Hz,1H),7.57(t,J=6.0Hz,1H),7.51( t,J=7.8Hz,1H),7.42(d,J=7.2Hz,1H),6.92-6.82(m,1H),6.20(dd,J=16.6,2.2Hz,1H),5.78(d,J=10.4Hz,1H),5.04-4.81(m,2H),4.4 8(s,1H),4.35-4.28(m,1H),4.17-4.11(m,1H),3.20-3.09(s,4H),3.02-2.90(m,3H),2.59-2.54(m,1H),2.35(d,J=2.0Hz,3H),2.18(d d,J=17.0,8.6Hz,1H),2.08(s,3H),1.98-1.90(m,1H),1.80-1.57(m,4H),0.81-0.71(m,1H),0.63-0.56(m,1H),0.47(t,J=7.8Hz,2H).

[0522] Example 11

[0523]

[0524] Step 1: Synthesis of compound 11-2

[0525]

[0526] To a cooled (0 ° C) solution of naphthalene-1,8-diamine (20 g, 126.58 mmol, 1.0 equivalent) in EtOH (400 mL) and AcOH (40 mL) is added isoamyl nitrite (16.6 mL, 124.05 mmol, 0.98 equivalent) dropwise. After addition, the reaction mixture was stirred at room temperature overnight. LCMS analysis showed that the starting material was exhausted and the desired product was formed. The solid was collected by filtration, washed with EtOH (200 mL), and dried under vacuum to give 1H-naphtho[1,8-de][1,2,3]triazine (18 g, 86%), which was used directly in the next step.

[0527] LCMS (ESI, m / z): [M+1] + =170; RT=1.219min.

[0528] Step 2: Synthesis of compound 11-3

[0529]

[0530] To a cooled (0 ° C) mixture of copper shavings (0.5 g, 7.81 mmol, 0.07 equiv) in aqueous HBr solution (48%, 200 mL) was slowly added 1H-naphtho[1,8-de][1,2,3]triazine (18 g, 106.51 mmol, 1.0 equiv). After addition, the reaction mixture was stirred at room temperature overnight. LCMS analysis showed that the starting material was consumed and the desired product was formed. The reaction mixture was diluted with EtOAc (50 mL), followed by addition of aqueous KOH (45%, w / w) to adjust pH = 11-12. The organic layer of the filtrate was separated, and the aqueous layer was extracted with EtOAc (50 mL × 2). The combined organics were dried over anhydrous Na2SO4 and concentrated to give 8-bromonaphthalene-1-amine (15.8 g, 67%), which was used directly in the next step.

[0531] LCMS (ESI, m / z): [M+1] + =222; RT=1.575min.

[0532] Step 3: Synthesis of compound 11-4

[0533]

[0534] To a solution of 8-bromonaphthalene-1-amine (1 g, 4.52 mmol, 1.0 equiv) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.14 g, 6.79 mmol, 1.5 equiv) in dioxane (10 mL) and H O (2 mL) was added Pd(dppf)Cl (0.33 g, 0.45 mmol, 0.1 equiv) and K CO (1.88 g, 13.56 mmol, 3.0 equiv). The mixture was stirred at 100 ° C under Ar overnight. LCMS analysis showed that the starting material was consumed and the desired product was formed. The reaction mixture was filtered through celite and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica eluting with EtOAc / petroleum ether (10%, v / v) to give 8-(prop-1-en-2-yl)naphthalen-1-amine (592 mg, 69%).

[0535] LCMS (ESI, m / z): [M+1] + =184; RT=1.726min.

[0536] Step 4: Synthesis of compound 11-5

[0537]

[0538] To a solution of 5-amino-6-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxylic acid (200 mg, 0.392 mmol, 1.0 equiv) and 8-(prop-1-en-2-yl)naphthalen-1-amine (71.9 mg, 0.392 mmol, 1.0 equiv) in anhydrous DMF (4 mL) was added DIEA (0.37 mL, 1.18 mmol, 3.0 equiv) followed by HATU (149 mg, 0.392 mmol, 1.0 equiv). The reaction mixture was stirred at 60 ° C under Ar for 1 hour. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was cooled to room temperature, diluted with water (30 mL) and extracted with EtOAc (15 mL×3). The combined organic fractions were washed with brine (20 ml), dried over anhydrous NaSO and concentrated. The residue was purified by silica column chromatography eluting with DCM / MeOH (10:1, v / v) to give (S)-benzyl 4-(5-amino-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-((8-(prop-1-en-2-yl)naphthalen-1-yl)carbamoyl)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (251 mg, 95%).

[0539] LCMS (ESI, m / z): [M+1] + =675; RT=1.265min.

[0540] Step 5: Synthesis of compound 11-6

[0541]

[0542] To a mixture of (S)-4-(5-amino-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-((8-(prop-1-en-2-yl)naphthalen-1-yl)carbamoyl)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (299.3 mg, 0.44 mmol, 1.0 equiv) and AcOH (3.0 mL) was added 1,1,1-triethoxyethane (1.08 g, 6.66 mmol, 15.0 equiv). The mixture was stirred at 135 ° C in a sealed tube for 2.5 min. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was quenched with aqueous NaHCO 3 solution (saturated, 30 mL) to adjust pH = 7-8 and extracted with DCM (15 mL×3). The combined organic fractions were dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by preparative TLC eluting with DCM / MeOH (10:1, v / v) to give (S)-benzyl 2-(cyanomethyl)-4-(6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7-(8-(prop-1-en-2-yl)naphthalen-1-yl)-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (91 mg, 29.6%).

[0543] LCMS (ESI, m / z): [M+1] + =699; RT=1.248min.

[0544] Step 6: Synthesis of compound 11-7

[0545]

[0546] To a solution of (S)-2-(cyanomethyl)-4-(6-methyl-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-8-oxo-7-(8-(prop-1-en-2-yl)naphthalen-1-yl)-7,8-dihydropyrimido[5,4- d]pyrimidin-4-yl)piperazine-1-carboxylic acid benzyl ester (45 mg, 0.064 mmol, 1.0 eq) in MeOH (3.0 mL) was added Pd(OH)2 / C (20% on carbon, wetted with ~50% water, 4.23 mg, 0.006 mmol, 0.1 eq) and the mixture was stirred under H2at room temperature for 1 h. LCMS showed starting material consumed and desired product formed. The reaction mixture was filtered and the filtrate was concentrated to dryness to give 2-((S)-4-(6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7-(8-(prop-1-en-2-yl)naphthalen-1-yl)-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (36 mg, 99%) which was used directly in the next step.

[0547] LCMS (ESI, m / z): [M+1] + = 565; RT = 0.728 min;

[0548] Step 7: Synthesis of compound 11

[0549]

[0550] To a cooled (0 °C) solution of (S)-2-(cyanomethyl)-4-(6-methyl-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)-8-oxo-7-(8-(prop-1-en-2-yl)naphthalen-1-yl)-7,8- dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid benzyl ester (36.4 mg, 0.065 mmol, 1.0 eq) and Et3N (19.6 mg, 0.194 mmol, 3.0 eq) in DCM (3.0 mL) was added acryloyl chloride (758 mg, 0.095 mmol, 1 eq) in DCM (3 mL) dropwise. After addition, the mixture was stirred at 0 °C for 30 min. LCMS showed starting material consumed and desired product formed. Water (20 mL) was added and the organic layer was separated. The aqueous layer was extracted with DCM (10 mL x 3). The combined organic portions were dried over anhydrous Na2SO4and concentrated. The residue was purified by prep-HPLC (ACN-H2O + 0.1% HCOOH) to give 2-((S)-1-acryloyl-4-(6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7-(8-(prop-1-en-2-yl)naphthalen-1-yl)-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (HCOOH salt, 2.21 mg, 5.5%, 11 · HCOOH) (C 35 H 38 N8O3·HCOOH).

[0551] LCMS (ESI, m / z): [M+1] + =619; RT=1.603min;

[0552] 1 H NMR (400MHz, CDCl3) δ8.35(s,1H),8.04(d,J=8.0Hz,1H),7.89(d,J=8.0Hz,1H),7.68-7.55(m,1 H),7.54-7.42(m,1H),7.42-7.27(m,2H),6.60(d,J=11.6Hz,1H),6.41(d,J=16.4Hz,1H),5.83(d ,J=10.4Hz,1H),5.09(s,1H),4.89(s,1H),4.83-4.63(m,3H),4.18-3.07(m,5H),2.96(s,5H),2 .76(d,J=15.6Hz,1H),2.29(s,2H),2.18-2.05(m,4H),2.02-1.88(m,4H),1.80(d,J=2.8Hz,3H).

[0553] Example 12

[0554]

[0555] Step 1: Synthesis of compound 12-2

[0556]

[0557] To a solution of naphthalene-1,3-diol (10.0 g, 62.5 mmol, 1.0 equiv) in MeOH (120 mL) was added concentrated HCl (4.0 mL, 62.5 mmol, 0.76 equiv). The reaction mixture was stirred at 80 ° C under Ar for 16 hours. TLC showed that the starting material was exhausted and a new product was formed. The reaction mixture was cooled to room temperature, diluted with NaHCO (60 mL) and extracted with DCM (60 mL × 3). The combined organic portions were combined, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica column chromatography eluted with petroleum ether / EtOAc (4: 1, v / v) to give 3-methoxynaphthalene-1-ol (7.2 g, 66.7%).

[0558] Step 2: Synthesis of compound 12-3

[0559]

[0560] To a solution of 3-methoxynaphthalen-1-ol (500 mg, 2.87 mmol, 1.0 equiv) in anhydrous DMF (5.0 mL) was added CsCO (1.87 g, 5.74 mmol, 2.0 equiv) and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (1.34 g, 3.74 mmol, 1.3 equiv). The reaction mixture was stirred at 0 ° C under Ar for 6 hours. TLC showed that the starting material was exhausted and a new product was formed. The reaction mixture was cooled to room temperature and diluted with EtOAc (20 mL × 3). The combined organic portion was washed with brine (25 mL × 3), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica column chromatography eluting with petroleum ether / EtOAc (4:1, v / v) to give 3-methoxynaphthalen-1-yl trifluoromethanesulfonate (689 mg, 78.4%).

[0561] Step 3: Synthesis of compound 12-4

[0562]

[0563] To a solution of 3-methoxynaphthalen-1-yl trifluoromethanesulfonate (389 mg, 1.27 mmol, 1.0 equiv) and benzophenone imine (299.1 mg, 1.65 mmol, 1.3 equiv) in toluene (4.0 mL) was added KCO (228.1 mg, 1.65 mmol, 1.3 equiv), CsCO (538.7 mg, 1.65 mmol, 1.3 equiv) and BINAP (102.6 mg, 0.165 mmol, 0.1 equiv) followed by Pd(dba) (75.6 mg, 0.083 mmol, 0.05 equiv) and the mixture was stirred at 110° C. under Ar for 3 h. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica column chromatography eluting with petroleum ether / EtOAc (10:1, v / v) to give N-(3-methoxynaphthalen-1-yl)-1,1-diphenylmethanimine (396 mg, 92%).

[0564] LCMS (ESI, m / z): [M+1] + =338; RT=2.321min.

[0565] Step 4: Synthesis of compound 12-5

[0566]

[0567] To a mixture of N-(3-methoxynaphthalene-1-yl)-1,1-diphenylmethaneimine (396 mg, 1.17 mmol) and MeOH (4.0 mL) and H2O (4.0 mL) was added dropwise HCl (1.5 mL). The mixture was stirred at 70 ° C for 1.5 hours. LCMS showed that the starting material was exhausted and the desired product was formed. The reaction mixture was quenched with NaHCO3 aqueous solution (saturated, 20 mL) to adjust the pH = 7-8, which was extracted with DCM (20 mL × 3). The combined organic portion was dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative TLC eluting with petroleum ether / EtOAc (10: 1, v / v) to give 3-methoxynaphthalene-1-amine (193 mg, 95.5%).

[0568] LCMS (ESI, m / z): [M+1] + =174; RT=1.428min.

[0569] Step 5: Synthesis of compound 12-6

[0570]

[0571] To a solution of 5-amino-6-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxylic acid (310 mg, 0.609 mmol, 1.0 equiv) and 3-methoxynaphthalen-1-amine (73.7 mg, 1.27 mmol, 0.7 equiv) in anhydrous DMF (5.0 mL) was added DIEA (0.30 mL, 1.827 mmol, 3.0 equiv) followed by HATU (232 mg, 0.609 mmol, 1.0 equiv). The reaction mixture was stirred at 60 ° C under Ar for 1 hour. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was cooled to room temperature, diluted with water (30 mL) and extracted with EtOAc (15 mL×3). The combined organic fractions were washed with brine (25 mL), dried over anhydrous NaSO, and concentrated. The residue was purified by silica column chromatography eluting with DCM / MeOH (10:1, v / v) to afford (S)-benzyl 4-(5-amino-6-((3-methoxynaphthalen-1-yl)carbamoyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (150 mg, 37.1%).

[0572] LCMS (ESI, m / z): [M+1] + =665; RT=1.218min.

[0573] Step 6: Synthesis of compound 12-7

[0574]

[0575] To a mixture of (S)-benzyl 4-(5-amino-6-((3-methoxynaphthalen-1-yl)carbamoyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (153 mg, 0.23 mmol, 1.0 equiv) and AcOH (1.2 mL) was added 1,1,1-triethoxyethane (559 mg, 3.45 mmol, 15.0 equiv). The mixture was stirred at 135 ° C in a sealed tube for 2.5 min. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was quenched with aqueous NaHCO 3 solution (saturated, 20 mL) to adjust pH = 7-8 and extracted with DCM (20 mL×3). The combined organic fractions were dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by preparative TLC eluting with DCM / MeOH (10:1, v / v) to give (S)-benzyl 2-(cyanomethyl)-4-(7-(3-methoxynaphthalen-1-yl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (126 mg, 79.7%).

[0576] LCMS (ESI, m / z): [M+1] + =689; RT=1.195min.

[0577] Step 7: Synthesis of Compound 12-8

[0578]

[0579] To a solution of (S)-benzyl 2-(cyanomethyl)-4-(7-(3-methoxynaphthalen-1-yl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (126 mg, 0.183 mmol, 1.0 equiv) in MeOH (8.0 mL) was added Pd(OH) / C (20% on carbon, wet with approximately 50% water, 12.6 mg, 0.018 mmol, 0.1 equiv) and the mixture was stirred at room temperature under H for 1 h. LCMS showed consumption of the starting material and formation of the desired product. The reaction mixture was filtered and the filtrate was concentrated to dryness to give 2-((S)-4-(7-(3-methoxynaphthalen-1-yl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (53 mg, 53%) which was used directly in the next step.

[0580] LCMS (ESI, m / z): [M+1] + =555; RT = 0.349min;

[0581] Step 8: Synthesis of Compound 12

[0582]

[0583] To a cooled (0 ° C) solution of 2-((S)-4-(7-(3-methoxynaphthalen-1-yl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (53 mg, 0.095 mmol, 1.0 equiv) and Et3N (29 mg, 0.287 mmol, 3.0 equiv) in DCM (5 mL) was added dropwise a solution of acryloyl chloride (8.6 mg, 0.095 mmol, 1 equiv) in DCM (5.0 mL). After the addition, the mixture was stirred at 0 ° C for 30 min. LCMS showed that the starting material was consumed and the desired product was formed. Water (20 mL) was added and the organic layer was separated. The aqueous layer was extracted with DCM (10 mL×3). The combined organic fractions were dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative HPLC (ACN-H2O + 0.1% HCOOH) to give 2-((S)-1-acryloyl-4-(7-(3-methoxynaphthalen-1-yl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (HCOOH salt, 20.3 mg, 35.2%, 12·HCOOH) (C 33 H 36 N8O4·HCOOH).

[0584] LCMS (ESI, m / z): [M+1] + =609; RT = 0.985min;

[0585] 1 H NMR (400MHz, DMSO-d6) δ8.32(s,1H),7.99(d,J=8.0Hz,1H),7.56(d,J=8.4Hz,2H),7.46-7.30(m ,3H),6.96-6.78(m,1H),6.28-6.13(m,1H),5.84-5.72(m,1H),5.53-4.42(m,4H),4.36-4.29(m, 1H),4.14(dd,J=10.8,5.6Hz,1H),3.95(s,3H),3.14(s,3H),3.01-2.92(m,3H),2.56(s,1H),2.3 6-2.32(m,3H),2.17(dd,J=17.2,8.6Hz,1H),2.05(s,3H),1.98-1.89(m,1H),1.72-1.57(m,3H).

[0586] Example 13

[0587]

[0588] Step 1: Synthesis of compound 13-2

[0589]

[0590] To a solution of 5-amino-6-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxylic acid (500 mg, 0.981 mmol, 1.0 equiv) and 8-chloronaphthalen-1-amine (122 mg, 0.687 mmol, 0.7 equiv) in anhydrous DMF (5.0 mL) was added DIEA (0.81 mL, 4.91 mmol, 5.0 equiv) followed by HATU (373 mg, 0.981 mmol, 1.0 equiv). The reaction mixture was stirred at 60 ° C under Ar for 1 hour. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was cooled to room temperature, diluted with water (30 mL) and extracted with EtOAc (15 mL×3). The combined organic fractions were washed with brine (20 ml), dried over anhydrous NaSO and concentrated. The residue was purified by silica column chromatography eluting with DCM / MeOH (15:1, v / v) to give (S)-benzyl 4-(5-amino-6-((8-chloronaphthalen-1-yl)carbamoyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (446 mg, 68%).

[0591] LCMS (ESI, m / z): [M+1] + =669; RT=1.226min.

[0592] Step 2: Synthesis of compound 13-3

[0593]

[0594] To a mixture of (S)-benzyl 4-(5-amino-6-((8-chloronaphthalen-1-yl)carbamoyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (210 mg, 0.314 mmol, 1.0 equiv) and AcOH (2.0 mL) was added 1,1,1-triethoxypropane (830 mg, 4.71 mmol, 15.0 equiv). The mixture was stirred at 135 ° C in a sealed tube for 7 min. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was quenched with aqueous NaHCO 3 solution (saturated, 90 mL) to adjust the pH = 7-8 and extracted with DCM (30 mL×3). The combined organic fractions were dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by preparative TLC eluting with DCM / MeOH (10:1, v / v) to give (S)-benzyl 4-(7-(8-chloronaphthalen-1-yl)-6-ethyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (65 mg, 29%).

[0595] LCMS (ESI, m / z): [M+1] + =707; RT=1.303min.

[0596] Step 3: Synthesis of compound 13-4

[0597]

[0598] To a solution of (S)-benzyl 4-(7-(8-chloronaphthalen-1-yl)-6-ethyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (65 mg, 0.092 mmol, 1.0 equiv) in anhydrous ACN (5.0 mL) was added TMSI (184 mg, 0.920 mmol, 10.0 equiv). The reaction mixture was stirred at 30 °C under Ar for 1 hour. LCMS showed that most of the starting material was consumed and the desired product was formed. EtN (0.5 mL, 3.60 mmol, 39.1 equiv) was added and the mixture was stirred at room temperature for 15 min. The mixture was then concentrated and the residue was purified by preparative TLC eluting with DCM / MeOH (8:1, v / v) to give 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-6-ethyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (48 mg, 91%).

[0599] LCMS (ESI, m / z): [M+1] + =573; RT=0.708min.

[0600] Step 4: Synthesis of compound 13

[0601]

[0602] To a cooled (0 ° C) solution of 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-6-ethyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (48 mg, 0.084 mmol, 1.0 equiv) and Et3N (42 mg, 0.419 mmol, 5.0 equiv) in DCM (3.0 mL) was added dropwise a solution of acryloyl chloride (9.1 mg, 0.100 mmol, 1.2 equiv) in DCM (0.5 mL). After the addition, the mixture was stirred at 0 ° C for 30 min. LCMS showed that most of the starting material was consumed and the desired product was formed. Water (10 mL) was added and the organic layer was separated. The aqueous layer was extracted with DCM (5 mL×3). The combined organic fractions were dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative HPLC (ACN-H2O + 0.1% HCOOH) to give 2-((S)-1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-6-ethyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (HCOOH salt, 16.0 mg, 30%, 13.0% HCOOH) (C 33 H 35 ClN8O3·0.3HCOOH).

[0603] LCMS (ESI, m / z): [M+1] + =627; RT=1.050min.

[0604] 1 H NMR (400MHz, DMSO-d6) δ8.31 (s, 0.3H), 8.26 (d, J = 7.2Hz, 1H), 8.15 (d, J = 8.4Hz, 1H), 7.83-7. 75(m,1H),7.75-7.64(m,2H),7.59(t,J=7.8Hz,1H),6.97-6.84(m,1H),6.21(d,J=18.4Hz,1H ),5.78(d,J=11.2Hz,1H),5.38-4.84(m,3H),4.51-4.09(m,3H),3.81-3.50(m,2H),3.26-3.1 1(m,2H),2.97-2.93(m,1H),2.60-2.51(m,2H),2.35(s,3H),2.22-2.06(m,2H),1.99-1.89(m 1H),1.74-1.54(m,3H),1.20-1.03(m,3H).

[0605] Example 14

[0606]

[0607] Step 1: Synthesis of compound 14-2

[0608]

[0609] To a solution of 5-amino-6-((S)-4-((benzyloxy)carbonyl)-3- (cyanomethyl)piperazin-l-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)pyrimidine- 4-carboxylic acid (500 mg, 0.982 mmol, 1.0 equiv) and naphthalen-l-amine (98.3 mg, 0.688 mmol, 0.7 equiv) in anhydrous DMF (10.0 mL) was added DIEA (0.49 mL, 2.58 mmol, 3.0 equiv) followed by HATU (373 mg, 0.982 mmol, 1.0 equiv). The reaction mixture was stirred at 60 °C under Ar for 1 h. LCMS showed the starting material was consumed and the desired product was formed. The reaction mixture was cooled to rt, diluted with water (40 mL) and extracted with EtOAc (20 mL x 3). The combined organic portion was washed with brine (30 mL), dried over anhydrous Na2S04and concentrated. The residue was purified by column chromatography on silica with DCM / MeOH (10: 1, v / v) as eluent to give (S)-4-(5-amino-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-6-(naphthalen-l- ylcarbamoyl)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-l-carboxylate (424 mg, 68.2%).

[0610] LCMS (ESI, m / z): [M+1] = 635; RT = 1.189 min. +

[0611] Step 2: Synthesis of compound 14-3

[0612]

[0613] ​To a mixture of (S)-benzyl 4-(5-amino-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-(naphthalen-1-ylcarbamoyl)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (140 mg, 0.220 mmol, 1.0 equiv) and AcOH (1.4 mL) was added 1,1,1-triethoxypropane (582.9 mg, 3.312 mmol, 15.0 equiv). The mixture was stirred at 135 ° C in a sealed tube for 2.5 min. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was quenched with aqueous NaHCO 3 solution (saturated, 25 mL) to adjust pH = 7-8 and extracted with DCM (12 mL×3). The combined organic fractions were dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by preparative TLC eluting with DCM / MeOH (10:1, v / v) to give (S)-benzyl 2-(cyanomethyl)-4-(6-ethyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (93 mg, 62.9%).

[0614] LCMS (ESI, m / z): [M+1] + =673; RT=1.271min.

[0615] Step 3: Synthesis of compound 14-4

[0616]

[0617] To a solution of (S)-benzyl 2-(cyanomethyl)-4-(6-ethyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (93 mg, 0.138 mmol, 1.0 equiv) in MeOH (8.0 mL) was added Pd(OH) / C (20% on carbon, wet with approximately 50% water, 9.8 mg, 0.014 mmol, 0.1 equiv) and the mixture was stirred at room temperature under H for 1 h. LCMS showed consumption of the starting material and formation of the desired product. The reaction mixture was filtered, and the filtrate was concentrated to dryness to give 2-((S)-4-(6-ethyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (36 mg, 48.6%), which was used directly in the next step.

[0618] LCMS (ESI, m / z): [M+1] + =539; RT = 0.355min;

[0619] 1. Step 4: Synthesis of Compound 14

[0620]

[0621] To a cooled (0 ° C) solution of 2-((S)-4-(6-ethyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (36 mg, 0.067 mmol, 1.0 equiv) and Et3N (25 mg, 0.20 mmol, 3.0 equiv) in DCM (5 mL) was added dropwise a solution of acryloyl chloride (7.8 mg, 0.86 mmol, 1.3 equiv) in DCM (0.5 mL). After the addition, the mixture was stirred at 0 ° C for 30 min. LCMS showed that the starting material was consumed and the desired product was formed. Water (20 mL) was added and the organic layer was separated. The aqueous layer was extracted with DCM (10 mL×3). The combined organic fractions were dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative HPLC (ACN-H2O + 0.1% HCOOH) to give 2-((S)-1-acryloyl-4-(6-ethyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (HCOOH salt, 6.6 mg, 16.7%, 14.7% HCOOH) (C 33 H 36 N8O3·HCOOH).

[0622] LCMS (ESI, m / z): [M+1] + =593; RT = 1.008min;

[0623] 1H NMR (400MHz, DMSO-d6) δ8.42 (s, 1H), 8.13 (dd, J = 14.0, 8.0Hz, 2H), 7.75-7.47 (m, 5H),6.89(s,1H),6.21(d,J=17.2Hz,1H),5.82-5.71(m,1H),5.62-4.74(m,3H),4. 55-4.11(m,3H),3.03-2.77(m,4H),2.67-2.53(m,2H),2.43-2.32(m,5H),2.17(dd ,J=16.8,8.8Hz,1H),2.04-1.90(m,2H),1.72-1.56(m,3H),1.06(t,J=7.2Hz,3H).

[0624] Example 15

[0625]

[0626] Step 1: Synthesis of compound 15-2

[0627]

[0628] To a mixture of 5-amino-6-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxylic acid (250 mg, 0.491 mmol, 1.0 equiv) and quinolin-5-amine (71 mg, 0.491 mmol, 1.0 equiv) in anhydrous DMF (5.0 mL) was added DIEA (190 mg, 1.473 mmol, 3.0 equiv) followed by HATU (187 mg, 0.491 mmol, 1.0 equiv). The reaction mixture was stirred at 60 °C under Ar for 1 hour. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was cooled to room temperature, diluted with EtOAc (30 mL) and washed with brine (3 x 30 mL), dried over anhydrous NaSO, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with DCM / MeOH (1 / 0-15:1, v / v) to give (S)-benzyl 4-(5-amino-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-(quinolin-5-ylcarbamoyl)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (140 mg, 45%).

[0629] LCMS: Rt: 0.851min; MS m / z(ESI): 636.3[M+H] + .

[0630] Step 2: Synthesis of compound 15-3

[0631]

[0632] To a mixture of (S)-benzyl 4-(5-amino-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-(quinolin-5-ylcarbamoyl)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (130 mg, 0.2046 mmol, 1.0 equiv) and AcOH (0.8 mL) was added 1,1,1-triethoxyethane (506 mg, 3.0694 mmol, 15.0 equiv). The mixture was stirred at 135 ° C in a sealed tube for 2.5 min. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was adjusted to pH = 8-9 with aqueous NaHCO 3 solution and extracted with DCM (3×20 mL). The combined organic layers were dried over anhydrous Na 2 SO 4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC eluting with DCM / MeOH (10:1, v / v) to give (S)-benzyl 2-(cyanomethyl)-4-(6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7-(quinolin-5-yl)-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (110 mg, 82%).

[0633] LCMS: Rt: 0.879min; MS m / z(ESI): 660.3[M+H] + .

[0634] Step 3: Synthesis of compound 15-5

[0635]

[0636] To a mixture of (S)-benzyl 2-(cyanomethyl)-4-(6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7-(quinolin-5-yl)-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (110 mg, 0.167 mmol) in MeOH (5.0 mL) was added Pd(OH) / C (50 mg, 20% wt) and the mixture was stirred at room temperature under H (50 psi) for 2 h. LCMS showed consumption of the starting material and formation of the desired product. The resulting mixture was filtered through celite. The filter cake was washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure to give 2-((S)-4-(6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7-(quinolin-5-yl)-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (84 mg, 95%), which was used directly in the next step without further purification.

[0637] LCMS: Rt: 0.352min; MS m / z(ESI): 526.3[M+H] + .

[0638] Step 4: Synthesis of compound 15

[0639]

[0640] To a mixture of 2-((S)-4-(6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7-(quinolin-5-yl)-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (84 mg, 0.16 mmol, 1.0 equiv) and EtN (48 mg, 0.48 mmol, 3.0 equiv) in DCM (2 mL) was added dropwise a solution of acryloyl chloride (14.4 mg, 0.16 mmol, 1.0 equiv) in DCM (0.2 mL) at -20 °C. After the addition, the mixture was stirred at -20 °C under N for 30 min. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was quenched with water (10 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was separated and purified by basic preparative HPLC to give 2-((S)-1-acryloyl-4-(6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7-(quinolin-5-yl)-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (20 mg, 21%, 15%).

[0641] LCMS: Rt: 0.996min; MS m / z(ESI): 580.2[M+H] + ;

[0642] 1 H NMR(400MHz, DMSO)δ9.02(dd,J=4.1,1.4Hz,1H),8.24(d,J=8.5Hz,1H),8.16-8.04(m,1H),7.97(t,J=8.0H z,1H),7.84-7.75(m,1H),7.63-7.54(m,1H),6.96-6.80(m,1H),6.21(dd,J=16.7,1.8Hz,1H),5.79(d,J=10 .6Hz,1H),5.64-4.70(m,3H),4.58-4.08(m,3H),3.84-3.35(m,2H),3.24-2.88(m,4H),2.61-2.54(m,1H), 2.35(d,J=1.5Hz,3H),2.17(q,J=8.7Hz,1H),2.03(d,J=10.7Hz,3H),1.98-1.85(m,1H),1.76-1.48(m,3H).

[0643] Example 16

[0644]

[0645] Step 1: Synthesis of 16-2-intermediate

[0646]

[0647] To a solution of N-benzyl-5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (2.00 g, 6.50 mmol, 1.0 equiv) in toluene (20 mL) was added phenylmethylamine (2.08 g, 19.5 mmol, 3.0 equiv), cesium carbonate (6.35 g, 19.5 mmol, 3.0 equiv), 1.1'-binaphthyl-2,2'-diphenylphosphine (404 mg, 0.65 mmol, 0.1 equiv) and Pd2(dba)3 (594 mg, 0.65 mmol, 0.1 equiv). The reaction mixture was stirred at 100 ° C overnight. LCMS analysis showed that the starting material was exhausted and the desired product was formed. The solution was concentrated and purified by silica gel column chromatography eluted with EtOAc / petroleum ether (10%, v / v) to give the title compound (1.9 g, 87% yield).

[0648] LCMS (ESI, m / z): [M+1] + =336; RT=2.047min.

[0649] Step 2: Synthesis of 16-2-intermediate

[0650]

[0651] To a solution of N-benzyl-5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (1.9 g) in methanol (20 mL) was added Pd / C (20%, w / w) and stirred at room temperature under a hydrogen atmosphere for 1 hour. LCMS analysis showed consumption of the starting material and formation of the desired product. The reaction mixture was filtered and concentrated to give the title compound (1.2 g, 86% yield), which was used directly in the next step.

[0652] LCMS: [M+1] + =246; RT=1.493min.

[0653] Step 3: Synthesis of compound 16-2

[0654]

[0655] To a solution of 5-amino-6-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxylic acid (400 mg, 0.786 mmol, 1.0 equiv) and 5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (135 mg, 0.550 mmol, 0.7 equiv) in anhydrous DMF (4 mL) was added DIEA (304 mg, 2.358 mmol, 3.0 equiv) followed by HATU (298 mg, 0.0.786 mmol, 1.0 equiv). The reaction mixture was stirred at 60 °C under Ar for 1 hour. LCMS analysis showed consumption of the starting material and formation of the desired product. The reaction mixture was cooled to room temperature, diluted with water (30 mL) and extracted with EtOAc (15 mL × 3). The combined organics were washed with brine (20 ml), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica column chromatography eluted with MeOH / DCM (10%, v / v) to give (2S)-4-(5-amino-6-((5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)carbamoyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (291 mg, 50%).

[0656] LCMS (ESI, m / z): [M+1] +=637; RT=0.915min.

[0657] Step 4: Synthesis of compound 16-3

[0658]

[0659] To a mixture of (2S)-4-(5-amino-6-((5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)carbamoyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (291 mg, 0.396 mmol, 1.0 equiv) and AcOH (1 mL) was added 1,1,1-triethoxyethane (962 mg, 5.940 mmol, 15.0 equiv). The mixture was stirred at 135 ° C in a sealed tube for 4 min. LCMS analysis showed that the starting material was consumed and the desired product was formed. The reaction mixture was quenched with aqueous NaHCO3 (saturated, 40 mL) to adjust pH = 7-8 and extracted with EtOAc (20 mL×3). The combined organics were dried over anhydrous Na2SO4 and concentrated to give (2S)-2-(cyanomethyl)-4-(7-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid benzyl ester (331 mg, 110%) which was used directly in the next step.

[0660] LCMS (ESI, m / z): [M+1] + =761; RT=0.915min.

[0661] Step 5: Synthesis of compound 16-4

[0662]

[0663] To a solution of (2S)-2-(cyanomethyl)-4-(7-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid benzyl ester (331 mg, 0.436 mmol, 1.0 equiv) in DCM (3 mL) was added TFA (1 mL), and the mixture was stirred at room temperature for 2 hours. LCMS analysis showed that the starting material was consumed and the desired product was formed. The reaction mixture was quenched with aqueous NaHCO3 (saturated, 10 mL) to adjust pH = 7-8, which was extracted with DCM (20 mL x 3). The combined organics were dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative TLC eluting with MeOH / DCM (10%, v / v) to give (S)-benzyl 2-(cyanomethyl)-4-(7-(5,6-dimethyl-1H-indazol-4-yl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (127 mg, 43%).

[0664] LCMS (ESI, m / z): [M+1] + =677; RT=0.898min.

[0665] Step 6: Synthesis of compound 16-5

[0666]

[0667] To a solution of (S)-benzyl 2-(cyanomethyl)-4-(7-(5,6-dimethyl-1H-indazol-4-yl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (127 mg, 0.189 mmol, 1.0 equiv) in MeOH (3 mL) was added Pd(OH) / C (10% on carbon, wet with approximately 50% water, 12 mg), and the reaction mixture was stirred at room temperature under H for 2 h. LCMS analysis showed consumption of the starting material and formation of the desired product. The resulting mixture was filtered through celite. The filtrate was concentrated to dryness to give 2-((S)-4-(7-(5,6-dimethyl-1H-indazol-4-yl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (92 mg, 90%).

[0668] LCMS (ESI, m / z): [M+1] + =543; RT=0.332min.

[0669] Step 7: Synthesis of Compound 16

[0670]

[0671] To a cooled (0 ° C) solution of 2-((S)-4-(7-(5,6-dimethyl-1H-indazol-4-yl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (92 mg, 0.170 mmol, 1.0 equiv) and Et3N (51 mg, 0.510 mmol, 3.0 equiv) in DCM (5 mL) was added dropwise a solution of acryloyl chloride (12 mg, 0.136 mmol, 0.8 equiv) in DCM (0.5 mL). After the addition, the mixture was stirred at 0 ° C for 30 min. LCMS analysis showed that the starting material was consumed and the desired product was formed. Water (3 mL) was added and the organic layer was separated. The aqueous layer was extracted with DCM (5 mL×3). The combined organic fractions were dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative HPLC (ACN-H2O + 0.1% NH4HCO3) to give 2-((S)-1-acryloyl-4-(7-(5,6-dimethyl-1H-indazol-4-yl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (5.82 mg, 5.8%, 16 (C 31 H 36 N 10 O3).

[0672] LCMS (ESI, m / z): [M+1] + =597; RT = 1.061min;

[0673] 1H NMR(400MHz, CDCl3)δ8.47(s,1H),7.63(d,J=12.8Hz,1H),7.37(s,1H),6.61(s,1H),6.4 0(d,J=16.6Hz,1H),5.85-5.80(m,1H),5.09(s,2H),4.87-4.57(m,3H),4.06-3.83(m,1H) ,3.66-3.34(m,4H),2.85-2.71(m,5H),2.42(s,3H),2.26-2.18(m,1H),2.11(s,3H),2.0 8(s,3H),2.02-1.93(m,2H),1.77-1.61(m,1H),1.47-1.23(m,1H),0.91(t,J=7.3Hz,1H).

[0674] Example 17

[0675]

[0676] Step 1: Synthesis of compound 17-1

[0677]

[0678] To a solution of 5-amino-6-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxylic acid (500 mg, 0.982 mmol, 1.0 equiv) and naphthalene-1-amine (98.3 mg, 0.688 mmol, 0.7 equiv) in anhydrous DMF (10.0 mL) was added DIEA (0.49 mL, 2.58 mmol, 3.0 equiv) followed by HATU (373 mg, 0.982 mmol, 1.0 equiv). The reaction mixture was stirred at 60 ° C under Ar for 1 hour. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was cooled to room temperature, diluted with water (40 mL) and extracted with EtOAc (20 mL×3). The combined organic fractions were washed with brine (30 mL), dried over anhydrous NaSO, and concentrated. The residue was purified by silica column chromatography eluting with DCM / MeOH (10:1, v / v) to give (S)-benzyl 4-(5-amino-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-(naphthalen-1-ylcarbamoyl)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (424 mg, 68.2%).

[0679] LCMS (ESI, m / z): [M+1] + =635; RT=1.189min.

[0680] 2. Step 2: Synthesis of Compound 17-3

[0681]

[0682] To a mixture of (S)-benzyl 4-(5-amino-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-(naphthalen-1-ylcarbamoyl)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (200 mg, 0.315 mmol, 1.0 equiv) and AcOH (2.0 mL) was added (triethoxymethyl)benzene (1.0 g, 4.725 mmol, 15.0 equiv). The mixture was stirred at 135 ° C in a sealed tube for 2.5 min. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was quenched with aqueous NaHCO 3 solution (saturated, 50 mL) to adjust pH = 7-8 and extracted with DCM (30 mL×3). The combined organic fractions were dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by preparative TLC eluting with DCM / MeOH (10:1, v / v) to give (S)-benzyl 2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-8-oxo-6-phenyl-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (85 mg, 37.5%).

[0683] LCMS (ESI, m / z): [M+1] + =721; RT=1.265min.

[0684] Step 3: Synthesis of compound 17-4

[0685]

[0686] To a solution of (S)-benzyl 2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-8-oxo-6-phenyl-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (85 mg, 0.118 mmol, 1.0 equiv) in MeOH (5.0 mL) was added Pd(OH) / C (20% on carbon, wet with approximately 50% water, 8.46 mg, 0.012 mmol, 0.1 equiv) and the mixture was stirred at room temperature under H for 1 h. LCMS showed consumption of the starting material and formation of the desired product. The reaction mixture was filtered, and the filtrate was concentrated to dryness to give 2-((S)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-8-oxo-6-phenyl-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (69 mg, 99%), which was used directly in the next step.

[0687] LCMS (ESI, m / z): [M+1] + =587; RT = 0.763min;

[0688] Step 4: Synthesis of compound 17

[0689]

[0690] To a cooled (0 ° C) solution of 2-((S)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-8-oxo-6-phenyl-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (69 mg, 0.118 mmol, 1.0 equiv) and Et3N (45.6 mg, 0.354 mmol, 3.0 equiv) in DCM (5 mL) was added dropwise a solution of acryloyl chloride (10.6 mg, 0.118 mmol, 1 equiv) in DCM (5.0 mL). After the addition, the mixture was stirred at 0 ° C for 30 min. LCMS showed that the starting material was consumed and the desired product was formed. Water (20 mL) was added and the organic layer was separated. The aqueous layer was extracted with DCM (10 mL×3). The combined organic fractions were dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative HPLC (ACN-H2O + 0.1% HCOOH) to give 2-((S)-1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-8-oxo-6-phenyl-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (HCOOH salt, 2.37 mg, 3.2%, 17.7% HCOOH) (C37 H 36 N8O3·HCOOH).

[0691] LCMS (ESI, m / z): [M+1] + =641; RT = 1.061min;

[0692] 1 H NMR(400MHz,DMSO-d6)δ8.32(s,1H),8.02-7.87(m,2H),7.79-7.70(m,1H),7.61-7.4(m,3H),7.34-7.21 (m,2H),7.19-6.99(m,3H),6.96-6.78(m,2H),6.19(d,J=16.4Hz,1H),5.76(d,J=12.0Hz,1H),5.15-4.84 (m,3H),4.40-4.33(m,1H),4.19(dd,J=16.4,9.0Hz,1H),3.22-3.09(m,4H),2.95(dd,J=9.2,3.6Hz,2H) ,2.61(d,J=6.0Hz,2H),2.37(s,3H),2.19(dd,J=16.8,8.4Hz,1H),1.99-1.92(m,1H),1.74-1.58(m,3H).

[0693] Example 18

[0694]

[0695] Step 1: Synthesis of compound 18-2

[0696]

[0697] To a mixture of (S)-benzyl 4-(5-amino-2-((1-methylpyrrolidin-2-yl)methoxy)-6-(naphthalen-1-ylcarbamoyl)pyrimidin-4-yl)piperazine-1-carboxylate (65.6 mg, 0.11 mmol, 1.0 equiv) and AcOH (0.4 mL) was added (triethoxymethyl)benzene (371 mg, 1.65 mmol, 15.0 equiv). The mixture was stirred at 135 ° C in a sealed tube for 2.5 min. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was quenched with aqueous NaHCO 3 solution (saturated, 25 mL) to adjust the pH = 7-8 and extracted with DCM (15 mL×3). The combined organic fractions were dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by preparative TLC eluting with DCM / MeOH (10:1, v / v) to give (S)-benzyl 4-(2-((1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-8-oxo-6-phenyl-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (27.3 mg, 36.4%).

[0698] LCMS (ESI, m / z): [M+1] + =682; RT=1.277min.

[0699] Step 2: Synthesis of compound 18-3

[0700]

[0701] To a solution of (S)-benzyl 4-(2-((1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-8-oxo-6-phenyl-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (65 mg, 0.095 mmol, 1.0 equiv) in DCM (4.0 mL) was added EtN (65 mg, 0.095 mmol, 10.0 equiv) and EtSiH (110.5 mg, 0.095 mmol, 1.0 equiv) followed by PdCl (16. mg, 0.951 mmol, 10.0 equiv). The reaction mixture was stirred at room temperature for 1 hour. LCMS showed consumption of the starting material and formation of the desired product. The reaction mixture was concentrated to dryness to give (S)-6-((1-methylpyrrolidin-2-yl)methoxy)-3-(naphthalen-1-yl)-2-phenyl-8-(piperazin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one (51 mg, 99%), which was used directly in the next step.

[0702] LCMS (ESI, m / z): [M+1] +=548; RT=0.868min.

[0703] Step 3: Synthesis of compound 18

[0704]

[0705] To a cooled (0 ° C) solution of (S)-6-((1-methylpyrrolidin-2-yl)methoxy)-3-(naphthalen-1-yl)-2-phenyl-8-(piperazin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one (52.2 mg, 0.095 mmol, 1.0 equiv) and Et3N (19.3 mg, 0.285 mmol, 0.7 equiv) in DCM (3 mL) was added a solution of acryloyl chloride (6.02 mg, 0.095 mmol, 1.0 equiv) in DCM (0.5 mL) dropwise. After the addition, the mixture was stirred at 0 ° C for 30 min. LCMS showed that the starting material was consumed and the desired product was formed. Water (15 mL) was added and the organic layer was separated. The aqueous layer was extracted with DCM (8 mL×3). The combined organic fractions were dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative HPLC (ACN-H2O + 0.1% HCOOH) to give (S)-8-(4-acryloylpiperazin-1-yl)-6-((1-methylpyrrolidin-2-yl)methoxy)-3-(naphthalen-1-yl)-2-phenylpyrimido[5,4-d]pyrimidin-4(3H)-one (HCOOH salt, 3.0 mg, 5.2%, 18·HCOOH) (C 35 H 35 N7O3·HCOOH).

[0706] LCMS (ESI, m / z): [M+1] + =602; RT = 1.055min;

[0707] 1H NMR (400MHz, DMSO-d6) δ8.32(s,1H),8.06-7.86(m,2H),7.77(dd,J=6.4,3.6Hz,1H),7.55(dd,J=6.4,2.6Hz,3H),7. 46(t,J=7.6Hz,1H),7.31-7.19(m,2H),7.14(t,J=7.6Hz,1H),7.05(t,J=7.6Hz,2H),6.85(dd,J=16.4,10.4Hz,1H), 6.15(dd,J=16.6,2.4Hz,1H),5.71(dd,J=10.4,2.4Hz,1H),4.59-4.01(m,6H),3.75(d,J=22.8Hz,5H),3.01-2.92(m ,1H),2.64-2.55(m,1H),2.35(d,J=15.6Hz,3H),2.29-2.10(m,1H),1.96(dd,J=11.6,7.6Hz,1H),1.80-1.54(m,3H).

[0708] Example 19

[0709]

[0710] Step 1: Synthesis of compound 19-3

[0711]

[0712] To a mixture of 5-amino-6-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxylic acid (200 mg, 0.393 mmol, 1.0 equiv) and 8-chloronaphthalen-1-amine (49 mg, 0.275 mmol, 1.0 equiv) in anhydrous DMF (5.0 mL) was added DIEA (152 mg, 1.179 mmol, 3.0 equiv) followed by HATU (149 mg, 0.393 mmol, 1.0 equiv). The reaction mixture was stirred at 60 °C under Ar for 1 hour. LCMS showed consumption of the starting material and formation of the desired product. The reaction mixture was cooled to room temperature, diluted with EtOAc (30 mL) and washed with brine (3 x 30 mL), dried over anhydrous NaSO, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with DCM / MeOH (1 / 0-10:1, v / v) to give (S)-benzyl 4-(5-amino-6-((8-chloronaphthalen-1-yl)carbamoyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (200 mg, 51%).

[0713] LCMS: Rt: 0.955min; MS m / z(ESI): 669.3[M+H] + .

[0714] Step 2: Synthesis of compound 19-4

[0715]

[0716] To a mixture of (S)-benzyl 4-(5-amino-6-((8-chloronaphthalen-1-yl)carbamoyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (80 mg, 0.120 mmol, 1.0 equiv) in DCM (2 mL) was added DIEA (46 mg, 0.360 mmol) followed by triphosgene (35 mg, 0.120 mmol) at 0°C. The mixture was stirred at 0°C under N2 for 1 hour. TLC (DCM / MeOH=10 / 1) showed that the starting material was consumed. The reaction mixture was quenched with water (15 mL) and extracted with DCM (3×15 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC eluting with DCM / MeOH (10:1, v / v) to give (S)-benzyl 4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,8-dioxo-5,6,7,8-tetrahydropyrimido[5,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (58 mg, 70%).

[0717] LCMS: Rt: 0.875min; MS m / z(ESI): 695.2[M+H] + .

[0718] Step 3: Synthesis of compound 19-5

[0719]

[0720] To a mixture of (S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)-6,8-dioxo-5,6,7,8-tetrahydropyrimido[5,4- d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (58 mg, 0.0836 mmol, 1 equiv) in CH3CN (2.0 mL) was added TMSI (134 mg, 0.6686 mmol, 8 equiv) and the mixture was stirred at 35 °C under N2for 1 h. TLC (DCM / MeOH = 10 / 1) showed the starting material was consumed. To the resulting mixture was added Et3N (135 mg, 1.3376 mmol, 16 equiv) and stirred at rt for 15 min. The mixture was concentrated under reduced pressure. The residue was diluted with H2O (15 mL) and extracted with DCM / MeOH (10 / 1, 3 x 15 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC eluting with DCM / MeOH (8:1, v / v) to give 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)-6,8-dioxo-5,6,7,8-tetrahydropyrimido[5,4- d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (46 mg, 100%).

[0721] LCMS: Rt: 0.379 min; MS m / z (ESI): 561.0 [M+H] + .

[0722] Step 4: Synthesis of compound 19

[0723]

[0724] To a mixture of 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,8-dioxo-5,6,7,8-tetrahydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (46 mg, 0.0821 mmol, 1.0 equiv) and EtN (25 mg, 0.2463 mmol, 3.0 equiv) in DCM (2 mL) and CHCN (2 mL) was added dropwise a solution of acryloyl chloride (7.4 mg, 0.0821 mmol, 1.0 equiv) in DCM (0.2 mL) at -20 °C. After the addition, the mixture was stirred at -20 °C under N for 30 min. LCMS showed consumption of the starting material and formation of the desired product. The mixture was quenched with water (10 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was separated and purified by HCOOH preparative HPLC to give 2-((S)-1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,8-dioxo-5,6,7,8-tetrahydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (HCOOH salt, 8 mg, 16%, 19.HCOOH).

[0725] LCMS: Rt: 0.737min; MS m / z(ESI): 615.3[M+H] + ;

[0726] 1 H NMR(400MHz,DMSO)δ8.27(s,1.42H,HCOOH),8.10-7.97(m,2H),7.70-7.62(m,1H),7.58-7.54(m ,1H),7.52-7.45(m,1H),7.41-7.30(m,1H),7.00-6.80(m,1H),6.20(d,J=16.5Hz,1H),5.77(d, J=10.4Hz,1H),5.42-4.60(m,1H),4.50-3.91(m,4H),3.71-3.60(m,1H),3.08-2.86(m,4H),2.8 2-2.61(m,2H),2.43(d,J=11.8Hz,3H),2.35-2.25(s,1H),2.04-1.87(m,1H),1.81-1.49(m,3H).

[0727] Example 20

[0728]

[0729] 3. Step 1: Synthesis of Compound 20-2

[0730]

[0731] To a solution of 4-bromo-5-methyl-1H-indazole (14.0 g, 66.67 mmol, 1.0 equiv) in anhydrous DCM (30 mL) was added PPTS (1.68 g, 6.68 mmol, 0.1 equiv) at room temperature. DHP (16.83 g, 200.02 mmol, 3 equiv) was subsequently added in one portion. The reaction mixture was stirred at 30 ° C overnight. LCMS analysis showed that the starting material was exhausted and the desired product was detected. The reactant was quenched with H2O (50 mL) and the layers were separated. The aqueous layer was extracted with DCM (30 mL × 3). The combined organics were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography on silica eluting with EtOAc / petroleum ether (15%, v / v) to give 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (10.8 g, 55%).

[0732] LCMS (ESI, m / z): [M+1] + =295; RT=2.158min.

[0733] Step 2: Synthesis of compound 20-3

[0734]

[0735] To a cooled (-78 ° C) solution of 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (5.0 g, 17.00 mmol, 1.0 equiv) in anhydrous THF (30 mL) was added B(O-iPr) (6.4 g, 34.00 mmol, 2.0 equiv). n-BuLi (2.5 mol / L in THF, 13.0 mL, 31.46 mmol, 1.85 equiv) was then added dropwise to the above solution over a period of 30 min, maintaining the reaction temperature between -70 ° C and -65 ° C. After addition, the reaction was stirred at -78 ° C for 3 hours. LCMS analysis showed that the starting material was consumed and the desired product was formed. The reaction mixture was quenched with saturated aqueous NH4Cl (20 mL) and diluted with MTBE (30 mL). The layers were separated and the aqueous layer was extracted with MTBE (30 mL×3). The combined organics were washed with brine (50 mL), dried over anhydrous Na SO and concentrated. The residue was dissolved in MTBE (10 mL). Petroleum ether was added dropwise to the solution at 0° C. A white solid precipitated during the addition of petroleum ether. The resulting suspension was filtered and the filter cake was washed with petroleum ether (30 mL). The filter cake was dried under vacuum to give (5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-yl)boronic acid (4.2 g, 95%).

[0736] LCMS (ESI, m / z): [M+1] + =261; RT=1.242min.

[0737] Step 3: Synthesis of compound 20-4

[0738]

[0739] To a solution of (5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)boronic acid (3.0 g, 11.54 mmol, 1.0 equiv) and cyclohept-2-en-1-one (3.8 g, 34.62 mmol, 3.0 equiv) in H O (20 mL) was added NaHCO (1.94 g, 23.08 mmol, 2.0 equiv) and [RhCl(COD)] (0.28 g, 0.58 mmol, 0.05 equiv). The mixture was stirred at 80 ° C under Ar overnight. LCMS analysis showed that the starting material was exhausted and the desired product was formed. The reaction mixture was diluted with EtOAc (30 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (30 mL×3). The combined organics were washed with brine (30 mL), dried over anhydrous Na SO and concentrated. The residue was purified by column chromatography on silica eluting with EtOAc / petroleum ether (20%, v / v) to give 3-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)cycloheptan-1-one (1.3 g, 35%).

[0740] LCMS (ESI, m / z): [M+1] + =327; RT=1.662min.

[0741] Step 4: Synthesis of compound 20-5

[0742]

[0743] To a solution of 3-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)cycloheptan-1-one (763 mg, 2.34 mmol, 1.0 equiv) and dimethyl carbonate (4.0 mL, 46.81 mmol, 20.0 equiv) in THF (5.0 mL) was added NaH (60% dispersion in mineral oil, 140 mg, 5.85 mmol, 2.5 equiv) and the mixture was stirred at 70 ° C for 2 hours. LCMS analysis showed that the starting material was consumed and the desired product was formed. The reaction mixture was quenched with H2O (10.0 mL) and extracted with EtOAc (20 mL×3). The combined organics were washed with brine (20 ml), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica column chromatography eluting with EtOAc / petroleum ether (20%, v / v) to give methyl 4-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-oxocycloheptane-1-carboxylate (684 mg, 76%).

[0744] LCMS (ESI, m / z): [M+1] +=385; RT = 1.918min and 2.315min

[0745] Step 5: Synthesis of Compound 20-6

[0746]

[0747] To a solution of methyl 4-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-oxocycloheptane-1-carboxylate (684 mg, 1.78 mmol, 1.0 equiv) and methyl carbamimidothioate (1238 mg, 8.90 mmol, 5.0 equiv) in anhydrous MeOH (4.0 mL) was added NaOMe (962 mg, 17.8 mmol, 10.0 equiv). The reaction mixture was stirred at 80 ° C under Ar overnight. LCMS analysis showed that the starting material was exhausted and the desired product was formed. The reaction mixture was cooled to room temperature, diluted with water (30 mL) and extracted with EtOAc (15 mL×3). The combined organics were washed with brine (20 ml), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica column chromatography eluting with EtOAc / petroleum ether (60%, v / v) to give 8-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-(methylthio)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-4-ol (40 mg, 5%).

[0748] LCMS (ESI, m / z): [M+1] + =425; RT=1.557min.

[0749] Step 6: Synthesis of Compound 20-7

[0750]

[0751] To a cooled (0 ° C) solution of 8- (5-methyl -1- (tetrahydro -2H- pyran -2-yl) -1H- indazol -4-yl) -2- (methylthio) -6,7,8,9-tetrahydro -5H- cyclohepta [d] pyrimidin-4-ol (40 mg, 0.094 mmol, 1.0 equiv) and DIEA (37 mg, 0.282 mmol, 3.0 equiv) in anhydrous DCM (3 mL) was added dropwise a solution of Tf2O (32 mg, 0.113 mmol, 1.2 equiv) in anhydrous DCM (1 mL). The mixture was stirred at 0 ° C for 1 hour. LCMS analysis showed that the starting material was exhausted and the desired product was formed. The reaction mixture was quenched with H2O (2 mL) and extracted with DCM (5 mL × 3). The combined organics were dried over anhydrous Na2SO4 and concentrated to give 8-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-(methylthio)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-4-yl trifluoromethanesulfonate (50 mg, 96%), which was used directly in the next step.

[0752] LCMS (ESI, m / z): [M+1] + =557; RT=1.988min.

[0753] Step 7: Synthesis of Compound 20-8

[0754]

[0755] To a stirred mixture of 8-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-(methylthio)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-4-yl trifluoromethanesulfonate (50 mg, 0.090 mmol, 1.0 equiv) and tert-butyl piperazine-1-carboxylate (33 mg, 0.180 mmol, 2.0 equiv) in anhydrous DMF (3 mL) was added DIEA (34 mg, 0.270 mmol, 3.0 equiv). The mixture was stirred at 100 ° C for 2 h. LCMS analysis showed that the starting material was exhausted and the desired product was formed. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL×3). The combined organics were washed with brine (5 ml), dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative TLC eluting with EtOAc / petroleum ether (60%, v / v) to give tert-butyl 4-(8-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-(methylthio)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-4-yl)piperazine-1-carboxylate (48 mg, 91%).

[0756] LCMS (ESI, m / z): [M+1] 406.0 + = 593; RT = 1.580 min;

[0757] Step 8: Synthesis of compound 20-9

[0758]

[0759] To a cooled (0 °C) solution of tert-butyl 4-(8-(5-methyl-l-(tetrahydro-2H-pyran-2- yl)-lH-indazol-4-yl)-2-(methylthio)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-4- yl)piperazine-l-carboxylate (48 mg, 0.082 mmol, 1.0 equiv) in dry DCM (3 mL) was added m-CPBA (33.47 mg, 0.165 mmol, 2.0 equiv). The mixture was stirred at 0 °C for 2 h. LCMS analysis showed the starting material was consumed and the desired product was formed. The reaction mixture was quenched with H2O (2 mL) and extracted with DCM (5 mL x 3). The combined organics were dried over anhydrous Na2SO4and concentrated to give tert-butyl 4-(8-(5-methyl-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-4-yl)-2- (methylsulfonyl)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-4-yl)piperazine-l- carboxylate (77 mg, 150%) which was used directly in the next step.

[0760] LCMS (ESI, m / z): [M+1] 406.0 + = 593; RT = 1.580 min;

[0761] Step 9: Synthesis of compound 20-10

[0762]

[0763] To a cooled (0 ° C) solution of ((S)-1-methylpyrrolidin-2-yl)methanol (28 mg, 0.248 mmol, 2.0 equiv) in anhydrous THF (5 mL) was added NaH (60% dispersion in mineral oil, 24 mg, 0.620 mmol, 5.0 equiv). The mixture was stirred at 0 ° C for 30 min. Then, tert-butyl 4-(8-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-(methylsulfonyl)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-4-yl)piperazine-1-carboxylate (77 mg, 0.124 mmol, 1.0 equiv) was added and the mixture was stirred at 0 ° C for 1 hour. LCMS analysis showed that the starting material was consumed and the desired product was formed. The reaction mixture was quenched with H2O (2 mL) and extracted with DCM (5 mL×3). The combined organics were dried over anhydrous Na2SO4 and concentrated to give tert-butyl 4-(8-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-4-yl)piperazine-1-carboxylate (70 mg, 85%) which was used directly in the next step.

[0764] LCMS (ESI, m / z): [M+1] + =660; RT=0.962min.

[0765] Step 10: Synthesis of Compound 20-11

[0766]

[0767] To a solution of tert-butyl 4-(8-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-4-yl)piperazine-1-carboxylate (70 mg, 0.106 mmol, 1.0 equiv) in DCM (3 mL) was added TFA (3 mL) and the mixture was stirred at room temperature for 1 hour. LCMS analysis showed consumption of the starting material and formation of the desired product. The reaction mixture was concentrated to dryness to give 8-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidine (75 mg, 150%) which was used directly in the next step.

[0768] LCMS (ESI, m / z): [M+1] + =476; RT=0.588min.

[0769] Step 11: Synthesis of Compound 20

[0770]

[0771] To a cooled (0 ° C) solution of 8-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidine (75 mg, 0.158 mmol, 1.0 equiv) and Et3N (48 mg, 0.474 mmol, 3.0 equiv) in DCM (3 mL) was added dropwise a solution of acryloyl chloride (14.29 mg, 0.158 mmol, 1.0 equiv) in DCM (1 mL). After the addition, the mixture was stirred at 0 ° C for 30 min. LCMS analysis showed that the starting material was consumed and the desired product was formed. Water (5 ml) was added and the organic layer was separated. The aqueous layer was extracted with DCM (5 mL×3). The combined organics were dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative HPLC (ACN-H2O + 0.1% NH4HCO3) to give 1-(4-(8-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one (2.42 mg, 2.9%, 20%) (C 30 H 39 N7O2).

[0772] LCMS (ESI, m / z): [M+1] + =530; RT = 1.493min;

[0773] 1 H NMR (400MHz, CDCl3) δ8.20(s,1H),7.25(s,1H),7.22-7.07(m,1H),6.70-6.52(m,1H),6.43-6.25(m,1H),5.84-5.66(m,1H),4.96 (s,1H),4.51(s,1H),3.97-3.67(m,4H),3.60-3.19(m,5H),3.16-2.59(m,6H),2.48-1.96(m,8H),1.65(s,3H),1.59-1.05(m,5H).

[0774] Example 21

[0775]

[0776] 4. Step 1: Synthesis of Compound 21-1

[0777]

[0778] To a solution of ethyl 1-benzyl-3-oxopiperidine-4-carboxylate (2.00 g, 7.66 mmol, 1.0 equiv) in anhydrous MeOH (25 mL) was added methyl carbamimidothioate (0.7 g, 7.66 mmol, 1.0 equiv) and NaOMe (2.1 g, 38.31 mmol, 5.0 equiv). After addition, the reaction mixture was stirred at room temperature for 16 hours. TLC showed that the starting material was exhausted and the desired product was detected. The reactants were concentrated and dissolved in water (100 mL) and filtered. The filter cake was concentrated to give 7-benzyl-2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol (1.2 g, 54%).

[0779] LCMS (ESI, m / z): [M+1] + =288; RT=0.798min.

[0780] Step 2: Synthesis of compound 21-2

[0781]

[0782] To a stirred mixture of 7-benzyl-2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol (1.0 g, 3.48 mmol, 1.0 equiv) and DIEA (0.6 mL, 3.48 mmol, 1.0 equiv) in anhydrous DCE (10 mL) was added POCl (5 mL, 28 mmol, 8.0 equiv). The mixture was stirred at 90 ° C for 3 h. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (30 mL×3). The combined organic fractions were washed with brine (50 mL), dried over anhydrous NaSO and concentrated to give 7-benzyl-4-chloro-2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (0.8 g, 75%).

[0783] LCMS (ESI, m / z): [M+1] + =306; RT=2.023min.

[0784] Step 3: Synthesis of compound 21-3

[0785]

[0786] To a stirred mixture of 7-benzyl-4-chloro-2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (500 mg, 1.64 mmol, 1.0 equiv) and DIEA (634 mg, 4.92 mmol, 3.0 equiv) in anhydrous DMF (10 mL) was added tert-butyl methyl(pyrrolidin-3-yl)carbamate (328 mg, 1.64 mmol, 1.0 equiv). The mixture was stirred at 100 ° C for 1 hour. LCMS showed that the starting material was exhausted and the desired product was formed. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (30 mL×3). The combined organic portions were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica column chromatography eluting with PE / EA (1:1, v / v) to give tert-butyl (1-(7-benzyl-2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate (520 mg, 68%).

[0787] LCMS (ESI, m / z): [M+1] + =470; RT=2.064min.

[0788] Step 4: Synthesis of compound 21-4

[0789]

[0790] To a solution of tert-butyl (1-(7-benzyl-2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate (500 mg, 1.1 mmol, 1.0 equiv) in anhydrous DCE (16 mL) was added 1-chloroethyl chloroformate (305 mg, 2.1 mmol, 2.0 equiv) and the mixture was stirred at room temperature under Ar for 15 hours. LCMS showed that most of the starting material was consumed and the desired product was formed. The reaction mixture was concentrated and purified by silica column chromatography eluting with DCM / MeOH (10: 1, v / v) to give tert-butyl methyl (1-(2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)pyrrolidin-3-yl)carbamate (180 mg, 45%).

[0791] LCMS (ESI, m / z): [M+1] + =380; RT=0.668min.

[0792] Step 5: Synthesis of compound 21-5

[0793]

[0794] To a solution of tert-butyl methyl (1-(2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)pyrrolidin-3-yl)carbamate (100 mg, 0.26 mmol, 1.0 equiv) and 1-bromo-8-chloronaphthalene (190 mg, 0.79 mmol, 3.0 equiv) in toluene (10 mL) was added CS2CO3 (258 mg, 0.26 mmol, 3.0 equiv), Ruphos (24 mg, 0.05 mmol, 0.2 equiv) and Pd2(dba)3 (36 mg, 0.04 mmol, 0.15 equiv) and the mixture was stirred at 110 ° C under Ar for 16 hours. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (30 mL×3). The combined organic portions were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica column chromatography eluting with PE / EA (3:1, v / v) to give tert-butyl (1-(7-(8-chloronaphthalen-1-yl)-2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate (48 mg, 33%).

[0795] LCMS (ESI, m / z): [M+1] + =540; RT=2.100min.

[0796] Step 6: Synthesis of compound 21-6

[0797]

[0798] To a solution of tert-butyl (1-(7-(8-chloronaphthalen-1-yl)-2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate (45 mg, 0.08 mmol, 1.0 equiv) in CHCl (4.0 mL) was added m-CPBA (16 mg, 0.09 mmol, 1.1 equiv). The reaction mixture was stirred at room temperature under Ar for 0.5 h. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was cooled to room temperature, diluted with water (30 mL) and extracted with DCM (15 mL×3). The combined organic portions were washed with brine (20 ml), dried over anhydrous NaSO and concentrated. The residue was purified by silica column chromatography eluting with DCM / MeOH (15:1, v / v) to give tert-butyl (1-(7-(8-chloronaphthalen-1-yl)-2-(methylsulfinyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate (23 mg, 50%).

[0799] LCMS (ESI, m / z): [M+1] + =556; RT=1.913min.

[0800] Step 7: Synthesis of compound 21-7

[0801]

[0802] To a mixture of tert-butyl (1-(7-(8-chloronaphthalen-1-yl)-2-(methylsulfinyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate (20 mg, 0.03 mmol, 1.0 equiv) in THF (5.0 mL) was added (S)-(1-methylpyrrolidin-2-yl)methanol (8.3 mg, 0.06 mmol, 2.0 equiv) and t-BuOK (4.4 mg, 0.04 mmol, 1.1 equiv). The mixture was stirred at room temperature for 30 minutes. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was diluted with water (30 mL) and extracted with DCM (15 mL×3). The combined organic portions were washed with brine (20 ml). The combined organic portions were dried over anhydrous NaSO and concentrated. The residue was purified by preparative TLC eluting with DCM / MeOH (10:1, v / v) to give tert-butyl (1-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate (16 mg, 72%).

[0803] Step 8: Synthesis of compound 21-8

[0804]

[0805] To a solution of tert-butyl (1-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate (16 mg, 0.02 mmol) in DCM (1.0 mL) was added TFA (1.0 mL), and the mixture was stirred at room temperature for 1 hour. LCMS showed consumption of the starting material and formation of the desired product. The reaction mixture was concentrated to dryness to give 1-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-N-methylpyrrolidin-3-amine (TFA salt, 12 mg, 90%), which was used directly in the next step.

[0806] Step 9: Synthesis of Compound 21

[0807]

[0808] To a cooled (0 ° C) solution of 1-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-N-methylpyrrolidin-3-amine (TFA salt, 12 mg, 0.02 mmol) and Et3N (12 mg, 0.12 mmol, 5.0 equiv) in DCM (2.5 mL) was added dropwise a solution of acryloyl chloride (2.6 mg, 0.028 mmol, 1.2 equiv) in DCM (0.5 mL). After the addition, the mixture was stirred at 0 ° C for 30 min. LCMS showed that the starting material was consumed and the desired product was formed. Water (15 mL) was added and the organic layer was separated. The aqueous layer was extracted with DCM (8 mL×3). The combined organic fractions were dried over anhydrous Na2SO4. The reaction was concentrated and purified by preparative HPLC (ACN-H2O + 0.1% HCOOH) to give N-(1-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)pyrrolidin-3-yl)-N-methylacrylamide (HCOOH salt, 2.02 mg, 12%, 21·HCOOH) (C 31 H 37 ClN6O2·HCOOH).

[0809] LCMS (ESI, m / z): [M+1] 299.0 + = 561 ; RT = 0.991 min;

[0810] 1 H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 3H), 7.92 (d, J = 8.0 Hz, 1H), 7.73 (t, J = 8.5 Hz, 1H), 7.60-7.50 (m, 2H), 7.47-7.41 (m, 1H), 7.36-7.29 (m, 1H), 6.77 (s, 1H), 6.15 (d, J = 17.3 Hz, 1H), 5.73 (d, J = 23.2 Hz, 1H), 5.07 (s, 1H), 4.75 (s, 1H), 4.27-4.18 (m, 1H), 4.08 (d, J = 17.4 Hz, 1H), 4.02-3.92 (m, 2H), 3.74 (s, 1H), 3.61 (s, 1H), 3.04-2.84 (m, 7H), 2.32 (d, J = 3.7 Hz, 6H), 2.22-1.98 (m, 4H), 1.92 (d, J = 8.0 Hz, 1H), 1.62 (m, 3H).

[0811] Example 22

[0812]

[0813] Step 1: Synthesis of compound 22-2

[0814]

[0815] To a solution of 4-bromo-5-methyl-lH-indazole (14.0 g, 66.67 mmol, 1.0 eq) in anhydrous DCM (30 mL) was added PPTS (1.68 g, 6.68 mmol, 0.1 eq) at room temperature. Then DHP (16.83 g, 200.02 mmol, 3 eq) was added in one portion. The reaction mixture was stirred at 30 °C for 16 h. LCMS analysis showed the starting material was consumed and the desired product was detected. The reaction was quenched with H2O (50 mL) and the layers were separated. The aqueous layer was extracted with DCM (30 mL x 3). The combined organics were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel eluting with petroleum ether / EtOAc (15%, v / v) to give 4-bromo-5-methyl-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole (10.8 g, 55%).

[0816] LCMS: Rt: 2.158 min; MS m / z (ESI): 297.1 [M+3] +.

[0817] Step 2: Synthesis of compound 22-3

[0818]

[0819] To a mixture of 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (2 g, 6.80 mmol, 1.0 equiv) in anhydrous dioxane (50 mL) was added BnNH (2.18 g, 20.4 mmol, 3 equiv), BINAP (423 mg, 0.68 mmol) and CsCO (6.63 g, 20.4 mmol), followed by Pd(dba) (622 mg, 0.68 mmol). The reaction mixture was stirred at 110 ° C under N for 16 h. LCMS analysis showed that the starting material was consumed and the desired product was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (5 / 1-2 / 1, v / v) to give N-benzyl-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (1.9 g, 87%).

[0820] LCMS: Rt: 1.813min; MS m / z(ESI): 322.1[M+H] + .

[0821] Step 3: Synthesis of compound 22-4

[0822]

[0823] To a mixture of N-benzyl-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-amine (1.95 g, 6.07 mmol, 1.0 equivalent) in anhydrous MeOH (20 mL) was added Pd / C (600 mg, 10% wt). The reaction mixture was stirred at 30 ° C under H2 (30 psi) for 16 h. LCMS analysis showed that the starting material was exhausted and the desired product was detected. The mixture was filtered and the filter cake was washed with MeOH (100 mL). The filtrate was concentrated under reduced pressure to give 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-amine (1.28 g, 91%), which was used in the next step without further purification.

[0824] LCMS: Rt: 1.249min; MS m / z(ESI): 232.1[M+H] + .

[0825] Step 4: Synthesis of compound 22-6

[0826]

[0827] To a mixture of (S)-5-amino-6-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxylic acid (160 mg, 0.34 mmol, 1.0 equiv) and 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (79 mg, 0.34 mmol, 1 equiv) in anhydrous DMF (3.0 mL) was added DIEA (155 mg, 1.02 mmol, 3.0 equiv) followed by HATU (155 mg, 0.408 mmol, 1.2 equiv). The reaction mixture was stirred at 60 ° C under N for 1 hour. LCMS showed the reaction was complete. The reaction mixture was cooled to room temperature, diluted with EtOAc (80 mL) and washed with brine (3×80 mL), dried over anhydrous Na 2 SO 4, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with DCM / MeOH (1 / 0-10:1, v / v) to give benzyl 4-(5-amino-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-((1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)carbamoyl)pyrimidin-4-yl)piperazine-1-carboxylate (100 mg, 26%).

[0828] LCMS: Rt: 0.946min; MS m / z(ESI): 684.4[M+H] + .

[0829] Step 5: Synthesis of Compound 22-8

[0830]

[0831] To a mixture of benzyl 4-(5-amino-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-((1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)carbamoyl)pyrimidin-4-yl)piperazine-1-carboxylate (45 mg, 0.0659 mmol, 1.0 equiv) in AcOH (0.5 mL) was added 1,1,1-triethoxyethane (160 mg, 0.988 mmol). The mixture was stirred at 135 ° C in a sealed tube for 8 min. LCMS showed that the reactant was observed. The reaction mixture was quenched with aqueous NaHCO solution (20 mL) to adjust to pH = 8-9 and extracted with DCM (3×20 mL). The combined organic layers were dried over anhydrous NaSO, filtered and concentrated under reduced pressure to give crude material benzyl 4-(6-methyl-7-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (60 mg, >100%), which was used in the next step without further purification.

[0832] LCMS: Rt: 0.946min; MS m / z(ESI): 708.4[M+H] + .

[0833] Step 6: Synthesis of Compound 22-9

[0834]

[0835] To a mixture of benzyl 4-(6-methyl-7-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (100 mg, 0.1415 mmol, 1 eq) in DCM (6 mL) was added TFA (2 mL) and the mixture was stirred at 15 ° C for 1 hour. LCMS showed that the starting material was consumed. The resulting mixture was concentrated under reduced pressure. The residue was adjusted to pH = 8-9 with aqueous NaHCO 3 solution and extracted with DCM (3×15 mL). The combined organic layers were dried over anhydrous Na 2 SO 4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC eluting with DCM / MeOH (10:1, v / v) to give (S)-benzyl 4-(6-methyl-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (69 mg, 78%).

[0836] LCMS: Rt: 0.887min; MS m / z(ESI): 624.3[M+H] + .

[0837] Step 7: Synthesis of Compound 22-10

[0838]

[0839] To (S)-benzyl 4-(6-methyl-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (69 mg, 0.1107 mmol) was added i To a mixture of PrOH (1 mL) and THF (1 mL) was added Pd(OH)2 / C (15 mg, 20% wt), and the mixture was stirred at 30 ° C under H2 (30 psi) for 41 h. LCMS showed that the desired MS was observed. The resulting mixture was filtered through celite. The filter cake was washed with MeOH (30 mL). The filtrate was concentrated under reduced pressure to give (S)-2-methyl-3-(5-methyl-1H-indazol-4-yl)-6-((1-methylpyrrolidin-2-yl)methoxy)-8-(piperazin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one (50 mg, 92%), which was used directly in the next step without further purification.

[0840] LCMS: Rt: 0.311min; MS m / z(ESI): 490.3[M+H] + .

[0841] Step 8: Synthesis of Compound 22

[0842]

[0843] To a mixture of (S)-2-methyl-3-(5-methyl-1H-indazol-4-yl)-6-((1-methylpyrrolidin-2-yl)methoxy)-8-(piperazin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one (50 mg, 0.1022 mmol, 1.0 equiv) and EtN (31 mg, 0.3066 mmol, 3.0 equiv) in DCM (1 mL) and THF (1 mL) was added a solution of acryloyl chloride (7.5 mg, 0.0818 mmol, 0.8 equiv) in DCM (0.2 mL) dropwise at -20 ° C. After the addition, the mixture was stirred at -20 ° C. under N 2 for 30 min. LCMS showed that the desired MS was observed. The mixture was quenched with water (10 mL) and extracted with DCM (3×10 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was separated and purified by HCOOH preparative HPLC to give (S)-8-(4-acryloylpiperazin-1-yl)-2-methyl-3-(5-methyl-1H-indazol-4-yl)-6-((1-methylpyrrolidin-2-yl)methoxy)pyrimido[5,4-d]pyrimidin-4(3H)-one (HCOOH salt, 2.5 mg, 4.5%, 22).

[0844] LCMS: Rt: 0.768min; MS m / z(ESI): 544.2[M+H] + ;

[0845] 1 H NMR (400MHz, DMSO) δ13.35(s,1H),8.33(s,1.85H),7.96(s,1H),7.64(d,J=8.5Hz,1H),7.42(d,J= 8.6Hz,1H),6.86(dd,J=16.7,10.4Hz,1H),6.17(dd,J=16.7,2.2Hz,1H),5.73(dd,J=10.5,2.2Hz, 1H),4.36-4.25(m,4H),4.15-4.11(m,1H),3.83-3.70(m,5H),2.97-2.91(m,1H),2.59-2.54(m,1H ),2.36(s,3H),2.23-2.15(m,1H),2.12(s,3H),2.01(s,3H),1.97-1.90(m,1H),1.71-1.59(m,3H).

[0846] Example 23

[0847]

[0848] Step 1: Synthesis of compound 23-2

[0849]

[0850] To a solution of 4-bromo-5-methyl-1H-indazole (14.0 g, 66.67 mmol, 1.0 equiv) in anhydrous DCM (30 mL) was added PPTS (1.68 g, 6.68 mmol, 0.1 equiv) at room temperature. DHP (16.83 g, 200.02 mmol, 3 equiv) was subsequently added in one portion. The reaction mixture was stirred at 30 ° C for 16 hours. LCMS analysis showed that the starting material was exhausted and the desired product was detected. The reactant was quenched with H2O (50 mL) and the layers were separated. The aqueous layer was extracted with DCM (30 mL × 3). The combined organics were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography on silica eluting with petroleum ether / EtOAc (15%, v / v) to give 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (10.8 g, 55%).

[0851] LCMS: Rt: 2.158min; MS m / z(ESI): 297.1[M+3] + .

[0852] Step 2: Synthesis of compound 23-3

[0853]

[0854] To a mixture of 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (2 g, 6.80 mmol, 1.0 equiv) in anhydrous dioxane (50 mL) was added BnNH (2.18 g, 20.4 mmol, 3 equiv), BINAP (423 mg, 0.68 mmol) and CsCO (6.63 g, 20.4 mmol), followed by Pd(dba) (622 mg, 0.68 mmol). The reaction mixture was stirred at 110 ° C under N for 16 h. LCMS analysis showed that the starting material was consumed and the desired product was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (5 / 1-2 / 1, v / v) to give N-benzyl-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (1.9 g, 87%).

[0855] LCMS: Rt: 1.813min; MS m / z(ESI): 322.1[M+H] + .

[0856] Step 3: Synthesis of compound 23-4

[0857]

[0858] To a mixture of N-benzyl-5-methyl-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-4-amine (1.95 g, 6.07 mmol, 1.0 equiv) in anhydrous MeOH (20 mL) was added Pd / C (600 mg, 10% wt). The reaction mixture was stirred at 30 °C under H2(30 psi) for 16 h. LCMS analysis showed starting material consumed and desired product detected. The mixture was filtered and the filter cake was washed with MeOH (100 mL). The filtrate was concentrated under reduced pressure to give 5-methyl-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-4-amine (1.28 g, 91%) which was used in the next step without further purification.

[0859] LCMS: Rt: 1.249 min; MS m / z (ESI): 232.1 [M+H] + .

[0860] Step 4: Synthesis of compound 23-6

[0861]

[0862] To a mixture of 5-amino-6-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-l-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxylic acid (250 mg, 0.491 mmol, 1.0 equiv) and 5-methyl-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-4-amine (79 mg, 0.344 mmol, 0.7 equiv) in anhydrous DMF (5.0 mL) was added DIEA (190 mg, 1.493 mmol, 3.0 equiv) followed by HATU (186 mg, 0.491 mmol, 1.0 equiv). The reaction mixture was stirred at 60 °C under Ar for 1 h. LCMS showed starting material consumed and formation of desired product. The reaction mixture was allowed to cool to room temperature, diluted with EtOAc (50 mL) and washed with brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica with elution by DCM / MeOH (1 / 0-10: 1, v / v) to give (2S)-4-(5-amino-6-((5-methyl-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-4-yl)carbamoyl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-l-carboxylic acid benzyl ester (120 mg, 34%).

[0863] LCMS: Rt: 0.937min; MS m / z(ESI): 723.3[M+H] + .

[0864] Step 5: Synthesis of compound 23-8

[0865]

[0866] To a mixture of (2S)-benzyl 4-(5-amino-6-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)carbamoyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (100 mg, 0.138 mmol, 1.0 equiv) in AcOH (0.75 mL) was added 1,1,1-triethoxyethane (342 mg, 2.077 mmol). The mixture was stirred at 135 ° C in a sealed tube for 7 min. LCMS showed that the reactant was observed. The reaction mixture was quenched with aqueous NaHCO solution (20 mL) to adjust to pH = 8-9 and extracted with DCM (3×20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude (2S)-2-(cyanomethyl)-4-(6-methyl-7-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (124 mg, 100%), which was used in the next step without further purification.

[0867] LCMS: Rt: 0.951min; MS m / z(ESI): 747.4[M+H] + .

[0868] Step 6: Synthesis of Compound 23-9

[0869]

[0870] To a mixture of (2S)-2-(cyanomethyl)-4-(6-methyl-7-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid benzyl ester (124 mg, 0.166 mmol, 1 equiv) in DCM (6 mL) was added TFA (2 mL) and the mixture was stirred at 15 ° C for 3 hours. LCMS showed that the starting material was consumed. The resulting mixture was concentrated under reduced pressure. The residue was adjusted to pH = 8-9 with aqueous NaHCO 3 solution and extracted with DCM (3×15 mL). The combined organic layers were dried over anhydrous Na 2 SO 4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC eluting with DCM / MeOH (10:1, v / v) to give (S)-benzyl 2-(cyanomethyl)-4-(6-methyl-7-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (73 mg, 66%).

[0871] LCMS: Rt: 0.864min; MS m / z(ESI): 663.3[M+H] + .

[0872] Step 7: Synthesis of Compound 23-10

[0873]

[0874] To a mixture of (S)-benzyl 2-(cyanomethyl)-4-(6-methyl-7-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (73 mg, 0.110 mmol) in MeOH (2 mL) was added Pd(OH) / C (20 mg, 20% wt) and the mixture was stirred at room temperature under H (50 psi) for 1 hour. LCMS showed that the starting material was consumed and the desired product was formed. The resulting mixture was filtered through celite. The filter cake was washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure to give 2-((S)-4-(6-methyl-7-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (45 mg, 77%), which was used directly in the next step without further purification.

[0875] LCMS: Rt: 0.934min; MS m / z(ESI): 529.2[M+H] + .

[0876] Step 8: Synthesis of Compound 23

[0877]

[0878] To a mixture of 2-((S)-4-(6-methyl-7-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (45 mg, 0.0852 mmol, 1.0 equiv) and EtN (26 mg, 0.2556 mmol, 3.0 equiv) in DCM (3 mL) was added dropwise a solution of acryloyl chloride (7.7 mg, 0.0852 mmol, 1.0 equiv) in DCM (0.2 mL) at -20 °C. After the addition, the mixture was stirred at -20 °C under N for 30 min. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was quenched with water (10 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was separated and purified by HCOOH preparative HPLC to give 2-((S)-1-acryloyl-4-(6-methyl-7-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (HCOOH salt, 4.0 mg, 8%, 23).

[0879] LCMS: Rt: 0.823min; MS m / z(ESI): 583.3[M+H] + ;

[0880] 1H NMR (400MHz, DMSO) δ13.37(s,1H),8.33(s,1.92H),7.92(d,J=12.4Hz,1H),7.64(d,J=8.5Hz,1H),7.43(d ,J=8.3Hz,1H),7.02-6.76(m,1H),6.20(d,J=18.2Hz,1H),5.79(d,J=10.3Hz,1H),5.63-4.73(m,3H),4.49 -4.30(m,1.5H),4.17-4.11(m,1.5H),3.78-3.64(m,2H),3.14-2.93(m,4H),2.60-2.52(m,1H),2.36(d,J =1.0Hz,3H),2.23-2.15(m,1H),2.12(d,J=5.9Hz,3H),2.03(s,3H),1.98-1.89(m,1H),1.71-1.59(m,3H).

[0881] Example 24

[0882]

[0883] Step 1: Synthesis of compound 24-2

[0884]

[0885] To a cooled (-60 ° C) solution of ethyl 2,6-dichloro-5-nitropyrimidine-4-carboxylate (5.0 g, 0.019 mol, 1.0 equiv) in anhydrous THF (50 mL) was added dropwise a solution of (S)-tert-butyl 3-methylpiperazine-1-carboxylate (3.75 g, 0.019 mol, 1.0 equiv) and DIEA (4.6 mL, 0.028 mol, 1.5 equiv) in anhydrous THF (30 mL). The mixture was stirred at -60 ° C under Ar for 1 hour. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was concentrated and the residue was purified by silica column chromatography eluting with petroleum ether / EtOAc (3:1, v / v) to give (S)-ethyl 6-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-2-chloro-5-nitropyrimidine-4-carboxylate (8.2 g, crude material).

[0886] LCMS (ESI, m / z): [M+1] + =430; RT=2.141min.

[0887] Step 2: Synthesis of compound 24-3

[0888]

[0889] To a solution of (S)-ethyl 6-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-2-chloro-5-nitropyrimidine-4-carboxylate (8.2 g, 0.019 mol, 1.0 equiv) and DIEA (6.3 mL, 0.038 mol, 2.0 equiv) in anhydrous DMF (60.0 mL) was added (S)-(1-methylpyrrolidin-2-yl)methanol (3.3 g, 0.029 mol, 1.5 equiv). The mixture was stirred at room temperature for 16 hours. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (80 mL×3). The combined organic fractions were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica column chromatography eluting with DCM / MeOH (15:1, v / v) to give ethyl 6-((S)-4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5-nitropyrimidine-4-carboxylate (8.8 g, 91% yield).

[0890] LCMS (ESI, m / z): [M+1] + =509; RT=1.099min.

[0891] Step 3: Synthesis of compound 24-4

[0892]

[0893] To a solution of ethyl 6-((S)-4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5-nitropyrimidine-4-carboxylate (8.8 g, 0.017 mol, 1.0 equiv) in anhydrous DMF (20 mL) / EtOH (60 mL) was added SnCl2 2H2O (19.6 g, 0.087 mol, 5.0 equiv). The mixture was stirred at room temperature under Ar for 16 h. LCMS showed that the starting material was exhausted and the desired product was formed. The reaction mixture was concentrated to remove EtOH and subsequently diluted with EtOAc (120 mL), followed by the addition of aqueous NaHCO3 (saturated, 180 mL). The resulting mixture was filtered through celite. The organic layer of the filtrate was separated, and the aqueous layer was extracted with EtOAc (100 mL×2). The combined organic portions were washed with brine (160 mL), dried over anhydrous NaSO and concentrated. The residue was purified by silica column chromatography eluting with DCM / MeOH (15:1, v / v) to give ethyl 5-amino-6-((S)-4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxylate (3.3 g, 40% yield).

[0894] LCMS (ESI, m / z): [M+1] + =479; RT=0.867min.

[0895] Step 4: Synthesis of compound 24-5

[0896]

[0897] To a mixture of ethyl 5-amino-6-((S)-4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxylate (3.3 g, 0.007 mol, 1.0 equiv) in MeOH (60 mL) and HO (10 mL) was added LiOH HO (1.45 g, 0.034 mol, 5.0 equiv). The mixture was stirred at room temperature for 2 hours. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was acidified to pH = 6 with aqueous HCl (0.5 M) and then concentrated to dryness to give 5-amino-6-((S)-4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxylic acid (5.06 g, crude material).

[0898] LCMS (ESI, m / z): [M+1] + =451; RT=0.928min.

[0899] Step 5: Synthesis of Compound 24-6

[0900]

[0901] To a solution of 5-amino-6-((S)-4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxylic acid (800 mg, 1.78 mmol, 1.0 equiv) and 8-methylnaphthalen-1-amine (220 mg, 1.24 mmol, 0.7 equiv) in anhydrous DMF (5.0 mL) was added DIEA (0.88 mL, 5.33 mmol, 3.0 equiv) followed by HATU (675 mg, 1.78 mmol, 1.0 equiv). The reaction mixture was stirred at 60 ° C under Ar for 1 hour. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was cooled to room temperature, diluted with water (30 mL) and extracted with EtOAc (20 mL×3). The combined organic fractions were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica column chromatography eluting with DCM / MeOH (15:1, v / v) to give (S)-tert-butyl 4-(5-amino-6-((8-chloronaphthalen-1-yl)carbamoyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (430 mg, 57% yield).

[0902] LCMS (ESI, m / z): [M+1] + =688.0; RT=1.406min.

[0903] Step 6: Synthesis of Compound 24-7

[0904]

[0905] To a cooled (0 ° C) solution of (S)-tert-butyl 4-(5-amino-6-((8-chloronaphthalen-1-yl)carbamoyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (200 mg, 0.33 mmol, 1.0 equiv) in anhydrous ACN (3.0 mL) was added pyridine (259 mg, 3.28 mmol, 10.0 equiv) followed by TFAA (414 mg, 1.97 mmol, 6.0 equiv). The mixture was stirred at 0 ° C for 1 hour. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was quenched with aqueous NH4Cl (saturated, 25 mL) and then extracted with EtOAc (15 mL×3). The combined organic portions were washed with brine (20 ml), dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative TLC eluting with DCM / MeOH (10:1, v / v) to give (S)-tert-butyl 4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (110 mg, 49% yield).

[0906] LCMS (ESI, m / z): [M+1] + =610; RT=1.227min.

[0907] Step 7: Synthesis of Compound 24-8

[0908]

[0909] To a solution of tert-butyl (S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (100 mg, 0.15 mmol) in anhydrous DCM (5.0 mL) was added TFA (3 mL), and the mixture was stirred at room temperature for 1 hour. LCMS showed consumption of the starting material and formation of the desired product. The reaction mixture was concentrated to give 3-(8-chloronaphthalen-1-yl)-8-((S)-2-methylpiperazin-1-yl)-6-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2-(trifluoromethyl)-2,3-dihydropyrimido[5,4-d]pyrimidin-4(1H)-one (TFA salt, 96 mg, 94% yield), which was used directly in the next step.

[0910] LCMS (ESI, m / z): [M+1] +=588; RT=0.791min.

[0911] Step 8: Synthesis of compounds 24-a and 24-b

[0912]

[0913] To a cooled (0 ° C) solution of 3-(8-chloronaphthalen-1-yl)-8-((S)-2-methylpiperazin-1-yl)-6-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2-(trifluoromethyl)-2,3-dihydropyrimido[5,4-d]pyrimidin-4(1H)-one (TFA salt, 96 mg, 0.14 mmol, 1.0 equiv) and Et3N (71 mg, 0.70 mmol, 5.0 equiv) in anhydrous DCM (2.5 mL) was added dropwise a solution of acryloyl chloride (13 mg, 0.14 mmol, 1.0 equiv) in anhydrous DCM (0.5 mL). After the addition, the mixture was stirred at 0 ° C for 30 min. LCMS showed that the starting material was consumed and the desired product was formed. Water (15 mL) was added and the organic layer was separated. The aqueous layer was extracted with DCM (8 mL×3). The combined organic portions were dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by preparative HPLC (ACN-H2O + 0.1% HCOOH) and then SFC to give 8-((S)-4-acryloyl-2-methylpiperazin-1-yl)-3-(8-chloronaphthalen-1-yl)-6-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one (6.4 mg, 15% yield, 24-a) and 8-((S)-4-acryloyl-2-methylpiperazin-1-yl)-3-(8-chloronaphthalen-1-yl)-6-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one (7.4 mg, 18% yield, 24-b).

[0914] 24-a:

[0915] LCMS (ESI, m / z): [M+1] + =642; RT = 1.840min; 1 H NMR (400 MHz, CDCl3) δ 8.07 (d,

[0916] J=8.4Hz,1H),7.90(d,J=8.0Hz,1H),7.66-7.53(m,2H),7.44(d,J=6.5Hz,2H),6.71 -6.53(m,1H),6.39(d,J=16.8Hz,1H),5.78(d,J=10.3Hz,1H),5.69-5.29(m,1H),4.6 9-4.27(m,3H),4.05-3.80(m,1H),3.71-3.52(m,2H),3.47-3.14(m,2H),2.93(s,1H) ,2.60(s,3H),2.44(s,1H),2.21-2.00(m,2H),1.97-1.78(m,3H),1.45-1.37(m,3H);

[0917] 19 F NMR (400 MHz, CDCl3) δ-64.8.

[0918] 24-b:

[0919] LCMS (ESI, m / z): [M+1] + =642; RT = 1.831min;

[0920] 1 H NMR (400MHz, CDCl3) δ8.06(d,J=8.1Hz,1H),7.89(d,J=8.1Hz,1H),7.66-7.53(m,2H),7.49- 7.37(m,2H),6.68-6.51(m,1H),6.39(d,J=16.6Hz,1H),5.78(d,J=10.0Hz,1H),5.69-5.28(m ,1H),4.74-4.29(m,3H),4.07-3.79(m,1H),3.69-3.49(m,2H),3.44-3.15(m,2H),2.85(s,1 H),2.55(s,3H),2.42-2.33(m,1H),2.28-1.97(m,2H),1.95-1.75(m,3H),1.48-1.37(m,3H);

[0921] 19 F NMR (400 MHz, CDCl3) δ-64.9.

[0922] Example 25

[0923]

[0924] Step 1: Synthesis of compound 25-3

[0925]

[0926] To a cooled (-60 ° C) solution of ethyl 2,6-dichloro-5-nitropyrimidine-4-carboxylate (5.0 g, 0.019 mol, 1.0 equiv) in anhydrous THF (50 mL) was added (S)-benzyl 2-(cyanomethyl)piperazine-1-carboxylate (4.9 g, 0.019 mol, 1.0 equiv) and DIEA (3.6 g, 0.028 mol, 1.5 equiv) in anhydrous THF (40 mL). The reaction mixture was stirred at -60 ° C under Ar for 1 hour. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was concentrated and purified by silica column chromatography eluting with petroleum ether / EtOAc (3:1, v / v) to give (S)-ethyl 6-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-5-nitropyrimidine-4-carboxylate (6.3 g, 69% yield).

[0927] LCMS (ESI, m / z): [M+1] + =489; RT=1.948min.

[0928] Step 2: Synthesis of compound 25-4

[0929]

[0930] To a mixture of (2S, 4R) -4- fluoropyrrolidine -1,2- dicarboxylic acid 1- (tert-butyl ester) 2-methyl ester (10.0 g, 0.040 mol, 1.0 equivalent) in anhydrous THF (100 mL) was added LiAlH4 (5.4 g, 0.142 mol, 3.5 equivalents) at one time. The mixture was stirred at room temperature for 16 hours. LCMS showed that the starting material was exhausted and the desired product was formed. The reaction mixture was diluted with EtOAc (100 mL) and subsequently quenched with H2O (54 mL), 15% NaOH aqueous solution (54 mL) and H2O (162 mL). The resulting mixture was vigorously stirred at room temperature for 30 min, and the precipitate was filtered out through diatomaceous earth. The filter cake was washed with EtOAc (20 mL × 3). The organic filtrates were combined, washed with brine (100 mL), dried over anhydrous Na 2 SO 4 and concentrated to give ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (4.06 g, 75% yield), which was used directly in the next step.

[0931] Step 3: Synthesis of compound 25-5

[0932]

[0933] To a solution of (S)-ethyl 6-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-2-chloro-5-nitropyrimidine-4-carboxylate (6.3 g, 0.013 mol, 1.0 equiv) and DIEA (3.3 g, 0.026 mol, 2.0 equiv) in anhydrous DMF (60 mL) was added ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (2.6 g, 0.019 mmol, 1.5 equiv). The mixture was stirred at room temperature for 16 h. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (80 mL×3). The combined organic fractions were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica column chromatography eluting with DCM / MeOH (15:1, v / v) to give ethyl 6-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-5-nitropyrimidine-4-carboxylate (4.4 g, 58% yield).

[0934] LCMS (ESI, m / z): [M+1] + =586; RT=1.092min.

[0935] Step 4: Synthesis of compound 25-6

[0936]

[0937] To a solution of ethyl 6-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-5-nitropyrimidine-4-carboxylate (4.0 g, 0.07 mol, 1.0 equiv) in anhydrous DMF (20 mL) / EtOH (60 mL) was added SnCl2·2H2O (7.7 g, 0.34 mol, 5.0 equiv). The reaction mixture was stirred at room temperature under Ar for 16 hours. LCMS showed that the starting material was exhausted and the desired product was formed. The reaction mixture was concentrated to remove EtOH and then diluted with EtOAc (120 mL), followed by the addition of aqueous NaHCO3 (saturated, 180 mL). The resulting mixture was filtered through celite. The organic layer of the filtrate was separated, and the aqueous layer was extracted with EtOAc (100 mL×2). The combined organic fractions were washed with brine (120 mL), dried over anhydrous NaSO, and concentrated. The residue was purified by silica column chromatography eluting with DCM / MeOH (15:1, v / v) to give ethyl 5-amino-6-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxylate (2.4 g, 63% yield).

[0938] LCMS (ESI, m / z): [M+1] + =556; RT=1.025min.

[0939] Step 5: Synthesis of compound 25-7

[0940]

[0941] To a solution of ethyl 5-amino-6-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxylate (2.4 g, 0.004 mol, 1.0 equiv) in MeOH (60 mL) and HO (10 mL) was added LiOH.HO (0.91 g, 0.022 mol, 5.0 equiv). The mixture was stirred at room temperature for 2 h. LCMS showed consumption of the starting material and formation of the desired product. The reaction mixture was acidified with aqueous HCl (1.0 M) to adjust to pH = 6, and then concentrated to dryness to give 5-amino-6-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxylic acid (3.9 g, crude), which was used directly in the next step.

[0942] LCMS (ESI, m / z): [M+1] + =528; RT=1.120min.

[0943] Step 6: Synthesis of compound 25-9

[0944]

[0945] To a solution of 5-amino-6-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxylic acid (3.9 g, 7.0 mmol, 1.0 equiv) and 8-methylnaphthalen-1-amine (0.9 g, 5.0 mmol, 0.7 equiv) in anhydrous DMF (10 mL) was added DIEA (2.9 g, 20 mmol, 3.0 equiv) followed by HATU (3.1 g, 8.0 mmol, 1.1 equiv). The reaction mixture was stirred at 60 °C under Ar for 1 hour. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was cooled to room temperature, diluted with water (80 mL) and extracted with EtOAc (50 mL x 3). The combined organic portions were washed with brine (80 mL), dried over anhydrous NaSO and concentrated. The residue was purified by silica column chromatography eluting with DCM / MeOH (15:1, v / v) to give (S)-benzyl 4-(5-amino-6-((8-chloronaphthalen-1-yl)carbamoyl)-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (2.0 g, 59% yield).

[0946] LCMS (ESI, m / z): [M+1] + =687; RT=1.222min.

[0947] Step 7: Synthesis of Compound 25-10

[0948]

[0949] To a cooled (0 ° C) solution of (S)-benzyl 4-(5-amino-6-((8-chloronaphthalen-1-yl)carbamoyl)-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (1.00 g, 1.46 mmol, 1.0 equiv) in anhydrous ACN (3.0 mL) was added pyridine (1.15 g, 14.6 mmol, 10.0 equiv) followed by TFAA (1.84 g, 8.75 mmol, 6.0 equiv). The mixture was stirred at 0 ° C for 0.5 h. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was quenched with aqueous NH4Cl (saturated, 40 mL) and extracted with EtOAc (20 mL×3). The combined organic fractions were dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative TLC eluting with DCM / MeOH (10:1, v / v) to give (S)-benzyl 4-(7-(8-chloronaphthalen-1-yl)-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (120 mg, 11% yield).

[0950] LCMS (ESI, m / z): [M+1] + =764; RT=1.371min.

[0951] Step 8: Synthesis of Compound 25-11

[0952]

[0953] To a solution of (S)-benzyl 4-(7-(8-chloronaphthalen-1-yl)-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (100 mg, 0.131 mmol) in anhydrous ACN (5.0 mL) was added TMSI (262 mg, 1.31 mmol), and the mixture was stirred at room temperature for 1 hour. LCMS showed consumption of the starting material and formation of the desired product. The reaction mixture was treated with Et3N (1.0 mL) and concentrated and purified by preparative TLC eluting with DCM / MeOH (10:1, v / v) to give 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (10 mg, 85% yield).

[0954] LCMS (ESI, m / z): [M+1] + =631; RT=0.870min.

[0955] Step 9: Synthesis of compounds 25-a and 25-b

[0956]

[0957] To a cooled (0 ° C) solution of 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (70 mg, 0.10 mmol, 1.0 equiv) and Et3N (31 mg, 0.31 mmol, 3.0 equiv) in DCM (2.5 mL) was added dropwise a solution of acryloyl chloride (13.8 mg, 0.14 mmol, 1.5 equiv) in DCM (0.5 mL). After the addition, the mixture was stirred at 0 ° C for 30 min. LCMS showed that the starting material was consumed and the desired product was formed. Water (15 mL) was added and the organic layer was separated. The aqueous layer was extracted with DCM (8 mL × 2). The combined organic fractions were dried over anhydrous Na SO and concentrated. The residue was purified by preparative HPLC (ACN-H O+0.1% HCOOH) and subsequent SFC to give 2-((S)-1-acryloyl-4-(7-(8-chloronaphthalene-1-yl)-2-(((2S, 4R)-4-fluoro-1-methylpyrrolidin-2-yl)) (3.2 mg, 4% yield, 25-a) and 2-((S)-1-acryloyl-4-(7-(8-chloronaphthalene-1-yl)-2-(((2S, 4R)-4-fluoro-1-methylpyrrolidin-2-yl)) (3.5 mg, 4% yield, 25-b).

[0958] 25-a:

[0959] LCMS (ESI, m / z): [M+1] + =685; RT = 1.178min;

[0960] 1 H NMR(400MHz, CDCl3)δ8.08(d,J=7.4Hz,1H),7.91(d,J=6.7Hz,1H),7.67-7.55(m,2H) ,7.52-7.41(m,2H),6.72-6.53(m,1H),6.41(d,J=16.6Hz,1H),5.84(d,J=10.0Hz,1H ),5.70-4.77(m,3H),4.64(s,2H),4.04(s,1H),3.86-3.45(m,2H),3.26(s,1H),2.98 -2.87(m,1H),2.87-2.71(m,2H),2.67(s,3H),2.41-2.09(m,3H),1.39-1.27(m,2H);

[0961] 19F NMR (400MHz, CDCl3) δ-64.79,-170.75.

[0962] 25-b:

[0963] LCMS (ESI, m / z): [M+1] + =685; RT = 1.704min;

[0964] 1 H NMR(400MHz, CDCl3)δ8.09(d,J=8.6Hz,1H),7.91(d,J=8.1Hz,1H),7.66-7.56(m,2H), 7.49-7.42(m,2H),6.71-6.53(m,1H),6.42(d,J=16.3Hz,1H),5.85(d,J=10.5Hz,1H), 5.56-4.84(m,3H),4.70-4.45(m,2H),4.13-3.82(m,1H),3.76-3.44(m,2H),3.20(s,1 H),2.89(s,1H),2.86-2.62(m,2H),2.61(s,3H),2.40-2.11(m,3H),1.39-1.26(m,2H);

[0965] 19 F NMR (400MHz, CDCl3) δ-64.83,-170.74.

[0966] Example 26

[0967]

[0968] Step 1: Synthesis of compound 26-3

[0969]

[0970] To a solution of 5-amino-6-((S)-4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxylic acid (1.80 g, 4.0 mmol, 1.0 equiv) and 8-chloronaphthalen-1-amine (0.49 g, 3.0 mmol, 0.7 equiv) in anhydrous DMF (20 mL) was added DIEA (1.55 g, 12.0 mmol, 3.0 equiv) followed by HATU (1.52 g, 4.0 mmol, 1.0 equiv). The mixture was stirred at 60 ° C under Ar for 1 hour. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with EtOAc (60 mL×3). The combined organic portions were washed with brine (100 mL), dried over anhydrous NaSO and concentrated. The residue was purified by silica column chromatography eluting with DCM / MeOH (10:1, v / v) to give (S)-tert-butyl 4-(5-amino-6-((8-chloronaphthalen-1-yl)carbamoyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (1.06 g, 63% yield, 26-3).

[0971] LCMS (ESI, m / z): [M+1] + =610; RT=1.259min.

[0972] Step 2: Synthesis of compound 26-5

[0973]

[0974] To a mixture of (S)-tert-butyl 4-(5-amino-6-((8-chloronaphthalen-1-yl)carbamoyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (500 mg, 0.82 mmol, 1.0 equiv) and AcOH (5.0 mL) was added 1,1,1-triethoxyethane (2.25 mL, 12.3 mmol, 15.0 equiv). The mixture was stirred at 135 ° C in a sealed tube for 3 min. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was cooled, quenched with aqueous NaHCO solution (120 mL) and extracted with DCM (60 mL×3). The combined organic fractions were dried over anhydrous Na SO and concentrated. The residue was purified by preparative TLC eluting with DCM / MeOH (10:1, v / v) to give (S)-tert-butyl 4-(7-(8-chloronaphthalen-1-yl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (180 mg, 35% yield, 26-5).

[0975] LCMS (ESI, m / z): [M+1] + =634; RT=1.174min.

[0976] Step 3: Synthesis of compound 26-6

[0977]

[0978] To a solution of (S)-4-(7-(8-chloronaphthalen-1-yl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (180 mg, 0.28 mmol) in DCM (5.0 mL) was added TFA (2.0 mL) and the mixture was stirred at room temperature for 1 hour. LCMS showed that the starting material was exhausted and the desired product was formed. The reaction mixture was concentrated and the residue was treated with aqueous NaHCO solution (saturated, 20 mL). The resulting mixture was extracted with DCM (10 mL × 3). The combined organic fractions were dried over anhydrous Na2SO4 and concentrated to give 3-(8-chloronaphthalen-1-yl)-2-methyl-8-((S)-2-methylpiperazin-1-yl)-6-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimido[5,4-d]pyrimidin-4(3H)-one (136 mg, 89% yield, 26-6), which was used directly in the next step.

[0979] LCMS (ESI, m / z): [M+1] + =534; RT=0.758min.

[0980] Step 4: Synthesis of compounds 26-a and 26-b

[0981]

[0982] To a cooled (0 ° C) solution of 3-(8-chloronaphthalen-1-yl)-2-methyl-8-((S)-2-methylpiperazin-1-yl)-6-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimido[5,4-d]pyrimidin-4(3H)-one (130 mg, 0.24 mmol, 1.0 equiv) and Et3N (74 mg, 0.73 mmol, 3.0 equiv) in anhydrous DCM (5 mL) was added dropwise a solution of acryloyl chloride (28 mg, 0.43 mmol, 1.3 equiv) in anhydrous DCM (0.5 mL). After the addition, the mixture was stirred at 0 ° C for 30 min. LCMS showed that the starting material was consumed and the desired product was formed. Water (15 mL) was added and the organic layer was separated. The aqueous layer was extracted with DCM (8 mL×3). The combined organic fractions were dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative HPLC (ACN-H2O + 0.1% HCOOH) and then SFC to give 8-((S)-4-acryloyl-2-methylpiperazin-1-yl)-3-(8-chloronaphthalen-1-yl)-2-methyl-6-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimido[5,4-d]pyrimidin-4(3H)-one (22 mg, 15% yield, 26-a) and 8-((S)-4-acryloyl-2-methylpiperazin-1-yl)-3-(8-chloronaphthalen-1-yl)-2-methyl-6-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimido[5,4-d]pyrimidin-4(3H)-one (20 mg, 15% yield, 26-b).

[0983] 26-a:

[0984] LCMS (ESI, m / z): [M+1] + =588; RT=1.745min;

[0985] 1H NMR (400MHz, CDCl3) δ8.05(d,J=7.4Hz,1H),7.91(d,J=7.3Hz,1H),7.67-7.61(m,1H),7.58(dd,J=7 .5,1.1Hz,1H),7.48-7.42(m,1H),7.39(d,J=7.1Hz,1H),6.71-6.53(m,1H),6.44-6.34(m,1H),5.7 7(d,J=10.7Hz,1H),5.34-4.27(m,3H),4.12-3.70(m,1H),3.67-3.48(m,2H),3.43-2.82(m,3H),2. 59(s,3H),2.46-2.27(m,1H),2.12(s,3H),2.11-2.01(m,1H),2.00-1.69(m,4H),1.40-1.35(m,3H).

[0986] 26-b:

[0987] LCMS (ESI, m / z): [M+1] + =588; RT = 1.752min;

[0988] 1 H NMR (400MHz, CDCl3) δ8.05(d,J=8.3Hz,1H),7.91(d,J=8.1Hz,1H),7.64(t,J=7.8Hz,1H),7.58(d,J=7.5 Hz,1H),7.45(t,J=7.8Hz,1H),7.40(d,J=7.2Hz,1H),6.69-6.53(m,1H),6.38(d,J=16.7Hz,1H),5.77(d ,J=10.2Hz,1H),5.35-4.32(m,3H),4.13-3.73(m,1H),3.67-3.47(m,2H),3.40-3.06(m,2H),2.92(s,1H ),2.57(s,3H),2.45-2.37(m,1H),2.29-2.21(m,1H),2.13(s,3H),2.10-2.05(m,1H),1.86-1.81(m,4H). 1.38(d,J=8.0Hz,3H).

[0989] Example 27

[0990]

[0991] Step 1: Synthesis of compound 27-3

[0992]

[0993] To a mixture of (S)-tert-butyl 4-(5-amino-6-((8-chloronaphthalen-1-yl)carbamoyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (500 mg, 0.82 mmol, 1.0 equiv) and AcOH (5.0 mL) was added 1,1,1-triethoxypropane (2.5 mL, 12.3 mmol, 15.0 equiv). The mixture was stirred at 135 ° C in a sealed tube for 3 min. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was cooled, quenched with aqueous NaHCO solution (120 mL) and extracted with DCM (60 mL×3). The combined organic fractions were dried over anhydrous Na SO and concentrated. The residue was purified by preparative TLC eluting with DCM / MeOH (10:1, v / v) to give (S)-benzyl 2-(cyanomethyl)-4-(7-(8-fluoronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (120 mg, 41% yield, 27-3).

[0994] LCMS (ESI, m / z): [M+1] + =648; RT=1.218min.

[0995] Step 2: Synthesis of compound 27-4

[0996]

[0997] To a solution of (S)-2-(cyanomethyl)-4-(7-(8-fluoronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid benzyl ester (220 mg, 0.34 mmol) in DCM (5.0 mL) was added TFA (2.0 mL) and the mixture was stirred at room temperature for 1 hour. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was concentrated and the residue was treated with aqueous NaHCO solution (saturated, 20 mL). The resulting mixture was extracted with DCM (10 mL×3). The combined organic fractions were dried over anhydrous Na2SO4 and concentrated to give 3-(8-chloronaphthalen-1-yl)-2-ethyl-8-((S)-2-methylpiperazin-1-yl)-6-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimido[5,4-d]pyrimidin-4(3H)-one (170 mg, 90% yield, 27-4), which was used directly in the next step.

[0998] LCMS (ESI, m / z): [M+1] + =548; RT=0.720min.

[0999] Step 3: Synthesis of compounds 27-a and 27-b

[1000]

[1001] To a cooled (0 ° C) solution of 3-(8-chloronaphthalen-1-yl)-2-ethyl-8-((S)-2-methylpiperazin-1-yl)-6-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimido[5,4-d]pyrimidin-4(3H)-one (170 mg, 0.31 mmol, 1.0 equiv) and Et3N (94 mg, 0.93 mmol, 3.0 equiv) in anhydrous DCM (5 mL) was added dropwise a solution of acryloyl chloride (42 mg, 0.47 mmol, 1.5 equiv) in anhydrous DCM (0.5 mL). After the addition, the mixture was stirred at 0 ° C for 30 min. LCMS showed that the starting material was consumed and the desired product was formed. Water (15 mL) was added and the organic layer was separated. The aqueous layer was extracted with DCM (8 mL×3). The combined organic fractions were dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative HPLC (ACN-H2O + 0.1% HCOOH) and then SFC to give 8-((S)-4-acryloyl-2-methylpiperazin-1-yl)-3-(8-chloronaphthalen-1-yl)-2-ethyl-6-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimido[5,4-d]pyrimidin-4(3H)-one (32 mg, 17% yield, 27-a) and 8-((S)-4-acryloyl-2-methylpiperazin-1-yl)-3-(8-chloronaphthalen-1-yl)-2-ethyl-6-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimido[5,4-d]pyrimidin-4(3H)-one (25 mg, 13% yield, 27-b).

[1002] 27-a:

[1003] LCMS (ESI, m / z): [M+1] + =602; RT = 1.840min;

[1004] 1H NMR (400MHz, CDCl3) δ8.03(d,J=8.1Hz,1H),7.89(d,J=8.1Hz,1H),7.62(t,J=7.7Hz,1H),7.55(d,J=7.3Hz ,1H),7.43(t,J=7.8Hz,1H),7.36(d,J=6.9Hz,1H),6.73-6.49(m,1H),6.37(d,J=16.7Hz,1H),5.76(d,J=9 .8Hz,1H),5.40-4.28(m,3H),4.13-3.70(m,1H),3.67-3.44(m,2H),3.38-3.03(m,2H),2.87(s,1H),2.56( s,3H),2.44-2.16(m,5H),2.13-2.02(m,1H),1.90-1.74(m,3H),1.43-1.33(m,3H),1.16(t,J=6.9Hz,3H).

[1005] 27-b:

[1006] CMS (ESI, m / z): [M+1] + =602; RT = 1.847min;

[1007] 1 H NMR (400MHz, CDCl3) δ8.03(d,J=8.3Hz,1H),7.89(d,J=7.6Hz,1H),7.65-7.59(m,1H),7.55(dd,J=7.4,0.9H z,1H),7.43(t,J=7.9Hz,1H),7.36(d,J=7.2Hz,1H),6.73-6.50(m,1H),6.37(d,J=16.7Hz,1H),5.76(d,J=10 .3Hz,1H),5.51-4.34(m,3H),4.09-3.77(m,1H),3.68-3.42(m,2H),3.37-3.05(m,2H),2.90(s,1H),2.56(s ,3H),2.46-2.13(m,5H),2.12-2.02(m,1H),1.92-1.74(m,3H),1.38(d,J=6.7Hz,3H),1.15(t,J=7.2Hz,3H).

[1008] Example 28

[1009]

[1010] Step 1: Synthesis of compound 28-3

[1011]

[1012] To a cooled (-60°C) solution of ethyl 2,6-dichloro-5-nitropyrimidine-4-carboxylate (6.21 g, 23.4 mmol, 1.0 equiv) in anhydrous THF (40 mL) was added dropwise a solution of tert-butyl (3S,5S)-3,5-dimethylpiperazine-1-carboxylate (5.00 g, 23.4 mmol, 1.0 equiv) and DIEA (4.52 g, 35.0 mmol, 1.5 equiv) in anhydrous THF (30 mL). The mixture was stirred at -60°C for 1 h. TLC indicated the reaction was complete. The mixture was concentrated in vacuo and purified by silica column chromatography eluting with petroleum ether / EtOAc (2:1, v / v) to give ethyl 6-((2S,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazin-1-yl)-2-chloro-5-nitropyrimidine-4-carboxylate (8.80 g, 85% yield, 28-3)

[1013] Step 2: Synthesis of compound 28-5

[1014]

[1015] To a solution of ethyl 6-((2S,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazin-1-yl)-2-chloro-5-nitropyrimidine-4-carboxylate (8.80 g, 19.7 mmol, 1.0 equiv) and DIEA (5.13 g, 39.7 mmol, 2.0 equiv) in anhydrous DMF (30 mL) was added (S)-(1-methylpyrrolidin-2-yl)methanol (3.43 g, 29.8 mmol, 1.5 equiv). The mixture was stirred at room temperature for 3 h. LCMS showed that the starting material was consumed and the desired product was formed. The solution was diluted with brine (120 mL) and extracted with EtOAc (80 mL×2). The combined organic layers were dried over anhydrous NaSO and concentrated. The residue was purified by silica column chromatography eluting with DCM / MeOH (15:1, v / v) to give ethyl 6-((2S,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5-nitropyrimidine-4-carboxylate (10.00 g, 96% yield, 28-5).

[1016] LCMS (ESI, m / z): [M+1] + =523; RT=1.125min.

[1017] Step 3: Synthesis of compound 28-6

[1018]

[1019] To a solution of ethyl 6-((2S,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5-nitropyrimidine-4-carboxylate (10.00 g, 19.2 mmol, 1.0 equiv) in anhydrous EtOH (50 mL) / DMF (50 mL) was added SnCl2 2H2O (21.66 g, 96.0 mmol, 5.0 equiv). The solution was stirred at room temperature for 3 hours. LCMS showed that the starting material was exhausted and the desired product was formed. The reaction mixture was concentrated to remove EtOH and then diluted with EtOAc (150 mL), followed by the addition of aqueous NaHCO3 (saturated, 200 mL). The resulting mixture was filtered through celite. The organic layer of the filtrate was separated, and the aqueous layer was extracted with EtOAc (120 mL×2). The combined organic fractions were washed with brine (200 ml), dried over anhydrous NaSO and concentrated. The residue was purified by silica column chromatography eluting with DCM / MeOH (10:1, v / v) to give ethyl 5-amino-6-((2S,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxylate (2.00 g, 21% yield, 28-6).

[1020] LCMS (ESI, m / z): [M+1] + =451; RT=0.928min.

[1021] Step 4: Synthesis of compound 26-7

[1022]

[1023] To a solution of 5-amino-6-((2S,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxylate (2.00 g, 4.06 mmol, 1.0 equiv) in MeOH (10 mL) and water (3 mL) was added LiOH·HO (854 mg, 20.3 mmol, 5.0 equiv). The mixture was stirred at room temperature for 3 h. LCMS showed consumption of the starting material and formation of the desired product. The mixture was acidified with aqueous HCl (0.5 M) to pH = 6 and then concentrated to dryness to give 5-amino-6-((2S,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxylic acid (3.38 g, crude, 28-7), which was used directly in the next step.

[1024] LCMS (ESI, m / z): [M+1] + =465; RT=1.079min.

[1025] Step 5: Synthesis of Compound 28-9

[1026]

[1027] To a solution of 6-amino-4-chloro-1-(2,6-dimethylphenyl)pyrimidin-2(1H)-one (3.38 g, 7.3 mmol, 1.0 equiv) and 8-chloronaphthalene-1-amine (1.03 g, 5.8 mmol, 0.8 equiv) in anhydrous DMF (30 mL) was added DIEA (2.82 g, 21.8 mmol, 3.0 equiv) followed by HATU (3.32 g, 8.7 mmol, 1.2 equiv). The solution was stirred at 60 ° C for 1 hour. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was cooled to room temperature, diluted with brine (120 mL) and extracted with EtOAc (80 mL×3). The combined organic fractions were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica column chromatography eluting with DCM / MeOH (10:1, v / v) to give tert-butyl (3S,5S)-4-(5-amino-6-((8-chloronaphthalen-1-yl)carbamoyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-3,5-dimethylpiperazine-1-carboxylate (1.30 g, 29% yield, 28-9).

[1028] LCMS (ESI, m / z): [M+1] + =624; RT=1.340min.

[1029] Step 6: Synthesis of Compound 28-11

[1030]

[1031] To a mixture of tert-butyl (3S,5S)-4-(5-amino-6-((8-chloronaphthalen-1-yl)carbamoyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-3,5-dimethylpiperazine-1-carboxylate (1.30 g, 2.1 mmol, 1.0 equiv) and AcOH (15 mL) was added 1,1,1-triethoxyethane (5.11 g, 31.5 mmol, 15.0 equiv). The mixture was stirred at 135 ° C for 3 min. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was cooled, quenched with aqueous NaHCO solution (120 mL) and extracted with DCM (60 mL×3). The combined organic fractions were dried over anhydrous Na SO and concentrated. The residue was purified by silica column chromatography eluting with DCM / MeOH (10:1, v / v) to give tert-butyl (3S,5S)-4-(7-(8-chloronaphthalen-1-yl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)-3,5-dimethylpiperazine-1-carboxylate (710 mg, 52% yield, 28-11).

[1032] LCMS (ESI, m / z): [M+1] + =648; RT=1.306min.

[1033] Step 7: Synthesis of Compound 28-12

[1034]

[1035] To a solution of tert-butyl 4-(1-(2,6-dimethylphenyl)-6-(2-fluorobenzamido)-2-oxo-1,2-dihydropyrimidin-4-yl)piperazine-1-carboxylate (710 mg, 1.1 mmol, 1.0 equiv) in DCM (5 mL) was added trifluoroacetic acid (2.5 mL) and the mixture was stirred at room temperature for 2 hours. LCMS showed that the starting material was exhausted and the desired product was formed. The reaction mixture was concentrated and the residue was treated with aqueous NaHCO solution (saturated, 30 mL) to adjust pH = 7-8, which was extracted with DCM (15 mL × 3). The combined organic fractions were dried over anhydrous Na2SO4 and concentrated to give 3-(8-chloronaphthalen-1-yl)-8-((2S,6S)-2,6-dimethylpiperazin-1-yl)-2-methyl-6-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimido[5,4-d]pyrimidin-4(3H)-one (550 mg, 92% yield, 28-12), which was used directly in the next step.

[1036] LCMS (ESI, m / z): [M+1]+ =548; RT=0.697min.

[1037] Step 9: Synthesis of compounds 28-a and 28-b

[1038]

[1039] To a cooled (0 ° C) solution of 3-(8-chloronaphthalen-1-yl)-8-((2S,6S)-2,6-dimethylpiperazin-1-yl)-2-methyl-6-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimido[5,4-d]pyrimidin-4(3H)-one (550 mg, 1.0 mmol, 1.0 equiv) and Et3N (305 mg, 3.0 mmol, 3.0 equiv) in anhydrous DCM (3 mL) was added dropwise a solution of acryloyl chloride (90.5 mg, 1.0 mmol, 1.0 equiv) in anhydrous DCM (0.5 mL). The mixture was stirred at 0 ° C for 30 min. LCMS showed that the starting material was consumed and the desired product was formed. Water (25 ml) was added and the organic layer was separated. The aqueous layer was extracted with DCM (10 mL×3). The combined organic portions were dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by preparative TLC and then SFC to give 8-((2S,6S)-4-acryloyl-2,6-dimethylpiperazin-1-yl)-3-(8-chloronaphthalen-1-yl)-2-methyl-6-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimido[5,4-d]pyrimidin-4(3H)-one (12.35 mg, 2% yield, 28-a) and 8-((2S,6S)-4-acryloyl-2,6-dimethylpiperazin-1-yl)-3-(8-chloronaphthalen-1-yl)-2-methyl-6-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimido[5,4-d]pyrimidin-4(3H)-one (3.56 mg, 0.6% yield, 28-b).

[1040] 28-a:

[1041] LCMS (ESI, m / z): [M+1] + =602; RT = 1.787min;

[1042] 1H NMR (400MHz, CDCl3) δ8.08(d,J=7.6Hz,1H),7.93(d,J=8.0Hz,1H),7.70-7.64(m,1H),7.59(dd,J= 7.4,1.0Hz,1H),7.47(dd,J=16.2,8.2Hz,2H),6.59(dd,J=16.8,10.3Hz,1H),6.44(dd,J=16.8,2. 0Hz,1H),5.80(dd,J=10.3,2.0Hz,1H),5.72-5.55(m,1H),4.92-4.77(m,2H),4.25-4.00(m,3H),3 .87-3.70(m,4H),3.04-2.90(m,4H),2.33(s,1H),2.13(s,3H),1.97(s,3H),1.49(t,J=6.8Hz,6H).

[1043] 28-b:

[1044] LCMS (ESI, m / z): [M+1] + =602; RT = 1.793min;

[1045] 1 H NMR (400MHz, CDCl3) δ8.05 (dd, J=8.3, 0.9Hz, 1H), 7.91 (dd, J=8.3, 0.9Hz, 1H), 7.68-7.62 (m, 1H), 7.58 ( dd,J=7.5,1.1Hz,1H),7.48-7.41(m,2H),6.60(dd,J=16.8,10.4Hz,1H),6.44(dd,J=16.8,2.0Hz,1H),5. 80(dd,J=10.3,2.0Hz,1H),5.72-5.50(m,1H),4.71-4.36(m,2H),4.21-4.03(m,2H),3.84-3.70(m,2H),3 .48-2.97(m,2H),2.88-2.26(m,5H),2.17(s,1H),2.11(s,3H),1.89(s,3H),1.48(dd,J=6.5,4.4Hz,6H).

[1046] Example 29

[1047]

[1048] Step 1: Synthesis of compound 29-2

[1049]

[1050] To a cooled (-60°C) solution of ethyl 2,6-dichloro-5-nitropyrimidine-4-carboxylate (6.21 g, 23.4 mmol, 1.0 equiv) in anhydrous THF (40 mL) was added dropwise a solution of tert-butyl (3S,5S)-3,5-dimethylpiperazine-1-carboxylate (5.00 g, 23.4 mmol, 1.0 equiv) and DIEA (4.52 g, 35.0 mmol, 1.5 equiv) in anhydrous THF (30 mL). The mixture was stirred at -60°C for 1 h. TLC indicated the reaction was complete. The mixture was concentrated in vacuo and purified by silica column chromatography eluting with petroleum ether / EtOAc (2:1, v / v) to give ethyl 6-((2S,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazin-1-yl)-2-chloro-5-nitropyrimidine-4-carboxylate (8.80 g, 85% yield, 29-2).

[1051] Step 2: Synthesis of compound 29-3

[1052]

[1053] To a solution of ethyl 6-((2S,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazin-1-yl)-2-chloro-5-nitropyrimidine-4-carboxylate (8.80 g, 19.7 mmol, 1.0 equiv) and DIEA (5.13 g, 39.7 mmol, 2.0 equiv) in anhydrous DMF (30 mL) was added (S)-(1-methylpyrrolidin-2-yl)methanol (3.43 g, 29.8 mmol, 1.5 equiv). The mixture was stirred at room temperature for 3 h. LCMS showed that the starting material was consumed and the desired product was formed. The solution was diluted with brine (120 mL) and extracted with EtOAc (80 mL×2). The combined organic layers were dried over anhydrous NaSO and concentrated. The residue was purified by silica column chromatography eluting with DCM / MeOH (15:1, v / v) to give ethyl 6-((2S,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5-nitropyrimidine-4-carboxylate (10.00 g, 96% yield, 29-3).

[1054] LCMS (ESI, m / z): [M+1] + =523; RT=1.125min.

[1055] Step 3: Synthesis of compound 29-4

[1056]

[1057] To a solution of ethyl 6-((2S,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5-nitropyrimidine-4-carboxylate (10.00 g, 19.2 mmol, 1.0 equiv) in anhydrous EtOH (50 mL) / DMF (50 mL) was added SnCl2 2H2O (21.66 g, 96.0 mmol, 5.0 equiv). The solution was stirred at room temperature for 3 hours. LCMS showed that the starting material was exhausted and the desired product was formed. The reaction mixture was concentrated to remove EtOH and then diluted with EtOAc (150 mL), followed by the addition of aqueous NaHCO3 (saturated, 200 mL). The resulting mixture was filtered through celite. The organic layer of the filtrate was separated, and the aqueous layer was extracted with EtOAc (120 mL×2). The combined organic fractions were washed with brine (200 ml), dried over anhydrous NaSO and concentrated. The residue was purified by silica column chromatography eluting with DCM / MeOH (10:1, v / v) to give ethyl 5-amino-6-((2S,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxylate (2.00 g, 21% yield, 29-4).

[1058] LCMS (ESI, m / z): [M+1] + =451; RT=0.928min.

[1059] Step 4: Synthesis of compound 29-5

[1060]

[1061] To a solution of ethyl 5-amino-6-((2S,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxylate (630 mg, 1.28 mmol, 1.0 equiv) in MeOH (6.0 mL) and H2O (1 mL) was added LiOH·H2O (269 mg, 6.40 mmol, 5.0 equiv). The mixture was stirred at room temperature for 1 hour. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was acidified with aqueous HCl (1.0 M) to pH = 6 and then concentrated to dryness to give 5-amino-6-((2S,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxylic acid (720 mg, crude, 29-5), which was used directly in the next step.

[1062] LCMS (ESI, m / z): [M+1] 462.0 + = 465; RT = 1.096 min.

[1063] Step 5: Synthesis of compound 29-6

[1064]

[1065] To a mixture of 5-amino-6-((2S,6S)-4-(tert-butoxycarbonyl)-2,6- dimethylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4- carboxylic acid (720 mg, 1.55 mmol, 1.0 equiv) and 8-chloronaphthalen-1-amine (192 mg, 1.09 mmol, 0.7 equiv) in anhydrous DMF (10 mL) was added DIEA (600 mg, 4.65 mmol, 3.0 equiv) followed by HATU (649 mg, 1.71 mmol, 1.1 equiv). The mixture was stirred at 60 °C under Ar for 1 h. LCMS showed the starting material was consumed and the desired product was formed. The reaction mixture was cooled to rt, diluted with water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic portion was washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography on silica with DCM / MeOH (10:1, v / v) as eluent to give (3S,5S)-4-(5-amino-6-((8-chloronaphthalen-1-yl)carbamoyl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-3,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (300 mg, 44% yield, 29-6).

[1066] LCMS (ESI, m / z): [M+1] 462.0 + = 465; RT = 1.096 min.

[1067] Step 6: Synthesis of compound 29-7

[1068]

[1069] To a solution of tert-butyl (3S,5S)-4-(5-amino-6-((8-chloronaphthalen-1-yl)carbamoyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-3,5-dimethylpiperazine-1-carboxylate (200 mg, 0.32 mmol, 1.0 equiv) in anhydrous ACN (10.0 mL) was added pyridine (254 mg, 3.20 mmol, 10.0 equiv) followed by TFAA (202 mg, 1.92 mmol, 6.0 equiv). The mixture was stirred at 0 ° C for 30 min. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was quenched with aqueous NH4Cl solution (saturated, 25 mL) and then extracted with EtOAc (15 mL×3). The combined organic fractions were washed with brine (20 ml), dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative TLC eluting with DCM / MeOH (10:1, v / v) to give tert-butyl (3S,5S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)-3,5-dimethylpiperazine-1-carboxylate (110 mg, 49% yield, 29-7).

[1070] LCMS (ESI, m / z): [M+1] + =702; RT=1.189min.

[1071] Step 7: Synthesis of Compound 29-8

[1072]

[1073] To a solution of tert-butyl (3S,5S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)-3,5-dimethylpiperazine-1-carboxylate (100 mg, 0.14 mmol) in DCM (5.0 mL) was added TFA (2.0 mL) and the mixture was stirred at room temperature for 1 hour. LCMS showed consumption of the starting material and formation of the desired product. The resulting mixture was concentrated to give 3-(8-chloronaphthalen-1-yl)-8-((2S,6S)-2,6-dimethylpiperazin-1-yl)-6-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one (TFA salt, 100 mg, crude, 29-8), which was used directly in the next step.

[1074] LCMS (ESI, m / z): [M+1] + =602.3; RT=0.955min.

[1075] Step 8: Synthesis of compounds 29a and 29b

[1076]

[1077] To a cooled (0 ° C) solution of 3-(8-chloronaphthalen-1-yl)-8-((2S,6S)-2,6-dimethylpiperazin-1-yl)-6-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one (100 mg, 0.14 mmol, 1.0 equiv) and Et3N (71 mg, 0.70 mmol, 5.0 equiv) in DCM (3 mL) was added a solution of acryloyl chloride (19 mg, 0.21 mmol, 1.5 equiv) in DCM (0.5 mL) dropwise. After the addition, the mixture was stirred at 0 ° C for 30 min. LCMS showed that the starting material was consumed and the desired product was formed. Water (15 mL) was added and the organic layer was separated. The aqueous layer was extracted with DCM (8 mL×3). The combined organic fractions were dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative HPLC (ACN-H2O + 0.1% HCOOH) and then SFC to give 8-((2S,6S)-4-acryloyl-2,6-dimethylpiperazin-1-yl)-3-(8-chloronaphthalen-1-yl)-6-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4(3H )-one (4.5 mg, 9% yield, 29-a) and 8-((2S,6S)-4-acryloyl-2,6-dimethylpiperazin-1-yl)-3-(8-chloronaphthalen-1-yl)-6-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one (5.6 mg, 11% yield, 29-b).

[1078] 29-a:

[1079] LCMS (ESI, m / z): [M+1] + =656; RT = 2.107min;

[1080] 1H NMR (400MHz, CDCl3) δ8.08(d,J=8.0Hz,1H),7.91(d,J=8.1Hz,1H),7.66-7.60( m,1H),7.56(d,J=7.4Hz,1H),7.48-7.40(m,2H),6.64-6.54(m,1H),6.50-6.41 (m,1H),5.84-5.77(m,1H),5.46-4.57(m,3H),4.23-4.05(m,2H),3.87-3.71(m ,2H),2.85(s,3H),2.34-1.92(m,5H),1.49(d,J=6.5Hz,6H),1.28-1.21(m,3H);

[1081] 19 F NMR (400 MHz, CDCl3) δ-64.7.

[1082] 29-b:

[1083] LCMS (ESI, m / z): [M+1] + =656; RT = 2.100min;

[1084] 1 H NMR (400MHz, CDCl3) δ8.08(d,J=7.9Hz,1H),7.90(d,J=7.9Hz,1H),7.63(t,J=7 .8Hz,1H),7.58(d,J=6.8Hz,1H),7.49-7.42(m,2H),6.64-6.55(m,1H),6.51-6 .41(m,1H),5.85-5.78(m,1H),5.49-4.45(m,3H),4.24-4.05(m,2H),3.86-3.7 0(m,2H),2.69(s,3H),2.20-1.85(m,5H),1.55-1.49(m,6H),1.29-1.22(m,3H);

[1085] 19 F NMR (400 MHz, CDCl3) δ-64.7.

[1086] Example 30

[1087]

[1088] Step 1: Synthesis of compound 30-2

[1089]

[1090] To a solution of 4-bromo-5-methyl-1H-indazole (14.0 g, 66.67 mmol, 1.0 equiv) in anhydrous DCM (30 mL) was added PPTS (1.68 g, 6.68 mmol, 0.1 equiv) at room temperature (rt). DHP (16.83 g, 200.02 mmol, 3 equiv) was subsequently added in one portion. The reaction mixture was stirred at 30 ° C overnight. LCMS analysis showed that the starting material was exhausted and the desired product was formed. The reactant was quenched with H2O (50 mL) and the layers were separated. The aqueous layer was extracted with DCM (30 mL×3). The combined organics were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica column chromatography eluting with EtOAc / petroleum ether (15%, v / v) to give 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (10.8 g, 55% yield, 30-2).

[1091] LCMS (ESI, m / z): [M+1] + =295; RT=2.158min.

[1092] Step 2: Synthesis of compound 30-3

[1093]

[1094] To a cooled (-78 ° C) solution of 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (5.0 g, 17.00 mmol, 1.0 equiv) in anhydrous THF (30 mL) was added (i-PrO) 3B (6.4 g, 34.00 mmol, 2.0 equiv). n-BuLi (2.5 mol / L in THF, 13.0 mL, 31.46 mmol, 1.85 equiv) was then added dropwise to the above solution over a period of 30 min, maintaining the reaction temperature between -70 ° C and -65 ° C. After addition, the reaction was stirred at -78 ° C for 3 hours. LCMS analysis showed that the starting material was consumed and the desired product was formed. The reaction mixture was quenched with saturated aqueous NH 4 Cl (saturated, 20 mL) and diluted with MTBE (30 mL). The layers were separated and the aqueous layer was extracted with MTBE (30 mL×3). The combined organic matter is washed with salt water (50mL), dried over anhydrous Na2SO4 and concentrated. The residue is dissolved in MTBE (10mL). Petroleum ether is added dropwise in the solution at 0°C. A white solid is precipitated during the addition of petroleum ether. The resulting suspension is filtered and the filter cake is washed with petroleum ether (30mL). The filter cake is dried under vacuum to obtain (5-methyl-1-(tetrahydro-2H-pyrans-2-yl)-1H-indazole-4-yl)boric acid (4.2g, 95% yield, 30-3), which is directly used in the next step.

[1095] LCMS (ESI, m / z): [M+1] + =261; RT=1.242min.

[1096] Step 3: Synthesis of compound 30-4

[1097]

[1098] To a mixture of (5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)boronic acid (3.0 g, 11.54 mmol, 1.0 equiv) and cyclohept-2-ene-1-one (3.8 g, 34.62 mmol, 3.0 equiv) in H2O (20 mL) was added NaHCO3 (1.94 g, 23.08 mmol, 2.0 equiv) and chloro(1,5-cyclooctadiene)rhodium(I) dimer (0.28 g, 0.58 mmol, 0.05 equiv). The mixture was stirred at 80 ° C under Ar overnight. LCMS analysis showed that the starting material was exhausted and the desired product was formed. The reaction mixture was diluted with EtOAc (30 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (30 mL × 3). The combined organics were washed with brine (30 mL), dried over anhydrous NaSO and concentrated. The residue was purified by silica column chromatography eluting with EtOAc / petroleum ether (20%, v / v) to give 3-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)cycloheptan-1-one (1.3 g, 35% yield, 30-4).

[1099] LCMS (ESI, m / z): [M+1] + =327; RT=1.662min.

[1100] Step 4: Synthesis of compound 30-5

[1101]

[1102] To a solution of 3-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)cycloheptan-1-one (763 mg, 2.34 mmol, 1.0 equiv) and dimethyl carbonate (4.0 mL, 46.81 mmol, 20.0 equiv) in THF (5.0 mL) was added NaH (60% dispersion in mineral oil, 140 mg, 5.85 mmol, 2.5 equiv) and the mixture was stirred at 70 ° C for 2 hours. LCMS analysis showed that the starting material was consumed and the desired product was formed. The reaction mixture was quenched with H2O (10.0 mL) and extracted with EtOAc (20 mL×3). The combined organics were washed with brine (20 ml), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica column chromatography eluting with EtOAc / petroleum ether (20%, v / v) to give methyl 4-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-oxocycloheptane-1-carboxylate (684 mg, 76%, 30-5).

[1103] LCMS (ESI, m / z): [M+1] + =385; RT = 1.918min and 2.315min

[1104] Step 5: Synthesis of compound 30-6

[1105]

[1106] To a solution of methyl 4-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-oxocycloheptane-1-carboxylate (1.74 g, 4.52 mmol, 1.0 equiv) and urea (1.09 g, 18.1 mmol, 4.0 equiv) in anhydrous MeOH (20 mL) was added NaOMe (1.0 M in MeOH, 13.6 mL, 13.6 mmol, 3.0 equiv). The reaction mixture was stirred at 80 ° C under Ar overnight. LCMS analysis showed that the starting material was consumed and the desired product was formed. The reaction mixture was cooled to room temperature and concentrated to dryness. The residue was purified by silica column chromatography eluting with MeOH / DCM (10%, v / v) to give 8-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1,5,6,7,8,9-hexahydro-2H-cyclohepta[d]pyrimidine-2,4(3H)-dione (732 mg, 41%, 30-6).

[1107] LCMS (ESI, m / z): [M+1] + =789; RT=1.507min.

[1108] Step 6: Synthesis of compound 30-7

[1109]

[1110] A mixture of 8-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1,5,6,7,8,9-hexahydro-2H-cyclohepta[d]pyrimidine-2,4(3H)-dione (732 mg, 1.86 mmol) and POCl (15 mL) was stirred at 110 ° C for 1 hour. LCMS analysis showed that the starting material was consumed and the desired product was formed. The reaction mixture was concentrated to dryness. The residue was dissolved in DCM (50 ml) and basified with DIEA to pH = 8-9. The organic layer was washed with H2O (15 mL x 2), dried over anhydrous Na2SO4 and concentrated to give 2,4-dichloro-8-(5-methyl-1H-indazol-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidine (1.40 g, crude, 30-7), which was used directly in the next step.

[1111] LCMS (ESI, m / z): [M+1] + =347; RT=1.972min.

[1112] Step 7: Synthesis of compound 30-9

[1113]

[1114] To a solution of 2,4-dichloro-8-(5-methyl-1H-indazol-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidine (1.40 g, 4.03 mmol, 1.0 equiv) and (S)-2-(cyanomethyl)piperazine-1-carboxylic acid benzyl ester (1.57 g, 6.05 mmol, 1.5 equiv) in anhydrous DMF (14 mL) was added DIEA (3.4 mL, 20.57 mmol, 5.1 equiv). The mixture was stirred at 80 ° C for 2 hours. LCMS analysis showed that the starting material was consumed and the desired product was formed. The reaction mixture was concentrated to dryness. The residue was diluted with water (50 mL) and extracted with DCM (25 mL×3). The combined organics were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica column chromatography eluting with EtOAc / petroleum ether (30% to 70%, v / v) to give (2S)-benzyl 4-(2-chloro-8-(5-methyl-1H-indazol-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (235 mg, 10%, 30-9).

[1115] LCMS (ESI, m / z): [M+1] + =570; RT=1.957min and 2.185min.

[1116] Step 8: Synthesis of Compound 30-10

[1117]

[1118] To a solution of (2S)-4-(2-chloro-8-(5-methyl-1H-indazol-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (235 mg, 0.412 mmol, 1.0 equiv) in anhydrous DCM (5 mL) was added PPTS (16 mg, 0.064 mmol, 0.15 equiv) in one portion followed by DHP (139 mg, 1.65 mmol, 4.0 equiv). The mixture was stirred at room temperature for 20 hours. LCMS analysis showed that most of the starting material was consumed and the desired product was formed. The reaction mixture was concentrated and the residue was purified by preparative TLC eluting with EtOAc / petroleum ether (2:1, v / v) to give (2S)-4-(2-chloro-8-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (236 mg, 87% yield, 30-10).

[1119] LCMS (ESI, m / z): [M+1] + =654; RT=1.940min and 2.107min.

[1120] Step 9: Synthesis of Compound 30-12

[1121]

[1122] To a mixture of (2S)-4-(2-chloro-8-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (236 mg, 0.361 mmol, 1.0 equiv), (S)-(1-methylpyrrolidin-2-yl)methanol (125 mg, 1.08 mmol, 3.0 equiv) and CsCO (353 mg, 1.08 mmol, 3.0 equiv) in toluene (10 mL) was added Pd(dba) (33 mg, 0.0361 mmol, 0.1 equiv) and BINAP (22 mg, 0.0361 mmol, 0.1 equiv). The mixture was stirred at 100° C. under Ar for 10 h. In the mixture of 4-nitro-2-nitro-1-pyrrolidone-2-yl)-2-nitro-2-nitropropene-6-yl)-1H-indazole-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydro-5H-cycloheptane [d] pyrimidine-4-yl)piperazine-1-carboxylic acid benzyl esters (76 mg, 29% yield, 30-12).

[1123] LCMS (ESI, m / z): [M+1] + =733; RT=1.162min.

[1124] Step 10: Synthesis of Compound 30-13

[1125]

[1126] To a solution of (2S)-2-(cyanomethyl)-4-(8-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-4-yl)piperazine-1-carboxylate (76 mg, 0.104 mmol) in anhydrous DCM (3.0 mL) was added TFA (1.0 mL) and the mixture was stirred at room temperature for 2 hours. LCMS analysis showed that the starting material was consumed and the desired product was formed. The reaction mixture was basified with aqueous NaHCO3 (saturated, 15 mL) to pH = 7-8. The organic layer was separated and the aqueous layer was extracted with DCM (8 mL×2). The combined organics were washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative TLC eluting with MeOH / DCM (1:10, v / v) to give (2S)-benzyl 2-(cyanomethyl)-4-(8-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-4-yl)piperazine-1-carboxylate (51 mg, 75% yield, 30-13).

[1127] LCMS (ESI, m / z): [M+1] + =649; RT=1.153min.

[1128] Step 11: Synthesis of Compound 30-14

[1129]

[1130] To a solution of (2S)-2-(cyanomethyl)-4-(8-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-4-yl)piperazine-1-carboxylate (50 mg, 0.077 mmol, 1.0 equiv) in MeOH (5.0 mL) was added Pd(OH) / C (10%, w / w) and the mixture was stirred at room temperature under H (balloon) for 1.5 h. LCMS analysis showed consumption of the starting material and formation of the desired product. The reaction mixture was filtered through celite. The filtrate was concentrated to dryness to give 2-((2S)-4-(8-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (36 mg, 91% yield, 30-14) which was used directly in the next step.

[1131] LCMS (ESI, m / z): [M+1] + =515; RT=0.449min and 0.573min.

[1132] Step 12: Synthesis of Compound 30

[1133]

[1134] To a cooled (-10 °C) solution of 2-((2S)-4-(8-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (36 mg, 0.070 mmol, 1.0 equiv) and EtN (35 mg, 0.350 mmol, 5.0 equiv) in anhydrous DCM (2.5 mL) was added a solution of acryloyl chloride (8.2 mg, 0.091 mmol, 1.3 equiv) in anhydrous DCM (0.5 mL) dropwise. After the addition, the mixture was stirred at -10 °C for 30 min. LCMS analysis showed consumption of the starting material and formation of the desired product. Water (10 mL) was added and the organic layer was separated. The aqueous layer was extracted with DCM (5 mL x 2). The combined organics were dried over anhydrous NaSO and concentrated. The residue was purified by preparative HPLC (ACN-H0 + 0.1% NHHCO) to afford 2-((2S)-1-acryloyl-4-(8-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (2.30 mg, 5.7%, 30).

[1135] LCMS (ESI, m / z): [M+1] + =569; RT = 1.506min;

[1136] 1H NMR (400MHz, CDCl3) δ10.09(s,1H),8.20(s,1H),7.24(s,1H),7.18(d,J=8.4Hz,1H),6.59(brs,1H),6.39(d,J=1 6.4Hz,1H),5.83(d,J=10.0Hz,1H),5.37-4.34(m,3H),4.22-4.13(m,1H),3.96(brs,0.5H),3.80(d,J=13.6Hz,1H ),3.77-3.75(m,0.5H),3.74-3.69(m,1H),3.64(d,J=12.0Hz,1H),3.35-3.24(m,2H),3.22-3.13(m,2H),3.09(d ,J=14.0Hz,1H),3.05-2.88(m,3H),2.80-2.68(m,3H),2.50(s,3H),2.38(s,3H),2.35-2.28(m,2H),2.27-2.19(m 1H),2.18-2.10(m,1H),2.09-2.02(m,1H),1.79-1.74(m,2H),1.53-1.47(m,1H).

[1137] Example 31

[1138]

[1139] Step 1: Synthesis of compound 31-3

[1140]

[1141] To a solution of ethyl 2,6-dichloro-5-nitropyrimidine-4-carboxylate (4.2 g, 0.016 mol, 1.0 equiv) and (S)-2-(cyanomethyl)piperazine-1-carboxylate (4.1 g, 0.016 mol, 1.0 equiv) in anhydrous THF (90 mL) was added DIEA (3.9 mL, 0.023 mol, 1.5 equiv). The reaction mixture was stirred at 0 ° C under Ar for 1 hour. LCMS showed that the starting material was exhausted and the desired product was formed. The reaction mixture was concentrated and purified by silica column chromatography eluted with PE / EA (3: 1, v / v) to give (S)-6-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazine-1-yl)-2-chloro-5-nitropyrimidine-4-carboxylate (5.4 g, 75%, 31-3).

[1142] LCMS (ESI, m / z): [M+1] + =489; RT=1.948min.

[1143] Step 2: Synthesis of compound 31-4

[1144]

[1145] To a mixture of (S)-ethyl 6-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-5-nitropyrimidine-4-carboxylate (5.4 g, 0.01 mol, 1.0 equiv) in anhydrous DMF (60.0 mL) was added (S)-(1-methylpyrrolidin-2-yl)methanol (1.9 g, 0.02 mmol, 1.5 equiv) and DIEA (3.6 mL, 0.02 mol, 2.0 equiv). The mixture was stirred at room temperature for 16 h. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was quenched with H2O (40 mL) and extracted with EA (100 mL×3). The combined organic fractions were washed with brine (20 ml), dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative TLC eluting with DCM / MeOH (15:1, v / v) to give ethyl 6-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5-nitropyrimidine-4-carboxylate (5.4 g, 86%, 31-4).

[1146] LCMS (ESI, m / z): [M+1] + =568; RT=1.097min.

[1147] Step 3: Synthesis of compound 31-5

[1148]

[1149] To a solution of ethyl 6-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin- 1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5-nitropyrimidine-4-carboxylate (5.4 g, 0.01 mol, 1.0 eq) in a mixture solvent of DMF (20 mL) and EtOH (60 mL) was added SnCl2·2H2O (10.8 g, 0.05 mol, 5.0 eq). The reaction mixture was stirred at room temperature under Ar for 16 h. LCMS showed the starting material was consumed and the desired product was formed. The reaction mixture was concentrated to remove EtOH, and then diluted with EtOAc (120 mL), followed by the addition of aq. NaHCO3 (sat., 180 mL). The resulting mixture was filtered through celite. The organic layer of the filtrate was separated, and the aqueous layer was extracted with EtOAc (160 mL x 2). The combined organic portion was washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography on silica with DCM / MeOH (15:1, v / v) as eluent to give ethyl 5-amino-6-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxylate (2.7 g, 53%, 31-5).

[1150] LCMS (ESI, m / z): [M+1] + = 538; RT = 0.984 min.

[1151] Step 4: Synthesis of compound 31-6

[1152]

[1153] To a mixture of ethyl 5-amino-6-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxylate (2.7 g, 0.005 mol, 1.0 eq) in a mixture solvent of MeOH (60 mL) and H2O (10 mL) was added LiOH·H2O (1.1 g, 0.025 mol, 5.0 eq). The mixture was stirred at room temperature for 2 h. LCMS showed the starting material was consumed and the desired product was formed. The reaction mixture was concentrated to give 5-amino-6-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxylic acid (3.7 g, crude, 31-6).

[1154] LCMS (ESI, m / z): [M+1] +=510; RT=0.973min.

[1155] Step 5: Synthesis of compound 31-8

[1156]

[1157] To a solution of 5-amino-6-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxylic acid (400 mg, 0.79 mmol, 1.0 equiv) and 8-chloronaphthalen-1-amine (84 mg, 0.471 mmol, 0.6 equiv) in anhydrous DMF (4.0 mL) was added DIEA (0.4 mL, 2.36 mmol, 3.0 equiv) followed by HATU (299 mg, 0.79 mmol, 1.0 equiv). The reaction mixture was stirred at 60 ° C under Ar for 1 hour. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was cooled to room temperature, diluted with water (30 mL) and extracted with EtOAc (50 mL×3). The combined organic fractions were washed with brine (20 ml), dried over anhydrous NaSO and concentrated. The residue was purified by silica column chromatography eluting with DCM / MeOH (15:1, v / v) to give (S)-benzyl 4-(5-amino-6-((8-chloronaphthalen-1-yl)carbamoyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (214 mg, 41%, 31-8).

[1158] LCMS (ESI, m / z): [M+1] + =669.4; RT=1.255min.

[1159] Step 6: Synthesis of compound 31-9

[1160]

[1161] To a cooled (0 ° C) solution of (S)-benzyl 4-(5-amino-6-((8-chloronaphthalen-1-yl)carbamoyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (189 mg, 0.282 mmol, 1.0 equiv) in anhydrous ACN (2.0 mL) was added pyridine (112 mg, 1.41 mmol, 5.0 equiv) followed by TFAA (178 mg, 0.847 mmol, 3.0 equiv). The mixture was stirred at 0 ° C for 1 hour and then heated to 40 ° C for 2 hours. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative TLC eluting with DCM / MeOH (10:1, v / v) to give (S)-benzyl 4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (49 mg, 23% yield, 31-9).

[1162] LCMS (ESI, m / z): [M+1] + =747.1; RT=1.280min.

[1163] Step 7: Synthesis of Compound 31-10

[1164]

[1165] To a solution of (S)-benzyl 4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (49 mg, 0.066 mmol) in anhydrous ACN (2.5 mL) was added TMSI (105 mg, 0.524 mmol), and the mixture was stirred at room temperature for 1 hour. LCMS showed consumption of the starting material and formation of the desired product. The reaction mixture was treated with Et3N (1.0 mL) and concentrated and purified by preparative TLC eluting with DCM / MeOH (10:1, v / v) to give 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (28 mg, 70% yield, 31-10).

[1166] LCMS (ESI, m / z): [M+1] + =613.2; RT=0.805min.

[1167] Step 8: Synthesis of compounds 31-a and 31-b

[1168]

[1169] To a cooled (0 ° C) solution of 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (140 mg, 0.228 mmol, 1.0 equiv) and Et3N (115 mg, 1.14 mmol, 5.0 equiv) in DCM (2.5 mL) was added dropwise a solution of acryloyl chloride (25 mg, 0.274 mmol, 1.2 equiv) in DCM (0.5 mL). After the addition, the mixture was stirred at 0 ° C for 30 min. LCMS showed that the starting material was consumed and the desired product was formed. Water (15 mL) was added and the organic layer was separated. The aqueous layer was extracted with DCM (8 mL×3). The combined organic fractions were dried over anhydrous NaSO and concentrated. The residue was purified by preparative HPLC (ACN-H0 + 0.1% NHHCO) to give 2-((S)-1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (40.45 mg, 26%, 31). 31:

[1171] LCMS (ESI, m / z): [M+1] + =667.1; RT = 1.669 min;

[1172] 1H NMR (400MHz, CDCl3) δ8.08(d,J=8.1Hz,1H),7.91(d,J=8.1Hz,1H),7.63(t,J=7.8Hz,1H),7.57(d,J=7. 2Hz,1H),7.45(t,J=7.8Hz,2H),6.71-6.55(m,1H),6.42(d,J=16.5Hz,1H),5.85(d,J=10.4Hz,1H),5.36 (d,J=49.2Hz,1H),5.09(s,1H),4.54(t,J=11.6Hz,1H),4.40(dt,J=11.1,5.7Hz,1H),4.20-3.39(m,4H) ,3.13(s,1H),2.96-2.68(m,3H),2.50(s,3H),2.36-2.26(m,1H),2.08-1.98(m,1H),1.87-1.75(m,4H).

[1173] 19 F NMR (376MHz, CDCl3) δ-64.50,-64.78,-64.81.

[1174] Compound 31 (23 mg) was isolated by SFC separation to give two products 31-a (1.76 mg) and 31-b (2.86 mg).

[1175] 31-a:

[1176] LCMS (ESI, m / z): [M+1] + =667.2; RT = 1.760min;

[1177] 31-b:

[1178] LCMS (ESI, m / z): [M+1] + =667.2; RT = 1.750min;

[1179] Step 9: Synthesis of compounds 32-a and 32-b

[1180]

[1181] To a solution of 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (100 mg, 0.163 mmol, 1.0 equiv) and 2-fluoroacrylic acid (29 mg, 0.327 mmol, 2 equiv) in anhydrous DMF (4.0 mL) was added DIEA (63 mg, 0.49 mmol, 3.0 equiv) followed by HATU (124 mg, 0.327 mmol, 2.0 equiv). The reaction mixture was stirred at room temperature under Ar for 2 h. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was cooled to room temperature, diluted with water (15 mL) and extracted with EtOAc (15 mL×2). The combined organic fractions were washed with brine (20 ml), dried over anhydrous NaSO, and concentrated. The residue was purified by preparative HPLC to afford 2-((S)-1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (22.30 mg, 20%, 32). The products were separated by SFC to afford two products, 32-a (4 mg) and 32-b (5 mg).

[1182] 32-a:

[1183] LCMS_(ESI, m / z): [M+1] + =685.4; RT = 1.030min;

[1184] 1 H NMR (400MHz, CDCl3) δ8.29(s,1H),8.09(d,J=7.7Hz,1H),7.92(d,J=7.7Hz,1H),7 .64(t,J=7.8Hz,1H),7.58(d,J=6.8Hz,1H),7.52(d,J=7.2Hz,1H),7.46(t,J=7.8 Hz,1H),5.44(d,J=48.5Hz,2H),5.27(dd,J=16.8,3.6Hz,1H),4.86(ddd,J=14.8, 11.6, 4.0Hz, 3H), 3.81 (t, J = 133.4Hz, 5H), 3.02-2.82 (m, 6H), 2.30-2.09 (m, 6H).

[1185] 19F NMR (376MHz, CDCl3) δ-64.83, -72.48, -74.38.

[1186] 32-b:

[1187] LCMS_(ESI, m / z): [M+1] + =685.3; RT = 1.175min;

[1188] 1 H NMR (400MHz, CDCl3) δ8.39(s,1H),8.09(dd,J=8.4,1.0Hz,1H),7.91(dd,J=8.2,0.9Hz,1H),7.66-7.61(m,1H),7.58(dd,J =7.5,1.1Hz,1H),7.46(dd,J=10.8,4.8Hz,2H),5.45(d,J=47.8Hz,2H),5.28(dd,J=16.8,3.7Hz,1H),5.02-4.77(m,2H),4 .62(dd,J=11.9,4.4Hz,1H),4.00(d,J=155.7Hz,2H),3.56(dd,J=12.5,...

Claims

1. A compound of formula (II) or (III), (II), (III), or a pharmaceutically acceptable salt thereof, in L 1 O or S; L 2 selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl; R 1 is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with one or more R b replace; R 2 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl and heteroaryl, wherein each of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted by one or more R c replace, R 3 Selected from the group consisting of: hydrogen, oxo, halogen, cyano, hydroxyl, -NR d R e 、-C(O)NR d R e , alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl and heteroaryl, wherein each of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with one or more R f replace; or W is a saturated or partially unsaturated cycloalkyl group, or a saturated or partially unsaturated heterocyclyl group, wherein each of the cycloalkyl group and the heterocyclyl group is optionally substituted by one or more R g replace, L 3 is a bond, an alkyl group or -NR d -; B is selected from the group consisting of: 、 、 、 and ; Each R b are independently selected from the group consisting of: oxo, cyano, halogen, hydroxy, acyl, -NR d R e , carbamoyl, carboxyl, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkylalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; Each R c are independently selected from the group consisting of: oxo, halogen, cyano, hydroxy, -NR d R e 、-C(O)OR a 、-C(O)N(R d )(R e ), alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, alkoxy, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl and heteroaryl; wherein, R a are independently hydrogen or alkyl; R d and R e each of is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, wherein each of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, and heteroaryl is optionally substituted with cyano, halogen, hydroxyl, or amino; Each R f are independently selected from the group consisting of: oxo, halogen, cyano, hydroxy, -NR c R d , alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; Each R g are independently selected from the group consisting of: oxo, cyano, halogen, hydroxyl, -NR d R e , carbamoyl, carboxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl and saturated or partially unsaturated heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl and heterocyclyl is optionally substituted by cyano, halogen, hydroxyl, -NR d R e , carboxyl, carbamoyl, haloalkyl, aryl or heteroaryl; Wherein, the compound is not the compound shown below: 、 、 、 、 、 、 、 、 、 、 、 、 or .

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 1 It is O.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 2 is the key.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 2 For alkyl.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein L 2 is methyl, ethyl or propyl.

6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R 1 is a saturated or partially unsaturated cycloalkyl group, or a saturated or partially unsaturated heterocyclic group, wherein each cycloalkyl group and heterocyclic group is optionally substituted by one or more R b replace.

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein each R b Selected from the group consisting of: oxo, cyano, halogen, hydroxy, acyl, -NR d R e , alkyl, alkoxy, alkoxyalkyl and cycloalkylalkyl.

8. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein R 1 is a saturated or partially unsaturated heterocyclic group selected from the group consisting of: 、 、 、 、 、 、 、 、 、 、 、 、 and , Each of which is optionally treated with one or more R b replace.

9. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein each R b Selected from the group consisting of: oxo, halogen, acyl, -NR d R e , alkyl, alkoxy, alkoxyalkyl and cycloalkylalkyl.

10. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein each R b is halogen or alkyl.

11. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein each R b is fluorine, chlorine or methyl.

12. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein R 1 for .

13. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein R 1 for .

14. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein -L 1 -L 2 -R 1 for 、 or .

15. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein -L 1 -L 2 -R 1 for 、 or .

16. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is optionally through one or more R c Substituted aryl.

17. The compound according to claim 16 or a pharmaceutically acceptable salt thereof, wherein each R c Selected from the group consisting of halogen, cyano, hydroxy, alkyl, alkenyl, alkoxy and saturated or partially unsaturated cycloalkyl.

18. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is an aryl group selected from the group consisting of: 、 and , Each of which is optionally treated with one or more R c replace.

19. The compound according to claim 18 or a pharmaceutically acceptable salt thereof, wherein each R c Selected from the group consisting of halogen, hydroxy, alkyl, alkenyl, alkoxy and saturated or partially unsaturated cycloalkyl.

20. The compound according to claim 18 or a pharmaceutically acceptable salt thereof, wherein each R c Selected from the group consisting of halogen, hydroxy, alkyl, alkenyl, alkoxy and saturated cycloalkyl.

21. The compound according to claim 18 or a pharmaceutically acceptable salt thereof, wherein each R c Selected from the group consisting of fluoro, chloro, hydroxy, methyl, ethyl, 2-methylpropenyl, methoxy and cyclopropyl.

22. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from the group consisting of: 、 、 、 、 、 、 、 、 and .

23. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is optionally through one or more R c Substituted heteroaryl.

24. The compound according to claim 23 or a pharmaceutically acceptable salt thereof, wherein each R c Selected from the group consisting of: halogen, cyano, hydroxy, -NR d R e , alkyl, alkenyl, alkoxy and saturated or partially unsaturated cycloalkyl.

25. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is a heteroaryl group selected from the group consisting of: 、 、 、 、 、 、 and , Each of which is optionally treated with one or more R c replace.

26. The compound according to claim 25 or a pharmaceutically acceptable salt thereof, wherein each R c Selected from the group consisting of: halogen, cyano, hydroxy, -NR d R e , alkyl, alkenyl, alkoxy and saturated or partially unsaturated cycloalkyl.

27. The compound according to claim 26 or a pharmaceutically acceptable salt thereof, wherein each R c is halogen or alkyl.

28. The compound according to claim 27 or a pharmaceutically acceptable salt thereof, wherein each R c Selected from the group consisting of fluoro, chloro, methyl and ethyl.

29. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from the group consisting of: 、 and .

30. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from the group consisting of: oxo, alkyl and aryl, wherein alkyl and aryl are optionally substituted by one or more R c replace.

31. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R c Selected from the group consisting of: halogen, cyano, hydroxy, -NR c R d ,alkyl.

32. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from the group consisting of oxo, methyl, ethyl, trifluoromethyl and phenyl.

33. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein two R 3 Together with the atoms to which they are attached, they form a saturated or partially unsaturated cycloalkyl group optionally substituted with one or more substituents selected from the group consisting of cyano, halogen, hydroxyl and -NR c R d .

34. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein W is optionally substituted with one or more R g a substituted saturated or partially unsaturated heterocyclic group.

35. The compound according to claim 32 or a pharmaceutically acceptable salt thereof, wherein R g is an alkyl group optionally substituted with one or more substituents selected from the group consisting of cyano, halogen and hydroxy.

36. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein W is a heterocyclic group selected from the group consisting of: 、 、 、 、 、 、 、 、 、 、 、 and , Each of which is optionally treated with one or more R g replace.

37. The compound according to claim 34 or a pharmaceutically acceptable salt thereof, wherein each R g is an alkyl group optionally substituted with a cyano group.

38. The compound according to claim 35 or a pharmaceutically acceptable salt thereof, wherein each R g is a methyl group optionally substituted by a cyano group.

39. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein W is selected from the group consisting of: 、 、 、 、 、 、 、 、 、 、 、 、 and .

40. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 3 is a bond or -NR d -.

41. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 Together with the atoms to which they are attached, they form a saturated or partially unsaturated cycloalkyl, or a saturated or partially unsaturated heterocyclyl, wherein each of the cycloalkyl and heterocyclyl groups is optionally substituted by cyano, halogen, hydroxy, -NR c R d , carboxyl, carbamoyl, aryl or heteroaryl; or R 3 Together with the atoms to which they are attached, they form a saturated or partially unsaturated cycloalkyl, or a saturated or partially unsaturated heterocyclyl, wherein each of the cycloalkyl and heterocyclyl groups is optionally substituted by cyano, halogen, hydroxy, -NR c R d , carboxyl, carbamoyl, aryl or heteroaryl.

42. The compound of claim 1 or a pharmaceutically acceptable salt thereof, having a formula selected from the group consisting of: (IIa)、 (IIIa)。 43. The compound of claim 1 or a pharmaceutically acceptable salt thereof, having a formula selected from the group consisting of: (IIb)、 (IIIb), Where m is 0, 1, 2, 3 or 4.

44. The compound of claim 1 or a pharmaceutically acceptable salt thereof, having a formula selected from the group consisting of: (IIc)、 (IIIc), Where m is 0, 1, 2, 3 or 4.

45. The compound of claim 1 or a pharmaceutically acceptable salt thereof, having a formula selected from the group consisting of: (IId)、 (IIId).

46. ​​The compound of claim 1 or a pharmaceutically acceptable salt thereof, having a formula selected from the group consisting of: (IIj) and (IIIj)。 47. The compound of claim 1 or a pharmaceutically acceptable salt thereof, having a formula selected from the group consisting of: (IIk) and (IIIk)。 48. A compound according to any one of claims 41 to 47, or a pharmaceutically acceptable salt thereof, wherein L 2 For alkyl.

49. A compound according to any one of claims 41 to 47, or a pharmaceutically acceptable salt thereof, wherein R 1 for or .

50. A compound according to any one of claims 41 to 47, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from methyl, ethyl or trifluoromethyl.

51. The compound of claim 1 or a pharmaceutically acceptable salt thereof, having a formula selected from the group consisting of: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 and .

52. A pharmaceutical composition comprising a compound according to any one of claims 1 to 51 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

53. The pharmaceutical composition of claim 52, wherein the pharmaceutical composition is formulated for oral administration.

54. The pharmaceutical composition of claim 52, wherein the pharmaceutical composition is formulated for injection.

55. Use of a compound according to any one of claims 1 to 51 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 52 to 54, in the manufacture of a medicament for treating cancer.

56. The use according to claim 55, wherein the cancer is lung cancer, bone cancer, pancreatic cancer, cancer of the head or neck, skin or intraocular melanoma, uterine cancer, ovarian cancer, cancer of the anal region, stomach cancer, breast cancer, blood cancer, colorectal cancer, fallopian tube cancer, vaginal cancer, vulvar cancer, esophageal cancer, small intestine cancer, endocrine system cancer, soft tissue sarcoma, penile cancer, prostate cancer, bladder cancer, cancer of the kidney or ureter, or a central nervous system (CNS) neoplasm.

57. The use according to claim 55, wherein the cancer is skin cancer, rectal cancer, endometrial cancer, cervical cancer, Hodgkin's Disease, thyroid cancer, parathyroid cancer, adrenal cancer, urethral cancer, chronic or acute leukemia, lymphocytic lymphoma, renal cell carcinoma, renal pelvis cancer, primary CNS lymphoma, spinal axis tumor, brainstem glioma, MYH-associated polyposis or pituitary adenoma.

58. The use according to claim 55, wherein the cancer is associated with KRas G12C mutation.

59. The use according to claim 58, wherein the cancer is a blood cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer or lung cancer.

60. Use of a compound according to any one of claims 1 to 51 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 52 to 54, in the manufacture of a medicament for modulating the activity of a KRas G12C mutant protein. A method for preparing a labeled KRas G12C mutant protein, comprising reacting the KRas G12C mutant protein with a compound according to any one of claims 1 to 51 or a pharmaceutically acceptable salt thereof to obtain the labeled KRas G12C mutant protein.

62. Use of a compound according to any one of claims 1 to 51 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 52 to 54, in the manufacture of a medicament for inhibiting tumor metastasis.

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