Disclosure of Invention
The present application provides novel compounds that are inhibitors of the PI3K subtype. Also provided are compositions, including pharmaceutical compositions, kits comprising the compounds, and methods of using and making the compounds. The compounds provided herein are useful for treating diseases, disorders, or conditions mediated by the PI3K subtype. The present application also provides compounds for use in therapy. The present application also provides compounds for use in methods of treating diseases, disorders, or conditions mediated by the PI3K subtype. Further, the present application provides the use of the compound in the manufacture of a medicament for the treatment of a disease, disorder or condition mediated by the PI3K subtype.
The present application provides compounds having the structure of formula (I):
wherein:
x, Y and Z are independently selected from C (R ') or N, wherein at least one of X, Y and Z is C (R');
n is 0, 1,2, 3 or 4;
m' is 0 or 1;
a is a single bond or C (O);
each R' is independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted haloalkyl, and optionally substituted cycloalkyl;
each R1Independently selected from halogen, cyano, optionally substituted C1-6Alkyl, optionally substituted C1-6Alkoxy, hydroxy, optionally substituted C3-8Cycloalkyl and optionally substituted sulfonyl;
each R2Independently selected from halogen, optionally substituted C1-6Alkyl, optionally substituted C1-6Haloalkyl and optionally substituted C3-8A cycloalkyl group;
R3is hydrogen, optionally substituted C1-6Alkyl, optionally substituted C3-8Cycloalkyl, or optionally substituted C6-10An aryl group;
R4is a 6 to 12 membered heteroaryl having at least two heteroatoms, wherein each heteroatom is independently selected from N, O or S, wherein the heteroaryl is optionally substituted with one, two or three members independently selected from: halogen, cyano, -NH2Optionally substituted C1-6Alkyl, optionally substituted C2-6An alkynyl group; and
R5is hydrogen or optionally substituted C1-6An alkyl group; r5And R3Optionally together with the atoms to which they are attached form a 4-to 8-membered hetero ringA ring;
or a pharmaceutically acceptable salt, isomer or mixture thereof.
In one aspect, the compounds of the present application have the structure of formula (I) wherein:
a is a single bond or C (O);
each R' is independently selected from hydrogen, halogen, C1-4Alkyl radical, C1-4Haloalkyl, or C3-6Cycloalkyl, wherein the alkyl moiety is optionally substituted with C1-4An alkoxy group;
each R1Independently selected from halogen, cyano, C1-4Alkyl radical, C1-4Haloalkyl, or-SO2C1-4An alkyl group;
each R2Independently selected from halogen, C1-4Alkyl radical, C1-4Haloalkyl, or C3-6Cycloalkyl, wherein the alkyl moiety is optionally substituted with C1-4An alkoxy group;
R3is hydrogen, C1-4Alkyl radical, C3-6Cycloalkyl, or C6-10An aryl group; wherein the alkyl moiety is optionally substituted with hydroxy or C1-4Alkoxy radical, wherein C1-4Alkoxy being optionally substituted by C6-10An aryl group;
R4is a 6 to 12 membered heteroaryl having at least one aromatic ring and at least two nitrogen atoms, wherein the heteroaryl is optionally substituted with one, two or three members independently selected from: halogen, cyano, -NH2、C2-4Alkynyl, C1-4Haloalkyl and C1-4Alkyl radical, wherein said C2-4Alkynyl moiety optionally substituted with C6-10Aryl or C3-8Heteroaryl group, wherein C6-10Aryl and C3-8Each of the heteroaryl moieties is optionally substituted with one, two or three members independently selected from: halogen and C1-6A haloalkyl group;
R5is hydrogen or C1-4An alkyl group; r5And R3Optionally together with the nitrogen to which they are attached form a 5-membered heterocyclic ring;
or a pharmaceutically acceptable salt, isomer or mixture thereof.
In other aspects, the compounds of the present application have the structure of formula (I), wherein each R is1Selected from the group consisting of fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyano, methylsulfonyl and ethylsulfonyl. In other aspects, each R2Selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, methoxymethyl, methoxyethyl, ethoxymethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, cyclopropyl and cyclobutyl. In some aspects, the compounds of the present application have the structure of formula (I), wherein R3Selected from the group consisting of methyl, ethyl, propyl, cyclopropyl, cyclobutyl, phenyl, benzyloxymethyl, benzyloxyethyl, benzyloxypropyl, -CH2OH、-C2H4OH or-C3H6And (5) OH. In a certain aspect, R5Selected from hydrogen, methyl, ethyl or propyl. In other aspects, R3And R5Optionally together with the atoms to which they are attached form a pyrrolidinyl group. In some aspects, wherein R4Is a monocyclic heteroaryl group having at least two nitrogen atoms, wherein R is4Optionally substituted with two or three members independently selected from: halogen, cyano, -NH2、C1-4Alkyl and optionally substituted C2-4Alkynyl. In some other aspects, R4Is a bicyclic heteroaryl having at least one aromatic ring, at least two nitrogen atoms and at least one other heteroatom selected from N, O or S, wherein R is4Optionally substituted with one, two or three members independently selected from: halogen, cyano, -NH2And C1-4An alkyl group. In other aspects, R4Selected from the group consisting of purinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolopyrimidinyl, pyridopyrimidinyl, thienopyrimidinyl, thionopyrimidinyl, and,A pyrrolopyrimidinyl, furopyrimidinyl or imidazotriazinyl group; wherein each moiety is optionally substituted with one, two or three members selected from: halogen, cyano, -NH2、C1-4Alkyl radical, C2-4Alkynyl, wherein said C2-4Alkynyl moiety optionally substituted with C6-10Aryl or C4-8Heteroaryl, wherein said C6-10Aryl or C3-8Each of the heteroaryl moieties is optionally substituted with one, two or three members independently selected from: fluorine, chlorine, bromine, iodine, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl and trifluoroethyl.
In certain embodiments, the PI3K inhibitor is a compound selected from table 1, a pharmaceutically acceptable salt, isomer, or a mixture thereof. In some embodiments, the PI3K inhibitor is a compound selected from table 1a, a pharmaceutically acceptable salt, isomer, or mixture thereof. In other embodiments, the compound is the (S) -enantiomer. In other embodiments, the compound is the (R) -enantiomer. In other embodiments, the compound is an atropisomer.
The present application also provides a pharmaceutical composition comprising a compound of formula (I), a pharmaceutically acceptable salt, isomer, or mixture thereof, and at least one pharmaceutically acceptable carrier. Examples of pharmaceutically acceptable carriers may be selected from carriers, adjuvants and excipients.
Also provided herein is a method of treating a disease, disorder or condition in a human in need thereof by administering to the human a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, isomer or mixture thereof. Also provided are compounds of formula (I) for use in a method of treating a PI3K subtype-mediated disease, disorder, or condition. The present application also provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment of a disease, disorder or condition mediated by the PI3K subtype. In certain embodiments, the disease, disorder or condition is associated with PI3K or mediated through PI 3K. In some embodiments, the disease, disorder, or condition is an inflammatory disease. In other embodiments, the disease, disorder, or condition is cancer.
Also provided herein are methods of inhibiting the activity of a phosphatidylinositol 3-kinase polypeptide by contacting the polypeptide with a compound of formula (I) or a pharmaceutically acceptable salt, isomer, or mixture thereof.
Also provided are methods of inhibiting an excessive or destructive immune response comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, isomer, or mixture thereof.
Also provided is a method of inhibiting the growth or proliferation of a cancer cell comprising contacting the cancer cell with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, isomer or mixture thereof.
Also provided are kits comprising a compound of formula (I) or a pharmaceutically acceptable salt, isomer, or mixture thereof. The kit may further comprise a label and/or instructions indicating that the compound is for use in treating a disease, disorder, or condition in a human in need thereof. In some embodiments, the disease, disorder or condition may be associated with PI3K activity or mediated by PI3K activity.
Also provided is an article of manufacture comprising a compound of formula (I) or a pharmaceutically acceptable salt, isomer, or mixture thereof and a container. In one embodiment, the container may be a bottle, a canister, an ampoule, a pre-loaded syringe, or an intravenous bag.
Detailed Description
The following description sets forth exemplary methods, parameters, and the like. These descriptions are not intended as limitations on the scope of the application, but are provided as exemplary embodiments.
As used herein, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except where the context indicates otherwise.
A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH2Attached via a carbon atom. A dashed line at the front or end of the chemical group is for convenience; chemical groups can be delineated with or without the presence of one or more dashed lines without losing their ordinary meaning. The wavy line drawn through the line in the structure indicates the point of attachment of the group. The order in which chemical groups are written or named does not indicate or imply directionality unless chemically or structurally required.
Prefix "Cu-v"represents that the following groups have u to v carbon atoms. For example, "C1-6Alkyl "means that the alkyl group has 1 to 6 carbon atoms.
Herein, reference to "about" a value or parameter includes (and describes) embodiments that are directed to that value or parameter itself. In certain embodiments, the term "about" includes the indicated amount ± 10%. In other embodiments, the term "about" includes the indicated amount ± 5%. In certain other embodiments, the term "about" includes the indicated amount ± 1%. Furthermore, the term "about X" includes a description of "X". Furthermore, the singular forms "a" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "the compound" includes a plurality of such compounds and reference to "the assay" includes reference to one or more assays and equivalents thereof known to those skilled in the art.
"alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As described herein, an alkyl group has 1 to 20 carbon atoms (i.e., C)1-20Alkyl group), 1 to 8 carbon atoms (i.e., C)1-8Alkyl group), 1 to 6 carbon atoms (i.e., C)1-6Alkyl), or 1 to 4 carbon atoms (i.e., C)1-4Alkyl groups). Examples of the alkyl group include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methylpentyl. When an alkyl group having a specific number of carbons is named, all geometric isomers having that number of carbons may be included; thus, for example, "butyl" includes n-butyl, sec-butyl, isobutyl, and tert-butyl; ' CThe group "includes n-propyl and isopropyl groups.
"alkenyl" means containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C)2-20Alkenyl) of 2 to 8 carbon atoms (i.e., C)2-8Alkenyl) of 2 to 6 carbon atoms (i.e., C)2-6Alkenyl), or 2 to 4 carbon atoms (i.e., C)2-4Alkenyl) groups. Examples of alkenyl groups include ethenyl, propenyl, butadienyl (including 1, 2-butadienyl and 1, 3-butadienyl).
"alkynyl" means containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C)2-20Alkynyl) of 2 to 8 carbon atoms (i.e., C)2-8Alkynyl) of 2 to 6 carbon atoms (i.e., C)2-6Alkynyl), or 2 to 4 carbon atoms (i.e., C)2-4Alkynyl) groups. The term "alkynyl" also includes those groups having one triple bond and one double bond.
"alkoxy" refers to the group "alkyl-O-". Examples of the alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy and 1, 2-dimethylbutoxy.
"acyl" refers to the group-C (═ O) R, where R is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of acyl groups include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl and benzoyl.
"amido" means a "C-amido" group (which means a group-C (═ O) NR)yRz) And an "N-amido" group (which refers to the group-NR)yC(═O)Rz) Wherein R isyAnd RzIndependently selected from hydrogen, alkyl, aryl, haloalkyl, or heteroaryl; each of which may be optionally substituted.
"amino" means a radical-NRyRzWherein R isyAnd RzIndependently selected from hydrogen, alkyl, haloalkyl, arylOr heteroaryl; each of which may be optionally substituted.
"aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) including fused systems. As described herein, an aryl group has from 6 to 20 ring carbon atoms (i.e., C)6-20Aryl group) of 6 to 12 carbon ring atoms (i.e., C)6-12Aryl), or 6 to 10 carbon ring atoms (i.e., C)6-10Aryl). Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthracenyl. However, aryl does not include or overlap in any way with heteroaryl as defined below. If one or more aryl groups are fused to the heteroaryl ring, the resulting ring system is heteroaryl.
"cyano" or "carbonitrile" refers to the group-CN.
"cycloalkyl" refers to a saturated or partially saturated cyclic alkyl group having a single ring or multiple rings (including fused, bridged, and spiro ring systems). The term "cycloalkyl" includes cycloalkenyl (i.e., a cyclic group having at least one alkenyl group). As described herein, cycloalkyl groups have from 3 to 20 ring carbon atoms (i.e., C)3-20Cycloalkyl) of 3 to 12 ring carbon atoms (i.e., C)3-12Cycloalkyl) of 3 to 10 ring carbon atoms (i.e., C)3-10Cycloalkyl) of 3 to 8 ring carbon atoms (i.e., C)3-8Cycloalkyl) or 3 to 6 ring carbon atoms (i.e., C)3-6Cycloalkyl groups). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
"halogen" or "halo" includes fluorine, chlorine, bromine and iodine. "haloalkyl" means an unbranched or branched alkyl group as defined above in which one or more hydrogen atoms are replaced by halogen. For example, when a group is substituted with more than one halogen, it can be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two ("di") or three ("tri") halo groups, which can be, but need not be, the same halo. Examples of haloalkyl groups include difluoromethyl (-CHF)2) And trifluoromethyl (-CF)3)。
"heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatom group. As an example, 1,2 or 3 carbon atoms may independently be replaced by the same or different heteroatom groups. Heteroatom groups include, but are not limited to, -NR-, -O-, -S-, -S (O) -, -S (O)2-and the like, wherein R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, or heterocycloalkyl, each of which may be optionally substituted. Examples of heteroalkyl groups include-OCH3、-CH2OCH3、-SCH3、-CH2SCH3、-NRCH3and-CH2NRCH3Wherein R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted. As described herein, heteroalkyl groups include 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.
"heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, wherein one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As described herein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., C)1-20Heteroaryl) of 3 to 12 ring carbon atoms (i.e., C)3-12Heteroaryl), or 3 to 8 carbon ring atoms (i.e., C)3-8Heteroaryl); and 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does not include or overlap with aryl as defined above.
"heterocycloalkyl" refers to a saturated or unsaturated cycloalkyl group in which one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur. The term "heterocycloalkyl" includes heterocycloalkenyl (i.e., a heterocycloalkyl group having at least one alkenyl group). The heterocycloalkyl group can be monocyclic or polycyclic, wherein the polycyclic can be fused, bridged, or spirocyclic. As described herein, heterocycloalkyl has 2 to 20 ring carbon atoms (I.e. C2-20Heterocycloalkyl), 2 to 12 ring carbon atoms (i.e., C)2-12Heterocycloalkyl group), 2 to 10 ring carbon atoms (i.e., C)2-10Heterocycloalkyl), 2 to 8 ring carbon atoms (i.e., C)2-8Heterocycloalkyl), 3 to 12 ring carbon atoms (i.e., C)3-12Heterocycloalkyl), 3 to 8 ring carbon atoms (i.e., C)3-8Heterocycloalkyl group), or 3 to 6 ring carbon atoms (i.e., C)3-6Heterocycloalkyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur, or oxygen. Examples of heterocycloalkyl include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl and morpholinyl.
"hydroxy" refers to the group-OH.
"oxo (oxo)" refers to a group (═ O) or (O).
"Sulfonyl" refers to the group-S (O)2R, wherein R is alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl. Examples of sulfonyl groups are methylsulfonyl, ethylsulfonyl, phenylsulfonyl and tosyl.
Certain common alternative chemical names may be used. For example, divalent groups such as divalent "alkyl", divalent "aryl", and the like may also be referred to as "alkylene or alkenyl", and "arylene" respectively. In addition, unless otherwise defined, where a combination of groups is referred to herein as a moiety (e.g., arylalkyl), the last-mentioned group contains an atom that connects the moiety to the rest of the molecule.
The terms "optional" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. Further, the term "optionally substituted" means that any one or more hydrogen atoms on the designated atom or group may or may not be replaced with a moiety other than hydrogen.
The term "substituted" means that any one or more hydrogen atoms on the designated atom or group is replaced with a moiety other than hydrogen, provided that the designated atom's normal valence is not exceeded. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amide, amidino, aryl, azido, carbamoyl, carboxyl ester, cyano, guanidino, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, hydroxyl, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, mercapto, thioketo, or combinations thereof. As an example, 1,2, 3,4,5 or 6 substituents may be present. It is contemplated herein to exclude polymers or similarly undefined structures obtained by further infinitely defined substituents with attached substituents (e.g., substituted aryl with substituted alkyl groups themselves substituted with substituted aryl groups, substituted aryl groups further substituted with substituted heteroalkyl groups, etc.). Unless otherwise stated, the maximum number of consecutive substitutions in the compounds described herein is 3. For example, sequential substitution of a substituted aryl group with 2 other substituted aryl groups is limited to substituted aryl groups (substituted aryl groups). Similarly, the above definitions are intended to exclude impermissible substitution patterns (e.g., methyl substituted with 5 fluorines or heteroaryl having two adjacent oxygen ring atoms). These impermissible substitution patterns are well known to those skilled in the art. When used to modify a chemical group, the term "substituted" can describe other chemical groups defined herein. For example, the term "substituted aryl" includes, but is not limited to, "alkylaryl". Unless otherwise stated, when a group is described as optionally substituted, any substitution of that group is essentially unsubstituted.
In some embodiments, the term "substituted alkyl" refers to alkyl groups having one or more substituents including hydroxy, halo, alkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. In other embodiments, "substitutionThe "cycloalkyl group" of (a) means a cycloalkyl group having one or more substituents including alkyl, haloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, halogen, hydroxy; "substituted aryl" refers to aryl having one or more substituents including halogen, alkyl, haloalkyl, heterocycloalkyl, heteroaryl, alkoxy, and cyano, and "substituted sulfonyl" refers to the group-S (O)2R, wherein R is substituted with one or more substituents selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In other embodiments, the one or more substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with halogen, alkyl, haloalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is unsubstituted.
PI3K inhibitor compounds
The present application provides compounds that are inhibitors of the PI3K subtype. In one aspect, the PI3K inhibitor is a compound having the structure of formula (J):
wherein:
w is CH or N;
x, Y and Z are independently selected from C (R ') or N, wherein at least one of X, Y and Z is C (R');
n is 0, 1,2, 3 or 4;
m' is 0 or 1; a' is OR4、N(R5)C(O)R4Or NR5R4；
Each R' is independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted haloalkyl, and optionally substituted cycloalkyl;
each R1Independently selected from the group consisting of halogen, cyano, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted sulfonyl;
each R2Independently selected from the group consisting of halogen, optionally substituted alkyl, optionally substituted haloalkyl, and optionally substituted cycloalkyl;
R3is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted aryl;
R4is heteroaryl optionally substituted with one, two or three members independently selected from: halogen, cyano, -NH2Optionally substituted alkyl, optionally substituted haloalkyl and optionally substituted alkynyl; and
R5is hydrogen or optionally substituted alkyl, wherein R5And R3Optionally together with the atoms to which they are attached form a heterocyclic ring;
or a pharmaceutically acceptable salt, isomer or mixture thereof.
In certain embodiments, the compound has formula (J), wherein
W is CH or N;
x, Y and Z are independently selected from C (R ') or N, wherein at least one of X, Y and Z is C (R');
n is 0, 1,2, 3 or 4;
m' is 0 or 1; a' is OR4、N(R5)C(O)R4Or NR5R4；
Each R' is independently selected from hydrogen, halogen, -NH2Optionally substituted alkyl, optionally substituted haloalkyl and optionally substituted cycloalkyl;
each R1Independently selected from the group consisting of halogen, cyano, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted sulfonyl;
each R2Independently selected from halogen, -NH2Optionally substituted alkyl, optionally substituted haloalkyl and optionally substituted cycloalkyl;
R3is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted aryl;
R4is heteroaryl optionally substituted with one, two or three members independently selected from: halogen, cyano, -NH2Optionally substituted alkyl, optionally substituted haloalkyl and optionally substituted alkynyl; and
R5is hydrogen or optionally substituted alkyl, wherein R5And R3Optionally together with the atoms to which they are attached form a heterocyclic ring;
or a pharmaceutically acceptable salt, isomer or mixture thereof.
In another aspect, the PI3K inhibitor is a compound having the structure of formula (I):
wherein:
x, Y and Z are independently selected from C (R ') or N, wherein at least one of X, Y and Z is C (R');
n is 0, 1,2, 3 or 4;
m' is 0 or 1;
a is a single bond or C (O);
each R' is independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted haloalkyl, and optionally substituted cycloalkyl;
each R1Independently selected from halogen, cyano, optionally substituted C1-6Alkyl, optionally substituted C1-6Alkoxy, hydroxy, optionally substituted C3-8Cycloalkyl and optionally substituted sulfonyl;
each R2Independently selected from halogen, optionally substituted C1-6Alkyl, optionally substituted C1-6Haloalkyl and optionally substituted C3-8A cycloalkyl group;
R3is hydrogen, optionally substituted C1-6Alkyl, optionally substituted C3-8Cycloalkyl, or optionally substituted C6-10An aryl group;
R4is a 6 to 12 membered heteroaryl having at least two heteroatoms, wherein each heteroatom is independently selected from N, O or S, wherein the heteroaryl is optionally substituted with one, two or three members independently selected from: halogen, cyano, -NH2Optionally substituted C1-6Alkyl, optionally substituted C2-6An alkynyl group; and
R5is hydrogen or optionally substituted C1-6An alkyl group; r5And R3Optionally taken together with the atoms to which they are attached form a 4-to 8-membered heterocyclic ring;
or a pharmaceutically acceptable salt, isomer or mixture thereof.
The present application also provides compounds of formula (I), wherein
X, Y and Z are independently selected from C (R') or N, wherein at least one of X, Y and Z is N;
n is 1 or 2;
m' is 0 or 1;
a is a single bond or C (O);
each R' is independently selected from hydrogen, halogen, C1-4Alkyl radical, C1-4Haloalkyl, or C3-6Cycloalkyl, wherein the alkyl moiety is optionally substituted with C1-4An alkoxy group;
each R1Independently selected from halogen, cyano, C1-4Alkyl radical, C1-4Haloalkyl, and-SO2C1-4An alkyl group;
each R2Independently selected from halogen, C1-4Alkyl radical, C1-4Haloalkyl, and C3-6Cycloalkyl, wherein the alkyl moiety is optionally substituted with C1-4An alkoxy group;
R3is hydrogen, C1-4Alkyl radical, C3-6Cycloalkyl, or C6-10An aryl group; wherein the alkyl moiety is optionally substituted with hydroxy or C1-4Alkoxy radical, wherein C1-4Alkoxy being optionally substituted by C6-10An aryl group;
R4is a 6 to 12 membered heteroaryl having at least one aromatic ring and at least two nitrogen atoms, wherein the heteroaryl is optionally substituted with 1 to 3 members independently selected from: halogen, cyano, -NH2、C2-4Alkynyl, C1-4Haloalkyl and C1-4Alkyl radical, wherein said C2-4Alkynyl moiety optionally substituted with C6-10Aryl or C3-8Heteroaryl group, wherein C6-10Aryl and C3-8Each of the heteroaryl moieties is optionally substituted with halogen or C1-6A haloalkyl group;
R5is hydrogen or C1-4An alkyl group; r5And R3Optionally together with the nitrogen to which they are attached form a 5-membered heterocyclic ring;
or a pharmaceutically acceptable salt, isomer or mixture thereof.
In certain embodiments, the compound has the structure of formula (I), wherein
X, Y and Z are independently selected from C (R') or N, wherein at least one of X, Y and Z is N;
n is 1 or 2;
m' is 0 or 1;
a is a single bond or C (O);
each R' is independently selected from hydrogen, halogen, -NH2、C1-4Alkyl radical, C1-4Haloalkyl, or C3-6Cycloalkyl, wherein the alkyl moiety is optionally substituted with C1-4An alkoxy group;
each R1Independently selected from halogen, cyano, C1-4Alkyl radical, C1-4Haloalkyl, and-SO2C1-4An alkyl group;
each R2Independently selected from halogen, -NH2、C1-4Alkyl radical, C1-4Haloalkyl, and C3-6Cycloalkyl, wherein the alkyl moiety is optionally substituted with C1-4An alkoxy group;
R3is hydrogen, C1-4Alkyl radical, C3-6Cycloalkyl, or C6-10An aryl group; wherein the alkyl moiety is optionally substituted with hydroxy or C1-4Alkoxy radical, wherein C1-4Alkoxy being optionally substituted by C6-10An aryl group;
R4is a 6 to 12 membered heteroaryl having at least one aromatic ring and at least two nitrogen atoms, wherein the heteroaryl is optionally substituted with 1 to 3 members independently selected from: halogen, cyano, -NH2、C2-4Alkynyl, C1-4Haloalkyl and C1-4Alkyl radical, wherein said C2-4Alkynyl moiety optionally substituted with C6-10Aryl or C3-8Heteroaryl group, wherein C6-10Aryl and C3-8Each of the heteroaryl moieties is optionally substituted with halogen or C1-6A haloalkyl group;
R5is hydrogen or C1-4An alkyl group; r5And R3Optionally together with the nitrogen to which they are attached form a 5-membered heterocyclic ring;
or a pharmaceutically acceptable salt, isomer or mixture thereof.
In one embodiment, the compound has the structure of formula (I), wherein
Each R1Selected from the group consisting of fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyano, methylsulfonyl, and ethylsulfonyl;
each R2Selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, methoxymethyl, methoxyethyl, ethoxymethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, cyclopropyl and cyclobutyl;
R3selected from the group consisting of methyl, ethyl, propyl, cyclopropyl, cyclobutyl, phenyl, benzyloxymethyl, benzyloxyethyl, benzyloxypropyl, -CH2OH、-C2H4OH or-C3H6OH；
R5Selected from hydrogen, methyl, ethyl or propyl; and
R4selected from purinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolopyrimidinyl, pyridopyrimidinyl, thienopyrimidinyl, pyrrolopyrimidinyl, furopyrimidinyl or imidazotriazinyl; wherein each of the purinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolopyrimidinyl, pyridopyrimidinyl, thienopyrimidinyl, pyrrolopyrimidinyl, furopyrimidinyl, or imidazotriazinyl moieties is optionally substituted with 1 to 3 members selected from: halogen, cyano, -NH2、C1-4Alkyl radical, C2-4Alkynyl, wherein said C2-4Alkynyl moiety optionally substituted with C6-10Aryl or C4-8Heteroaryl, wherein said C6-10Aryl or C3-8Each of the heteroaryl moieties is optionally substituted with one, two or three members selected from: fluorine, chlorine, bromine, iodine, fluoromethaneAnd (b) a group selected from the group consisting of difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl and trifluoroethyl.
In one embodiment, the compound has the structure of formula (I), wherein
Each R1Selected from the group consisting of fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyano, methylsulfonyl, and ethylsulfonyl;
each R2Selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, methoxymethyl, methoxyethyl, ethoxymethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, cyclopropyl, cyclobutyl and-NH2；
R3Selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, phenyl, benzyloxymethyl, benzyloxyethyl, benzyloxypropyl, -CH2OH、-C2H4OH or-C3H6OH；
R5Selected from hydrogen, methyl, ethyl or propyl; and
R4selected from purinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolopyrimidinyl, pyridopyrimidinyl, thienopyrimidinyl, pyrrolopyrimidinyl, furopyrimidinyl, imidazotriazinyl, or pyrazolopyrimidinyl; wherein each of the purinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolopyrimidinyl, pyridopyrimidinyl, thienopyrimidinyl, pyrrolopyrimidinyl, furopyrimidinyl, imidazotriazinyl, or pyrazolopyrimidinyl moieties is optionally substituted with 1 to 3 members selected from: halogen, cyano, -NH2、C1-4Alkyl radical, C1-4Haloalkyl, C2-4Alkynyl, wherein said C2-4Alkynyl moiety optionally substituted with C6-10Aryl or C4-8Heteroaryl, wherein said C6-10Aryl or C3-8Each of the heteroaryl moieties is optionally substituted with one, two or three members selected from: fluorine, chlorine, bromine, iodine, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl and trifluoroethyl.
The present application also provides compounds of formula (J) or (I) having the structure of formula (Ia):
wherein n, A, R1、R2、R3、R4And R5As defined herein;
m is 0, 1 or 2;
or a pharmaceutically acceptable salt, isomer or mixture thereof.
Furthermore, the compounds of formula (J) or (I) may have the structure of formula (Ib)
Wherein n, m, A, R1、R2、R3、R4And R5As defined herein;
or a pharmaceutically acceptable salt, isomer or mixture thereof.
Furthermore, the compounds of formula (J) or (I) may have the structure of formula (II)
Wherein n, m, A, R1、R2、R3、R4And R5As defined herein;
or a pharmaceutically acceptable salt, isomer or mixture thereof.
The present application also provides compounds of formula (J) or (I) having the structure of formula (IIa)
Wherein n, m, R1、R2、R3And R5As defined herein;
p is 0, 1,2 or 3;
each R4aIndependently selected from halogen, cyano, NH2、C2-4Alkynyl, C1-4Haloalkyl and C1-4Alkyl radical, wherein said C2-4Alkynyl moiety optionally substituted with C6-10Aryl or C3-8Heteroaryl group, wherein C6-10Aryl and C3-8Each of the heteroaryl moieties is optionally substituted with one, two or three members independently selected from: halogen and C1-6A haloalkyl group;
or a pharmaceutically acceptable salt, isomer or mixture thereof.
The present application also provides compounds of formula (J) or (I) having the structure of formula (IIb)
Wherein n, m, p, R1、R2、R3、R4aAnd R5As defined herein;
or a pharmaceutically acceptable salt, isomer or mixture thereof.
Further, the compound of formula (J) or (I) may have the structure of formula (III):
wherein n, m, A, R1、R2、R3、R4And R5As defined herein;
or a pharmaceutically acceptable salt, isomer or mixture thereof.
The present application also provides compounds having the structure of formula (IIIa):
wherein n, m, p, R1、R2、R3、R4aAnd R5As defined herein;
or a pharmaceutically acceptable salt, isomer or mixture thereof.
The present application also provides compounds of formula (J) or (I) having the structure of formula (IIIb)
Wherein n, m, p, R1、R2、R3、R4aAnd R5As defined herein;
or a pharmaceutically acceptable salt, isomer or mixture thereof.
The present application also provides compounds of formula (J) or (I) having the structure of formula (IV):
wherein n, m, A, R1、R2、R3、R4And R5As defined herein;
or a pharmaceutically acceptable salt, isomer or mixture thereof.
The compound of formula (J) or (I) may have the structure of formula (IVa):
wherein n, m, p, R1、R2、R3、R4aAnd R5As defined herein;
or a pharmaceutically acceptable salt, isomer or mixture thereof.
The compound of formula (J) or (I) may have the structure of formula (IVb)
Wherein n, m, p, R1、R2、R3、R4aAnd R5As defined herein;
or a pharmaceutically acceptable salt, isomer or mixture thereof.
In other embodiments, the compound has any one of the structures of formula (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb), wherein each R4aIndependently selected from halogen, cyano, -NH2、C2-4Alkynyl, C1-4Haloalkyl and C1-4Alkyl radical, wherein said C2-4Alkynyl moiety optionally substituted with C6-10Aryl or C3-8Heteroaryl group, wherein C6-10Aryl and C3-8Each of the heteroaryl moieties is optionally substituted with one, two or three members independently selected from: halogen and C1-6A haloalkyl group. In some other embodiments, each R is4aIndependently selected from bromine, fluorine, chlorine, cyano, -NH2Methyl, ethyl, propyl, fluoromethyl, difluoromethylAlkyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl and C2-4Alkynyl, wherein said C2-4Alkynyl moiety optionally substituted with C6-10Aryl or C4-8Heteroaryl, wherein said C6-10Aryl or C3-8Each of the heteroaryl moieties is optionally substituted with one or two members independently selected from: fluorine, chlorine, bromine, iodine, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl and trifluoroethyl.
In any of the above formulae (Ia), (Ib), (II), (III) and (IV), wherein n, R1、R2、R3、R4And R5As described herein; m is 0, 1 or 2; and A is a single bond or C (O). Further, in any of the above formulas (IIa) (IIb), (IIIa), (IIIb), (IVa) and (IVb), wherein n, R1、R2、R3And R5As described herein; m is 0 or 1; p is 2 or 3; and each R4aIndependently selected from halogen, cyano, C2-4Alkynyl, C1-4Haloalkyl and C1-4Alkyl radical, wherein said C2-4Alkynyl moiety optionally substituted with C6-10Aryl or C4-8Heteroaryl, wherein said C6-10Aryl or C3-8Each of the heteroaryl moieties is optionally substituted with one or two members independently selected from: fluorine, chlorine, bromine, iodine, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl and trifluoroethyl.
In one embodiment, n is 0. In some embodiments, n is 1,2, 3, or 4. In some embodiments, n is 1,2, or 3. In other embodiments, n is 1 or 2. In certain embodiments, n is 1 and R1The moiety can be located at any position of the phenyl group of the quinazolinone ring. In another embodiment, n is 2. Two R1The substituents or moieties may be the same or different. Two R1Moieties may be located at any two positions of the phenyl group of the quinazolinone ring. As an example, the first R1Can be located at the second R1Ortho, meta or para. In another embodiment, n is 3. All R1Substituents or moietiesMay be the same or different, or two R1May be associated with a third R1The same or different. Three R1The moiety can be located at any three positions of the phenyl group of the quinazolinone ring. For example, the first R1Can be located at the second R1Ortho to (b), and the first R1Can be located in the third R1And (4) contraposition. In another embodiment, n is 4. All R1The substituents may be the same or different, three R1May be combined with a fourth R1Identical or different, two R1May be combined with the third and fourth R1The same or different.
In some other embodiments, each R is1Independently halogen, cyano, optionally substituted C1-6Alkyl, optionally substituted C1-6Haloalkyl, optionally substituted C1-6Alkoxy, hydroxy, optionally substituted C3-6Cycloalkyl, optionally substituted C3-6Heterocycloalkyl, optionally substituted C6-10Aryl, optionally substituted C4-8Heteroaryl, or optionally substituted C1-6An alkylsulfonyl group. In certain embodiments, each R is1Independently halogen, cyano, optionally substituted C1-4Alkyl, optionally substituted C1-4Haloalkyl, optionally substituted C1-4Alkoxy, optionally substituted C3-6Cycloalkyl, or optionally substituted C1-4An alkylsulfonyl group. In other embodiments, each R is1Independently of one another halogen, cyano, C1-4Haloalkyl, C1-4Alkyl, or C1-4An alkylsulfonyl group. In certain embodiments, each R is1Independently selected from fluoro, chloro, iodo, bromo, cyano, methyl, ethyl, propyl, butyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, methylsulfonyl, ethylsulfonyl, or propylsulfonyl. In some embodiments, each R is1Independently fluorine, chlorine, iodine, cyano, methyl, ethyl, difluoromethyl (-CHF)2) Trifluoromethyl (-CF)3) Methoxy, methylsulfonyl (-SO)2CH3) Cyclopropylmethyl, or cyclopropyl. In one embodiment, each R is1Independently fluorine, chlorine, cyano, methylsulfonyl, methyl, or trifluoromethyl.
In one embodiment, m is 0. In some embodiments, m is 1,2, or 3. In certain other embodiments, m is 1 or 2. In other embodiments, m is 1 and R2The substituents or moieties may be located anywhere on the ring. In embodiments where m is 2, two R2The substituents may be the same or different. Two R2The portions may be located at any two positions of the ring. For example, the first R2Can be located at the second R2Ortho to (b), and the first R2Can be located at the third R2And (4) contraposition. In embodiments where m is 3, all three R2May be the same or different, or two R2May be associated with a third R2The same or different. Three R2The portions may be located at any three positions of the ring. It is understood that when two of X, Y and Z are N, m can be 0, 1, or 2.
In one embodiment, m' is 0. In some embodiments, m' is 1 and R2May be located at a carbon ring atom on the ring (e.g., other than X, Y or Z, where one of X, Y or Z is the point of attachment to the quinazolinone ring).
In certain embodiments, each R is2Independently selected from the group consisting of halogen, optionally substituted alkyl, optionally substituted haloalkyl, and optionally substituted cycloalkyl. In some embodiments, each R is2Independently of one another, halogen, C1-4Haloalkyl, C3-6Cycloalkyl or optionally substituted by C1-4C of alkoxy1-4An alkyl group. In some other embodiments, each R is2Independently fluorine, chlorine, iodine, bromine, -CH2F、-CHF2、-CF3Fluoroethyl, difluoroethyl, trifluoroethyl, fluoropropyl, difluoropropyl, trifluoropropyl, methyl, ethyl, propyl, butyl, methoxymethyl, methoxyethyl, ethoxymethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In one embodiment, each R is2Independently fluorine,Chlorine, methyl, -CH2F、-CHF2、-CF3Methoxyethyl, or cyclopropyl.
In certain embodiments, R3Is hydrogen, optionally substituted C1-6Alkyl, optionally substituted C3-8Cycloalkyl, or optionally substituted C6-10And (4) an aryl group. In one embodiment, R3Is hydrogen, C3-6Cycloalkyl radical, C6-10Aryl, or C optionally substituted with hydroxy1-4Alkyl radical, C6-10Aryl radical C1-4Alkoxy, or C3-6A cycloalkyl group. In some embodiments, R3Is hydrogen, methyl, ethyl, propyl, butyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2OH、-C2H4OH、-C3H6OH, benzyloxymethyl (i.e. R)) Or phenyl (i.e. a)。
In other embodiments, R5Is hydrogen or optionally substituted C1-6An alkyl group. In some embodiments, R5Is hydrogen or C1-4An alkyl group. In certain embodiments, R5Hydrogen, methyl, ethyl, propyl or butyl. In certain other embodiments, R5Is hydrogen.
In other embodiments, R3And R5The atoms to which they are attached (e.g., carbon and nitrogen, respectively) optionally form a heterocyclic ring. In other embodiments, the R is3-R5A heterocycle is a 3-to 8-membered heterocycloalkyl (i.e., a heterocycloalkyl having 3 to 8 ring members with at least one ring member being a heteroatom). In other embodiments, the R is3-R5A heterocycle is a 4-to 7-membered heterocycloalkyl (i.e., a heterocycloalkyl having 4 to 7 ring members with at least one ring member being a heteroatom). In thatIn other embodiments, the R is3-R5The heterocycle is optionally substituted with halogen. In one embodiment, said R is3-R5Heterocycle is a 5-membered heterocycloalkyl. In certain other embodiments, the R is3-R5The heterocyclic ring being C3-8A heterocycloalkyl group. In certain embodiments, the R is3-R5The heterocycle is azepanyl, azetidinyl, piperidinyl, or pyrrolidinyl. In some other embodiments, the R is3-R5The heterocycle is pyrrolidinyl. In one other embodiment, the R is3-R5Heterocycle is a 5-membered heterocycloalkyl substituted with halogen. In other embodiments, the R is3-R5Heterocycle is pyrrolidinyl substituted with fluoro, chloro, bromo, or iodo.
In one embodiment, R4Is heteroaryl having at least two nitrogen atoms and at least one aromatic ring, and R4Heteroaryl is optionally substituted with one, two or three members independently selected from: halogen, cyano, -NH2、C1-6Alkyl, and C1-6A haloalkyl group. In certain embodiments, R4Heteroaryl is 6 to 12 membered heteroaryl (i.e., heteroaryl having 6 to 12 ring members). R4Heteroaryl groups may be monocyclic or bicyclic heteroaryl groups. In some embodiments, R4Heteroaryl is a monocyclic heteroaryl having at least two nitrogen atoms. In certain embodiments, R4Heteroaryl is a bicyclic heteroaryl having at least one aromatic ring, at least two nitrogen atoms and at least one other heteroatom selected from N, O or S. In certain other embodiments, R4The heteroaryl group is selected from the group consisting of purinyl, pyrimidinyl, thiazolopyrimidinyl, pyridopyrimidinyl, thienopyrimidinyl, pyrrolopyrimidyl, furopyrimidinyl, and imidazotriazinyl. In other embodiments, R4The heteroaryl group is selected from the group consisting of purinyl, pyrimidinyl, thiazolopyrimidinyl, pyridopyrimidinyl, thienopyrimidinyl, pyrrolopyrimidinyl, furopyrimidinyl, imidazotriazinyl, and pyrazolopyrimidinyl. In some other embodiments, R4Heteroaryl is pyrazolopyrimidinyl.
In any of the above formulae, R4Is heteroaryl optionally substituted with one, two or three members independently selected from: halogen, cyano, -NH2、C1-6Alkyl radical, C1-6Haloalkyl, C2-6Alkynyl, wherein C2-6Alkynyl optionally substituted with C6-10Aryl or C4-8Heteroaryl, wherein said C6-10Aryl or C3-8Each of the heteroaryl moieties is optionally substituted with one, two or three members independently selected from: fluorine, chlorine, bromine, iodine, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl and trifluoroethyl, wherein R is4Heteroaryl is selected from
In other embodiments, the R is4Heteroaryl is selected from
In any of the above formulae, R4Heteroaryl being optionally substituted by C2-6Alkynyl radical, the C2-6Alkynyl optionally substituted with C6-10Aryl or C4-8Heteroaryl of the formula6-10Aryl or C4-8Heteroaryl is each optionally substituted by halogen or C1-6A haloalkyl group. In some embodiments, R4Is heteroaryl, optionally substituted with one member of: quilt C6-10Aryl or C4-8Heteroaryl substituted C2-6Alkynyl, wherein said C6-10Aryl or C3-8Each of the heteroaryl moieties is optionally substituted with one member selected from the group consisting of: fluorineChlorine, bromine, iodine, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl and trifluoroethyl. In some other embodiments, R4Heteroaryl is optionally substituted with 1 to 3 members independently selected from: fluoro, chloro, bromo, iodo, cyano, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, -NH2and-C ≡ C, these substituents being optionally substituted with
In certain other embodiments, R4Selected from the group consisting of purinyl, pyrimidinyl, thiazolopyrimidinyl, pyridopyrimidinyl, thienopyrimidinyl, pyrrolopyrimidinyl, furopyrimidinyl, and imidazotriazinyl, each of which is optionally substituted with one, two, or three members independently selected from the group consisting of: chloro, fluoro, bromo, iodo, methyl, ethyl, propyl, cyano and-NH2. In certain other embodiments, R4Selected from the group consisting of purinyl, pyrimidinyl, isothiazolopyrimidinyl, thiazolopyrimidinyl, pyridopyrimidinyl, thienopyrimidinyl, pyrrolopyrimidinyl, furopyrimidinyl, imidazotriazinyl, and pyrazolopyrimidinyl, each of which is optionally substituted with one, two, or three members independently selected from the group consisting of: chlorine, fluorine, bromine, iodine, methyl, ethyl, propyl, cyano, -NH2Fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl and trifluoroethyl. In certain other embodiments, R4Selected from the group consisting of thiazolopyrimidinyl, pyridopyrimidinyl, thienopyrimidinyl, pyrrolopyrimidinyl, furopyrimidinyl, and imidazotriazinyl, each of which is optionally substituted with one or two members independently selected from the group consisting of: chlorine, fluorine, bromine, iodine, methyl, ethyl, propyl and-NH2. In other embodiments, R4Selected from the group consisting of thiazolopyrimidinyl, pyridopyrimidinyl, thienopyrimidinyl, pyrrolopyrimidinyl, furopyrimidinyl, and imidazotriazinyl, each of which is optionally substituted with two members independently selected from the group consisting of: chlorineFluorine, bromine, iodine, methyl, ethyl, propyl and-NH2. In other embodiments, R4Selected from the group consisting of thiazolopyrimidinyl, pyridopyrimidinyl, thienopyrimidinyl, pyrrolopyrimidinyl, furopyrimidinyl, and imidazotriazinyl, each of which is optionally substituted with one member selected from the group consisting of: chlorine, fluorine, bromine, iodine and-NH2. In some other embodiments, R4Is pyrimidinyl or pyrazinyl and R4Optionally substituted with at least one-NH2. In certain other embodiments, R4Is pyrimidinyl or pyrazinyl, each substituted with two or three members independently selected from: chloro, fluoro, bromo, iodo, methyl, ethyl, propyl, cyano and-NH2And at least one of the two or three members is-NH2. In other embodiments, R4Is pyrimidinyl or pyrazinyl, each substituted with two or three members independently selected from: chloro, fluoro, bromo, iodo, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyano and-NH2And at least one of the two or three members is-NH2. In other embodiments, R4Is isothiazolopyrimidinyl or pyrazolopyrimidinyl, each substituted with two or three members independently selected from: chlorine, fluorine, bromine, iodine, methyl, ethyl, propyl, cyano, -NH2Fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, and at least one of the two or three members is-NH2。
In some embodiments, a is c (o). In certain embodiments, a is a single bond. Various and all variations of A may be combined with n, m ', m, X, Y, Z, R' described above1、R2、R3、R4And R5Various and all combinations of variations of. In some other embodiments, A is C (O) and R4Heteroaryl is a bicyclic group as defined above. In other embodiments, A is a single bond and R is4Heteroaryl is a bicyclic group as defined above. In other embodiments, A is C (O) and R4Heteroaryl is selected from pyrimidineMonocyclic radicals of the radicals and pyrazinyl radicals. In other embodiments, A is a single bond and R is4Heteroaryl is a monocyclic group selected from pyrimidinyl and pyrazinyl.
In other embodiments, A' is OR4. In some other embodiments, a' is N (R)5)C(O)R4. In other embodiments, A' is NR5R4. Various and all variations of A ' may be combined with n, m ', X, Y, Z, R ', R described above1、R2、R3、R4And R5Various and all combinations of variations of.
In other embodiments, X, Y and Z are independently C (R ') or N, wherein at least one of X, Y and Z is C (R'). For example, in formulae (Ia) and (Ib) wherein X is C (R '), when Y is C (R '), Z is N or C (R '); when Y is N, Z is N or C (R'); when Z is C (R '), Y is N or C (R'); and when Z is N, Y is N or C (R'). In formula (I), X, Y and Z are independently C (R ') or N, wherein at least one of X, Y and Z is C (R'). In certain embodiments, both X, Y and Z are C (R'). In some embodiments, at least two of X, Y and Z are C (R'). In other embodiments, at least one of X, Y or Z is C (R'). In certain other embodiments, at least two of X, Y and Z are N. In some other embodiments, at least one of X, Y and Z is N. It is understood that R' may be the point of attachment to the quinazolinone ring. In these embodiments, X, Y or Z is the point of attachment to the quinazolinone ring via an R 'linkage (R' attachment). R' is independently halogen, optionally substituted alkyl, optionally substituted haloalkyl, and optionally substituted cycloalkyl. In some embodiments, each R' is independently halogen, optionally substituted with C1-4C of alkoxy1-4Alkyl radical, C1-4Haloalkyl or C3-6A cycloalkyl group. In some other embodiments, each R' is independently fluoro, chloro, iodo, bromo, -CH2F、-CHF2、-CF3,Fluoroethyl, difluoroethyl, trifluoroethyl, fluoropropyl, difluoropropyl, trifluoropropyl, methyl, ethyl, propyl, butyl, methoxymethyl, methoxyethylA group, ethoxymethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In one embodiment, each R' is independently fluoro, chloro, methyl, -CH2F、-CHF2、-CF3Methoxyethyl, or cyclopropyl. In one embodiment, each R' is independently-NH2. In other embodiments, each R' is independently halogen, -NH2Optionally substituted with C1-4C of alkoxy1-4Alkyl radical, C1-4Haloalkyl or C3-6A cycloalkyl group. In some other embodiments, each R' is independently-NH2Fluorine, chlorine, methyl, -CH2F、-CHF2、-CF3Methoxyethyl, or cyclopropyl.
In certain embodiments, W is CH or N. In certain other embodiments, W is CH. In other embodiments, W is N. Various and all variations of W may be combined with n, m ', X, Y, Z, A ', R ' described above1、R2And R3Various and all combinations of variations of.
In formulae (IIa), (IIb), (IIIa), (IIIb), (IVa) and (IVb), n, R1、R2、R3And R5As described in formulas (I) and (J); m is 0, 1 or 2; p is 0, 1,2 or 3; and R is4aIndependently selected from halogen, cyano, -NH2And optionally substituted C1-6An alkyl group.
In one embodiment, p is 0. In certain embodiments, p is 1,2, or 3. In some embodiments, p is 1 or 2. In some embodiments, p is 1 and R4aThe moiety may be located anywhere in the pyrimidinyl or pyrazinyl ring. In another embodiment, p is 2 and two R are4aThe substituents or moieties may be the same or different; the two R4aEach of the moieties may be located at any position of the pyrimidinyl or pyrazinyl ring. In another embodiment, p is 3 and all R4aThe substituents may be the same or different, or two R4aMay be associated with a third R4aThe same or different.
In the present application, each R4aIndependently selected from halogen, -NH2Cyano, C2-4Alkynyl, C1-4Haloalkyl and C1-4Alkyl radical, wherein said C2-4Alkynyl moiety optionally substituted with C6-10Aryl or C4-8Heteroaryl, wherein said C6-10Aryl or C3-8Each of the heteroaryl moieties is optionally substituted with one or two members independently selected from: fluorine, chlorine, bromine, iodine, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl and trifluoroethyl. In some embodiments, each R is4aIndependently selected from fluorine, chlorine, bromine, iodine, cyano, -NH2Methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl and difluoroethyl groups, wherein at least one R is4ais-NH2. In other embodiments, p is 2 or 3, and at least one R4ais-NH 2. p and R4aCan be varied from n, m, R1、R2、R3And R5Various and all combinations of variations of.
The compounds of the present application may carry one or more chiral centers. Compounds carrying chiral centers have the same molecular formula and the same chemical name, with different stereoisomeric designations. For example, the following 2, 4-diamino-6- ((1- (5-chloro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) propyl) amino) pyrimidine-5-carbonitrile, which carries a chiral center, can be resolved into the (S) and (R) enantiomers, (S) -2, 4-diamino-6- ((1- (5-chloro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) propyl) amino) pyrimidine-5-carbonitrile and ((R) -2, 4-diamino-6- ((1- (5-chloro-4-oxo-3-yl) -3, 4-dihydroquinazolin-2-yl) propyl) amino) pyrimidine-5-carbonitrile - (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) propyl) amino) pyrimidine-5-carbonitrile.
Representative compounds of the present application are listed in table 1 below. Other representative compounds are listed in table 1a below. The compounds may be named using nomenclature systems and symbols recognized in the Chemical arts, including, for example, ChemBioDraw Ultra 12.0, Chemical Abstract Service (CAS), and International Union of Pure and Applied Chemistry (IUPAC). For example, compound 1 in table 1 may be named 2, 4-diamino-6- [ [ (1S) -1- [ 5-chloro-4-oxo-3- (1H-pyrazol-3-yl) quinazolin-2-yl ] propyl ] amino ] pyrimidine-5-carbonitrile or (S) -2, 4-diamino-6- ((1- (5-chloro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) propyl) amino) pyrimidine-5-carbonitrile using IUPAC or ChemBioDraw Ultra 12.0, respectively.
TABLE 1 representative Compounds
Table 1a. representative compounds
The present application provides pharmaceutically acceptable salts, hydrates, solvates, isomers, tautomers, stereoisomers, enantiomers, racemic compounds, atropisomers, polymorphs, prodrugs, or mixtures thereof, of the compounds described herein. In addition, the present application provides compounds wherein 1 to n hydrogen atoms attached to a carbon atom may be replaced with deuterium atoms or D, wherein n is the number of hydrogen atoms in the molecule. Deuterium atoms are known to be nonradioactive isotopes of hydrogen atoms. Such compounds may increase antimetabolite and, therefore, may be useful for increasing the half-life of a compound of any of the formulae described herein, or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof, when administered to a mammal. See, for example, Foster, "Deuterium Isotrope Effects in students of Drug Metabolism", trends Pharmacol. Sci., 5(12): 524-. Such compounds are synthesized by means well known in the art, for example, by employing starting materials in which one or more hydrogen atoms have been replaced by deuterium.
The terms "compound of the present application", "compound described herein", "compound of any of the formulae described herein" or variants thereof refer to compounds having any one of the structures of formulae (J), (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa) and (IVb). In some embodiments, the compound of the present application is compound 1-291 described herein.
"pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other substances suitable for use in the preparation of pharmaceutical compositions suitable for veterinary or human pharmaceutical use. "pharmaceutically acceptable salt" or "physiologically acceptable salt" refers to a salt of a pharmaceutical compound that retains the biological effectiveness and properties of the base compound and is not biologically or otherwise undesirable. Acid addition salts and base addition salts exist. Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Acids and bases suitable for reaction with a base compound to form a pharmaceutically acceptable salt (acid addition salt or base addition salt, respectively) are known to those skilled in the art. Similarly, methods for preparing pharmaceutically acceptable salts from the base compounds (when disclosed) are known to those skilled in the art and are disclosed, for example, in Berge et al Journal of Pharmaceutical Science, vol.1/1977, vol.66, phase 1 and other sources. If the compounds described herein are obtained in the form of acid addition salts, the free base can be obtained by basifying an acid salt solution. Relatively speaking, if the product is a free base, an addition salt, in particular a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from base compounds.
"isomers" refer to compounds having the same molecular formula. As used herein, the term isomer includes double bond isomers, racemates, stereoisomers, enantiomers, diastereomers and atropisomers. Single isomers, such as enantiomers or diastereomers, can be obtained by asymmetric synthesis or by resolution of a mixture of isomers. Resolution of the isomeric mixture (e.g. the racemic compound) may be achieved, for example, by conventional methods, such as crystallization in the presence of a resolving agent, or chromatography, using, for example, a chiral High Pressure Liquid Chromatography (HPLC) column. "double bond isomers" refers to the Z-and E-forms (or cis-and trans-forms) of compounds having carbon-carbon double bonds.
"atropisomer" refers to a conformational stereoisomer that results when rotation about a single bond in a molecule is hindered or greatly hindered by steric interaction with other parts of the molecule and the substituents at the ends of the single bond are asymmetric, i.e., they do not require stereocenters. Separation and separation of isomeric species may be allowed with sufficiently high rotational energy barriers around single bonds and sufficiently slow interconversion between conformations. Atropisomers can be isolated by methods well known in the art. Unless otherwise stated, the specification is intended to include the atropisomers individually as well as mixtures. Furthermore, as understood by those skilled in the art, atropisomers may be represented by the same chemical name, with different atropisomer designations. By way of example, the following structure is an atropisomer of compound 84, (S) -2, 4-diamino-6- ((1- (3- (4-bromo-1H-pyrazol-3-yl) -5-chloro-4-oxo-3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile.
By "racemic compound" is meant a mixture of enantiomers.
"stereoisomers" or "stereoisomeric forms" refer to compounds that differ in chirality at one or more stereogenic centers. Stereoisomers include enantiomers and diastereomers. If a compound has one or more asymmetric centers or asymmetrically substituted double bonds, it may exist in stereoisomeric forms and, therefore, may be prepared as individual stereoisomers or mixtures. Unless otherwise stated, this specification is intended to include individual stereoisomers as well as mixtures. Methods for determining stereochemistry and separation of stereoisomers are well known in the art (see, e.g., Advanced Organic Chemistry chapter 4, 4 th edition, j. march, John Wiley and Sons, New York, 1992).
"tautomer" or "tautomeric form" refers to alternating forms of a compound that differ in the position of the proton, such as enol-ketone and imine-enamine tautomers, or heteroaryl groups such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.
"solvates" are formed by the interaction of a solvent and a compound. Solvates of salts of any of the compounds of the general formula described herein are also provided. Hydrates of the compounds of the formula are also provided.
"prodrugs" are defined in the pharmaceutical arts as biologically inactive derivatives of a drug that, upon administration to the human body, are converted to the biologically active parent drug according to some chemical or enzymatic pathway.
In any of the embodiments above, the compound described herein or a pharmaceutically acceptable salt thereof is the (S) -enantiomer. In any of the embodiments above, the compound described herein or a pharmaceutically acceptable salt thereof is the (R) -enantiomer. In any of the embodiments above, the compound described herein or a pharmaceutically acceptable salt thereof is an atropisomer.
The present application also provides compositions comprising a mixture of enantiomers of the compound or a pharmaceutically acceptable salt thereof. In one embodiment, the mixture is a racemic mixture. In other embodiments, the composition comprises the (S) -enantiomer of the compound in excess of the (R) -enantiomer of the corresponding compound. In some embodiments, the composition comprises the (S) -enantiomer of the compound and is substantially free of its corresponding (R) -enantiomer. In certain embodiments, a composition substantially free of (R) -enantiomer has less than about 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, 1%, 0.05%, or 0.01% of (R) -enantiomer. In other embodiments, a composition comprising the (S) -enantiomer of a compound, or a pharmaceutically acceptable salt thereof, predominates over its corresponding (R) -enantiomer at a molar ratio of at least or about 9:1, at least or about 19:1, at least or about 40:1, at least or about 80:1, at least or about 160:1, or at least or about 320: 1.
Compositions comprising a compound according to any of the general formulae described herein, or a pharmaceutically acceptable salt thereof, may also comprise the compound in enantiomeric excess (e.e.). As an example, a compound with 95% (S) -isomer and 5% (R) -isomer would have 90% e.e. In some embodiments, the compound has an e.e. of at least about 60%, 75%, 80%, 85%, 90%, 95%, 98% or 99%.
In any of the embodiments above, the compound or pharmaceutically acceptable salt thereof is an atropisomer. Another embodiment provides a composition comprising a mixture of atropisomers of the compound or a pharmaceutically acceptable salt thereof. As an example, the compound has 95% of one atropisomer and 5% of the other atropisomer. In some embodiments, the compound has about 90, 80, 70, 60, 50, 40, 30, 20, or 10% of one atropisomer and 10, 20, 30, 40, 50, 60, 70, 80, or 90% of the other atropisomer, respectively.
The present application also provides free base forms of the compounds described herein. In certain embodiments, provided herein are enantiomers, (R) or (S) configurations of compounds of the formulae described herein. In other embodiments, provided herein are atropisomers of the compounds of the formulae described herein.
The present application also provides compositions comprising a compound described herein, or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof. The composition may comprise a racemic mixture, a mixture containing an enantiomeric excess of one enantiomer, or a single diastereomer or mixture of diastereomers. All such isomeric forms of these compounds are expressly included herein as if each and every isomeric form were specifically and individually recited.
In certain embodiments, also provided herein are polymorphs, such as crystalline and amorphous forms, of the compounds described herein. In some embodiments, chelates, non-covalent complexes of compounds of the formulae described herein, or pharmaceutically acceptable salts, prodrugs, or solvates thereof, and mixtures thereof, are also provided. "chelate" is formed by coordinating a compound to a metal ion at two (or more) sites. A "non-covalent complex" is formed by the interaction of a compound with another molecule, wherein no covalent bond is formed between the compound and the molecule. For example, complexation can occur through van der waals interactions, hydrogen bonding, and electrostatic interactions (also referred to as ionic bonding).
Therapeutic use of compounds
Compounds of the formulae described herein, or pharmaceutically acceptable salts, isomers, prodrugs or solvates thereof, are useful for treating diseases and/or conditions mediated by the PI3K subtype. In addition, the present application provides compounds for use in therapy. Further, provided herein are methods of inhibiting one or more PI3K subtypes. In one embodiment, methods of inhibiting PI3K activity using a compound described herein, or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof, are provided. In other embodiments, methods of inhibiting PI3K and/or PI3K β activity using the compounds, or pharmaceutically acceptable salts, isomers, prodrugs, or solvates thereof, are provided. The present application also provides methods for these methods. The PI3K subtype may be selectively or specifically inhibited. Furthermore, the compounds may be used for the therapeutic or prophylactic inhibition of PI3K activity, such as PI3K and/or PI3K β.
The compounds according to the present application may be used in combination with one or more other therapeutic agents. The therapeutic agent may be in the form of a compound, antibody, polypeptide or polynucleotide. The therapeutic agent includes, but is not limited to, a chemotherapeutic agent, an immunotherapeutic agent, a radiotherapeutic agent, an antineoplastic agent, an anti-cancer agent, an antiproliferative agent, an anti-fibrotic agent, an anti-angiogenic agent, a therapeutic antibody, or any combination thereof. In one embodiment, the application provides a product comprising a compound described herein and an additional therapeutic agent as a combined preparation for simultaneous, separate or sequential use in a method of treatment, e.g., treatment of a disease, disorder or condition mediated by the PI3K subtype.
In addition, the therapeutic agents may be those that inhibit or modulate the activity of the following kinases: bruton's tyrosine kinase, spleen tyrosine kinase, apoptosis signal-regulating kinase, Janus kinase, lysyl oxidase-like protein, matrix metallopeptidase, bromodomain-containing protein, adenosine A2B receptor, isocitrate dehydrogenase, serine/threonine kinase TPL2, discoid domain receptor (discoidin domain receptor), serine/threonine-protein kinase, IKK, MEK, EGFR, histone deacetylase, protein kinase C, or any combination thereof. In certain embodiments, the therapeutic agent may be selected from PI3K (including PI3K γ, PI3K, PI3K β, PI3K α, and/or pan-PI 3K) inhibitors, JAK (Janus kinases including JAK1, JAK2, and/or JAK3) inhibitors, SYK (spleen tyrosine kinase) inhibitors, BTK (bruton tyrosine kinase) inhibitors, A2B (adenosine A2B receptor) inhibitors, ACK (activated CDC kinases including ACK1) inhibitors, ASK (apoptosis signal-regulating kinases including ASK1) inhibitors, Aurora kinases, BRD (bromodomain-containing proteins including BRD4) inhibitors, Bcl (B-cell CLL/lymphomas including Bcl-1 and/or Bcl-2) inhibitors, CAK (CDK-activated kinase) inhibitors, CAK 6356-dependent protein kinase inhibitors, Bcl 1 (CDK-dependent cyclin kinase including CDK 83, CDK 1) inhibitors, 2.3, 4 and/or 6) inhibitors, CK (casein kinase, including CK1 and/or CK2) inhibitors, DDR (discoidin domain receptor, including DDR1 and/or DDR2) inhibitors, EGFR inhibitors, FXR (farnesoid x receptor) inhibitors, FAK (focal adhesion kinase) inhibitors, GSK (glycogen synthase kinase) inhibitors, HDAC (histone deacetylase) inhibitors, IDO (indoleamine 2, 3-dioxygenase) inhibitors, IDH (isocitrate dehydrogenase, including IDH1) inhibitors, IKK (l-Kappa-B kinase) inhibitors, KDM5 (lysine demethylase) inhibitors, LCK (lymphocyte-specific protein tyrosine kinase) inhibitors, LOX (lysyl oxidase) inhibitors, LOXL (lysyl oxidase-like proteins, including LOXL1, LOXL2, LOXL3, LOXL4, and/or LOXL5) inhibitors, MTH (mutT homolog) inhibitors, MEK (mitogen-activated protein kinase) inhibitors, matrix metalloproteinases (MMP, including MMP2 and/or MMP9) inhibitors, mitogen-activated protein kinase (MAPK) inhibitors, PD-1 (programmed cell death protein 1) inhibitors, PD-L1 (programmed death-ligand 1) inhibitors, PDGF (platelet-derived growth factor) inhibitors, Phosphorylase Kinase (PK) inhibitors, PLK (polo-like kinase, including PLK1, 2, 3) inhibitors, protein kinases (PK, including protein kinase a, B, C) inhibitors, STK (serine/threonine kinase) inhibitors, STAT (signal transduction and transcription) inhibitors, serine/threonine-protein kinase inhibitors, TBK (tank-binding kinase) inhibitors, and the like, TLR (toll-like receptor modulators, including TLR-1, TLR-2, TLR-3, TLR-4, TLR-5, TLR-6, TLR-7, TLR-8, TLR-9, TLR-10, TLR-11, TLR-12, and/or TLR-13) inhibitors, TK (tyrosine kinase) inhibitors, TPL2 (serine/threonine kinase) inhibitors, NEK9 inhibitors, Abl inhibitors, p38 kinase inhibitors, PYK inhibitors, c-Kit inhibitors, NPM-ALK inhibitors, Flt-3 inhibitors, c-Met inhibitors, KDR inhibitors, TIE-2 inhibitors, VEGFR inhibitors, SRC inhibitors, HCK inhibitors, LYN inhibitors, FYN inhibitors, YES inhibitors, chemotherapeutic agents, immunotherapeutic agents, radiotherapeutic agents, antineoplastic agents, An anti-cancer agent, an anti-proliferative agent, an anti-fibrotic agent, an anti-angiogenic agent, a therapeutic antibody, or any combination thereof. In some embodiments, the JAK inhibitor is N- (cyanomethyl) -4- [2- (4-morpholinoanilino) pyrimidin-4-yl ] benzamide (named by ChemDraw) (also known as CYT0387 or momelotinib) and may be synthesized by the method described in U.S. patent No. 8,486,941. In certain embodiments, the SyK inhibitor is 6- (1H-indazol-6-yl) -N- (4-morpholinophenyl) imidazo [1,2-a ] pyrazin-8-amine (named by ChemDraw) (also known as 6- (1H-indazol-6-yl) -N- [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine) and can be synthesized by the methods described in U.S. patent No. 8,450,321. In other embodiments, the BTK inhibitor is (S) -6-amino-9- (1- (but-2-alkynoyl) pyrrolidin-3-yl) -7- (4-phenoxyphenyl) -7H-purin-8 (9H) -one (also 6-amino-9- [ (3R) -1- (2-butynoyl) -3-pyrrolidinyl ] -7- (4-phenoxyphenyl) -7, 9-dihydro-8H-purin-8-one) according to ChemDraw designation and can be synthesized by the methods of U.S. patent 8,557,803.
Chemotherapeutic agents can be classified by their mechanism of action, for example, into the following groups: antimetabolite/anticancer agents, such as pyrimidine analogs (floxuridine, capecitabine, and cytarabine); and purine analogs, folic acid antagonists and related inhibitors; antiproliferative/antimitotic agents comprising natural products such as vinca alkaloids (vinblastine, vincristine, and tubulin inhibitors such as taxanes (paclitaxel, docetaxel), vinblastine, nocodazole, epothilones (epothilones) and navelbines (navelbines), epipodophyllotoxins (epidophyllotoxins) (etoposide, teniposide), DNA damaging agents (actinomycin, amsacrine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide (cyclophosphamide), cyclophosphamide (Cytoxan), actinomycin D, daunorubicin, doxorubicin, epirubicin, ifosfamide, melphalan, mechlorethamine (merchrehtamine), mitomycin, mitoxantrone, nitrosoureas, procarbazine, taxol, taxotere, teniposide, etoposide, triethylenethiophosphoramide, antibiotics such as dactinomycin (dactinomycin), dactinomycin (daunorubicin), and tubulin inhibitors, Doxorubicin (adriamycin), idarubicin, anthracyclines, mitoxantrone, bleomycin, plicamycin (mithramycin), and mitomycin; enzymes (L-asparaginase, which systemically metabolizes L-asparagine and eliminates cells that are unable to synthesize their own asparagine); anti-platelet agents; antiproliferative/antimitotic alkylating agents, such as the nitrogen mustards cyclophosphamide and the like, melphalan, chlorambucil, and (hexamethylmelamine and thiotepa), alkyl nitrosoureas (BCNU) and the like, streptozocin), triazene-Dacarbazine (DTIC); antiproliferative/antimitotic antimetabolites, such as folic acid analogs (methotrexate); platinum coordination complexes (cisplatin, oxaliplatin (oxilplatinim), carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide; hormones, hormone analogues (estrogens, tamoxifen, goserelin (goserelin), bicalutamide (bicalutamide), nilutamide (nilutamide)), and aromatase inhibitors (letrozole, anastrozole); anticoagulants (heparin, synthetic heparin salts and other thrombin inhibitors); fibrinolytic agents (e.g., tissue plasminogen activator, streptokinase, and urokinase), aspirin, dipyridamole, ticlopidine, clopidogrel; an anti-transfer agent; antisecretory agents (breveldin); immunosuppressants, tacrolimus, sirolimus, azathioprine, mycophenolate mofetil; compound (TNP-470, genistein) and growth factor inhibitors (vascular endothelial growth factor inhibitors, fibroblast growth factor inhibitors); angiotensin receptor blockers, nitric oxide donors; an antisense oligonucleotide; antibodies (trastuzumab, rituximab); cell cycle inhibitors and differentiation inducers (tretinoin); inhibitors, topoisomerase inhibitors (doxorubicin (adriamycin), daunorubicin, dactinomycin, teniposide, epirubicin, etoposide, idarubicin, irinotecan and mitoxantrone, topotecan, irinotecan, camptothecin), corticosteroids (cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisone and prednisolone); growth factor signal transduction kinase inhibitors; a dysfunction-inducing agent, a toxin such as cholera toxin, ricin toxin, pseudomonas exotoxin, bordetella pertussis adenylate cyclase toxin, or diphtheria toxin, and a caspase activator; and chromatin.
The term "chemotherapeutic agent" or "chemotherapeutic agent" (or "chemotherapy," in the context of treatment with a chemotherapeutic agent) as used herein refers to any non-proteinaceous (i.e., non-peptidic) chemical compound comprising a peptide useful for treating cancer. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and Cyclophosphamide (CYTOXAN); alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa and uredopa; ethyleneimine (ethylenimine) and methylaminoacridine (methyamelamine), including hexamethylmelamine, triimizine (triethyleneemimine), triethylenephosphoramide (triethylenephosphoramide), triethylenephosphoramide (triethylenethiophosphamide), and trimethymelamine; annonaceous acetogenin (especially bullatacin and bullatacin); camptothecin (including the synthetic analog topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin (adozelesin), carvelesin (carzelesin), and bizelesin (bizelesin) synthetic analogs); cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatin (dolastatin); duocarmycins (including the synthetic analogs KW-2189 and CB1-TM 1); eiscosahol (eleutherobin); pancratistatin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlorophosphamide (chlorophosphamide), estramustine, ifosfamide, mechlorethamine (mechlorethamine), mechlorethamine hydrochloride (mechlorethamine oxydichloride), melphalan, neomustard (novembichin), benzene mustard cholesterol (phenylesterine), prednimustine (prednimustine), trofosfamide (trofosfamide), uracil mustard (uracil musard); nitroureas such as carmustine, chlorozotocin (chlorozotocin), fotemustine, lomustine, nimustine and ranimustine; antibiotics such as enediyne (enediyne) antibiotics (e.g., calicheamicin, especially calicheamicin γ 1I, calicheamicin phi 1(Angew chem. int. Ed. Engl. 199433: 183-186), anthracyclines (dynemicin), including dynemicin A, bisphosphonates (bisphospates), such as clodronate), esperamicin (esperamicin), and neooncostatin chromophores (neoazinostatin chromophores) and related chromoprotein enediyne antibiotics (enediyne idiophores), acrinomycin, actinomycin (actinomycin), aureomycin, azaserine (azacine), bleomycin, actinomycin C, actinomycin, carmycin, carminomycin (5-carboxymycin), erythromycin (5-oxophostatin), normycin (normycin-6), noramycin (5-azomycin), nortetracycline (nortetracycline-6-5-azomycin), nortetracycline (nortetracycline-5-nortetracycline), nortetracycline (nortetracycline-6-nortetracycline), nortetracycline (nortetracycline-5-nortetracycline), nortetracycline (nortetracycline-6-D), nortetracycline (nortetracycline-5-normycin-D), nortetracycline (normycin-2, normycin, Doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin (epirubicin), esorubicin, idarubicin, marijumycin (marcelomycin), mitomycins such as mitomycin C, mycophenolic acid (mycophenolic acid), noramycin (nogalamycin), olivomycin (olivomycin), pelomycin (polyplomycin), pofiomycin (porfiromycin), puromycin (puromycin), triiron doxorubicin (quelamycin), roxobicin (rodorubicin), streptomycin (streptonigrin), streptozocin (streptozocin), tubercidin (tubicidin), ubenimex (enux), setastin (zinostatin), zotocin (zotocin); antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin (pteropterin), trimetrexate (trimetrexate); purine analogs such as fludarabine (fludarabine), 6-mercaptopurine, thiamiprine (thiamiprine), thioguanine (thioguanine); pyrimidine analogs such as ancitabine (ancitabine), azacitidine (azacitidine), 6-azaguanosine (6-azauridine), carmofur (carmofur), cytarabine (cytarabine), dideoxyuridine (dideoxyuridine), doxifluridine (doxifluridine), enocitabine (enocitabine), floxuridine (floxuridine); androgens such as carposterone (calusterone), methyl androsterone propionate (dromostanolone propionate), epitioandrostanol (epitiostanol), mepiquane (mepiquitane), testolactone (testolactone); anti-adrenaline (anti-adrenaline) such as aminoglutethimide, mitotane, trilostane; folic acid replenisher (folic acid replenisher) such as folinic acid (frilic acid); acetoglucurolactone (acegultone); (ii) an aldophosphamide glycoside; aminolevulinic acid (aminolevulinic acid); eniluracil (eniluracil); amsacrine (amsacrine); bestrabuucil; bisantrene; idazot (edatraxate); desphosphamide (defofamine); colchicine (demecolcine); diazaquinone (diaziqutone); elfornitine; ammonium etitanium acetate; epothilone (epothilone); etoglut (etoglucid); gallium nitrate (gallium nitrate); hydroxyurea (hydroxyurea); lentinan (lentinan); leucovorin; lonidamine (lonidainine); maytansinol (maytansinoids) such as maytansinoids (maytansine) and ansamitocins (ansamitocins); mitoguazone (mitoguzone); mitoxantrone (mitoxantrone); mopidanmol; rhizobia (nitrarine); pentostatin (pentostatin); methionine mustard (phenamett); pirarubicin (pirarubicin); losoxantrone (losoxantrone); fluoropyrimidines; folinic acid; podophyllinic acid (podophyllic acid); 2-ethyl hydrazine; procarbazine (procarbazine); PSK (r); razoxane (rizoxane); rhizomycin (rhizoxin); sizofuran (sizofiran); germanium spiroamines (spirogyranium); tenuazonic acid (tenuazonic acid); triimine quinone (triaziquone); 2,2' -trichlorotriethylamine; trichothecenes (trichothecene) (especially T-2 toxin, veracurin A, bacillocin A and anguidine); uratan; vindesine; dacarbazine (dacarbazine); mannomustine (mannomustine); dibromomannitol (mitobronitol); dibromodulcitol (mitolactol); pipobromane (pipobroman); a polycytidysine; cytarabine (arabine) ("Ara-C"); cyclophosphamide; thiotepa; taxanes, such as paclitaxel (taxol (r)) and docetaxel (taxotere (r)); chlorambucil; gemcitabine (gemzar (r)); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs, such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine (vancristine); vinorelbine (navelbine (r)); norfloxacin (novantrone); teniposide (teniposide); idazocide (edatrexate); daunorubicin; aminopterin; (xioloda); ibandronate (ibandronate); CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid (retinoid); capecitabine (capecitabine); FOLFIRI (fluorouracil, leucovorin and irinotecan), and pharmaceutically acceptable salts, acids or derivatives of any of the above. One or more chemotherapeutic agents are used or included in the present application.
The definition of "chemotherapeutic agent" also includes anti-hormonal agents used to modulate or inhibit the effects of hormones on tumors, such as anti-estrogens and Selective Estrogen Receptor Modulators (SERMs), including, for example, tamoxifen (including Nolvadex)TM) Raloxifene, droloxifene, 4-hydroxyttamoxifen, troloxifene, raloxifene (keoxifene), LY117018, onapristone, and toremifene (Fareston (r)); aromatase inhibitors which modulate the production of estrogen in the adrenal gland, e.g. 4(5) -imidazoles, aminoglutethimide(aminoglutethimide), megestrol acetate (Megace (r)), exemestane, formestane, fadrozole, vorozole (Rivisor (r)), letrozole (Femara (r)), and anastrozole (Arimidex (r)); and antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; and a pharmaceutically acceptable salt, acid or derivative of any of the above.
Examples of anti-angiogenic agents include, but are not limited to, retinoic acid and its derivatives, 2-methoxyestradiol, angiostatin (r), endostatin (r), suramin, squalamine, tissue inhibitors of metalloproteinase-1, tissue inhibitors of metalloproteinase-2, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, cartilage-derived inhibitors, paclitaxel (protein-bound paclitaxel), platelet factor 4, protamine sulfate (herring sperm), sulfated chitin derivatives (prepared from crab shells), sulfated polysaccharide peptide polysaccharide complex (sp-pg), staurosporine, matrix metabolism modulators, including, for example, proline analogs ((1-azetidine-2-carboxylic acid (LACA), cis-hydroxyproline, d, I-3, 4-dehydroproline, thiaproline (thiaproline), α -bipyridine, β -aminopropionitrile fumaric acid, 4-propyl-5- (4-pyridine) -2(3h) -oxazolone; methotrexate, mitoxantrone, heparin, interferon, 2-macroglobulin serum, chimp-3, chymostatin, beta-cyclodextrin tetradecyl sulfate, eponemycin; fumagillin, gold sodium thiomalate, d-penicillamine (CDPT), beta-1-antithrombin-serum, alpha-2-antiplasmin, bisantrene, disodium clobenzaprine, disodium n-2-carboxyphenyl-4-chlorophthalic acid or "CCA", thalidomide; angiostatic steroids, carboxyaminoimidazoles (carboxynaminolimidazole); metalloproteinase inhibitors such as BB 94. Other anti-angiogenic agents include antibodies, preferably monoclonal antibodies directed against the following angiogenic factors: beta-FGF, alpha-FGF, FGF-5, VEGF isoforms, VEGF-C, HGF/SF and Ang-1/Ang-2. See Ferrara N. and Alitalo, K. "Clinical application of inflammatory growth factors and the same inhibitors" (1999) Nature Medicine5: 1359-.
Anti-fibrotic agents include, but are not limited to, compounds such as β -aminopropionitrile (BAPN), and the compounds disclosed below: the compounds disclosed in U.S. patent 4,965,288 entitled "Inhibitors of lysyl oxidase", published by Palfreyman et al at 1990, 10 and 23, and which relates to lysyl oxidase Inhibitors and their use in the treatment of diseases and disorders associated with abnormal deposition of collagen; the compounds in U.S. patent 4,997,854 entitled "anti-fibrotic agents and methods for inhibiting the activity of lysine oxidase in a single use induced fibrosis protein substrate" published by Kagan et al on 3/5/1991, which is directed to compounds that inhibit LOX to treat a variety of pathological fibrotic conditions, is incorporated herein by reference. Other exemplary Inhibitors are described in Palfreyman et al, published 24.7.1990, U.S. Pat. No. 4,943,593 entitled "Inhibitors of lysylxidise", which relates to compounds such as 2-isobutyl-3-fluoro-, chloro-, or bromo-allylamine; and, for example, U.S. patent 5,021,456; us patent 5,5059,714; us patent 5,120,764; us patent 5,182,297; the compound of U.S. Pat. No. 5,252,608 (related to 2- (1-naphthyloxymethyl) -3-fluoroallylamine); and U.S. patent application No. 2004/0248871, which is incorporated herein by reference. Exemplary anti-fibrotic agents also include primary amines that react with the carbonyl group of the active site of lysyl oxidase, and more particularly those that upon binding to the carbonyl group yield a resonance-stabilized product, such as the following primary amines: ethylenediamine, hydrazine, phenylhydrazine, and their derivatives, semicarbazides, and urea derivatives, aminonitriles, such as β -aminopropionitrile (BAPN), or 2-nitroethylamine, unsaturated or saturated haloamines, such as 2-bromo-ethylamine, 2-chloroethylamine, 2-trifluoroethylamine, 3-bromopropylamine, p-halobenzylamine, seleno-homocysteine lactone. In addition, the anti-fibrotic agent is a copper chelator, either penetrating or impermeable to cells. Exemplary compounds include indirect inhibitors, such as compounds that block aldehyde derivatives (derived from oxidative deamination of lysyl and hydroxylysyl residues by lysyl oxidase), such as thiolamines, particularly D-penicillamine, or analogs thereof such as 2-amino-5-mercapto-5-methylhexanoic acid, D-2-amino-3-methyl-3- ((2-acetamidoethyl) dithio) butyric acid, p-2-amino-3-methyl-3- ((2-aminoethyl) dithio) butyric acid, 4- ((p-1-dimethyl-2-amino-2-carboxyethyl) dithio) butane sodium sulfide (sodium-4- ((p-1-dimethyl-2-amino-2-carboxthyl) dithio) butane sulfate, 2-Acetaminoethyl-2-acetamidoethane mercaptan sulfonate (sulfosalt), sodium 4-mercaptobutanesulfinate trihydrate.
Immunotherapeutics include, and are not limited to, therapeutic antibodies suitable for treating patients; such as abamectin (abagagozumab), adalimumab (adematumab), atolizumab (afutuzumab), alemtuzumab (alemtuzumab), alemtuzumab (aleumumab), amatuximab (amatuximab), anatumumab (aratuzumab), alemtuzumab (acituximab), baviximab (bavituximab), betuzumab (bectuzumab), bevacizumab (bevacizumab), bivatuzumab (bivatuzumab), brenmumab (blinatumumab), civil berentitumumab (brentuximab), tocuzumab (cantutuzumab), kavazumab (cataaxolob), cetuximab (cetuximab), cetuximab (sitatuzumab), cetuximab (cituzumab), cetuximab (cytuzumab (cyacib), adalimumab (gentab (gentuzumab), adoxib (deguzumab), rituximab (degumumab), meduttuzumab (degumumab), castumumab (degumumab), castumumab (degumumab), castumumab (castumumab), cast, Enzenstuzumab (ensituximab), itomumab (ertumaxomab), edamazumab (etaracimab), farizumab (farietuzumab), fertuzumab (fiblatuzumab), non-gemumab (figitumumab), flanuzumab (flantuzumab), flouximab (futuzumab), ganitumab (ganitumab), gemtuzumab (gemtuzumab), gemtuzumab (giritumumab), gemtuzumab (girrituximab), granzumab (regitumumab), ibritumomab (ibritumomab), golivumab (igovamab), gammaduzumab (immatuzumab), induzumab (indotuzumab), itumumab (infliximab), rituzumab (infliximab), rituximab (intumumab), bemazumab (immitumumab), bematuzumab (immitumumab), yamazumab (indtuzumab), rituzumab (rituzumab), yamazumab (ritujimatuzumab), yamazumab (ritukumazumab), yamakumakumab (ritukumab), yamakumakumab (indtuzumab), yamakumakumab (lat), yamakumakumakumab (lat-kumakumakumab), yama), yamakumakumakumakumab (lat-kumakumab (lat-kumakumakub), yab), yamakumakumakumakumakumakumakumakumakumakumakumakumakumakumakub), yama (ritukumaku, Minritumomab (minretumomab), mitumomab (mitumomab), mototumomab (moxetumomab), nanatumumab (narnatumumab), natumumab (naptiumomab), nimotuzumab (necitumumab), nimotuzumab (nimotuzumab), norvaruzumab (nofetumobn), ocalizumab (ocalatuzumab), ofatumumab (ofatumumab), olanzumab (olanzumab), olaratumumab (olanzumab), onartuatummab (onartutumab), agorguzumab (oredomab), panitumumab (panitumumab), pactamumab (saprotuzumab), pactamumab (panitumumab), pactamab (saprotuzumab), patritumumab), pertuzumab (pertuzumab), ritumumab (ritumumab), rituximab (ritumumab), ritumumab (ritumumab), ritumumab (ritumumab), ritum, Simtuzumab (simtuzumab), solituzumab (solitomab), tacatuzumab (tacatuzumab), tacatuzumab (tapritumomab), tacrolimus (tapritumomab), tenatemab (tenatemomab), tipuzumab (tigtuzumab), tositumomab (tositumomab), trastuzumab (trastuzumab), tuzumab (tuzumab), uubixib (ublitumomab), vituzumab (tuzumab), vorsetuzumab (vortuzumab), zalumumab (zalutumumab), obituzumab ozolob (obinutuzumab), CC49 and 3F 8. The exemplified therapeutic antibodies can be further labeled with or combined with radioisotope particles such as indium In 111, yttrium Y90, iodine 1-131.
The present application also provides methods of treating a subject undergoing one or more standard treatments, such as chemotherapy, radiation therapy, immunotherapy, surgery, or a combination thereof. Thus, one or more therapeutic agents or inhibitors may be administered before, during, or after administration of chemotherapy, radiation therapy, immunotherapy, surgery, or a combination thereof.
Other examples of chemotherapeutic treatments, including standard or experimental chemotherapies, are described below. In addition, some lymphomas are treated by Cheson, B.D., Leonard, J.P., "Monoclonal Antibody Therapy for B-CellNon-Hodgkin's Lymphoma" The New England and Journal of Medicine 2008 (359 (6)), p.613-626; and Wierda, W.G. "Current and Investigational therapeutics for Patients with CLL" Hematology 2006, pp. 285-294. In the United States, the pattern of Lymphoma development is analyzed in Morton, L.M., et al, "Lymphoma Inc. Patterns by WHO Subtype in the United States, 1992-.
Examples of immunotherapeutic agents include, but are not limited to, rituximab (e.g., Rituxan), alemtuzumab (e.g., Campath, MabCampath), anti-CD 19 antibody, anti-CD 20 antibody, anti-MN-14 antibody, anti-TRAIL DR4 and DR5 antibody, anti-CD 74 antibody, aprepizumab, bevacizumab, CHIR-12.12, epratuzumab (hLL 2-anti-CD 22 humanized antibody), galiximab, ha20, ibritumomab tiuxemab, luximab, milnacumab, ofamumab, PRO 921, SGN-40, WT-1 analog peptide vaccine, WT 1126-134 peptide vaccine, tositumomab, autologous human tumor-derived HSPPC-96, and Vitrozumab. Other immunotherapeutics include cancer vaccines that use genetic constructs (genetcmakeup) based on individual patient tumors, such as lymphoma vaccine for example GTOP-99
Examples of chemotherapeutic agents include aldesleukin, alvocidib, anticancer peptide AS2-1, anticancer peptide A10, antithymocyte globulin, amifostine trihydrate, aminocamptothecin, arsenic trioxide, β alethine, Bcl-2 family protein inhibitor ABT-263, ABT-199, BMS-345541, bortezomibBryostatin 1, busulfan, carboplatin, campath-1H, CC-5103, carmustineStatin, caspofungin acetate, clofarabine, cisplatin, cladribine (Leutarin), chlorambucil (Leukeran), curcumin, cyclosporin, cyclophosphamide (Cyloxan, Endoxan, Endoxana, Cyclostatin), cytarabine, dinil, dexamethasone, DT PACE, docetaxel, dolastatin 10, doxorubicin (doxorubicin: (L))Adribilastine), doxorubicin hydrochloride, enzastaurin, alfapentin, etoposide, everolimus (RAD001), fenretinide, filgrastim, melphalan, mesna, flazaquin, fludarabine (Fladara), geldanamycin (17-AAG), ifosfamide, irinotecan hydrochloride, ixabepilone, lenalidomide (R) (L, RCC-5013), lymphokine-activated killer cell, melphalan, methotrexate, mitoxantrone hydrochloride, motesafen gadolinium, mycophenolate mofetil, nelarabine, olmersen (Genasense) Obatoclax (GX15-070), orlistat, octreotide acetate, omega-3 fatty acid, oxaliplatin, paclitaxel, PD0332991, PEGylated liposomal doxorubicin HCl, pefilgrastim, pentostatin (Nipent), piperafoscin, prednisolone, prednisone, R-roscovitine (Selicilib, CYC202), recombinant interferon α, recombinant interleukin-12, recombinant interleukin-11, recombinant flt3 ligand, recombinant human thrombopoietin, rituximab, sargrastim, sildenafil citrate, simvastatin, sirolimus, styryl sulfone, tacrolimus, spiramycin, tacrolimus (CCl-779), therapeutic lymphotherapy, tiprolimus, allogenic exogenous pirimiphos,(bortezomib or PS-341), vincristine (Oncovin), vincristine sulfate, vinorelbine ditartrate, vorinostat (SAHA), vorinostat, and FR (fludarabine, rituximab), CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), CVP (cyclophosphamide, vincristine, and prednisone),FCM (fludarabine, cyclophosphamide, mitoxantrone), FCR (fludarabine, cyclophosphamide, rituximab), HyperCVAD (hyperfractionated cyclophosphamide), vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine, ICE (ifosfamide, carboplatin, and etoposide), MCP (mitoxantrone, chlorambucil, and prednisolone), R-CHOP (rituximab plus CHOP), R-CVP (rituximab plus CVP), R-FCM (rituximab plus FCM), R-ICE (rituximab-ICE), and R-MCP (R-MCP).
The treatment may be supplemented with or combined with any of the treatments described above with stem cell transplantation or treatment. An example of an improved method is radioimmunotherapy, In which monoclonal antibodies are combined with radioisotope particles such as indium In 111, yttrium Y90, iodine I-131. Examples of combination therapies include, but are not limited to, iodine-131 tositumomabYttrium-90 ibritumomab tiuxetanAnd CHOP.
Other therapeutic procedures include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, systemic irradiation, infusion of stem cells, bone marrow ablation supported by stem cells (bone marrow eradication supported by stem cells), peripheral blood stem cell transplantation by extracorporeal treatment, cord blood transplantation, immunoenzyme technology, pharmacological studies, low-LET cobalt-60 gamma ray therapy, bleomycin, routine surgery, radiotherapy, and allogeneic hematopoietic stem cell transplantation other than bone marrow eradication.
In some embodiments, the method comprises administering to a human in need thereof a compound described herein, or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof, in a therapeutically effective amount. The methods are useful for treating a patient having or believed to have a disease or disorder whose symptoms or pathology are mediated by the expression or activity of PI3K β and/or PI 3K. The patient may be a mammal or a human. In a certain embodiment, the patient may be a human.
"treatment" or "treating" is a method for obtaining a beneficial or desired result, including a clinical result. Beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or disorder (e.g., reducing one or more symptoms caused by the disease or disorder and/or alleviating the extent of the disease or disorder); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or disorder (e.g., stabilizing the disease or disorder, preventing or delaying the worsening or progression of the disease or disorder, and/or preventing or delaying the spread of the disease or disorder (e.g., metastasis)); and/or c) alleviating the disease, i.e., causing regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or complete remission of the disease or disorder, enhancing the efficacy of other medications, delaying disease progression, increasing quality of life, and/or prolonging survival).
"prevent" or "prevention" refers to any treatment of a disease or disorder such that the clinical symptoms of the disease or disorder do not develop. In some embodiments, the compound may be administered to a subject (including a human) at risk for or having a family history of a disease or disorder.
"subject" or "patient" refers to an animal, such as a mammal (including a human), who has been, or will be, the subject of treatment, observation or experiment. The methods described herein are useful for human therapy and veterinary applications. In some embodiments, the subject is a mammal; in one embodiment, the subject is a human. By "subject in need thereof" is meant a human that may have, or is suspected of having, a disease, disorder or condition that would benefit from a treatment (e.g., treatment with a PI3K inhibitor compound according to the present application). In certain embodiments, the subject may be a human that (i) has not received any treatment, including chemotherapeutic treatment, (ii) is substantially refractory to at least one chemotherapeutic treatment, (iii) is in relapse after treatment with chemotherapy, or both (i) and (ii). In some embodiments, the subject is refractory to at least one, at least two, at least three, or at least four chemotherapeutic treatments (including standard or experimental chemotherapy).
The term "therapeutically effective amount" or "effective amount" of a compound of the present application, or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof, refers to an amount sufficient to effect treatment when administered to a subject to provide a therapeutic benefit, such as ameliorating symptoms or slowing disease progression. For example, a therapeutically effective amount may be an amount sufficient to reduce the symptoms of a disease or disorder responsive to inhibition of PI3K and PI3K β activity. The therapeutically effective amount may vary depending on the subject and the disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the manner of administration, which can be readily determined by one of ordinary skill in the art.
In addition to the therapeutic uses, the compounds described herein have selective or selective inhibition of certain PI3K subtypes. In one embodiment, the compound is selective for PI3K β. In some embodiments, the compound is selective for PI 3K. In other embodiments, the compounds are selective for PI3K β and PI 3K. Selectivity for PI3K subtype can be determined by measuring the activity of compounds in inhibiting certain PI3K subtypes using the tests described in the examples below or commonly used methods. It is understood that conditions (e.g., reagent concentration or incubation temperature) may vary and that test results may vary. In some cases, the value may vary from 1 to 3 times.
The term "inhibition" indicates a decrease in the baseline activity of a biological activity or process. The term "inhibition of the activity of PI3K subtype" or variant thereof refers to a reduction in the activity of any PI3K subtype (e.g., α, β, γ or) present in response, directly or indirectly, to the compound of any one of the formulae described herein relative to the activity of PI3K subtype in the absence of the compound described herein. By "inhibition of PI3K and/or PI3K β activity" or variants thereof is meant a decrease in PI3K and/or PI3K β activity, directly or indirectly, in response to the presence of a compound described herein, relative to the activity of PI3K and/or PI3K β in the absence of a compound described herein. In some embodiments, inhibition of PI3K subtype activity may be compared in the same subject prior to treatment, or compared to other subjects not receiving the treatment.
Without wishing to be bound by any theory, the reduction in PI3K activity may be due to direct interaction of the compound with PI3K, or due to interaction of the compounds described herein with one or more other factors that affect PI3K activity. For example, the presence of the compound may reduce the activity of PI3K and/or PI3K β by binding directly to PI3K and/or PI3K β, by causing (directly or indirectly) another factor to reduce PI3K and/or PI3K β activity, or by reducing (directly or indirectly) the amount of PI3K and/or PI3K β present in the cell or organism.
The term "PI 3K inhibitor" or variants thereof refers to a compound that inhibits the activity of PI 3K. The term "PI 3K subtype selective inhibitor" or variants thereof refers to compounds that inhibit the activity of one or more PI3K subtypes more effectively than the other remaining PI3K subtypes. As an example, the term "PI 3K β selective inhibitor" generally refers to a compound that inhibits the activity of the PI3K β subtype more effectively than other subtypes of the PI3K family, and the term "PI 3K selective inhibitor" generally refers to a compound that inhibits the activity of the PI3K subtype more effectively than other subtypes of the PI3K family. The term "dual PI3K/β selective inhibitor" generally refers to compounds that inhibit both PI3K and PI3K β subtypes more effectively than other subtypes of the PI3K family (e.g., PI3K α or γ).
The relative efficacy of a compound as an inhibitor of enzymatic activity (or other biological activity) can be established as follows: the concentration of each compound that inhibits the activity to a predetermined degree is determined, and the results are compared. In one embodiment, the efficacy of a compound as an inhibitor of one or more PI3K subtypes can be measured by the concentration of the compound that inhibits 50% of activity in a biochemical assay, i.e., 50% inhibitory concentration or "IC50”。IC50The determination of the values can be accomplished using conventional techniques known in the art, including the techniques described in the examples below. In general, ICs50Can be determined by measuring the activity of a given enzyme in the presence of a range of concentrations of the compound under investigation. The experimentally obtained enzyme activity values can then be plotted against the compound concentration used. Concentration of inhibitor showing 50% enzyme activity (compared to activity in the absence of any inhibitor) as IC50The value is obtained. Similarly, other inhibitory concentrations may be defined by appropriate determination of activity. For example, in some cases it may be desirable to establish a 90% inhibitory concentration, i.e., IC90。
According to the application, a selective inhibitor of PI3K β is a compound having a 50% Inhibitory Concentration (IC) against PI3K β50) Is IC for PI3K α or PI3K γ or both PI3K α and PI3K γ50Up to one-10, up to one-20, up to one-30, up to one-50, up to one-100, up to one-200, or up to one-500, in addition, the PI3K/β selective inhibitor is a compound having a 50% Inhibitory Concentration (IC) for PI3K β and PI3K50) IC for PI3K α or PI3K gamma50Up to one-10, up to one-20, up to one-30, up to one-50, up to one-75, up to one-100, up to one-200, and up to one-500, dual PI3K/β selective inhibitors may have the same or similar IC for both PI3K and PI3K β50Or may have a different IC for PI3K or PI3K β50. The terms "efficacy", "effective", or variants thereof, as used herein, refer to the IC possessed by the compound50Values were less than 100 nM. When comparing the two compounds, has a lower IC50Compounds of value are referred to as more potent inhibitors.
As shown in the examples, certain compounds in Table 1 show low IC for both PI3K β and PI3K50Values (e.g., 1 to 100 nM). Certain compounds in table 1a also show this selectivity for the PI3K subtype. Furthermore, certain compounds of formula (I)IC displaying PI3K β50Values of up to one 10-fold to one 400-fold of PI3K γ indicate that the compound exhibits greater selectivity for PI3K β than PI3K γ (i.e., inhibits the activity of the PI3K β subtype more effectively than the PI3K γ, as indicated by the PI3K γ/PI3K β ratio). further, the compounds described herein exhibit selectivity for both PI3K β and PI3K the compound (S) -2, 4-diamino-6- ((1- (5-chloro-4-oxo-3-phenyl-3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile described in U.S. provisional application No. 61/745,437 exhibits less selectivity for PI3K γ (e.g., the PI 3K/PI 3K β ratio is less than 1-fold). the results of this application indicate that certain of the compounds described herein are dual selective inhibitors of PI3K and PI3K β and exhibit greater selectivity for PI3K β than PI3K γ. this application is hereby incorporated by reference in its entirety.
The methods described herein can be applied to a population of cells in vivo or ex vivo. By "in vivo" is meant within a living individual, such as within an animal or human. In this case, the methods described herein can be used therapeutically in an individual. By "ex vivo" is meant outside a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including fluid or tissue samples obtained from individuals. Such samples may be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. Exemplary tissue samples include tumors and biopsies thereof. In this case, the compounds may be used for various purposes, including therapeutic and experimental purposes. For example, it can be used ex vivo to determine the optimal dosing schedule and/or dose of a selective inhibitor of PI3K for a given indication, cell type, individual, and other parameters. Information gleaned from such use may be used for experimental purposes or in the clinic to set an in vivo treatment regime. Other ex vivo uses to which the invention may be adapted are described below or will be apparent to those skilled in the art. A compound of the formulae described herein, or a pharmaceutically acceptable salt, prodrug or solvate thereof, can be further characterized to check the safety or tolerated dose in a human or non-human subject. Such properties can be checked using methods generally known to those skilled in the art.
PI3K is commonly expressed in hematopoietic cells compared to other PI3K subtypes. In addition, PI3K β is often deregulated in certain cancer cells. Abnormal proliferation of cells often interferes with normal tissue function, which can lead to abnormal cellular responses such as immunity, inflammation, and/or apoptosis. Selective inhibitors of PI3K and/or PI3K β are useful for treating, inhibiting, or preventing cancer and/or abnormal proliferation of hematopoietic cells and ameliorating the symptoms and secondary conditions.
The compounds described herein are useful for treating subjects suffering from a variety of disease states, disorders, and conditions (also collectively referred to as "indications") associated with the PI3K subtype or its activity. As used herein, the terms "disease," "disorder," "condition" are used interchangeably. Such indications may include, for example, cancer, including hematological malignancies (e.g., leukemias and lymphomas, myeloproliferative diseases, myelodysplastic syndromes, plasma cell tumors) and solid tumors, inflammation, fibrosis, allergic conditions (including hypersensitivity reactions), cardiovascular diseases, neurodegenerative diseases, kidney diseases, viral infections, obesity, and autoimmune diseases.
In other embodiments, the compounds described herein may be used to treat cancers mediated by, dependent on, or associated with PI3K activity. In certain embodiments, the disease or disorder is an autoimmune disease, an inflammatory disease, or cancer. In some embodiments, the disease or disorder is selected from rheumatoid arthritis, osteoarthritis, atherosclerosis, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, asthma, chronic obstructive airways disease, pneumonia, dermatitis, alopecia, nephritis, vasculitis, atherosclerosis, alzheimer's disease, hepatitis, primary biliary cirrhosis, sclerosing cholangitis, diabetes (including type I diabetes), acute rejection of transplanted organs, lymphoma, multiple myeloma, leukemia, tumors, and solid tumors.
In other embodiments, the disease is a solid tumor. By way of example, the solid tumor includes, but is not limited to, pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, kidney cancer, hepatocellular cancer, lung cancer, ovarian cancer, cervical cancer, rectal cancer, liver cancer, kidney cancer, stomach cancer, skin cancer, stomach cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS cancer (e.g., neuroblastoma), brain tumor (e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma), bone cancer, or soft tissue sarcoma. In some embodiments, the solid tumor is non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, pancreatic cancer, prostate cancer, or breast cancer.
The present application also provides methods of treating a human in need thereof, having or suspected of having a disease or disorder responsive or believed to be responsive to inhibition of PI3K and/or PI3K β activity by administering to the subject a compound described herein, or a pharmaceutically acceptable salt, enantiomer, atropisomer, tautomer, prodrug or solvate thereof.
Further, the present application provides methods of inhibiting kinase activity of PI3K and/or PI3K β polypeptides by contacting the polypeptides with a compound described herein, or a pharmaceutically acceptable salt, isomer, prodrug, solvate or mixture thereof.
Further, the present application provides methods of reducing cell viability, increasing cell death or apoptosis, increasing interference with PI3K signaling pathways (including AKT, S6RP, ERK phosphorylation), and/or reducing chemokine production by using an effective amount of a compound of any one of the formulas described herein, or a pharmaceutically acceptable salt, isomer, prodrug, solvate or mixture thereof.
The present application also provides a method of disrupting leukocyte function comprising contacting leukocytes with an effective amount of a compound of any one of the formulae described herein, or a pharmaceutically acceptable salt, isomer, prodrug, solvate or mixture thereof, in a human in need thereof.
Also provided are methods of inhibiting growth or proliferation of a cancer cell comprising contacting the cancer cell with an effective amount of a compound described herein, or a pharmaceutically acceptable salt, isomer, prodrug, solvate or mixture thereof.
Reagent kit
Also provided herein is a kit comprising a compound of the formula or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof, and a suitable package. In one embodiment, the kit further comprises instructions for use. In one aspect, a kit comprises a compound described herein, or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof, and a label and/or instructions for use of the compound in a therapeutic indication, including a disease or condition described herein.
Also provided herein is an article of manufacture comprising a compound of any of the formulae herein, or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof, in a suitable container. The container may be a bottle, a can, an ampoule, a pre-loaded syringe and an intravenous bag.
Pharmaceutical compositions and modes of administration
The compounds provided herein are typically administered in the form of a pharmaceutical composition. Accordingly, also provided herein are pharmaceutical compositions comprising one or more compounds of any of the formulae described herein, or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof, and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients. Suitable pharmaceutically acceptable carriers can include, for example, inert solid diluents and fillers, diluents (including sterile aqueous solutions and various organic solvents), penetration enhancers, solubilizers, and excipients. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington's Pharmaceutical Sciences, machine Publishing co., philiadelphia, pa.17thed. (1985); and Modern pharmaceuticals, Marcel Dekker, inc.3rd Ed. (g.s.banker & c.t.rhodes, Eds.).
The pharmaceutical compositions may be administered in a single dose or in multiple doses. The pharmaceutical compositions can be administered by a variety of methods including, for example, rectal, buccal, intranasal, and transdermal routes. In certain embodiments, the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or in the form of an inhalant. In some embodiments, the pharmaceutical composition is administered orally.
One mode of administration is parenteral, for example by injection. The forms that may be incorporated into the pharmaceutical compositions described herein for administration by injection include, for example, aqueous or oily suspensions or emulsions containing sesame oil, corn oil, cottonseed or peanut oil, as well as elixirs, mannitol, dextrose or sterile aqueous solutions, and similar pharmaceutical vehicles.
Oral administration may be another route for administration of the compounds described herein. For example, administration can be by capsule or tablet coated with an enteric coating. In making a pharmaceutical composition comprising at least one compound of any of the formulae described herein, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, the active ingredient is typically diluted by an excipient and/or sealed within a carrier, which may be in the form of a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it may be in the form of a solid, semi-solid or liquid material (as described above) which acts as a vehicle, carrier or medium for the active ingredient. Thus, the composition may be in the form of: tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders. In certain embodiments, the pharmaceutical composition is in the form of a tablet.
Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulation may additionally include: lubricants, such as talc, magnesium stearate and mineral oil; a humectant; emulsifying and suspending agents; preservatives, such as methyl and propyl hydroxybenzoate; a sweetener; and a flavoring agent.
A composition comprising at least one compound of any of the formulae described herein, or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof, can be formulated so as to provide rapid, sustained or delayed release of the active ingredient after administration to a subject by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer coated reservoirs (reservoir) or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Pat. nos. 3,845,770, 4,326,525, 4,902,514, and 5,616,345. Another formulation for use in the methods of the present invention employs a transdermal delivery device ("patch"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts. The construction and use of transdermal patches for delivering pharmaceutical agents is well known in the art. See, for example, U.S. patent nos. 5,023,252, 4,992,445, and 5,001,139. Such patches may be constructed to deliver the agent continuously, in pulses, or on demand.
For preparing solid compositions such as tablets, the principal active ingredient may be mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of a compound of any of the formulae described above or a pharmaceutically acceptable salt, prodrug or solvate thereof. When referring to these preformulation compositions as homogeneous compositions, the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
Tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of having a prolonged period of action or protection from the acidic conditions of the stomach. For example, a tablet or pill can include an inner dosage and an outer dosage component, the latter being in an encapsulated form on the former. The two components may be separated by an enteric coating layer to resist disintegration in the stomach and to allow the inner component to pass intact into the duodenum or to be delayed in release. A number of materials may be used as the enteric layer or coating, including a number of polymeric acids, and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
Compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. The liquid or solid composition may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effects. In other embodiments, the composition in a pharmaceutically acceptable solvent may be nebulized by using an inert gas. The nebulized solution may be inhaled directly from the nebulizing device or the nebulizing device may be connected to a mask support or an intermittent positive pressure ventilator. Solution, suspension or powder compositions may be administered, preferably orally or nasally in an appropriate manner, from a device for delivering the formulation.
Administration of drugs
For any particular subject, the particular dosage level of a compound of the formulae described herein will depend upon a variety of factors including the activity, age, body weight, general health, sex, diet, time of administration, route of administration and rate of excretion, drug combination and the severity of the particular disease in the subject undergoing therapy. For example, the dose can be expressed as milligrams of the compound of formula (i) per kilogram of the subject's body weight (mg/kg). A dosage of about 0.01 to 200mg/kg may be appropriate. In some embodiments, about 0.01 to 150mg/kg may be suitable. In other embodiments, a dosage of 0.05 to 100mg/kg may be appropriate. Normalization to the body weight of a subject is particularly useful when adjusting the dose between subjects of widely varying size, for example when using drugs in children and adults or when converting an effective dose in a non-human subject (e.g. a dog) to a dose suitable for a human subject.
The daily dose may also be described as the total amount of the compound of formula (la) administered per dose or per day. The daily dose of the compound may be about 1mg to 2,000mg, about 1,000 to 2,000 mg/day, about 1 to 1,000 mg/day, about 1 to 500 mg/day, about 100 to 150 mg/day, about 1 to 100 mg/day, about 1 to 50 mg/day, about 50 to 100 mg/day, about 100 to 125 mg/day, about 100 to 150 mg/day, about 100 to 175 mg/day, about 100 to 200 mg/day, about 100 to 225 mg/day, about 100 to 250 mg/day, about 100 to 350 mg/day, about 100 to 400 mg/day, about 100 to 450 mg/day, or about 100 to 500 mg/day.
When administered orally, the total daily dose for a human subject may be 1mg to 1,000 mg/day, about 1 to 100 mg/day, about 1 to 50 mg/day, about 50 to 100 mg/day, 100 to 200 mg/day, about 200 to 300 mg/day, about 300 to 400 mg/day, about 400 to 500 mg/day, about 100 to 150 mg/day, about 150 to 200 mg/day, about 200 to 250 mg/day, about 75 to 150 mg/day, or about 150 to 300 mg/day.
The compounds of the present application or compositions thereof may be administered once, twice, three times or four times daily using any suitable mode described above. Furthermore, administration or treatment of a compound according to any of the formulae described herein may last for multiple days; for example, treatment will typically last for at least 7, 14 or 28 days for one treatment cycle. In some treatments, the compound or composition thereof is administered continuously, i.e., daily. Treatment cycles are well known in cancer chemotherapy and are often alternated with rest periods of about 1 to 28 days, usually about 7 days or about 14 days between cycles. In other embodiments, the treatment cycle may also be continuous.
In a specific embodiment, the method comprises administering to the subject an initial daily dose of about 1 to 500mg of a compound of the above formula and increasing the dose in increments until clinical efficacy is achieved. The dosage may be increased using increments of about 1,5, 10, 25, 50, 75 or 100 mg. The dose may be increased daily, every other day, twice weekly, or once weekly.
Synthesis of Compounds
The compounds of the present invention may be prepared using the methods and route variations disclosed herein which will be apparent in light of the disclosure and methods well known in the art. Conventional well-known synthetic methods may also be used in addition to those taught in the present application. The synthesis of typical compounds described herein can be achieved as described in the examples below. Reagents, if available, may be purchased commercially, for example, from SigmaAldrich or other chemical suppliers. Generally, the compounds described herein are generally stable and isolatable at room temperature and pressure.
General Synthesis
Typical embodiments of the compounds of the present invention may be synthesized using the general reaction schemes described below. It is evident in view of the description of the present application that this general reaction scheme can be varied by replacing the starting materials by other materials having a similar structure, resulting in correspondingly different products. The following synthetic description gives a number of examples of how the starting materials may be varied to give the corresponding products. In the case of a given desired product defined by the substituent groups, the necessary starting materials can generally be determined by inspection. The starting materials are typically obtained from commercial sources or synthesized using published methods. To synthesize a compound as an embodiment of the present invention, examining the structure of the compound to be synthesized provides identification of the individual substituents. In view of the examples given herein, the identification of the final product generally makes clear the identification of the essential raw materials by a simple examination method.
Parameters of the Synthesis reaction
The terms "solvent", "inert organic solvent" or "inert solvent" refer to a solvent (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), chloroform, methylene dichloride (or dichloromethane), diethyl ether, methanol, and the like) that is inert under the reaction conditions described therewith. Unless specified to the contrary, the solvent used in the reaction of the present invention is an inert organic solvent, and the reaction is carried out in an inert gas (preferably nitrogen).
The compounds of formula (J) can be prepared using the methods shown in reaction scheme I. Further, the compound of formula (I) can be prepared using the method shown below.
Reaction scheme I
Step 1-preparation of Compound of formula (1)
Compounds of formula (1) may be prepared by treating a 5-substituted-2, 4, 6-trihalopyrimidine (a) wherein G is halogen (e.g. iodine, bromine, chlorine or fluorine) with ammonium hydroxide in a suitable solvent such as dioxane. The reaction is carried out at 30 ℃ to 80 ℃ for 2 to 8 hours or until the reaction is complete. Once complete, water was added to the cooled solution and the precipitate was collected by filtration. The nitrile can be converted into formamide using generally known methods.
Step 2-preparation of Compound of formula (2)
The compound of formula (2) can be prepared by mixing the compounds (B), (C) and (D) in the presence of a dehydrating agent. Compounds (B), (C) and (D) are commercially available or can be prepared by methods known in the art. X, Y, Z, n, m', R1、R2、R3And R5As defined above. Compound (B) is mixed with compound (D) in the presence of a coupling agent such as diphenyl phosphite in a solvent such as pyridine. After stirring at a temperature of from ambient temperature (i.e. room temperature) to 100 ℃ for 1 to 5 hours, compound (C) is added. After further stirring at a temperature of ambient to 100 ℃ for 5 to 24 hours, the reaction mixture was cooled to room temperature. For extraction of formula (2)The compound may be added with an organic solvent such as ethyl acetate (EtOAc) and then washed with a weak base, water and brine. The organic phase may be concentrated to give the compound of formula (2). The compound of formula (2) may be purified by any suitable method known in the art, such as silica gel chromatography. Alternatively, the compound of formula (2) is purified directly without aqueous workup. Alternatively, the compound of formula (2) can be used in the next step without purification. The alkylsulfonyl and cyano compounds may be prepared by replacing halogen from the corresponding halogen-containing compound using a commonly known method. In some cases, the compound (C) may be protected with a group such as triphenylmethyl, Boc, or trimethylsilyloxymethyl, and removed by a generally known method at a subsequent step.
Step 3-preparation of Compound of formula (3)
The compound of formula (3) can be prepared by removing the protecting group from the compound of formula (2). The compound of formula (2) is dissolved in a suitable solvent and treated (i.e. mixed) with a suitable acid. Suitable solvents may include, for example, dichloromethane, dioxane, or other suitable solvents. Suitable acids may include, for example, trifluoroacetic acid or hydrochloric acid. The reaction may be carried out at a temperature of-78 ℃ to ambient temperature. After completion of the reaction, the solvent is removed to obtain a compound of formula (3).
Step 4-preparation of Compounds of formula (I)
The compound of formula (I-1) can be generally prepared by coupling the compound of formula (3) and the compound of formula (1) in a suitable solvent in the presence of a suitable base. Further, the compound of formula (J), wherein a is a single bond, can be generally prepared by coupling the compound of formula (3) and the compound of formula (1) in the presence of a suitable base in a suitable solvent. A suitable base may be, for example, diisopropylethylamine. Suitable solvents may for example be Isopropanol (IPA), DMSO, DMF, ethylene glycol or ethanol. The reaction is generally carried out at a temperature of 50 ℃ to 150 ℃ for about 30 minutes to 24 hours. Alternatively, the reaction may be performed by microwave at a temperature of 100 ℃ to 150 ℃ for about 30 minutes to 24 hours. Alternatively, the reaction may be carried out in a sealed tube at a temperature of 50 ℃ to 150 ℃. The compound of formula (I-2) can be generally prepared by coupling the compound of formula (3) with a suitable acid in the presence of a coupling agent such as HATU, DCC or carbonyldiimidazole in the presence of a base such as triethylamine or diisopropylethylamine in a suitable solvent such as dichloromethane or THF. Further, the compound of formula (I-2), wherein a is c (o), can be generally prepared by coupling the compound of formula (3) with a suitable acid in the presence of a coupling agent such as HATU, DCC or carbonyldiimidazole in the presence of a base such as triethylamine or diisopropylethylamine in a suitable solvent such as dichloromethane or THF. The resulting compounds can be isolated by methods known in the art; for example, by removing the solvent or aqueous solution under reduced pressure. The product may be purified using any suitable method known in the art; for example, the residue is chromatographed on a column of silica gel, chromatographed on HPLC, or crystallized.
After synthesis, the compound can be isolated as the free base or salt form (which includes and is not limited to the hydrochloride or trifluoroacetate salt form) and characterized by NMR. Thus, the resulting compound and its NMR characterization can be as the free base or as a salt. The ratio of parent to corresponding salt is uncertain.
Example 4 preparation of a Compound of formula (I)
A. Preparation of a compound of formula (I) wherein X is CH, Y is N, Z is C and is the point of attachment to a quinazolinone, A is a single bond, N is 1, R1Is chlorine, m' is 0, R3Is CH2CH3，R5Is hydrogen, is R4Is 2, 6-diamino-5-cyanopyrimidin-4-yl
2-propanol (3mL) was added to (S) -2- (1-aminopropyl) -5-chloro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one 2,2, 2-trifluoroacetate salt (0.25mmol) and the resulting solution was transferred to a bottle containing 2, 4-diamino-6-chloropyrimidine-5-carbonitrile (42mg, 0.25 mmol). Diisopropylethylamine (0.25mL, 1.5mmol) was added to the suspension and the reaction mixture was heated to 130 ℃ in a microwave for 14 hours. The reaction was cooled to room temperature and concentrated. The DMSO solution of the crude mixture was then purified by HPLC eluting with 5% -95% water/acetonitrile (0.1% v/v trifluoroacetic acid). The appropriate fractions were pooled and lyophilized to give (S) -2, 4-diamino-6- ((1- (5-chloro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) propyl) amino) pyrimidine-5-carbonitrile (compound 1).1H NMR(400MHz，DMSO)13.21(br s，1H)，7.92(d，J＝2.4Hz，1H)，7.80(dd，J＝8.3，7.8Hz，1H)，7.64–7.57(m，2H)，6.58(d，J＝2.4Hz，1H)，4.69–4.62(m，1H)，2.05–1.93(m，1H)，1.85–1.75(m，1H)，0.75(t，J＝7.3Hz，3H)。ES/MS437.1(M+H+)。
B. The following compound of formula (I) was prepared using the procedure and reaction scheme I of example 4A:
(S) -4-amino-6- ((1- (5-chloro-4-oxo-3- (1H-pyrazol-4-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (compound 2): 1H NMR (400MHz, DMSO)8.04(s, 1H), 7.84(s, 2H), 7.75(d, J ═ 8Hz, 2H), 7.60(dd, J ═ 8.4, 1.2Hz, 1H), 7.57(dd, J ═ 6.4, 1.2Hz, 1H), 7.45(bs, 2H), 4.94(m, 1H), 1.38(d, J ═ 6.8Hz, 3H). ES/MS 408.1(M + H)+)；
(S) -4-amino-6- ((1- (5-chloro-3- (4-methyl-1H-pyrazol-3-yl) -4-oxo-3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (compound 3): 1H NMR (400MHz, DMSO)12.82(bs, 1H), 7.81(s, 1H), 7.71(t, J ═ 8Hz, 1H), 7.61-7.57(m, 2H), 7.57-7.53(m, 2H), 7.21(m, 2H), 4.80 (apparent quintet (app pent), J ═ 7Hz, 1H), 1.87(s, 3H), 1.45(d, J ═ 7Hz, 3H). ES/MS 422.1(M + H)+)；
(S) -4-amino-6- ((1- (5-chloro-3- (5-isobutyl-1H-pyrazol-3-yl) -4-oxo-3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (compound 4): 1H NMR (400MHz, DMSO)12.98(s, 1H), 7.87(s, 1H), 7.73(t, J ═ 8Hz, 1H), 7.57(dd, J ═ 8,1Hz, 1H), 7.53(dd, J ═ 8,1Hz, 1H), 7.44(d, J ═ 6Hz, 1H), 7.21(s, 1H), 4.80 (apparent quintuple, J ═ 7Hz, 1H), 2.14(m, 2H), 1.79(m, 1H), 1.35(d, J ═ 7Hz, 3H), 1.01(d, J ═ 6Hz, 6H). 464.1.ES/MS 422.1(M + H)+)；
(S) -4-amino-6- ((1- (5-chloro-3- (5-cyclopropyl-1H-pyrazol-3-yl) -4-oxo-3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (compound 5): 1H NMR (400MHz, DMSO)12.82(bs, 1H), 7.81(s, 1H), 7.71(t, J ═ 8Hz, 1H), 7.61-7.57(m, 2H), 7.57-7.53(m, 2H), 7.21(m, 2H), 4.80 (apparent quintuple, J ═ 7Hz, 1H), 1.87(s, 3H), 1.45(d, J ═ 7Hz, 3H). ES/MS 422.1(M + H)+)；
(S) -4-amino-6- ((1- (5-chloro-4-oxo-3- (5- (trifluoromethyl) -1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (compound 6): 1H NMR (400MHz, DMSO)7.52(d, J ═ 2Hz, 1H), 7.20(t, J ═ 8Hz, 1H), 6.74(d, J ═ 8Hz, 1H), 6.67(m, 1H), 5.68(s, 1H), 4.28(m, 1H), 1.50(d, J ═ 6Hz, 3H). ES/MS 476.1(M + H)+)；
(S) -4-amino-6- ((1- (5-chloro-3- (5-methyl-1H-pyrazol-3-yl) -4-oxo-3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (Compound 7): 1H NMR (400MHz, DMSO)12.77(s, 1H), 7.92(s, 1H),7.75(t, J ═ 8Hz, 1H), 7.58(dd, dd, J ═ 8,1Hz, 1H), 7.54(dd, J ═ 8,1Hz, 1H), 7.41(d, J ═ 6Hz, 1H), 7.25(s, 1H), 6.09(s, 1H), 4.93 (apparent quintuple, J ═ 7Hz, 1H), 2.21(s, 3H), 1.37(d, J ═ 7Hz, 3H). ES/MS 422.1(M + H)+)；
(S) -5-chloro-3- (5-methyl-1H-pyrazol-3-yl) -2- (1- (thiazolo [5, 4-d)]Pyrimidin-7-ylamino) ethyl) quinazolin-4 (3H) -one (compound 8): 1H NMR (400MHz, DMSO)9.24(s, 1H), 8.32(d, J ═ 7Hz, 1H), 8.30(s, 1H), 7.68(t, J ═ 8Hz, 1H), 7.53(d, J ═ 8Hz, 1H), 7.49(d, J ═ 8Hz, 1H), 6.08(s, 1H), 5.00(app pent J ═ 7Hz, 1H), 2.10(s, 3H), 1.44(d, J ═ 7Hz, 3H). ES/MS 439.1(M + H)+)；
(S) -5-chloro-2- (1- (furo [2, 3-d)]Pyrimidin-4-ylamino) ethyl) -3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (compound 9).1H NMR(400MHz，DMSO)8.41(d，J＝6.7Hz，1H)，8.36(br s，1H)，8.18(s，1H)，7.88(d，J＝2.3Hz,1H)，7.80(d，J＝2.4Hz，1H)，7.77–7.65(m，1H)，7.58–7.54(m，2H)，7.14(d，J＝2.4Hz，1H)，6.51(d，J＝2.6Hz，1H)，4.84(p，J＝6.8Hz，1H)，1.50(d，J＝6.9Hz，3H)。ES/MS 408.1(M+H+)；
(S) -2- (cyclopropyl ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) methyl) -5-fluoro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 10).1H NMR(400MHz，DMSO)13.18(br s，1H)，7.95–7.83(m，2H)，7.58(dd，J＝8.3，1.0Hz，1H)，7.55–7.42(m，3H)，7.37(ddd，J＝10.9，8.2，1.0Hz，1H)，6.37(d，J＝2.4Hz，1H)，4.72(t，J＝7.7Hz，1H)，1.42–1.32(m，1H)，0.52–0.34(m，3H)，0.21–0.14(m，1H)。ES/MS 442.1(M+H+)；
(S) -2- (cyclopropyl ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) methyl) -5, 8-difluoro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 11).1H NMR(400MHz，DMSO)13.20(br s，1H)，7.86(d，J＝2.5Hz，1H)，7.82(dt，J＝9.4，4.7Hz，1H)，7.52–7.34(m，4H)，7.29(br s，3H)，6.37(d，J＝2.3Hz，1H)，4.73(t，J＝7.7Hz，1H)，1.45–1.31(m，1H)，0.54–0.35(m，3H)，0.21–0.14(m，1H)。ES/MS 460.1(M+H+)；
(S) -2- (cyclopropyl ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) methyl) -8-fluoro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 12).1H NMR(400MHz，DMSO)13.20(br s，1H)，7.99–7.93(m，1H)，7.86(d，J＝2.4Hz，1H)，7.80(ddd，J＝10.5，8.1，1.4Hz，1H)，7.60(td，J＝8.1，4.7Hz，1H)，7.47(br s，3H)，7.31(br s，2H)，6.38(d，J＝2.3Hz，1H)，4.78(t，J＝7.7Hz，1H)，1.45–1.33(m，1H)，0.53–0.36(m，3H)，0.21–0.14(m，1H)。ES/MS 442.1(M+H+)；
(S) -8-chloro-2- (cyclopropyl ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) methyl) -3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 13).1H NMR(400MHz，DMSO)13.24(br s，1H)，8.13–8.07(m，2H)，7.91(d，J＝2.4Hz，1H)，7.59(t，J＝7.9Hz，1H)，7.53–7.19(m，4H)，6.42(d，J＝2.3Hz，1H)，4.93(dd，J＝7.7，6.6Hz，1H)，1.45–1.33(m，1H)，0.50–0.36(m，3H)，0.21–0.14(m，1H)。ES/MS458.1(M+H+)；
(S) -5-chloro-3- (5-chloro-1H-pyrazol-3-yl) -2- (cyclopropyl ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) methyl) quinazolin-4 (3H) -one (Compound 14).1H NMR(400MHz，DMSO)7.84(t，J＝8.0Hz，1H)，7.72(dd，J＝8.2，1.2Hz，1H)，7.66(d，J＝7.7Hz，1H)，7.59(br s，1H)，7.50(br s，2H)，7.37(br s，2H)，6.39(br s，1H)，4.68(br s，1H)，1.50(br s，1H)，0.62–0.38(m，3H)，0.17(brs，1H)。ES/MS 492.1(M+H+)；
(S) -2, 4-diamino-6- ((1- (5-chloro-4-oxo-3- (1H-pyrazol-4-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (Compound 15).1H NMR(400MHz，DMSO)7.89(br s，2H)，7.82–7.74(m，1H)，7.62–7.57(m，2H)，4.91(p，J＝6.7Hz，1H)，1.36(d，J＝6.7Hz，3H)。ES/MS423.1(M+H+)；
(S) -2, 4-diamino-6- ((1- (5-chloro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (Compound 16).1H NMR(400MHz，DMSO)13.20(br s，1H)，7.91(d，J＝2.4Hz，1H)，7.84–7.77(m，1H)，7.65–7.59(m，2H)，6.55–6.52(m，1H)，4.85–4.75(m，1H)，1.41(d，J＝6.7Hz，3H)。ES/MS423.1(M+H+)；
(S) -2, 4-diamino-6- (((5-chloro-4-oxo-3- (1H-pyrazol-4-yl) -3, 4-dihydroquinazolin-2-yl) (cyclopropyl) methyl) amino) pyrimidine-5-carbonitrile (Compound 17).1H NMR(400MHz，DMSO)7.87(br s 2H)，7.83–7.70(m，3H)，7.70–7.56(m，2H)，4.80(t，J＝7.5Hz，1H)，1.45–1.34(m，1H)，0.53–0.36(m，3H)，0.18–0.09(m，1H)。ES/MS 449.1(M+H+)；
(S) -2, 4-diamino-6- (((5-chloro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) (cyclopropyl) methyl) amino) pyrimidine-5-carbonitrile (Compound 18).1H NMR(400MHz，DMSO)13.15(br s，1H)，7.90–7.74(m，2H)，7.69–7.61(m，2H)，6.38(d，J＝2.3Hz，1H)，4.72(t，J＝7.6Hz，1H)，1.47–1.37(m，1H)，0.53–0.36(m，3H)，0.24–0.14(m，1H)。ES/MS 449.1(M+H+)；
(S) -5-chloro-2- (cyclopropyl ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) methyl) -3- (1H-pyrazol-4-yl) quinazolin-4 (3H) -one (Compound 19).1H NMR(400MHz，DMSO)7.84–7.70(m，2H)，7.68(dd，J＝8.2，1.2Hz，1H)，7.61(dd，J＝7.8，1.2Hz，1H)，7.57–7.30(m，4H)，4.78(t，J＝7.6Hz，1H)，1.45–1.34(m，1H)，0.55–0.34(m，3H)，0.16–0.08(m，1H)。ES/MS 458.1(M+H+)；
(S) -5-chloro-2- (cyclopropyl ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) methyl) -3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 20).1H NMR(400MHz，DMSO)13.17(br s，1H)，7.86(d，J＝2.3Hz，1H)，7.82(t，J＝8.0Hz，1H)，7.70(dd，J＝8.2，1.2Hz，1H)，7.63(dd，J＝7.8，1.2Hz，1H)，7.49(br s，3H)，7.35(br s，2H)，6.38(d，J＝2.3Hz，1H)，4.71(t，J＝7.7Hz，1H)，1.42–1.32(m，1H)，0.53–0.37(m，3H)，0.22–0.13(m，1H)。ES/MS 458.1(M+H+)；
(S) -2, 4-diamino-6- ((1- (5-chloro-4-oxo-3- (1H-pyrazol-4-yl) -3, 4-dihydroquinazolin-2-yl) propyl) amino) pyrimidine-5-carbonitrile (Compound 21).1H NMR(400MHz，DMSO)7.93(br s，2H)，7.77(dd，J＝8.4，7.6Hz，1H)，7.60–7.56(m，2H)，4.78(td，J＝7.7，4.2Hz，1H)，1.93–1.72(m，2H)，0.72(t，J＝7.3Hz，3H)。ES/MS 437.1(M+H+)；
(S) -4-amino-6- ((1- (5-chloro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (Compound 22).1H NMR (400MHz, DMSO)13.14(bs, 1H), 7.93(s, 1H), 7.87(d, J ═ 2Hz, 1H), 7.75(t, J ═ 8Hz, 1H), 7.58(dd, J ═ 8, 1Hz), 7.54(dd, J ═ 8,1Hz, 1H), 7.43(d, J ═ 7Hz, 1H), 7.26(s, 2H), 6.40(d, J ═ 2Hz, 1H), 4.82 (apparent quintet, J ═ 7Hz, 1H), 1.36(d, J ═ 7Hz, 3H). ES/MS 408.1(M + H)+)；
(S) -2, 4-diamino-6- (2- (5-chloro-4-oxo-3- (1H-pyrazol-4-yl) -3, 4-dihydroquinazolin-2-yl) pyrrolidin-1-yl) pyrimidine-5-carbonitrile (Compound 23).1H NMR(400MHz，DMSO)8.06(br s，2H)，8.00(br s，1H)，7.71(t，J＝8.0Hz，1H)，7.53(td，J＝8.3，1.1Hz，1H)，4.96–4.87(m，1H)，4.16–4.04(m，1H)，4.01–3.90(m，1H)，2.26–2.02(m，2H)，2.06–1.85(m，2H)。ES/MS 449.1(M+H+)；
(S) -2, 4-diamino-6- (2- (5-chloro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) pyrrolidin-1-yl) pyrimidine-5-carbonitrile (Compound 24).1H NMR(400MHz，DMSO)13.26(br s，1H)，7.96(d，J＝2.3Hz，1H)，7.72(t，J＝8.0Hz，1H)，7.56–7.51(m，2H)，6.79(br s，1H)，4.61(br s，1H)，4.07–3.96(m，1H)，3.94–3.86(m，1H)，2.24–2.04(m，2H)，1.97(d，J＝13.6Hz，2H)。ES/MS 449.1(M+H+)；
(S) -5-chloro-2- (cyclopropyl (thiazolo [5, 4-d))]Pyrimidin-7-ylamino) methyl) -3- (1H-pyrazol-4-yl) quinazolin-4 (3H) -one (compound 25).1H NMR(400MHz，DMSO)9.32(s，1H)，8.38(s，1H)，8.23(d，J＝7.3Hz，1H)，7.82(br s，2H)，7.76(t，J＝7.8Hz，1H)，7.64(dd，J＝8.2，1.2Hz，1H)，7.57(dd，J＝7.8，1.2Hz，1H)，4.87(t，J＝7.6Hz，1H)，1.55–1.45(m，1H)，0.56–0.46(m，2H)，0.43–0.34(m，1H)，0.27–0.20(m，1H)。ES/MS 451.1(M+H+)；
(S) -5-chloro-2- (cyclopropyl (thiazolo [5, 4-d))]Pyrimidin-7-ylamino) methyl) -3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (compound 26).1H NMR(400MHz，DMSO)9.31(s，1H)，8.34(s，1H)，8.16(d，J＝7.4Hz，1H)，7.82–7.77(m，2H)，7.68(dd，J＝8.2，1.2Hz，1H)，7.60(dd，J＝7.8，1.2Hz，1H)，6.40(d，J＝2.3Hz，1H)，4.75(t，J＝7.7Hz，1H)，1.59–1.49(m，1H)，0.52–0.44(m，2H)，0.42–0.33(m，2H)。ES/MS 451.1(M+H+)；
(S) -2-amino-4- (((5-chloro-4-oxo-3- (1H-pyrazol-4-yl) -3, 4-dihydroquinazolin-2-yl) (cyclopropyl) methyl) amino) -6-methylpyrimidine-5-carbonitrile (Compound 27).1H NMR(400MHz，DMSO)7.83–7.77(m，2H)，7.63(dd，J＝8.2，1.2Hz，1H)，7.60(dd，J＝7.8，1.2Hz，1H)，4.81(t，J＝7.5Hz，1H)，2.32(s，3H)，1.45–1.35(m，1H)，0.53–0.35(m，3H)，0.16–0.08(m，1H)。ES/MS 448.1(M+H+)；
(S) -2-amino-4- (((5-chloro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) (cyclopropyl) methyl) amino) -6-methylpyrimidine-5-carbonitrile (Compound 28).1H NMR(400MHz，DMSO)13.11(br s，1H)，7.87–7.79(m，2H)，7.67(dd，J＝8.2，1.2Hz，1H)，7.62(dd，J＝7.8，1.2Hz，1H)，6.38(d，J＝2.3Hz，1H)，4.73(t，J＝7.6Hz，1H)，2.30(s，3H)，1.47–1.37(m，1H)，0.53–0.37(m，3H)，0.24–0.15(m，1H)。ES/MS 448.1(M+H+)；
(S) -2, 4-diamino-6- (((8-chloro-4-oxo-3- (1H-pyrazol-4-yl) -3, 4-dihydroquinazolin-2-yl) (cyclopropyl) methyl) amino) pyrimidine-5-carbonitrile (Compound 29).1H NMR(400MHz，DMSO)8.05(dd，J＝8.0，1.4Hz，1H)，8.01(dd，J＝7.8，1.4Hz，1H)，7.80(br s，2H)，7.52(t，J＝7.9Hz，1H)，4.99(t，J＝7.2Hz，1H)，1.37–1.27(m，1H)，0.47–0.23(m，3H)，0.18–0.08(m，1H)。ES/MS 449.1(M+H+)；
(S) -2, 4-diamino-6- (((8-chloro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) (cyclopropyl) methyl) amino) pyrimidine-5-carbonitrile (Compound 30).1H NMR(400MHz，DMSO)13.18(br s，1H)，8.07(dd，J＝7.9，1.4Hz，1H)，8.03(dd，J＝7.9，1.4Hz，1H)，7.86(d，J＝2.4Hz，1H)，7.54(t，J＝7.9Hz，1H)，6.39(d，J＝2.3Hz，1H)，4.94–4.88(m，1H)，1.44–1.34(m，1H)，0.46–0.32(m，3H)，0.20–0.10(m，1H)。ES/MS 449.1(M+H+)；
(S) -2, 4-diamino-6- ((cyclopropyl (5, 8-dichloro-4-oxo-3- (1H-pyrazol-4-yl) -3, 4-dihydroquinazolin-2-yl) methyl) amino) pyrimidine-5-carbonitrile (Compound 31).1H NMR(400MHz，DMSO)7.96(d，J＝8.6Hz，1H)，7.78(br s，2H)，7.56(d，J＝8.5Hz，1H)，4.94(t，J＝7.2Hz，1H)，1.36–1.26(m，1H)，0.46–0.28(m，3H)，0.16–0.09(m，1H)。ES/MS 483.1(M+H+)；
(S) -2, 4-diamino-6- ((cyclopropyl (5, 8-dichloro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) methyl) amino) pyrimidine-5-carbonitrile (Compound 32).1H NMR(400MHz，DMSO)13.18(br s，1H)，7.97(d，J＝8.6Hz，1H)，7.86(br s，1H)，7.58(d，J＝8.6Hz，1H)，6.39(br s，1H)，4.87(t，J＝7.1Hz，1H)，1.40–1.30(m，1H)，0.44–0.32(m，3H)，0.18–0.11(m，1H)。ES/MS 483.1(M+H+)；
(S) -2, 4-diamino-6- ((1- (8-methyl-4-oxo-3- (1H-pyrazol-4-yl) -3, 4-dihydroquinazolin-2-yl) propyl) amino) pyrimidine-5-carbonitrile (Compound 33).1H NMR(400MHz，DMSO)7.96–7.86(m，4H)，7.72–7.68(m，1H)，7.44–7.39(m，1H)，4.94(td，J＝7.1，4.2Hz，1H)，2.57(s，3H)，1.93–1.83(m，1H)，1.75–1.63(m，1H)，0.70(t，J＝7.3Hz，3H)。ES/MS 417.1(M+H+)；
(S) -2, 4-diamino-6- ((1- (8-methyl-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) propyl) amino) pyrimidine-5-carbonitrile (Compound 34).1H NMR(400MHz，DMSO)13.19(br s，1H)，7.97–7.88(m，2H)，7.77–7.67(m，2H)，7.61–7.52(m，1H)，7.44(t，J＝7.6Hz，1H)，6.49(d，J＝2.3Hz，1H)，4.86(td，J＝6.8，4.4Hz，1H)，2.58(s，3H)，2.05–1.91(m，1H)，1.77–1.65(m，1H)，0.72(t，J＝7.3Hz，3H)。ES/MS 417.1(M+H+)；
(S) -2, 4-diamino-6- ((1- (5-fluoro-8-methyl-4-oxo-3- (1H-pyrazol-4-yl) -3, 4-dihydroquinazolin-2-yl) propyl) amino) pyrimidine-5-carbonitrile (Compound 35).1H NMR(400MHz，DMSO)7.87(br s，2H)，7.68(ddd，J＝8.3，5.5，1.0Hz，1H)，7.50(br s，2H)，7.19(dd，J＝11.0，8.3Hz，1H)，4.90(td，J＝7.2，4.1Hz，1H)，2.49(s，3H)，1.92–1.82(m，1H)，1.75–1.62(m，1H)，0.70(t，J＝7.3Hz，3H)。ES/MS435.2(M+H+)；
(S) -2, 4-diamino-6- ((1- (5-fluoro-8-methyl-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) propyl) amino) pyrimidine-5-carbonitrile (Compound 36).1H NMR(400MHz，DMSO)13.19(br s，1H)，7.90(dd，J＝2.4，0.8Hz，1H)，7.70(dd，J＝8.4，5.4Hz，1H)，7.63(br s，2H)，7.45(br s，J＝8.3Hz，1H)，7.21(dd，J＝10.9，8.3Hz，1H)，6.49(dd，J＝2.4，0.8Hz，1H)，4.81(td，J＝7.1，4.4Hz，1H)，2.51(s，3H)，1.96(ddt，J＝14.4，11.6，7.1Hz，1H)，1.71(dp，J＝14.5，7.2Hz，1H)，0.72(t，J＝7.3Hz，3H)。ES/MS 435.2(M+H+)；
(S) -5, 8-dichloro-2- (cyclopropyl (thiazolo [5, 4-d))]Pyrimidin-7-ylamino) methyl) -3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (compound 37).1H NMR(400MHz，DMSO)9.27(s，1H)，8.30(s，1H)，8.02(d，J＝7.6Hz，1H)，7.96(d，J＝8.5Hz，1H)，7.75(d，J＝2.4Hz，1H)，7.56(d，J＝8.5Hz，1H)，6.31(d，J＝2.4Hz，1H)，4.90(t，J＝7.6Hz，1H)，1.58–1.47(m，1H)，0.51–0.35(m，3H)，0.32–0.24(m，1H)。ES/MS 485.1(M+H+)；
(S) -5, 8-dichloro-2- (cyclopropyl (thiazolo [5, 4-d))]Pyrimidin-7-ylamino) methyl) -3- (1H-pyrazol-4-yl) quinazolin-4 (3H) -one (compound 38).1H NMR(400MHz，DMSO)9.28(s，1H)，8.32(s，1H)，8.07(d，J＝7.5Hz，1H)，7.94(dd，J＝8.5，0.7Hz，1H)，7.74(br s，2H)，7.54(dd，J＝8.5，0.7Hz，1H)，5.00(t，J＝7.5Hz，1H)，1.54–1.45(m 1H)，0.52–0.36(m，4H)，0.27–0.19(m，1H)。ES/MS485.1(M+H+)；
(S) -5, 8-dichloro-3- (1H-pyrazol-4-yl) -2- (1- (thiazolo [5, 4-d)]Pyrimidin-7-ylamino) propyl) quinazolin-4 (3H) -one (compound 39).1H NMR(400MHz，DMSO)9.28(d，J＝0.8Hz，1H)，8.37(d，J＝0.8Hz，1H)，8.33(d，J＝7.3Hz，1H)，7.90(dd，J＝8.6，0.9Hz，1H)，7.81(br s，2H)，7.51(dd，J＝8.5，0.8Hz，1H)，5.02(td，J＝7.6，4.8Hz，1H)，2.07–1.94(m，1H)，1.93–1.80(m，1H)，0.82(t，J＝7.3Hz，3H)。ES/MS 473.1(M+H+)；
(S) -5, 8-dichloro-2- (1- (imidazo [2, 1-f))][1,2,4]Triazin-4-ylamino) propyl) -3- (1H-pyrazol-4-yl) quinazolin-4 (3H) -one (compound 40).1H NMR(400MHz，DMSO)8.88(d，J＝7.2Hz，1H)，8.07(s，1H)，8.05(d，J＝1.1Hz，1H)，7.91(d，J＝8.5Hz，1H)，7.80(br s，2H)，7.60(d，J＝1.2Hz，1H)，7.52(d，J＝8.5Hz，1H)，4.96(td，J＝7.6，4.9Hz，1H)，2.06–1.95(m，1H)，1.93–1.86(m，1H)，0.82(t，J＝7.3Hz，3H)。ES/MS 456.1(M+H+)；
(S) -5, 8-dichloro-3- (1H-pyrazol-4-yl) -2- (1- (pyrido [3, 2-d)]Pyrimidin-4-ylamino) propyl) quinazolin-4 (3H) -one (compound 41).1H NMR(400MHz，DMSO)13.24(br s，1H)，9.31(br s，1H)，8.92(dt，J＝4.4，1.1Hz，1H)，8.62(s，1H)，8.15(dt，J＝8.5，1.2Hz，1H)，7.99–7.90(m，2H)，7.88(dd，J＝2.4，0.9Hz，1H)，7.57(dd，J＝8.5，0.9Hz，1H)，6.42(dd，J＝2.4，0.9Hz，1H)，5.14(td，J＝7.6，4.6Hz，1H)，2.16–2.03(m，1H)，1.94–1.82(m，1H)，0.87–0.77(t，J＝7.3Hz，3H)。ES/MS 467.1(M+H+)；
(S) -5, 8-dichloro-2- (1- ((6-chloropyrido [3, 2-d)]Pyrimidin-4-yl) amino) propyl) -3- (1H-pyrazol-4-yl) quinazolin-4 (3H) -one (compound 42).1H NMR(400MHz，DMSO)9.13(d，J＝7.5Hz，1H)，8.61(s，1H)，8.19(d，J＝8.8Hz，1H)，7.97(d，J＝4.7Hz，1H)，7.95(d，J＝4.5Hz，1H)，7.81(s，2H)，7.56(d，J＝8.5Hz，1H)，5.17(td，J＝7.4，4.6Hz，1H)，2.13–2.01(m，1H)，1.89–1.79(m，1H)，0.82(t，J＝7.3Hz，3H)。ES/MS 501.1(M+H+)；
(S) -5, 8-dichloro-2- (1- (imidazo [2, 1-f))][1,2,4]Triazin-4-ylamino) propyl) -3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 43).1H NMR(400MHz，DMSO)8.76(d，J＝7.3Hz，1H)，8.05(d，J＝1.1Hz，1H)，8.04(s，1H)，7.93(d，J＝8.5Hz，1H)，7.84(d，J＝2.4Hz，1H)，7.60(d，J＝1.2Hz，1H)，7.55(d，J＝8.5Hz，1H)，6.38(d，J＝2.4Hz，1H)，4.91(td，J＝7.6，4.8Hz，1H)，2.13–2.02(m，1H)，1.92–1.83(m，1H)，0.81(t，J＝7.3Hz，3H)。ES/MS 456.1(M+H+)；
(S) -5, 8-dichloro-3- (1H-pyrazol-3-yl) -2- (1- (pyrido [3, 2-d)]Pyrimidin-4-ylamino) propyl) quinazolin-4 (3H) -one (compound 44).1H NMR(400MHz，DMSO)13.24(br s，1H)，8.94–8.90(m，1H)，8.65–8.60(m，1H)，8.15(d，J＝8.6Hz，1H)，7.96(d，J＝8.5Hz，1H)，7.88(d，J＝2.4Hz，1H)，7.57(d，J＝8.5Hz，1H)，6.42(d，J＝2.4Hz，1H)，5.17–5.11(m，1H)，2.16–2.05(m，1H)，1.94–1.82(m，1H)，0.82(t，J＝7.3Hz，3H)。ES/MS 467.1(M+H+)；
(S) -5, 8-dichloro-2- (1- ((6-chloropyrido [3, 2-d)]Pyrimidin-4-yl) amino) propyl) -3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (compound 45).1H NMR(400MHz，DMSO)8.97(br s，1H)，8.55(s，1H)，8.18(d，J＝8.8Hz，1H)，7.97(d，J＝8.5Hz，1H)，7.95(d，J＝8.8Hz，1H)，7.58(d，J＝8.5Hz，1H)，6.41(d，J＝2.4Hz，1H)，5.13(td，J＝7.3，4.6Hz，1H)，2.15–2.04(m，1H)，1.86–1.75(m，1H)，0.80(t，J＝7.3Hz，3H)。ES/MS 501.1(M+H+)；
(S) -5, 8-dichloro-3- (1H-pyrazol-3-yl) -2- (1- (thiazolo [5, 4-d)]Pyrimidin-7-ylamino) propyl) quinazolin-4 (3H) -one (compound 46).1H NMR(400MHz，DMSO)9.28(s，1H)，8.33(s，1H)，8.22(d，J＝7.5Hz，1H)，7.93(d，J＝8.5Hz，1H)，7.83(d，J＝2.4Hz，1H)，7.54(d，J＝8.5Hz，1H)，6.39(d，J＝2.4Hz，1H)，5.03–4.93(m，1H)，2.11–2.02(m，1H)，1.89–1.79(m，1H)，0.81(t，J＝7.3Hz，3H)。ES/MS 473.1(M+H+)；
(R) -2- (2- (benzyloxy) -1- (thiazolo [5, 4-d)]Pyrimidin-7-ylamino) ethyl) -5-chloro-3- (1H-pyrazol-4-yl) quinazolin-4 (3H) -one (compound 47).1H NMR(400MHz，DMSO)13.15(s，1H)，9.28(s，1H)，8.47(d，J＝7.0Hz，1H)，8.39(s，1H)，7.96(s，1H)，7.71(dd，J＝8.4，7.7Hz，1H)，7.58(s，1H)，7.57–7.51(m，2H)，7.27–7.17(m，2H)，7.17–7.11(m，2H)，5.30(q，J＝6.4Hz，1H)，4.43–4.33(ABq，2H)，3.94(dd，J＝10.1，5.4Hz，1H)，3.85(dd，J＝10.1，7.0Hz，1H)。ES/MS531.1(M+H+)；
(R) -2- (2- (benzyloxy) -1- (thiazolo [5, 4-d)]Pyrimidin-7-ylamino) ethyl) -5-chloro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (compound 48).1H NMR(400MHz，DMSO)13.19(br s，1H)，9.28(s，1H)，8.37–8.29(m，2H)，7.85–7.79(m，1H)，7.78–7.70(m，1H)，7.63–7.55(m，2H)，7.26–7.12(m，5H)，6.33(t，J＝2.2Hz，1H)，5.30(dt，J＝7.5，5.3Hz，1H)，4.42–4.33(ABq，2H)，3.98(dd，J＝10.1，4.7Hz，1H)，3.82(dd，J＝10.1，6.9Hz，1H)。ES/MS 531.1(M+H+)；
(S) -2, 4-diamino-6- ((1- (5-chloro-3- (5- (3-methoxypropyl) -1H-pyrazol-3-yl) -4-oxo-3, 4-dihydroquinazolin-2-yl) propyl) amino) pyrimidine-5-carbonitrile (Compound 49).1H NMR(400MHz，DMSO)12.86(br s，1H)，7.85–7.62(m，6H)，7.57(ddt，J＝9.1，7.6，1.3Hz，2H)，7.44–7.12(br s，3H)，6.24(s，1H)，4.74(q，J＝6.9Hz，1H)，3.36–3.28(m，2H)，3.21(d，J＝1.0Hz，3H)，2.70–2.59(m，2H)，2.04–1.92(m，1H)，1.82–1.71(m，3H)，0.75(t，J＝7.3Hz，3H)。ES/MS 509.2(M+H+)；
(R) -5-chloro-2- (2-hydroxy-1- (thiazolo [5, 4-d)]Pyrimidin-7-ylamino) ethyl) -3- (1H-pyrazol-4-yl) quinazolin-4 (3H) -one (compound 50).1H NMR(400MHz，DMSO)9.31(s，0.2H)，9.29(s，0.8H)，8.41(s，0.8H)，8.37(s，0.2H)，8.17–8.10(m，1H)，7.90–7.83(m，2H)，7.69(t，J＝8.0Hz，1H)，7.57–7.50(m，2H)，5.12–5.05(m，1H)，4.42(d，J＝5.0Hz，0.4H)，3.86(dd，J＝11.2，5.5Hz，0.8H)，3.75(dd，J＝11.3，6.2Hz，0.8H)。ES/MS 441.1(M+H+)；
(R) -5-chloro-2- (2-hydroxy-1- (thiazolo [5, 4-d)]Pyrimidin-7-ylamino) ethyl) -3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (compound 51).1H NMR(400MHz，DMSO)9.30(s，1H)，8.35(s，1H)，8.12(d，J＝7.7Hz，0.2H)，8.00(d，J＝7.1Hz，0.8H)，7.96(d，J＝2.4Hz，0.2H)，7.88(d，J＝2.3Hz，0.8H)，7.73(t，J＝8.0Hz，1H)，7.61–7.46(m，2H)，6.48(d，J＝2.4Hz，0.2H)，6.44(d，J＝2.4Hz，0.8H)，5.07–4.98(m，1H)，4.38(d，J＝5.5Hz，0.4H)，3.84(dd，J＝11.4，4.5Hz，0.8H)，3.75(dd，J＝11.3，5.6Hz，0.8H)。ES/MS 441.1(M+H+)；
(S) -2- (1- ((9H-purin-6-yl) amino) propyl) -5, 8-dichloro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 52).1H NMR(400MHz，DMSO)13.24(br s，1H)，8.35(br s，2H)，7.98–7.89(m，2H)，7.61–7.56(m，1H)，6.50(br s，1H)，5.01–4.92(m，1H)，2.20–2.07(m，1H)，1.91–1.80(m，1H)，0.87(t，J＝7.3Hz，3H)。ES/MS 456.0(M+H+)；
(S) -5, 8-dichloro-2- (1- ((2-fluoro-9H-purin-6-yl) amino) propyl) -3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 53).1H NMR(400MHz，DMSO)13.25(br s，1H)，8.27(d，J＝7.4Hz，1H)，8.18(s，1H)，7.96(d，J＝8.5Hz，1H)，7.89(d，J＝2.4Hz，1H)，7.57(d，J＝8.5Hz，1H)，6.41(d，J＝2.4Hz，1H)，4.85–4.74(m，1H)，2.15–2.00(m，1H)，1.92–1.83(m，1H)，0.86(t，J＝7.3Hz，3H)。ES/MS 474.0(M+H+)；
(S) -5, 8-dichloro-3- (1H-pyrazol-3-yl) -2- (1- (thieno [2, 3-d)]Pyrimidin-4-ylamino) propyl) quinazolin-4 (3H) -one (compound 54).1H NMR(400MHz，DMSO)8.42(d，J＝7.3Hz，1H)，8.33(s，1H)，7.94(d，J＝8.5Hz，1H)，7.85(d，J＝2.4Hz，1H)，7.81(d，J＝6.0Hz，1H)，7.63(d，J＝5.9Hz，1H)，7.56(d，J＝8.5Hz，1H)，6.45(d，J＝2.3Hz，1H)，4.87(ddd，J＝9.0，7.1，4.5Hz，1H)，2.21–2.08(m，1H)，1.96–1.85(m，1H)，0.90(t，J＝7.3Hz，3H)。ES/MS 472.0(M+H+)；
(S) -5, 8-dichloro-2- (1- ((2-fluoro-9H-purin-6-yl) amino) propyl) -3- (1H-pyrazol-4-yl) quinazolin-4 (3H) -one (Compound 55).1H NMR(400MHz，DMSO)8.38(d，J＝7.3Hz，1H)，8.21(s，1H)，7.94(d，J＝8.5Hz，1H)，7.82(s，2H)，7.55(d，J＝8.5Hz，1H)，4.95–4.85(m，1H)，2.06–1.96(m，1H)，1.93–1.83(m，1H)，0.87(t，J＝7.3Hz，3H)。ES/MS 474.0(M+H+)；
(S) -5, 8-dichloro-3- (1H-pyrazol-4-yl) -2- (1- (thieno [2, 3-d)]Pyrimidin-4-ylamino) propyl) quinazolin-4 (3H) -one (compound 56).1H NMR(400MHz，DMSO)8.43(d，J＝7.2Hz，1H)，8.38(s，1H)，7.91(d，J＝8.5Hz，1H)，7.87(s，2H)，7.82(d，J＝6.0Hz，1H)，7.63(d，J＝6.0Hz，1H)，7.54(d，J＝8.5Hz，1H)，4.97–4.90(m，1H)，2.12–1.99(m，1H)，1.97–1.84(m，1H)，0.90(t，J＝7.3Hz，3H)。ES/MS 472.0(M+H+)；
(S) -2- (1- ((5-bromothieno [2,3-d ] pyrimidin-4-yl) amino) ethyl) -5-chloro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (compound 126);
(S) -2- (1- ((9H-purin-6-yl) amino) propyl) -5, 8-dichloro-3- (1H-pyrazol-4-yl) quinazolin-4 (3H) -one (Compound 57).1H NMR(400MHz，DMSO)8.71(br s，1H)，8.49(br s，1H)，8.45(br s，1H)，7.96–7.86(m，3H)，7.56(d，J＝8.5Hz，1H)，5.09–5.00(m，1H)，2.14–2.02(m，1H)，1.96–1.80(m，1H)，0.89(t，J＝7.3Hz，3H)。ES/MS 456.0(M+H+)；
(S) -5, 8-dichloro-2- (1- ((5-fluoro-7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) amino) propyl) -3- (1H-pyrazol-4-yl) quinazolin-4 (3H) -one (compound 58).1H NMR(400MHz，DMSO)8.17(s，1H)，7.98(d，J＝8.5Hz，1H)，7.88(s，2H)，7.58(d，J＝8.5Hz，1H)，7.28(br s，1H)，7.21(s，1H)，5.21(td，J＝7.2，4.6Hz，1H)，2.05–1.97(m，1H)，1.82–1.72(m，1H)，0.82(t，J＝7.3Hz，3H)。ES/MS 473.0(M+H+)；
(S) -5, 8-dichloro-2- (1- ((5-fluoro-7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) amino) propyl) -3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (compound 59).1H NMR(400MHz，DMSO)13.31(br s，1H)，11.67(br s，1H)，8.13(s，1H)，8.00(d，J＝8.5Hz，1H)，7.94(d，J＝2.4Hz，1H)，7.60(d，J＝8.6Hz，1H)，7.19(s，1H)，6.48(d，J＝2.4Hz，1H)，5.21–5.13(m，1H)，2.12–1.98(m，1H)，1.83–1.68(m，1H)，0.81(t，J＝7.3Hz，3H)。ES/MS 473.0(M+H+)；
(S) -5-chloro-3- (1H-pyrazol-3-yl) -2- (1- (thieno [2, 3-d)]Pyrimidin-4-ylamino) ethyl) quinazolin-4 (3H) -one (compound 60).1H NMR(400MHz，DMSO)8.57(d，J＝6.6Hz，1H)，8.35(s，1H)，7.88(d，J＝2.4Hz，1H)，7.78(d，J＝6.0Hz，1H)，7.74–7.70(m，1H)，7.63(d，J＝6.0Hz，1H)，7.57(s，1H)，7.55(s，1H)，6.52(d，J＝2.3Hz，1H)，4.88(p，J＝6.8Hz，1H)，1.54(d，J＝6.9Hz，3H)。ES/MS 424.1(M+H+)；
(S) -5-chloro-2- (1- (furo [3, 2-d)]Pyrimidin-4-ylamino) ethyl) -3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (compound 61).1H NMR(400MHz，DMSO)13.20(s，1H)，9.48(br s，1H)，8.56(s，1H)，8.47(dt，J＝2.1，1.0Hz，1H)，7.89(d，J＝2.4Hz，1H)，7.75(dd，J＝8.5，7.6Hz，1H)，7.59(s，1H)，7.57(s，1H)，7.12(dd，J＝2.0，1.0Hz，1H)，6.54(d，J＝2.3Hz，1H)，5.00–4.90(m，1H)，1.55(d，J＝6.8Hz，3H)。ES/MS 408.1(M+H+)；
(S) -5, 8-dichloro-2- (1- (furo [3, 2-d)]Pyrimidin-4-ylamino) propyl) -3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (compound 62).1H NMR(400MHz，DMSO)13.20(br s，1H)，9.23(br s，1H)，8.51(s，1H)，8.46(d，J＝2.2Hz，1H)，7.95(d，J＝8.5Hz，1H)，7.86(d，J＝2.4Hz，1H)，7.58(d，J＝8.5Hz，1H)，7.12(d，J＝2.2Hz，1H)，6.48(d，J＝2.4Hz，1H)，4.93–4.85(m，1H)，2.21–2.09(m，1H)，2.00–1.88(m，1H)，0.88(t，J＝7.2Hz，3H)。ES/MS 456.0(M+H+)；
(S) -2-amino-4-chloro-6- (((5-chloro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) (cyclopropyl) methyl) amino) pyrimidine-5-carbonitrile (Compound 63).1H NMR(400MHz，DMSO)13.08(br s，1H)，7.85–7.78(m，2H)，7.67(dd，J＝8.2，1.2Hz，1H)，7.62(dd，J＝7.8，1.2Hz，1H)，7.57(d，J＝7.4Hz，1H)，7.29(br s，1H)，6.35(d，J＝2.4Hz，1H)，4.71(t，J＝7.7Hz，1H)，1.48–1.39(m，1H)，0.54–0.38(m，3H)，0.22–0.13(m，1H)。ES/MS 468.1(M+H+)；
(S) -5-chloro-2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) ethyl) -3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 64).1H NMR(400MHz，DMSO)13.22(br s，1H)，7.91(d，J＝2.4Hz，1H)，7.81(t，J＝8.0Hz，1H)，7.71(d，J＝6.8Hz，1H)，7.66(dd，J＝8.2，1.2Hz，1H)，7.62(dd，J＝7.8，1.2Hz，1H)，7.52(br s，2H)，7.38(br s，2H)，6.54(d，J＝2.4Hz，1H)，4.79(p，J＝6.7Hz，1H)，1.43(d，J＝6.8Hz，3H)。ES/MS 432.1(M+H+)；
(S) -5-chloro-2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) propyl) -3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 65).1H NMR(400MHz，DMSO)13.26(br s，1H)，7.94(d，J＝2.4Hz，1H)，7.80(t，J＝8.0Hz，1H)，7.66–7.58(m，3H)，7.50(br s，2H)，7.30(br s，2H)，6.59(d，J＝2.3Hz，1H)，4.64(td，J＝7.5，3.9Hz，1H)，2.07–1.94(m，1H)，1.89–1.77(m，1H)，0.74(t，J＝7.3Hz，3H)。ES/MS 446.1(M+H+)；
(S) -5, 8-dichloro-2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) propyl) -3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 66).1H NMR(400MHz，DMSO)13.28(br s，1H)，8.01(d，J＝8.5Hz，1H)，7.95(d，J＝2.4Hz，1H)，7.61(d，J＝8.5Hz，1H)，7.56(br s，1H)，7.49(br s，1H)，7.34(br s，2H)，6.52(d，J＝2.3Hz，1H)，4.83(td，J＝7.0，4.5Hz，1H)，2.07–1.95(m，1H)，1.83–1.72(m，1H)，0.77(t，J＝7.3Hz，3H)。ES/MS 480.0(M+H+)；
(S) -5-chloro-2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) ethyl) -8-fluoro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 67).1H NMR(400MHz，DMSO)13.25(br s，1H)，7.92(d，J＝2.3Hz，1H)，7.77(t，J＝9.2Hz，1H)，7.68(d，J＝6.6Hz，1H)，7.62(dd，J＝8.8，4.5Hz，1H)，7.49(br s，2H)，7.34(br s，2H)，6.53(d，J＝2.3Hz，1H)，4.81(p，J＝6.6Hz，1H)，1.44(d，J＝6.7Hz，3H)。ES/MS 450.1(M+H+)；
(S) -5-chloro-2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) propyl) -8-fluoro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 68).1H NMR(400MHz，DMSO)13.27(s，1H)，7.94(d，J＝2.4Hz，1H)，7.76(dd，J＝9.6，8.8Hz，1H)，7.61(dd，J＝8.8，4.5Hz，1H)，7.53(br s，2H)，7.41(br s，3H)，7.19(br s，2H)，6.58(d，J＝2.3Hz，1H)，4.68–4.61(m，1H)，2.06–1.95(m，1H)，1.88–1.76(m，1H)，0.76(t，J＝7.3Hz，3H)。ES/MS 464.1(M+H+)；
(S) -5, 8-dichloro-2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) ethyl) -3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 69).1H NMR(400MHz，DMSO)13.27(s，1H)，8.02(d，J＝8.6Hz，1H)，7.94(d，J＝2.4Hz，1H)，7.71(br s，1H)，7.62(d，J＝8.5Hz，1H)，7.48(br s，2H)，7.41(br s，3H)，6.49(d，J＝2.3Hz，1H)，4.88(p，J＝6.7Hz，1H)，1.43(d，J＝6.7Hz，3H)。ES/MS466.0(M+H+)；
(S) -5-chloro-2- (cyclopropyl ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) methyl) -8-fluoro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 70).1H NMR(400MHz，DMSO)13.20(s，1H)，7.86(d，J＝2.4Hz，1H)，7.79(dd，J＝9.6，8.8Hz，1H)，7.64(dd，J＝8.8，4.5Hz，1H)，7.49(br s，5H)，7.34(br s，2H)，6.37(d，J＝2.4Hz，1H)，4.73(t，J＝7.7Hz，1H)，1.45–1.33(m，1H)，0.54–0.36(m，3H)，0.23–0.15(m，1H)。ES/MS 476.1(M+H+)；
(S) -5, 8-dichloro-2- (cyclopropyl ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) methyl) -3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 71).1H NMR(400MHz，DMSO)13.24(s，1H)，8.03(d，J＝8.6Hz，1H)，7.90(d，J＝2.4Hz，1H)，7.63(d，J＝8.5Hz，1H)，7.51(br s，2H)，7.42(br s，5H)，6.40(d，J＝2.3Hz，1H)，4.88(t，J＝7.2Hz，1H)，1.46–1.36(m，1H)，0.50–0.37(m，3H)，0.21–0.13(m，1H)。ES/MS 492.0(M+H+)；
(S) -2- (1- ((6-amino-5- ((5-fluoropyridin-2-yl) ethynyl) pyrimidin-4-yl) amino) ethyl) -5-chloro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (compound 72).1H NMR(400MHz，DMSO)13.30(s，1H)，8.78(d，J＝2.9Hz，1H)，8.08(s，1H)，8.01–7.85(m，4H)，7.63(dd，J＝7.4，1.6Hz，1H)，7.48–7.29(m，2H)，6.52(d，J＝2.3Hz，1H)，4.91–4.82(m，1H)，1.39(d，J＝6.6Hz，3H)。ES/MS502.1(M+H+)；
(S) -4-oxo-3- (1H-pyrazol-3-yl) -2- (1- (thiazolo [5, 4-d)]Pyrimidin-7-ylamino) propyl) -3, 4-dihydroquinazoline-5-carbonitrile (compound 73).1H NMR(400MHz，DMSO-d6)13.26(s，1H)，9.28(s，1H)，8.38(d，J＝7.3Hz，1H)，8.33(s，1H)，8.02(dd，J＝6.1，2.6Hz，1H)，7.97–7.82(m，3H)，6.50(d，J＝2.3Hz，1H)，4.87(td，J＝8.2，4.3Hz，1H)，2.13–1.81(m，2H)，0.79(t，J＝7.2Hz，3H)。ES/MS430.1(M+H+)；
(S) -4-oxo-3- (1H-pyrazol-3-yl) -2- (1- (thiazolo [5, 4-d)]Pyrimidin-7-ylamino) propyl) -3, 4-dihydroquinazoline-8-carbonitrile (compound 74).1H NMR(400MHz，DMSO-d6)13.19(s，1H)，9.27(s，1H)，8.39–8.30(m，3H)，8.29(d，J＝7.4Hz，1H)，7.82(dd，J＝2.3，1.4Hz，1H)，7.65(t，J＝7.8Hz，1H)，6.39(t，J＝2.1Hz，1H)，5.05–4.94(m，1H)，2.17–1.83(m，2H)，0.83(t，J＝7.3Hz，3H)。ES/MS 430.1(M+H+)；
(S) -2- (1- ((2, 6-diamino-5-cyanopyrimidin-4-yl) amino) propyl) -4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazoline-8-carbonitrile (Compound 75).1H NMR(400MHz，DMSO-d6)13.16(br.s，1H)，8.37(d，J＝7.8Hz，1H)，8.03–7.85(m，3H)，7.84(d，J＝2.3Hz，1H)，7.68(t，J＝7.8Hz，1H)，7.64–7.23(m，2H)，6.45(d，J＝2.3Hz，1H)，4.85(td，J＝7.5，5.3Hz，1H)，2.13–1.97(m，1H)，1.92–1.75(m，1H)，0.81(t，J＝7.3Hz，3H)。ES/MS 428.1(M+H+)；
(S) -2- (1- ((2-amino-5-cyano-6-methylpyrimidin-4-yl) amino) propyl) -4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazoline-8-carbonitrile (Compound 76).1H NMR(400MHz，DMSO-d6)13.14(s，1H)，8.37(d，J＝7.8Hz，1H)，8.20(s，1H)，7.81(d，J＝2.4Hz，1H)，7.74(s，2H)，7.68(t，J＝7.8Hz，1H)，6.43(d，J＝2.3Hz，1H)，4.89(td，J＝7.4，5.4Hz，1H)，2.33(s，3H)，2.19–2.01(m，1H)，1.97–1.77(m，1H)，0.83(t，J＝7.3Hz，3H)。ES/MS 427.2(M+H+)；
(S) -3- (4-bromo-1H-pyrazol-3-yl) -5-chloro-2- (1- (thiazolo [5, 4-d)]Pyrimidin-7-ylamino) propyl) quinazolin-4 (3H) -one (compound 77).1H NMR(400MHz，DMSO-d6)13.65(br.s，1H)，9.30–9.24(m，1H)，8.47(d，J＝7.7Hz，1H)，8.33–8.23(m，1H)，8.23–8.10(m，2H)，7.83–7.69(m，1H)，7.69–7.53(m，2H)，5.21–4.69(m，1H)，2.27–1.69(m，2H)，0.88–0.74(m，3H)。ES/MS 517.0(M+H+)；
(S) -2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) propyl) -4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazoline-8-carbonitrile (Compound 78).1H NMR(400MHz，DMSO-d6)13.26(s，1H)，8.54–8.23(m，2H)，7.91(d，J＝2.4Hz，1H)，7.69(t，J＝7.8Hz，1H)，7.63–7.09(m，4H)，6.50(d，J＝2.3Hz，1H)，4.82(td，J＝7.1，4.5Hz，1H)，2.09–1.93(m，1H)，1.85–1.67(m，1H)，0.74(t，J＝7.3Hz，3H)。ES/MS 437.1(M+H+)；
(S) -2- (1- ((6-amino-3-bromo-1H-pyrazolo [3, 4-d)]Pyrimidin-4-yl) amino) propyl) -4-oxo-3- (1H-pyrazol-4-yl) -3, 4-dihydroquinazoline-5-carbonitrile (compound 79).1H NMR(400MHz，DMSO-d6)13.30(br.s，1H)，8.11(dd，J＝8.1，1.3Hz，1H)，8.05(dd，J＝7.5，1.3Hz，1H)，8.01–7.90(m，3H)，7.63(br.s，1H)，7.01(br.s，2H)，5.13(td，J＝6.2，4.0Hz，1H)，2.07–1.92(m，1H)，1.72–1.57(m，1H)，0.73(t，J＝7.4Hz，3H)。ES/MS 506.1(M+H+)；
(S) -2- (1- ((6-amino-3-bromo-1H-pyrazolo [3, 4-d)]Pyrimidin-4-yl) amino) propyl) -4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazoline-8-carbonitrile (compound 80).1H NMR(400MHz，DMSO-d6)13.58–12.88(m，2H)，8.45–8.34(m，2H)，7.99(d，J＝2.4Hz，1H)，7.77–7.64(m，1H)，7.46(s，1H)，6.83(br.s，2H)，6.55(d，J＝2.3Hz，1H)，5.10–5.17(m，1H)，2.13–1.94(m，1H)，1.84–1.64(m，1H)，0.78(t，J＝7.4Hz，3H)。ES/MS 506.1(M+H+)；
(S) -2- (1- ((6-amino-3-bromo-1H-pyrazolo [3, 4-d)]Pyrimidin-4-yl) amino) propyl) -5, 8-dichloro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (compound 81).1H NMR(400MHz，DMSO-d6)13.29(br.s，2H)，8.02–7.89(m，2H)，7.57(d，J＝8.5Hz，1H)，7.30(br.s，1H)，6.81(br.s，2H)，6.55(d，J＝2.4Hz，1H)，5.05–5.12(m，1H)，2.10–1.93(m，1H)，1.80–1.60(m，1H)，0.77(t，J＝7.4Hz，3H)。ES/MS550.1(M+H+)；
(S) -5, 8-dichloro-2- (1- ((6-chloro-1H-pyrazolo [3, 4-d)]Pyrimidin-4-yl) amino) propyl) -3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (compound 82).1H NMR(400MHz，DMSO-d6)13.20(br.s，1H)，9.03(d，J＝7.0Hz，1H)，8.22(s，1H)，7.90(d，J＝8.5Hz，1H)，7.87(d，J＝2.4Hz，1H)，7.53(d，J＝8.5Hz，1H)，6.46(d，J＝2.3Hz，1H)，4.60–4.70(m，1H)，2.19–2.02(m，1H)，1.84(ddt，J＝16.9，14.4，7.3Hz，1H)，0.85(t，J＝7.3Hz，3H)。ES/MS 491.99(M+H+)；
(S) -2, 4-diamino-6- ((1- (3- (4-bromo-1H-pyrazol-3-yl) -5-chloro-4-oxo-3, 4-dihydroquinazolin-2-yl) propyl) amino) pyrimidine-5-carbonitrile (Compound 83).1H NMR(400MHz，DMSO-d6)13.61–13.53(m，1H)，8.18–8.03(m，1H)，7.87–7.78(m，1H)，7.80-7.49(br.s，2H)，7.70–7.58(m，2H)，7.22(br.s，3H)，5.02–4.69(m，1H)，2.13–1.90(m，1H)，1.84–1.51(m，1H)，0.82–0.71(m，3H)。ES/MS 515.0(M+H+)；
(S) -2, 4-diamino-6- ((1- (3- (4-bromo-1H-pyrazol-3-yl) -5-chloro-4-oxo-3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (Compound 84).1H NMR(400MHz，DMSO-d6)13.74–13.41(m，1H)，8.21–8.07(m，1H)，8.04–7.60(m，2H)，7.83(t，J＝8.0Hz，1H)，7.78–7.53(m，2H)，7.28(br.s，2H)，5.21–4.83(m，1H)，1.47–1.26(m，3H)。ES/MS 500.99(M+H+)；
(S) -3- (4-bromo-1H-pyrazol-3-yl) -5, 8-dichloro-2- (1- (thiazolo [5, 4-d)]Pyrimidin-7-ylamino) ethyl) quinazolin-4 (3H) -one (compound 85).1H NMR(400MHz，DMSO-d6)13.75–13.42(m，1H)，9.31–9.20(m，1H)，8.53–8.25(m，2H)，8.24–8.03(m，1H)，8.02–7.90(m，1H)，7.66–7.49(m，1H)，5.35–4.88(m，1H)，1.66–1.35(m，3H)。ES/MS 536.9(M+H+)；
(S) -3- (4-bromo-1H-pyrazol-3-yl) -5, 8-dichloro-2- (1- (thiazolo [5, 4-d)]Pyrimidin-7-ylamino) propyl) quinazolin-4 (3H) -one (compound 86).1H NMR(400MHz，DMSO-d6)13.76–13.34(m，1H)，9.31–9.21(m，1H)，8.39–8.22(m，2H)，8.22–8.03(m，1H)，8.02–7.90(m，1H)，7.63–7.51(m，1H)，5.24–4.77(m，1H)，2.28–1.65(m，2H)，0.91–0.73(m，3H)。ES/MS 552.9(M+H+)；
(S) -5- (methylsulfonyl) -3- (1H-pyrazol-3-yl) -2- (1- (thiazolo [5, 4-d)]Pyrimidin-7-ylamino) propyl) quinazolin-4 (3H) -one (compound 87).1H NMR(400MHz，DMSO-d6)13.27(br.s，1H)，9.28(s，1H)，8.46(d，J＝7.2Hz，1H)，8.35(s，1H)，8.25(dd，J＝7.6，1.5Hz，1H)，8.06–7.81(m，3H)，6.50(d，J＝2.3Hz，1H)，4.850–4.90(m，1H)，3.48(s，3H)，2.13–1.73(m，2H)，0.80(t，J＝7.2Hz，3H)。ES/MS483.1(M+H+)；
(S) -5, 8-dichloro-2- (1- ((6-chloro-3-methyl-1H-pyrazolo [3, 4-d)]Pyrimidin-4-yl) amino) propyl) -3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (compound 88).1H NMR(400MHz，DMSO-d6)13.26(br.s，1H)，7.96(d，J＝8.5Hz，1H)，7.89(d，J＝2.4Hz，1H)，7.56(d，J＝8.5Hz，1H)，7.37(d，J＝7.7Hz，1H)，6.44(d，J＝2.3Hz，1H)，5.01–5.09(m，1H)，2.62(s，3H)，2.12–1.96(m，1H)，1.89–1.72(m，1H)，0.79(t，J＝7.3Hz，3H)。ES/MS 504.0(M+H+)；
(S) -5-chloro-2- (1- ((6-chloro-3-methyl-1H-pyrazolo [3, 4-d)]Pyrimidin-4-yl) amino) ethyl) -3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (compound 89).1H NMR(400MHz，DMSO-d6)13.17(s，1H)，7.87–7.82(m，1H)，7.75(t，J＝8.0Hz，1H)，7.70(d，J＝6.7Hz，1H)，7.61–7.51(m，2H)，6.48(d，J＝2.2Hz，1H)，4.96–4.84(m，1H)，2.58(s，3H)，1.47(d，J＝6.8Hz，3H)。ES/MS 456.1(M+H+)；
(S) -2- (1- ((6-amino-1H-pyrazolo [3, 4-d)]Pyrimidin-4-yl) amino) ethyl) -5-chloro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (compound 90).1H NMR(400MHz，DMSO-d6)13.72(br.s，1H)，13.16(s，1H)，12.64(s，1H)，9.66(s，1H)，8.41(s，1H)，7.84(d，J＝2.4Hz，1H)，7.74(dd，J＝8.4，7.6Hz，1H)，7.70–7.25(m，2H)，6.62(d，J＝2.4Hz，1H)，4.80–4.92(m，1H)，1.50(d，J＝6.8Hz，3H)。ES/MS 423.1(M+H+)；
(S) -5-chloro-2- (1- ((6-chloro-1H-pyrazolo [3, 4-d)]Pyrimidin-4-yl) amino) ethyl) -3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (compound 91).1H NMR(400MHz，DMSO-d6)13.18(s，1H)，9.18(d，J＝6.5Hz，1H)，8.19(s，1H)，7.90(d，J＝2.4Hz，1H)，7.71(t，J＝8.0Hz，1H)，7.59–7.46(m，2H)，6.53(d，J＝2.4Hz，1H)，4.66–4.78(m，1H)，1.49(d，J＝6.8Hz，3H)。ES/MS 442.0(M+H+)；
(S) -2- (1- ((6-amino-3-bromo-1H-pyrazolo [3, 4-d)]Pyrimidin-4-yl) amino) ethyl) -5-chloro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (compound 92).1H NMR(400MHz，DMSO-d6)13.29(s，1H)，13.03(s，1H)，7.98(d，J＝2.4Hz，1H)，7.84–7.71(m，2H)，7.70–7.49(m，2H)，6.62(br.s，2H)，6.55(d，J＝2.3Hz，1H)，4.82–4.94(m，1H)，1.41(d，J＝6.5Hz，3H)。ES/MS 501.0(M+H+)；
(S) -2- (1- ((2-amino-5-cyano-6-methylpyrimidin-4-yl) amino) propyl) -4-oxo-3- (1H-pyrazol-4-yl) -3, 4-dihydroquinazoline-8-carbonitrile (Compound 93).1H NMR(400MHz，DMSO-d6)8.44–8.24(m，2H)，8.00–7.71(m，3H)，7.65(t，J＝7.8Hz，1H)，7.40(s，2H)，4.84–4.93(m，1H)，2.30(s，3H)，2.03–1.75(m，2H)，0.78(t，J＝7.3Hz，3H)。ES/MS 427.1(M+H+)；
(S) -2- (1- ((6-chloropyrido [3, 2-d)]Pyrimidin-4-yl) amino) propyl) -4-oxo-3- (1H-pyrazol-4-yl) -3, 4-dihydroquinazoline-8-carbonitrile (compound 94).1H NMR(400MHz，DMSO-d6)9.05(br.d，J＝4.7Hz，1H)，8.59(s，1H)，8.41–8.29(m，2H)，8.18(d，J＝8.8Hz，1H)，7.96(d，J＝8.7Hz，1H)，7.79(s，2H)，7.66(t，J＝7.8Hz，1H)，5.16–5.25(m，1H)，2.19–2.04(m，1H)，2.04–1.86(m，1H)，0.86(t，J＝7.3Hz，3H)。ES/MS 458.1(M+H+)；
(S) -2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) propyl) -4-oxo-3- (1H-pyrazol-4-yl) -3, 4-dihydroquinazoline-8-carbonitrile (Compound 95).1H NMR(400MHz，DMSO-d6)8.36(d，J＝7.8Hz，2H)，7.87(br.s，2H)，7.67(t，J＝7.8Hz，1H)，7.62–7.07(m，5H)，4.86–4.95(m，1H)，2.00–1.83(m，1H)，1.84–1.66(m，1H)，0.73(t，J＝7.3Hz，3H)。ES/MS 437.1(M+H+)；
(S) -2- (1- ((2-amino-6-chloro-5-cyanopyrimidin-4-yl) amino) propyl) -4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazoline-8-carbonitrile (Compound 96).1H NMR(400MHz，DMSO-d6)13.12(s，1H)，8.36(d，J＝7.8Hz，2H)，7.81(d，J＝2.4Hz，1H)，7.72–7.61(m，2H)，7.53(s，1H)，7.15(s，1H)，6.44(d，J＝2.3Hz，1H)，4.86–4.75(m，1H)，2.16–1.97(m，1H)，1.93–1.75(m，1H)，0.81(t，J＝7.2Hz，3H)。ES/MS 447.1(M+H+)；
(S) -2- (1- ((2, 6-diamino-5-cyanopyrimidin-4-yl) amino) propyl) -4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazoline-5-carbonitrile (Compound 97).1H NMR(400MHz，DMSO-d6)13.26(s，1H)，8.02(dd，J＝7.1，1.6Hz，1H)，7.99–7.85(m，3H)，6.77(d，J＝7.2Hz，1H)，6.66–6.52(m，3H)，6.47–5.97(m，3H)，4.62–4.47(m，1H)，2.02–1.66(m，2H)，0.71(t，J＝7.2Hz，3H)。ES/MS428.1(M+H+)；
(S) -2, 4-diamino-6- ((1- (5-bromo-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) propyl) amino) pyrimidine-5-carbonitrile (Compound 98).1H NMR(400MHz，DMSO-d6)13.20(s，1H)，7.91(s，1H)，7.76(dd，J＝7.6，1.4Hz，1H)，7.68–7.55(m，2H)，6.69(d，J＝7.4Hz，1H)，6.57(d，J＝9.7Hz，2H)，6.49–6.03(m，2H)，4.49–4.58(m，1H)，1.99–1.62(m，2H)，0.69(t，J＝7.3Hz，3H)。ES/MS481.0(M+H+)；
(S) -2, 4-diamino-6- ((1- (5-bromo-4-oxo-3- (1H-pyrazol-4-yl) -3, 4-dihydroquinazolin-2-yl) propyl) amino) pyrimidine-5-carbonitrile (Compound 99).1H NMR(400MHz，DMSO-d6)13.18(s，1H)，8.13(s，1H)，7.77–7.70(m，2H)，7.66–7.53(m，2H)，6.64(d，J＝7.5Hz，1H)，6.57(s，2H)，6.33(s，2H)，4.63–4.73(m，1H)，1.86–1.57(m，2H)，0.67(t，J＝7.2Hz，3H)。ES/MS 481.0(M+H+)；
(S) -5-bromo-3- (1H-pyrazol-4-yl) -2- (1- (thiazolo [5, 4-d)]Pyrimidin-7-ylamino) propyl) quinazolin-4 (3H) -one (compound 100).1H NMR(400MHz，DMSO-d6)13.19(s，1H)，9.28(s，1H)，8.43(d，J＝6.8Hz，1H)，8.39(s，1H)，8.08(s，1H)，7.76–7.63(m，2H)，7.63–7.51(m，2H)，4.86–4.95(m，1H)，2.07–1.84(m，4H)，0.79(t，J＝7.3Hz，3H)。ES/MS 482.7(M+H+)；
(S) -5-bromo-3- (1H-pyrazol-3-yl) -2- (1- (thiazolo [5, 4-d)]Pyrimidin-7-ylamino) propyl) quinazolin-4 (3H) -one (compound 101).1H NMR(400MHz，DMSO-d6)13.20(s，1H)，9.28(s，1H)，8.37–8.27(m，2H)，7.88(t，J＝2.0Hz，1H)，7.75(dd，J＝7.0，2.1Hz，1H)，7.67–7.55(m，2H)，6.47(t，J＝2.2Hz，1H)，4.88–4.75(m，1H)，2.09–1.77(m，2H)，0.78(t，J＝7.3Hz，3H)。ES/MS 483.00(M+H+)；
(S) -2- (1- ((2, 6-diamino-5-cyanopyrimidin-4-yl) amino) propyl) -4-oxo-3- (1H-pyrazol-4-yl) -3, 4-dihydroquinazoline-5-carbonitrile (Compound 102).1H NMR(400MHz，DMSO-d6)8.03(dd，J＝7.2，1.5Hz，1H)，8.00–7.87(m，4H)，7.78–6.83(m，5H)，4.73–4.81(m，1H)，1.71–1.91(m，2H)，0.70(t，J＝7.3Hz，3H)。ES/MS427.9(M+H+)；
(S) -4-oxo-3- (1H-pyrazol-4-yl) -2- (1- (thiazolo [5, 4-d)]Pyrimidin-7-ylamino) propyl) -3, 4-dihydroquinazoline-5-carbonitrile (compound 103).1H NMR(400MHz，DMSO-d6)9.29(s，1H)，8.50(d，J＝7.1Hz，1H)，8.40(s，1H)，8.00(dd，J＝6.6，2.1Hz，1H)，7.96–7.81(m，4H)，4.90–5.00(m，1H)，2.01–1.86(m，2H)，0.80(t，J＝7.3Hz，3H)。ES/MS 429.8(M+H+)；
(S) -3- (4-bromo-1H-pyrazol-3-yl) -5-chloro-2- (1- (thiazolo [5, 4-d)]Pyrimidin-7-ylamino) ethyl) quinazolin-4 (3H) -one (compound 104).1H NMR(400MHz，DMSO-d6)13.61(br.s，1H)，9.30–9.23(m，1H)，8.55(d，J＝7.0Hz，1H)，8.36–8.27(m，1H)，8.23–8.08(m，1H)，7.83–7.69(m，1H)，7.69–7.53(m，2H)，5.34–4.80(m，1H)，1.62–1.35(m，3H)。ES/MS 502.9(M+H+)；
(S) -2, 4-diamino-6- (((5-chloro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) (phenyl) methyl) amino) pyrimidine-5-carbonitrile (Compound 105).1H NMR(400MHZ，DMSO-D6)7.95–7.56(m，4H)，7.44(s，2H)，7.46–6.88(m，6H)，6.29–5.90(m，1H)。ES/MS 484.8(M+H+)；
(S) -2, 4-diamino-6- (((5-chloro-4-oxo-3- (1H-pyrazol-4-yl) -3, 4-dihydroquinazolin-2-yl) (phenyl) methyl) amino) pyrimidine-5-carbonitrile (Compound 106).1H NMR(400MHZ，DMSO-D6)7.85(t，J＝8.0Hz，2H)，7.65(ddd，J＝10.4，8.1，1.2Hz，2H)，7.36–7.00(m，6H)，6.02(d，J＝6.8Hz，1H)。ES/MS484.8(M+H+)；
(S) -5-chloro-2- (((2, 6-diamino-5-chloropyrimidin-4-yl) amino) (phenyl) methyl) -3- (1H-pyrazol-4-yl) quinazolin-4 (3H) -one (Compound 107).1H NMR(400MHZ，DMSO-D6)7.84(t，J＝8.0Hz，2H)，7.75(dd，J＝8.1，1.2Hz，1H)，7.65(dd，J＝7.8，1.2Hz，2H)，7.33–7.16(m，3H)，7.18–7.02(m，2H)，6.01(d，J＝6.9Hz，1H)。ES/MS 494.1(M+H+)；
(S) -2-amino-4- (((5-chloro-4-oxo-3- (1H-pyrazol-4-yl) -3, 4-dihydroquinazolin-2-yl) (phenyl) methyl) amino) -6-methylpyrimidine-5-carbonitrile (Compound 108).1H NMR(400MHZ，DMSO-D6)7.84(t，J＝8.0Hz，2H)，7.65(ddd，J＝9.8，8.0，1.2Hz，2H)，7.39–7.16(m，4H)，7.20–7.05(m，2H)，6.01(d，J＝6.7Hz，1H)，2.36–2.17(m，3H)。ES/MS 484.1(M+H+)；
(S) -5-chloro-2- (((2, 6-diamino-5-chloropyrimidin-4-yl) amino) (phenyl) methyl) -3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 109).1H NMR(400MHZ，DMSO-D6)13.16(s，1H)，7.99–7.51(m，4H)，7.23(t，J＝3.5Hz，3H)，7.15–6.75(m，2H)，6.16(d，J＝7.2Hz，1H)，6.00(s，1H)。ES/MS494.1(M+H+)；
(S) -2-amino-4- (((5-chloro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) (phenyl) methyl) amino) -6-methylpyrimidine-5-carbonitrile (Compound 110).1H NMR(400MHZ，DMSO-D6)7.92–7.75(m，2H)，7.66(ddd，J＝7.9，5.4，1.2Hz，2H)，7.39–7.04(m，6H)，6.22–6.00(m，1H)，2.28(d，J＝2.1Hz，3H)。ES/MS 484.1(M+H+)；
(S) -2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) ethyl) -6-fluoro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 111).1H NMR(400MHZ，DMSO-D6)13.21(s，1H)，7.92(dd，J＝2.4，1.7Hz，1H)，7.85–7.63(m，2H)，6.57(t，J＝2.2Hz，1H)，6.25(d，J＝7.4Hz，1H)，5.96(s，2H)，5.50(s，2H)，4.62(p，J＝6.8Hz，1H)，1.34(d，J＝6.7Hz，3H)。ES/MS 416.1(M+H+)；
(S) -2, 4-diamino-6- ((1- (6-fluoro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) propyl) amino) pyrimidine-5-carbonitrile (Compound 112).1H NMR(400MHZ，DMSO-D6)13.20(s，1H)，8.11–7.85(m，1H)，7.85–7.63(m，3H)，6.68(d，J＝7.4Hz，1H)，6.65–6.34(m，3H)，6.36–6.03(m，2H)，4.59(td，J＝7.9，3.9Hz，1H)，2.07–1.83(m，1H)，1.71(dt，J＝14.4，7.5Hz，1H)，0.69(t，J＝7.2Hz，3H)。ES/MS 421.2(M+H+)；
(S) -2, 4-diamino-6- ((cyclopropyl (6-fluoro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) methyl) amino) pyrimidine-5-carbonitrile (Compound 113).1H NMR(400MHZ，DMSO-D6)13.34–13.06(m，1H)，7.98–7.63(m，4H)，6.60(s，2H)，6.48–6.36(m，2H)，6.28(s，2H)，4.75(t，J＝7.1Hz，2H)，1.26(d，J＝7.5Hz，1H)，0.41–0.21(m，3H)，0.23–0.08(m，1H)。ES/MS 433.2(M+H+)
(S) -2- (cyclopropyl ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) methyl) -6-fluoro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 114).1H NMR(400MHZ，DMSO-D6)13.23(s，1H)，7.92(dd，J＝2.4，1.6Hz，1H)，7.85–7.61(m，3H)，6.47(t，J＝2.2Hz，1H)，5.99(d，J＝7.5Hz，3H)，5.52(s，2H)，4.72(dd，J＝8.0，6.5Hz，1H)，1.18(dd，J＝13.3，6.5Hz，1H)，0.39–0.09(m，4H)。ES/MS442.1(M+H+)；
(S) -2, 4-diamino-6- ((1- (6-fluoro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (Compound 115).1H NMR(400MHZ，DMSO-D6)13.18(d，J＝2.2Hz，1H)，7.90(dd，J＝2.4，1.4Hz，1H)，7.87–7.58(m，2H)，6.80(d，J＝6.8Hz，1H)，6.67–6.40(m，2H)，6.26(s，2H)，4.81–4.59(m，1H)，1.36(d，J＝6.8Hz，3H)。ES/MS 407.1(M+H+)；
(S)-2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) propyl) -6-fluoro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (compound 116).1H NMR(400MHZ，DMSO-D6)13.22(s，1H)，7.93(dd，J＝2.4，1.6Hz，1H)，7.85–7.56(m，3H)，6.59(t，J＝2.2Hz，1H)，6.23–5.90(m，3H)，5.51(s，2H)，4.53(td，J＝8.2，3.7Hz，1H)，1.90(ddd，J＝13.8，7.2，3.7Hz，1H)，1.67(dt，J＝14.5，7.4Hz，1H)，0.70(t，J＝7.3Hz，3H)。ES/MS 430.1(M+H+)；
(S) -8-chloro-2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) ethyl) -6-fluoro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 123).1H NMR(400MHZ，DMSO-D6)13.26(s，1H)，8.10(dd，J＝8.5，2.9Hz，1H)，7.94(dd，J＝2.4，1.6Hz，1H)，7.78(dd，J＝8.2，2.9Hz，1H)，6.53(t，J＝2.2Hz，1H)，6.39(d，J＝7.5Hz，1H)，5.97(s，2H)，5.55(s，2H)，4.71(dd，J＝7.4，6.6Hz，1H)，1.33(d，J＝6.6Hz，3H)。ES/MS 450.1(M+H+)；
(S) -5-chloro-2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) butyl) -3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 124).1H NMR(400MHZ，DMSO-D6)13.23(d，J＝4.4Hz，1H)，7.96(d，J＝2.2Hz，1H)，7.75(t，J＝8.0Hz，1H)，7.56(tt，J＝5.7，1.4Hz，2H)，6.66(t，J＝2.2Hz，1H)，6.18–5.93(m，2H)，5.50(s，2H)，4.60(t，J＝8.9Hz，1H)，1.82(t，J＝9.9Hz，1H)，1.70(d，J＝11.4Hz，1H)，1.30(d，J＝11.8Hz，1H)，1.10(dt，J＝14.3，7.5Hz，1H)，0.65(t，J＝7.3Hz，3H)。ES/MS 460.1(M+H+)；
(S) -2, 4-diamino-6- (((8-chloro-6-fluoro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) (cyclopropyl) methyl) amino) pyrimidine-5-carbonitrile (Compound 125).1H NMR(400MHZ，DMSO-D6)13.38–13.15(m，1H)，8.14(dd，J＝8.5，2.9Hz，1H)，7.94(dd，J＝2.4，1.6Hz，1H)，7.82(dd，J＝8.1，2.9Hz，1H)，6.65(s，2H)，6.52–6.42(m，2H)，6.36(s，2H)，4.96(dd，J＝7.7，6.2Hz，1H)，1.43–1.26(m，1H)，0.50–0.29(m，3H)，0.18(tt，J＝8.5，3.3Hz，1H)。ES/MS 467.1(M+H+) (ii) a And
(S) -2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) ethyl) -5- (difluoromethyl) -3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 126).1H NMR(400MHz，DMSO-d6)13.23(s，1H)，8.01–7.68(m，5H)，6.59(t，J＝2.2Hz，1H)，6.33(br.s，1H)，6.03(br.s，2H)，5.59(br.s，2H)，4.67–4.55(m，1H)，1.36(d，J＝6.7Hz，3H)。ES/MS 448.1(M+H+)。
(S) -5-chloro-2- (cyclobutyl ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) methyl) -3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 127).1H NMR(400MHz，DMSO-d6)7.94–7.89(m，1H)，7.75(t，J＝8.0Hz，1H)，7.61(dd，J＝8.2，1.1Hz，1H)，7.55(dd，J＝7.8，1.3Hz，1H)，6.46(t，J＝2.2Hz，1H)，6.07–5.95(m，3H)，5.50(s，2H)，4.89(dd，J＝8.7，5.9Hz，1H)，1.90–1.55(m，8H)。ES/MS 572.1(M+H+)。
(S) -2, 4-diamino-6- (((5-chloro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) (cyclobutyl) methyl) amino) pyrimidine-5-carbonitrile (Compound 128).1H NMR(400MHz，DMSO-d6)7.86(dd，J＝2.4，1.6Hz，1H)，7.80–7.75(m，1H)，7.61(d，J＝1.2Hz，1H)，7.58(dd，J＝4.0，1.2Hz，1H)，7.56(d，J＝1.2Hz，0H)，6.62(s，2H)，6.47(s，1H)，6.43–6.37(m，2H)，5.01(dd，J＝8.2，6.3Hz，1H)，2.07(s，1H)，1.90–1.57(m，8H)。ES/MS 463.1(M+H+)。
(S) -8-chloro-2- (cyclobutyl ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) methyl) -6-fluoro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 129).1H NMR(400MHz，DMSO-d6)8.12(dd，J＝8.5，2.9Hz，1H)，7.93(dd，J＝2.4，1.6Hz，1H)，7.80(dd，J＝8.2，2.9Hz，1H)，6.47(t，J＝2.2Hz，1H)，6.21(d，J＝8.7Hz，1H)，6.04(s，2H)，5.53(s，2H)，4.99(dd，J＝8.7，5.2Hz，1H)，1.83–1.58(m，6H)，1.38–1.21(m，2H)。ES/MS 490.1(M+H+)。
(S) -2, 4-diamino-6- (((8-chloro-6-fluoro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) (cyclobutyl) methyl) amino) pyrimidine-5-carbonitrile (Compound 130).1H NMR(400MHz，DMSO-d6)8.13(dt，J＝8.6，3.0Hz，2H)，7.88–7.77(m，1H)，6.69–6.36(m，1H)，5.15(dd，J＝8.3，5.8Hz，4H)，3.01–2.90(m，1H)，2.02–1.58(m，7H)。ES/MS 481.1(M+H+)。
(S) -2, 4-diamino-6- ((cyclobutyl (5- (difluoromethyl) -4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) methyl) amino) pyrimidine-5-carbonitrile (Compound 131).1H NMR(400MHz，DMSO-d6)8.00(t，J＝7.9Hz，1H)，7.90–7.85(m，3H)，6.63(s，2H)，6.46–6.39(m，2H)，5.08(s，J＝8.2，6.5Hz，4H)，1.95–1.58(m，2H)，1.28–1.14(m，7H)。ES/MS 479.2(M+H+)。
(S) -2- (cyclobutyl ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) methyl) -5- (difluoromethyl) -3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 132).1H NMR(400MHz，DMSO-d6)8.06–7.92(m，3H)，7.87(dt，J＝7.4，3.3Hz，3H)，6.50(dt，J＝4.4，2.2Hz，1H)，6.09–5.97(m，2H)，5.51(s，2H)，4.95(dd，J＝8.7，6.0Hz，1H)，4.03(q，J＝7.1Hz，1H)，1.90–1.60(m，6H)。ES/MS 488.1(M+H+)。
(S) -2, 4-diamino-6- ((cyclopropyl (4-oxo-3- (1H-pyrazol-3-yl) -8- (trifluoromethyl) -3, 4-dihydroquinazolin-2-yl) methyl) amino) pyrimidine-5-carbonitrile (Compound 133).1H NMR(400MHz，DMSO-d6)8.05–7.97(m，1H)，7.91(dd，J＝2.4，1.7Hz，2H)，6.64(s，1H)，6.51–6.44(m，2H)，4.76(t，J＝7.3Hz，1H)，0.38(dd，J＝16.1，6.7Hz，6H)。ES/MS 483.1(M+H+)。
(S) -2- (cyclopropyl ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) methyl) -3- (1H-pyrazol-3-yl) -8- (trifluoromethyl) quinazoline-4 (3H)-ketones (compound 134).1H NMR(400MHz，DMSO-d6)8.04–7.96(m，1H)，6.52(t，J＝2.2Hz，2H)，6.03(d，J＝9.7Hz，1H)，5.56(d，1H)，4.72(dd，J＝7.9，6.7Hz，1H)，1.25(s，1H)，0.41–0.29(m，5H)ES/MS 492.1(M+H+)。
(S) -2, 4-diamino-6- ((1- (4-oxo-3- (1H-pyrazol-3-yl) -8- (trifluoromethyl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (Compound 135).1H NMR(400MHz，DMSO-d6)8.03–7.92(m，1H)，6.87(d，J＝6.8Hz，1H)，6.64–6.56(m，2H)，6.31(s，1H)，4.72(t，J＝6.8Hz，1H)，1.43(m，1H)，1.41(d，J＝6.7Hz，3H)。ES/MS 457.1(M+H+)。
(S) -2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) ethyl) -3- (1H-pyrazol-3-yl) -8- (trifluoromethyl) quinazolin-4 (3H) -one (Compound 136).1H NMR(400MHz，DMSO-d6)8.06–7.93(m，3H)，6.64(t，J＝2.2Hz，1H)，6.02(s，1H)，5.57(s，1H)，4.64(t，J＝7.0Hz，1H)，1.42(m，1H)，1.39(d，J＝6.7Hz，3H)。ES/MS466.1(M+H+)。
(S) -2, 4-diamino-6- ((1- (8- (difluoromethyl) -4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (Compound 137).1H NMR(400MHz，DMSO)13.23(br s，1H)，8.33–8.28(m，1H)，8.18–8.13(m，1H)，7.92(d，J＝2.4Hz，1H)，7.88–7.57(m，5H)，6.53(d，J＝2.4Hz，1H)，4.95(p，J＝6.7Hz，1H)，1.43(d，J＝6.7Hz，3H)。ES/MS 439.1(M+H+)；
(S) -2, 4-diamino-6- ((1- (6-chloro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (Compound 137).1H NMR(400MHz，DMSO)13.21(br s，1H)，8.08(dd，J＝2.5，0.5Hz，1H)，7.94–7.88(m，2H)，7.73(dd，J＝8.7，0.5Hz，1H)，6.53(d，J＝2.3Hz，1H)，4.91–4.82(m，1H)，1.42(d，J＝6.7Hz，3H)。ES/MS 423.1(M+H+)；
(S) -2, 4-diamino-6- ((1- (7-chloro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (Compound 138).1H NMR(400MHz，DMSO)13.21(br s，1H)，8.14(dd，J＝8.5，0.4Hz，1H)，7.90(d，J＝2.4Hz，1H)，7.72(dd，J＝2.1，0.4Hz，1H)，7.62(dd，J＝8.5，2.1Hz，1H)，6.54(d，J＝2.3Hz，1H)，4.83(p，J＝6.7Hz，1H)，1.42(d，J＝6.8Hz，3H)。ES/MS 423.1(M+H+)；
(S) -2, 4-diamino-6- ((cyclopropyl (8- (difluoromethyl) -4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) methyl) amino) pyrimidine-5-carbonitrile (Compound 140).1H NMR(400MHz，DMSO)13.25(brs，1H)，8.10–8.00(m，2H)，7.93(d，J＝2.4Hz，1H)，7.88–7.50(m，3H)，6.53(d，J＝2.3Hz，1H)，4.95(p，J＝6.7Hz，1H)，1.42(d，J＝6.7Hz，3H)。ES/MS 457.1(M+H+)；
(S) -2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) ethyl) -8- (difluoromethyl) -6-fluoro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 141).1H NMR(400MHz，DMSO)13.26(bs，1H)，8.10–8.01(m，2H)，7.92(d，J＝2.4Hz，1H)，7.83–7.20(m，6H)，6.52(d，J＝2.3Hz，1H)，4.93(p，J＝6.7Hz，1H)，1.43(d，J＝6.7Hz，3H)。ES/MS 466.1(M+H+)；
(S) -2-amino-4- (difluoromethyl) -6- ((1- (8- (difluoromethyl) -6-fluoro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (Compound 142).1H NMR(400MHz，DMSO)13.22(s，1H)，8.07(dd，J＝8.6，3.0Hz，1H)，8.02(dd，J＝8.2，3.0Hz，1H)，7.89(d，J＝2.4Hz，1H)，7.86–7.51(m，3H)，7.26(brs，1H)，6.84–6.51(m，2H)，4.96(p，J＝6.7Hz，1H)，1.45(d，J＝6.7Hz，3H)。ES/MS 492.1(M+H+)；
(S) -2, 4-diamino-6- ((cyclopropyl (8- (difluoromethyl) -6-fluoro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) methyl) amino) pyrimidine-5-carbonitrile (Compound 143).1H NMR(400MHz，DMSO)13.19(br s，1H)，8.09(dd，J＝8.6，3.0Hz，1H)，8.03(dd，J＝8.1，3.0Hz，1H)，7.90–7.59(m，2H)，6.41(d，J＝2.4Hz，1H)，4.87(t，J＝7.5Hz，1H)，1.50–1.39(m，1H)，0.50–0.37(m，3H)，0.21–0.14(m，2H)。ES/MS 482.1(M+H+)；
(S) -2- (cyclopropyl ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) methyl) -8- (difluoromethyl) -6-fluoro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 144).1H NMR(400MHz，DMSO)13.19(br s，1H)，8.09(dd，J＝8.7，3.0Hz，1H)，8.03(dd，J＝8.2，3.0Hz，1H)，7.89–7.58(m，2H)，7.52–7.15(m，3H)，6.39(d，J＝2.3Hz，1H)，4.84(t，J＝7.7Hz，1H)，1.49–1.39(m，1H)，0.53–0.39(m，3H)，0.21–0.13(m，1H)。ES/MS 492.1(M+H+)；
(S) -2-amino-4- ((cyclopropyl (8- (difluoromethyl) -6-fluoro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) methyl) amino) -6- (difluoromethyl) pyrimidine-5-carbonitrile (Compound 145).1H NMR(400MHz，DMSO)13.15(br s，1H)，8.08(dd，J＝8.7，3.0Hz，1H)，8.03(dd，J＝8.3，3.0Hz，1H)，7.90–7.54(m，3H)，7.43(d，J＝7.6Hz，1H)，7.26(br s，1H)，6.83–6.50(t，J＝53.4Hz，1H)，6.39(d，J＝2.4Hz，1H)，4.92(t，J＝7.5Hz，1H)，1.51–1.43(m，1H)，0.53–0.39(m，3H)，0.21–0.13(m，1H)。ES/MS 518.1(M+H+)；
(S) -5-chloro-2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) -2-methylpropyl) -3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 146).1H NMR(400MHz，DMSO)13.24(br s，1H)，7.93(d，J＝2.4Hz，1H)，7.83–7.78(m，1H)，7.67(dd，J＝8.2，1.2Hz，1H)，7.62(dd，J＝7.8，1.2Hz，1H)，7.50(br s，2H)，7.27(br s，2H)，7.05(br s，1H)，6.46(d，J＝2.3Hz，1H)，4.96–4.89(m，1H)，2.26–2.16(m，1H)，0.82(d，J＝2.7Hz，3H)，0.81(d，J＝2.8Hz，3H)。ES/MS 460.1(M+H+)；
(S) -8-chloro-2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) ethyl) -5-fluoro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (compound 147).1H NMR(400MHz，DMSO)13.26(br s，1H)，8.07(dd，J＝8.9，4.8Hz，1H)，7.93(d，J＝2.4Hz，1H)，7.68(d，J＝6.8Hz，1H)，7.45(br s，2H)，7.40(dd，J＝10.5，8.9Hz，1H)，6.49(d，J＝2.3Hz，1H)，4.88(p，J＝6.7Hz，1H)，1.43(d，J＝6.7Hz，3H)。ES/MS 450.1(M+H+)；
(S) -8-chloro-2- (cyclopropyl ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) methyl) -5-fluoro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 148).1H NMR(400MHz，DMSO)13.24(br s，1H)，8.08(dd，J＝8.9，4.8Hz，1H)，7.90(d，J＝2.4Hz，1H)，7.51–7.24(m，4H)，6.40(d，J＝2.3Hz，1H)，4.94–4.87(m，1H)，1.43–1.35(m，1H)，0.51–0.36(m，3H)，0.22–0.13(m，1H)。ES/MS 476.1(M+H+)；
(R) -8-chloro-2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) -2-hydroxyethyl) -6-fluoro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 149).1H NMR(400MHz，DMSO)13.30(br s，1H)，8.15(dd，J＝8.5，2.9Hz，1H)，7.97(d，J＝2.4Hz，1H)，7.85(dd，J＝8.1，2.9Hz，1H)，7.39(brs，3H)，6.53(d，J＝2.3Hz，1H)，4.95–4.89(m，1H)，3.78–3.70(m，2H)。ES/MS 466.1(M+H+)；
(S) -2- (1- ((5-bromothieno [2, 3-d)]Pyrimidin-4-yl) amino) ethyl) -5-chloro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (compound 150).1H NMR(400MHz，DMSO)13.36(br s，1H)，8.40(s，1H)，8.38(d，J＝6.8Hz，1H)，8.03(d，J＝2.4Hz，1H)，7.89(s，1H)，7.86–7.79(m，2H)，7.63(dd，J＝6.5，2.5Hz，1H)，6.57(d，J＝2.3Hz，1H)，5.12(p，J＝6.6Hz，1H)，1.44(d，J＝6.5Hz，3H)。ES/MS 502.0(M+H+)；
(S) -2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) ethyl) -5-fluoro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 151).1H NMR(400MHz，DMSO)13.21(br s，1H)，7.90(d，J＝2.3Hz，1H)，7.89–7.82(m，1H)，7.71(d，J＝6.7Hz，1H)，7.56–7.48(m，2H)，7.43–7.28(m，4H)，6.53(d，J＝2.4Hz，1H)，4.79(p，J＝6.7Hz，1H)，1.43(d，J＝6.8Hz，3H)。ES/MS 416.1(M+H+)；
(S) -2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) ethyl) -5, 8-difluoro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 152).1H NMR(400MHz，DMSO)13.24(br s，1H)，7.91(d，J＝2.4Hz，1H)，7.81(td，J＝9.5，4.1Hz，1H)，7.67(br s，1H)，7.44(br s，2H)，7.37(ddd，J＝10.3，9.0，3.6Hz，1H)，7.30(br s，2H)，6.53(d，J＝2.3Hz，1H)，4.80(p，J＝6.7Hz，1H)，1.44(d，J＝6.7Hz，3H)。ES/MS 434.1(M+H+)；
(S) -2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) ethyl) -8-fluoro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 153).1H NMR(400MHz，DMSO)13.24(br s，1H)，7.98–7.94(m，1H)，7.91(d，J＝2.4Hz，1H)，7.78(ddd，J＝10.5，8.1，1.4Hz，1H)，7.72(d，J＝6.7Hz，1H)，7.58(td，J＝8.1，4.7Hz，1H)，7.48(br s，2H)，7.33(br s，2H)，6.54(d，J＝2.3Hz，1H)，4.85(p，J＝6.6Hz，1H)，1.45(d，J＝6.7Hz，3H)。ES/MS 416.1(M+H+)；
(S) -5-chloro-3- (5-chloro-1H-pyrazol-3-yl) -2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) ethyl) quinazolin-4 (3H) -one (Compound 154).1H NMR(400MHz，DMSO)7.86–7.80(m，1H)，7.75(brs，1H)，7.67–7.62(m，2H)，7.51(br s，2H)，7.40(br s，2H)，6.61(s，1H)，4.98–4.80(m，1H)，1.45(d，J＝6.7Hz，3H)。ES/MS 466.0(M+H+)；
(S) -5-chloro-2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) ethyl) -3- (5-fluoro-1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 155).1H NMR(400MHz，DMSO)13.01(br s，1H)，7.89–7.25(m，8H)，6.37(br s，1H)，4.90–4.75(s，1H)，1.48–1.44(m，3H)。ES/MS 450.1(M+H+)；
(S) -8-chloro-2- (1- ((2, 6-diamino)Yl-5-Chloropyrimidin-4-yl) amino) ethyl) -3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 156).1H NMR(400MHz，DMSO)13.26(br s，1H)，8.11(dd，J＝7.9，1.4Hz，1H)，8.07(dd，J＝7.9，1.4Hz，1H)，7.93(d，J＝2.4Hz，1H)，7.75(br s，1H)，7.58(t，J＝7.9Hz，1H)，7.47(br s，1H)，7.38(br s，1H)，6.50(d，J＝2.3Hz，1H)，4.92(p，J＝6.6Hz，1H)，1.44(d，J＝6.6Hz，3H)。ES/MS 432.1(M+H+)；
(S) -5-chloro-2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) ethyl) -3- (1H-pyrazol-4-yl) quinazolin-4 (3H) -one (Compound 157).1H NMR(400MHz，DMSO)7.88(s，2H)，7.81–7.70(m，2H)，7.66–7.54(m，4H)，7.48(br s，2H)，4.90(p，J＝6.7Hz，1H)，1.39(d，J＝6.7Hz，3H)。ES/MS432.1(M+H+)；
(S) -5, 8-dichloro-2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) ethyl) -3- (1H-pyrazol-4-yl) quinazolin-4 (3H) -one (Compound 158).1H NMR(400MHz，DMSO)8.00(d，J＝8.5Hz，1H)，7.86(brs，2H)，7.74(br s，1H)，7.60(d，J＝8.6Hz，1H)，7.50(br s，3H)，4.95(p，J＝6.7Hz，1H)，1.39(d，J＝6.6Hz，3H)。ES/MS 466.0(M+H+)；
(S) -5-chloro-2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) ethyl) -8-fluoro-3- (1H-pyrazol-4-yl) quinazolin-4 (3H) -one (Compound 159).1H NMR(400MHz，DMSO)7.86(br s，4H)，7.78–7.71(m，1H)，7.60(dd，J＝8.8，4.5Hz，1H)，7.46(br s，3H)，4.90(p，J＝6.8Hz，1H)，1.39(d，J＝6.7Hz，3H)。ES/MS 450.1(M+H+)；
(R) -5-chloro-2- (cyclopropyl ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) methyl) -3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 160).1H NMR(400MHz，DMSO)13.13(br s，1H)，7.82(d，J＝2.4Hz，1H)，7.79(t，J＝8.0Hz，1H)，7.67(dd，J＝8.2，1.2Hz，1H)，7.60(dd，J＝7.8，1.2Hz，1H)，7.52–7.42(m，3H)，7.34(br s，2H)，6.34(d，J＝2.3Hz，1H)，4.68(t，J＝7.7Hz，1H)，1.39–1.28(m，1H)，0.50–0.34(m，3H)，0.18–0.10(m，1H)。ES/MS 458.1(M+H+)；
(S) -2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) ethyl) -6, 8-difluoro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 161).1H NMR(400MHz，DMSO)13.22(br s，1H)，7.95–7.85(m，1H)，7.87(d，J＝2.3Hz，1H)，7.74–7.69(m，1H)，7.67(ddd，J＝8.3，3.0，1.3Hz，1H)，7.50(brs，2H)，7.36(br s，2H)，6.49(d，J＝2.4Hz，1H)，4.83(p，J＝6.7Hz，1H)，1.41(d，J＝6.7Hz，3H)。ES/MS 434.1(M+H+)；
(S) -2- (cyclopropyl ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) methyl) -6, 8-difluoro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 162).1H NMR(400MHz，DMSO)13.16(br s，1H)，7.92(ddd，J＝10.3，9.0，2.9Hz，1H)，7.82(d，J＝2.4Hz，1H)，7.68(ddd，J＝8.3，2.8，1.3Hz，1H)，7.49(br s，3H)，7.33(br s，2H)，6.32(d，J＝2.3Hz，1H)，4.72(t，J＝7.8Hz，1H)，1.42–1.33(m，1H)，0.52–0.35(m，3H)，0.19–0.11(m，1H)。ES/MS 460.1(M+H+)；
(S) -5-chloro-2- (1- ((2, 6-diaminopyrimidin-4-yl) amino) ethyl) -3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 163).1H NMR(400MHz，DMSO)13.17(s，1H)，10.89(s，1H)，8.22(d，J＝6.6Hz，1H)，7.89(s，1H)，7.78–7.70(m，1H)，7.60–7.52(m，2H)，7.11(s，1H)，7.02(s，1H)，6.66(d，J＝2.4Hz，1H)，5.17(s，1H)，4.57–4.47(m，1H)，1.34(d，J＝6.9Hz，3H)。ES/MS398.1(M+H+)；
(S) -2- (1- ((6-amino-5-chloropyrimidin-4-yl) amino) ethyl) -5-chloro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 164).1H NMR(400MHz，DMSO)13.19(s，1H)，7.92(s，1H)，7.88(d，J＝2.4Hz，1H)，7.75(dd，J＝7.8Hz，1H)，7.60(dd，J＝8.2，1.2Hz，1H)，7.56(dd，J＝7.8，1.2Hz，1H)，7.20(br s，1H)，7.03br(s，2H)，6.44(d，J＝2.4Hz，1H)，4.77(p，J＝6.7Hz，1H)，1.38(d，J＝6.8Hz，3H)。ES/MS 417.1(M+H+)；
(S) -2- (((6-amino-5-chloropyrimidin-4-yl) amino) (cyclopropyl) methyl) -5-chloro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 165).1H NMR(400MHz，DMSO)13.16(s，1H)，7.86(s，1H)，7.84(d，J＝2.4Hz，1H)，7.80–7.74(m，1H)，7.65(dd，J＝8.2，1.2Hz，1H)，7.57(dd，J＝7.8，1.2Hz，1H)，7.00(br s，2H)，6.90(br s，1H)，6.39(d，J＝2.3Hz，1H)，4.62(t，J＝7.6Hz，1H)，1.41–1.32(m，1H)，0.42–0.36(m，2H)，0.30–0.19(m，2H)。ES/MS 443.1(M+H+)；
(S) -2-amino-4- ((1- (5-chloro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) -6- (difluoromethyl) pyrimidine-5-carbonitrile (Compound 166).1H NMR(400MHz，DMSO)13.15(br s，1H)，7.84(d，J＝2.4Hz，1H)，7.80–7.73(m，2H)，7.58(td，J＝7.9，1.2Hz，2H)，7.55(br s，1H)，7.21(br s，1H)，6.64(t，J＝53.6Hz，1H)，6.52(d，J＝2.4Hz，1H)，4.77(p，J＝6.6Hz，1H)，1.41(d，J＝6.7Hz，3H)。ES/MS 458.1(M+H+)；
(S) -5-chloro-2- (1- (isothiazolo [5, 4-d)]Pyrimidin-4-ylamino) ethyl) -3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (compound 167).1H NMR(400MHz，DMSO)9.32(s，1H)，9.14(d，J＝6.6Hz，1H)，8.39(s，1H)，7.82(d，J＝2.4Hz，1H)，7.71(dd，J＝8.3，7.8Hz，1H)，7.58–7.52(m，2H)，6.48(d，J＝2.4Hz，1H)，4.95(p，J＝6.8Hz，1H)，1.52(d，J＝6.9Hz，3H)。ES/MS 425.1(M+H+)；
(S) -2-amino-4- ((1- (5-chloro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) -6- (trifluoromethyl) pyrimidine-5-carbonitrile (Compound 168).1H NMR(400MHz，DMSO)13.17(s，1H)，7.99(d，J＝6.5Hz，1H)，7.87(d，J＝2.4Hz，1H)，7.84–7.78(m，2H)，7.66–7.59(m，2H)，7.48(br s，1H)，6.53(d，J＝2.4Hz，1H)，4.86(p，J＝6.7Hz，1H)，1.45(d，J＝6.7Hz，3H)。ES/MS476.1(M+H+)；
(S) -2, 4-diamino-6- ((1- (6, 8-difluoro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (Compound 169).1H NMR(400MHz，DMSO)13.24(s，1H)，7.94(dd，J＝2.4，1.6Hz，1H)，7.92–7.87(m，1H)，7.71–7.66(m，1H)，6.87(d，J＝6.7Hz，1H)，6.62–6.53(m，3H)，6.30(br s，2H)，4.73(p，J＝6.7Hz，1H)，1.40(d，J＝6.7Hz，3H)。ES/MS425.1(M+H+)；
(S) -2, 4-diamino-6- ((cyclopropyl (6, 8-difluoro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) methyl) amino) pyrimidine-5-carbonitrile (Compound 170).1H NMR(400MHz，DMSO)13.24(br s，1H)，7.97–7.89(m，2H)，7.69(ddd，J＝8.3，2.9，1.3Hz，1H)，6.63(s，2H)，6.48–6.41(m，2H)，6.31(br s，2H)，4.78(t，J＝7.3Hz，1H)，1.37–1.25(m，1H)，0.43–0.31(m，3H)，0.23–0.16(m，1H)。ES/MS 451.1(M+H+)；
(S) -2-amino-4- (((5-chloro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) (cyclopropyl) methyl) amino) -6- (difluoromethyl) pyrimidine-5-carbonitrile (Compound 171).1H NMR(400MHz，DMSO)13.10(br s，1H)，7.82–7.75(m，2H)，7.63(dd，J＝8.2，1.2Hz，1H)，7.59(dd，J＝7.8，1.2Hz，1H)，7.54(br s，1H)，7.42(d，J＝7.4Hz，1H)，7.22(br s，1H)，6.63(t，J＝53.6Hz，1H)，6.34(d，J＝2.4Hz，1H)，4.74(t，J＝7.5Hz，1H)，1.43–1.32(m，1H)，0.48–0.34(m，3H)，0.19–0.11(m，1H)。ES/MS 484.1(M+H+)；
(S) -2-amino-4- (((8-chloro-6-fluoro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) (cyclopropyl) methyl) amino) -6- (difluoromethyl) pyrimidine-5-carbonitrile (Compound 172).1H NMR(400MHz，DMSO)13.15(s，1H)，8.13(dd，J＝8.5，2.9Hz，1H)，7.84–7.78(m，2H)，7.55(br s，1H)，7.37(d，J＝7.5Hz，1H)，7.29(br s，1H)，6.64(t，J＝53.6Hz，1H)，6.35(d，J＝2.4Hz，1H)，4.95(t，J＝7.2Hz，1H)，1.48–1.34(m，1H)，0.48–0.33(m，3H)，0.19–0.10(m，1H)。ES/MS 502.1(M+H+)；
(S) -2-amino-4- ((1- (8-chloro-6-fluoro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) -6- (difluoromethyl) pyrimidine-5-carbonitrile (Compound 173).1H NMR(400MHz，DMSO)13.19(s，1H)，8.11(dd，J＝8.5，2.9Hz，1H)，7.86(d，J＝2.4Hz，1H)，7.80(dd，J＝8.2，2.9Hz，1H)，7.72(d，J＝6.6Hz，1H)，7.54(br s，1H)，7.30(br s，1H)，6.64(t，J＝53.6Hz，1H)，6.46(d，J＝2.4Hz，1H)，4.94(p，J＝6.6Hz，1H)，1.42(d，J＝6.6Hz，3H)。ES/MS 476.1(M+H+)；
(R) -8-chloro-2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) ethyl) -6-fluoro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 174).1H NMR(400MHz，DMSO)13.27(s，1H)，8.19–8.14(m，1H)，7.93(d，J＝2.4Hz，1H)，7.87–7.82(m，1H)，7.68(d，J＝6.9Hz，1H)，7.44(br s，2H)，7.34(br s，2H)，6.49(d，J＝2.3Hz，1H)，4.91(p，J＝6.5Hz，1H)，1.43(d，J＝6.6Hz，3H)。ES/MS 450.1(M+H+)；
(R) -2, 4-diamino-6- ((1- (8-chloro-6-fluoro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (Compound 175).1H NMR(400MHz，DMSO)13.25(s，1H)，8.15(dd，J＝8.5，2.9Hz，1H)，7.92(d，J＝2.4Hz，1H)，7.84(dd，J＝8.2，2.9Hz，1H)，6.49(d，J＝2.3Hz，1H)，4.95(p，J＝6.6Hz，1H)，1.42(d，J＝6.6Hz，3H)。ES/MS 441.1(M+H+)；
(S) -2-amino-4- (difluoromethyl) -6- ((1- (5- (difluoromethyl) -4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (Compound 176).1H NMR(400MHz，DMSO)13.20(s，1H)，8.05–7.74(m，6H)，7.57(br s，1H)，7.23(br s，1H)，6.67(t，J＝53.5Hz，1H)，6.56(d，J＝2.4Hz，1H)，4.87(p，J＝6.6Hz，1H)，1.46(d，J＝6.7Hz，3H)。ES/MS 474.1(M+H+)；
(S) -2-amino-4- ((cyclopropyl (5- (difluoromethyl) -4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) methyl) amino) -6- (difluoromethyl) pyrimidine-5-carbonitrile (Compound 177).1H NMR(400MHz，DMSO)13.20(br s，1H)，8.06–7.73(m，5H)，7.57(br s，1H)，7.50(d，J＝7.4Hz，1H)，7.23(br s，1H)，6.67(t，J＝53.5Hz，1H)，6.38(d，J＝2.3Hz，1H)，4.81(t，J＝7.6Hz，1H)，1.51–1.39(m，1H)，0.53–0.39(m，3H)，0.23–0.15(m，1H)。ES/MS 500.1(M+H+)；
(S) -2-amino-4- (difluoromethyl) -6- ((1- (4-oxo-3- (1H-pyrazol-3-yl) -5- (trifluoromethyl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (Compound 178).1H NMR(400MHz，DMSO)13.21(s，1H)，8.05–7.95(m，3H)，7.88(d，J＝2.4Hz，1H)，7.83(d，J＝6.5Hz，1H)，7.58(brs，1H)，7.24(br s，1H)，6.67(7，J＝53.6Hz，1H)，6.57(d，J＝2.4Hz，1H)，4.87(p，J＝6.7Hz，1H)，1.46(d，J＝6.7Hz，3H)。ES/MS 492.1(M+H+)；
(S) -2-amino-4- (difluoromethyl) -6- ((1- (5- (difluoromethyl) -4-oxo-3- (1H-pyrazol-4-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (Compound 179).1H NMR(400MHz，DMSO)8.08–7.74(m，7H)，7.57(br s，1H)，7.34(br s，1H)，6.68(t，J＝53.5Hz，1H)，5.01–4.91(m，1H)，1.42(d，J＝6.7Hz，3H)。ES/MS 474.1(M+H+)；
(S) -2-amino-4- ((1- (8-chloro-6-fluoro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) propyl) amino) -6- (difluoromethyl) pyrimidine-5-carbonitrile (Compound 180).1H NMR(400MHz，DMSO)13.24(brs，1H)，8.14(dd，J＝8.5，2.9Hz，1H)，7.89(d，J＝2.4Hz，1H)，7.83(dd，J＝8.2，2.9Hz，1H)，7.62(d，J＝7.1Hz，1H)，7.58(br s，1H)，7.23(br s，1H)，6.68(t，J＝53.5Hz，1H)，6.52(d，J＝2.4Hz，1H)，4.94–4.88(m，1H)，2.12–1.99(m，1H)，1.78(dq，J＝14.1，7.1Hz，1H)，0.79(t，J＝7.3Hz，3H)。ES/MS 490.1(M+H+)；
(R) -2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) ethyl) -5- (difluoromethyl) -3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 181).1H NMR(400MHz，DMSO)13.24(s，1H)，8.05–7.70(m，5H)，7.49(br s，2H)，7.34(br s，2H)，6.56–6.53(m，1H)，4.88–4.81(m，1H)，1.45(d，J＝6.8Hz，3H)。ES/MS 448.1(M+H+)；
(R) -2, 4-diamino-6- ((1- (5- (difluoromethyl) -4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (Compound 182).1H NMR(400MHz，DMSO)13.25(s，1H)，8.18–7.73(m，8H)，6.54(d，J＝2.4，1H)，4.93–4.86(m，1H)，1.47–1.41(m，3H)。ES/MS 439.1(M+H+)；
(S) -2-amino-4- ((1- (8-chloro-6-fluoro-4-oxo-3- (1H-pyrazol-4-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) -6- (difluoromethyl) pyrimidine-5-carbonitrile (Compound 183).1H NMR(400MHz，DMSO)8.13(dd，J＝8.5，2.9Hz，1H)，7.89(br s，2H)，7.82(dd，J＝8.2，2.9Hz，1H)，7.75(d，J＝6.6Hz，1H)，7.58(br s，1H)，7.42(br s，1H)，6.68(t，J＝53.5Hz，1H)，5.02(p，J＝6.6Hz，1H)，1.40(d，J＝6.6Hz，3H)。ES/MS 476.1(M+H+)；
(S) -2-amino-4- (((8-chloro-6-fluoro-4-oxo-3- (1H-pyrazol-4-yl) -3, 4-dihydroquinazolin-2-yl) (cyclopropyl) methyl) amino) -6- (difluoromethyl) pyrimidine-5-carbonitrile (compound 184).1H NMR(400MHz，DMSO)8.14(dd，J＝8.5，2.9Hz，1H)，7.87–7.78(m，3H)，7.58(br s，1H)，7.42(br s，1H)，7.33(d，J＝7.4Hz，1H)，6.67(t，J＝53.5Hz，1H)，5.06(t，J＝7.1Hz，1H)，1.43–1.32(m，1H)，0.50–0.36(m，3H)，0.18–0.09(m，1H)。ES/MS 502.1(M+H+)；
(S) -2-amino-4- ((1- (5-chloro-8-fluoro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) -6- (difluoromethyl) pyrimidine-5-carbonitrile (Compound 185).1H NMR(400MHz，DMSO)13.20(s，1H)，7.87(d，J＝2.4Hz，1H)，7.83–7.71(m，2H)，7.60(dd，J＝8.8，4.5Hz，1H)，7.25(br s，1H)，6.67(t，J＝53.5Hz，1H)，6.53(d，J＝2.4Hz，1H)，4.83(p，J＝6.7Hz，1H)，1.45(d，J＝6.7Hz，3H)。ES/MS 476.1(M+H+)；
(S) -2-amino-4- (difluoromethyl) -6- ((1- (8-fluoro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (Compound 186).1H NMR(400MHz，DMSO)13.19(br s，1H)，7.97–7.93(m，1H)，7.87(d，J＝2.4Hz，1H)，7.83(d，J＝6.5Hz，1H)，7.77(ddd，J＝10.5，8.0，1.4Hz，1H)，7.60–7.53(m，2H)，7.24(br s，1H)，6.67(t，J＝53.5Hz，1H)，6.54(d，J＝2.4Hz，1H)，4.88(p，J＝6.7Hz，1H)，1.46(d，J＝6.7Hz，3H)。ES/MS 442.1(M+H+)；
(S) -2-amino-4- ((1- (6, 8-difluoro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) -6- (difluoromethyl) pyrimidine-5-carbonitrile (Compound 187).1H NMR(400MHz，DMSO)13.21(brs，1H)，7.92(ddd，J＝10.3，8.9，2.9Hz，1H)，7.87(d，J＝2.4Hz，1H)，7.82(d，J＝6.5Hz，1H)，7.70(ddd，J＝8.2，2.9，1.2Hz，1H)，7.57(br s，1H)，7.23(br s，1H)，6.67(t，J＝53.5Hz，1H)，6.54(d，J＝2.4Hz，1H)，4.88(p，J＝6.7Hz，1H)，1.45(d，J＝6.7Hz，3H)。ES/MS460.1(M+H+)；
(S) -2-amino-4- ((1- (8-chloro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) -6- (difluoromethyl) pyrimidine-5-carbonitrile (Compound 188).1H NMR(400MHz，DMSO)13.22(br s，1H)，8.10(dd，J＝8.0，1.4Hz，1H)，8.05(dd，J＝7.9，1.4Hz，1H)，7.89(d，J＝2.4Hz，1H)，7.77(d，J＝6.6Hz，1H)，7.56(t，J＝7.9Hz，1H)，7.34(br s，1H)，6.67(t，J＝53.5Hz，1H)，6.51(d，J＝2.4Hz，1H)，4.97(p，J＝6.6Hz，1H)，1.45(d，J＝6.6Hz，3H)。ES/MS 458.1(M+H+)；
(S) -2-amino-4- (2- (5-chloro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) pyrrolidin-1-yl) -6- (bisFluoromethyl) pyrimidine-5-carbonitrile (Compound 189).1H NMR(400MHz，DMSO)7.96(d，J＝2.3Hz，1H)，7.70(t，J＝8.0Hz，1H)，7.56–7.49(m，3H)，6.99–6.57(m，3H)，4.58(br s，1H)，4.10–3.92(m，2H)，2.26–1.88(m，4H)。ES/MS 484.1(M+H+)；
(S) -2-amino-4- ((1- (5, 8-dichloro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) -6- (difluoromethyl) pyrimidine-5-carbonitrile (Compound 190).1H NMR(400MHz，DMSO)13.23(s，1H)，7.99(d，J＝8.5Hz，1H)，7.89(d，J＝2.3Hz，1H)，7.72(d，J＝6.6Hz，1H)，7.60(d，J＝8.5Hz，1H)，7.35(br s，1H)，6.67(t，J＝53.6Hz，1H)，6.51–6.48(m，1H)，4.97–4.89(m，1H)，1.44(d，J＝6.6Hz，3H)。ES/MS 492.0(M+H+)；
(S) -2-amino-4- (difluoromethyl) -6- ((1- (5-fluoro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (Compound 191).1H NMR(400MHz，DMSO)13.18(br s，1H)，7.90–7.82(m，2H)，7.80(d，J＝6.4Hz，1H)，7.58(br s，1H)，7.52–7.47(m，1H)，7.34(ddd，J＝11.0，8.2，1.0Hz，1H)，7.23(br s，1H)，6.67(t，J＝53.6Hz，1H)，6.55(d，J＝2.4Hz，1H)，4.80(p，J＝6.6Hz，1H)，1.44(d，J＝6.7Hz，3H)。ES/MS 442.0(M+H+)；
(S) -2-amino-4- ((1- (5, 8-difluoro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) -6- (difluoromethyl) pyrimidine-5-carbonitrile (Compound 192).1H NMR(400MHz，DMSO)13.20(s，1H)，7.87(d，J＝2.4Hz，1H)，7.84–7.75(m，2H)，7.58(br s，1H)，7.36(ddd，J＝10.5，9.1，3.6Hz，1H)，7.24(br s，1H)，6.67(t，J＝53.6Hz，1H)，6.54(d，J＝2.4Hz，1H)，4.82(p，J＝6.7Hz，1H)，1.45(d，J＝6.7Hz，3H)。ES/MS 460.0(M+H+)；
(S) -2-amino-4- (difluoromethyl) -6- ((1- (6-fluoro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (Compound 193).1H NMR(400MHz，DMSO)13.19(br s，1H)，7.87(d，J＝2.4Hz，1H)，7.85–7.74(m，4H)，7.57(br s，1H)，7.23(br s，1H)，)，6.67(t，J＝53.6Hz，1H)，6.55(d，J＝2.4Hz，1H)，4.87(p，J＝6.6Hz，1H)，1.45(d，J＝6.7Hz，3H)。ES/MS 442.1(M+H+)；
(S) -2-amino-4- (((5-chloro-8-fluoro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) (cyclopropyl) methyl) amino) -6- (difluoromethyl) pyrimidine-5-carbonitrile (compound 194).1H NMR(400MHz，DMSO)13.14(br s，1H)，7.81–7.74(m，2H)，7.62(dd，J＝8.8，4.5Hz，1H)，7.57(br s，1H)，7.45(d，J＝7.4Hz，1H)，7.25(br s，1H)，6.67(t，J＝53.6Hz，1H)，6.35(d，J＝2.4Hz，1H)，4.79(t，J＝7.6Hz，1H)，1.48–1.37(m，1H)，0.52–0.39(m，3H)，0.22–0.15(m，1H)。ES/MS 502.1(M+H+)；
(S) -2-amino-4- ((cyclopropyl (6, 8-difluoro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) methyl) amino) -6- (difluoromethyl) pyrimidine-5-carbonitrile (Compound 195).1H NMR(400MHz，DMSO)13.14(br s，1H)，7.94(ddd，J＝10.3，9.0，2.8Hz，1H)，7.79(d，J＝2.4Hz，1H)，7.70(ddd，J＝8.3，2.8，1.3Hz，1H)，7.56br(s，1H)，7.48(d，J＝7.4Hz，1H)，7.23(br s，1H)，6.66(t，J＝53.6Hz，1H)，6.35(d，J＝2.4Hz，1H)，4.82(t，J＝7.6Hz，1H)，1.50–1.40(m，1H)，0.52–0.39(m，3H)，0.24–0.14(m，1H)。ES/MS 486.1(M+H+)；
(S) -2-amino-4- (((8-chloro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) (cyclopropyl) methyl) amino) -6- (difluoromethyl) pyrimidine-5-carbonitrile (Compound 196).1H NMR(400MHz，DMSO)13.19(br s，1H)，8.10(dd，J＝8.0，1.4Hz，1H)，8.07(dd，J＝7.9，1.4Hz，1H)，7.84(d，J＝2.4Hz，1H)，7.64–7.53(m，2H)，7.40(d，J＝7.4Hz，1H)，7.33(br s，1H)，6.67(t，J＝53.6Hz，1H)，6.40(d，J＝2.4Hz，1H)，5.01(t，J＝7.1Hz，1H)，1.49–1.38(m，1H)，0.50–0.37(m，3H)，0.22–0.14(m，1H)。ES/MS 484.1(M+H+)；
(S) -4-amino-6- ((1- (5-chloro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) -2- (difluoromethyl) pyrimidine-5-carbonitrile (Compound 197).1H NMR(400MHz，DMSO)13.18(br s，1H)，7.99(d，J＝6.4Hz，1H)，7.89(d，J＝2.4Hz，1H)，7.76(dd，J＝8.2，7.8Hz，1H)，7.61–7.55(m，2H)，6.43(d，J＝2.4Hz，1H)，6.37(t，J＝54.4Hz，1H)，4.76(p，J＝6.7Hz，1H)，1.44(d，J＝6.8Hz，3H)。ES/MS 458.1(M+H+)；
(S) -4-amino-6- ((1- (8-chloro-6-fluoro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) -2- (difluoromethyl) pyrimidine-5-carbonitrile (Compound 198).1H NMR(400MHz，DMSO)13.23(s，1H)，8.11(ddd，J＝8.5，2.9，0.8Hz，1H)，7.92–7.78(m，3H)，7.69(br s，1H)，6.41(dd，J＝2.4，0.7Hz，1H)，6.36(t，J＝54.4Hz，1H)，4.93(p，J＝6.7Hz，1H)，1.45(d，J＝6.8Hz，3H)。ES/MS 476.1(M+H+)；
(S) -3- (5-amino-1H-pyrazol-3-yl) -5-chloro-2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) ethyl) quinazolin-4 (3H) -one (compound 199).1H NMR(400MHz，DMSO)11.81(s，1H)，7.81–7.75(m，1H)，7.64(dd，J＝8.2，1.2Hz，1H)，7.59(dd，J＝7.8，1.2Hz，1H)，5.49(s，1H)，4.95–4.86(m，1H)，1.46(d，J＝6.7Hz，3H)。ES/MS 447.1(M+H+)；
(S) -2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) ethyl) -8- (difluoromethyl) -3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 200).1H NMR(400MHz，DMSO)13.25(s，1H)，8.30(dd，J＝7.6，1.3Hz，1H)，8.15(d，J＝7.5Hz，1H)，7.92(d，J＝2.4Hz，1H)，7.84–7.53(m，3H)，7.47(br s，2H)，7.32(br s，2H)，6.53(d，J＝2.3Hz，1H)，4.97–4.88(m，1H)，1.44(d，J＝6.7Hz，3H)。ES/MS 448.1(M+H+)；
(S) -2- (((2-amino-5-cyano-6-methylpyrimidin-4-yl) amino) (cyclopropyl) methyl) -3- (4-methyl-1H-pyri-dineOxazol-3-yl) -4-oxo-3, 4-dihydroquinazoline-8-carbonitrile (compound 203):1H NMR(400MHz，DMSO-d6)12.69(br s，1H)，8.62–8.07(m，2H)，8.07–7.22(m，4H)，5.26–4.42(m，1H)，2.42–2.27(m，3H)，1.88–1.71(m，3H)，1.71–1.18(m，1H)，0.70–0.41(m，3H)，0.35–0.08(m，1H)。ES/MS453.2(M+H+)；
(S) -2- (cyclopropyl ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) methyl) -3- (4-methyl-1H-pyrazol-3-yl) -4-oxo-3, 4-dihydroquinazoline-8-carbonitrile (compound 204):1H NMR(400MHz，DMSO-d6)13.18–12.64(m，1H)，8.57–8.28(m，2H)，7.90–7.63(m，2H)，7.63–7.11(m，5H)，5.18–4.83(m，1H)，1.91–1.71(m，3H)，1.58–1.15(m，1H)，0.62–0.34(m，4H)，0.26–0.01(m，1H)。ES/MS 463.1(M+H+)；
(S) -2, 4-diamino-6- ((1- (4-oxo-3- (1H-pyrazol-3-yl) -5- (trifluoromethyl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (compound 205):1H NMR(400MHz，DMSO-d6)13.19(s，1H)，8.02–7.90(m，3H)，7.88(d，J＝2.4Hz，1H)，7.86–6.84(br m，4H)，6.53(d，J＝2.4Hz，1H)，4.89–4.75(m，1H)，1.40(d，J＝6.7Hz，3H)。ES/MS 457.1(M+H+)；
(S) -2, 4-diamino-6- ((1- (4-oxo-3- (1H-pyrazol-4-yl) -5- (trifluoromethyl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (compound 206):1H NMR(400MHz，DMSO-d6)8.11–7.71(m，7H)，7.42(br.s，1H)，4.95(p，J＝6.8Hz，1H)，1.36(d，J＝6.7Hz，3H)。ES/MS 457.1(M+H+)；
(S) -2, 4-diamino-6- ((cyclopropyl (4-oxo-3- (1H-pyrazol-3-yl) -5- (trifluoromethyl) -3, 4-dihydroquinazolin-2-yl) methyl) amino) pyrimidine-5-carbonitrile (compound 207):1H NMR(400MHz，DMSO-d6)13.13(brs，1H)，8.07–7.96(m，4H)，7.88(s，2H)，7.81(d，J＝2.4Hz，1H)，7.79–7.67(m，1H)，6.35(d，J＝2.3Hz，1H)，4.72(t，J＝7.8Hz，1H)，1.50–1.36(m，1H)，0.53–0.33(m，3H)，0.22–0.11(m，1H)。ES/MS 483.2(M+H+)；
(S) -2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) ethyl) -3- (1H-pyrazol-3-yl) -5- (trifluoromethyl) quinazolin-4 (3H) -one (compound 208):1H NMR(400MHz，DMSO-d6)13.22(s，1H)，8.04–7.94(m，3H)，7.88(d，J＝2.4Hz，1H)，7.73(d，J＝6.8Hz，1H)，7.64–7.48(m，2H)，7.39(s，2H)，6.52(d，J＝2.3Hz，1H)，4.82(p，J＝6.7Hz，1H)，1.42(d，J＝6.8Hz，3H)。ES/MS 466.1(M+H+)；
(S) -2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) ethyl) -3- (1H-pyrazol-4-yl) -5- (trifluoromethyl) quinazolin-4 (3H) -one (compound 209):1H NMR(400MHz，DMSO-d6)7.99–7.90(m，3H)，7.86(s，2H)，7.74(d，J＝6.9Hz，1H)，7.53(s，2H)，7.43(br.s，2H)，4.92(p，J＝6.7Hz，1H)，1.37(d，J＝6.7Hz，3H)。ES/MS 466.1(M+H+)；
(S) -2- (cyclopropyl ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) methyl) -3- (1H-pyrazol-3-yl) -5- (trifluoromethyl) quinazolin-4 (3H) -one (compound 210):1H NMR(400MHz，DMSO-d6)13.18(br.s，1H)，8.11–7.97(m，3H)，7.86(d，J＝2.4Hz，1H)，7.71–7.52(m，3H)，7.44(s，2H)，6.38(d，J＝2.4Hz，1H)，4.75(t，J＝7.8Hz，1H)，1.51–1.34(m，1H)，0.59–0.37(m，3H)，0.25–0.12(m，1H)。ES/MS 492.1(M+H+)；
(S) -2, 4-diamino-6- ((1- (5- (difluoromethyl) -4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (compound 211):1H NMR(400MHz，DMSO-d6)13.20(s，1H)，8.13–7.21(m，11H)，6.51(d，J＝2.4Hz，1H)，4.91–4.79(m，1H)，1.41(d，J＝6.7Hz，3H)。ES/MS 439.2(M+H+)；
(S) -2, 4-diamino-6- ((1- (5- (difluoromethyl) -4-oxo-3- (1H-pyrazol-4-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile(Compound 212):1H NMR(400MHz，DMSO-d6)8.04–7.79(m，11H)，5.02–4.90(m，1H)，1.36(d，J＝6.7Hz，3H)。ES/MS 439.2(M+H+)；
(S) -2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) ethyl) -5- (difluoromethyl) -3- (1H-pyrazol-4-yl) quinazolin-4 (3H) -one (compound 213):1H NMR(400MHz，DMSO-d6)8.04–7.70(m，7H)，7.55(s，2H)，7.43(s，2H)，4.98–4.87(m，1H)，1.37(d，J＝6.7Hz，3H)。ES/MS 448.1(M+H+)；
(S) -2, 4-diamino-6- ((cyclopropyl (5- (difluoromethyl) -4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) methyl) amino) pyrimidine-5-carbonitrile (compound 214):1H NMR(400MHz，DMSO-d6)13.12(s，1H)，8.04–7.49(m，9H)，6.35(d，J＝2.3Hz，1H)，4.72(t，J＝7.7Hz，1H)，1.50–1.34(m，1H)，0.52–0.33(m，3H)，0.22–0.11(m，1H)。ES/MS 465.2(M+H+)；
(S) -2- (cyclopropyl ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) methyl) -5- (difluoromethyl) -3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (compound 215):1H NMR(400MHz，DMSO-d6)13.16(s，1H)，8.03–7.69(m，5H)，7.57–7.45(m，3H)，7.37(s，2H)，6.34(d，J＝2.3Hz，1H)，4.72(t，J＝7.8Hz，1H)，1.37(dq，J＝13.7，6.9，6.3Hz，1H)，0.51–0.35(m，3H)，0.20–0.09(m，1H)。ES/MS474.1(M+H+)；
(S) -2, 4-diamino-6- ((1- (5-chloro-3- (3-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (compound 216):1H NMR(400MHz，DMSO-d6)8.17–7.82(m，3H)，7.82–7.71(m，1H)，7.71–7.61(m，1H)，7.61–7.26(m，2H)，5.28–4.87(m，1H)，2.10–1.93(m，3H)，1.42–1.20(m，3H)。ES/MS 437.1(M+H+)；
(S) -2, 4-diamino-6- ((1- (5, 8-dichloro-4-oxo-3- (1H-pyrazol-4-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino)Pyrimidine-5-carbonitrile (compound 217):1H NMR(400MHz，DMSO-d6)8.03–7.59(m，6H)，7.95(d，J＝8.5Hz，1H)，7.56(d，J＝8.5Hz，1H)，7.40(br.s，2H)，5.01–4.90(m，1H)，1.35(d，J＝6.6Hz，3H)。ES/MS 457.1(M+H+)；
(S) -5, 8-dichloro-2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) ethyl) -3- (3-methyl-1H-pyrazol-4-yl) quinazolin-4 (3H) -one (compound 218):1H NMR(400MHz，DMSO-d6)13.05–12.80(m，1H)，8.03–7.55(br.m，1H)，7.96–7.90(m，1H)，7.57–7.49(m，1H)，6.62–6.28(m，1H)，6.11–5.94(m，2H)，5.81–5.50(m，2H)，5.00–4.82(m，1H)，2.17–1.91(m，3H)，1.36–1.12(m，3H)。ES/MS480.1(M+H+)；
(S) -2, 4-diamino-6- ((1- (5, 8-dichloro-3- (3-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (compound 219):1H NMR(400MHz，DMSO-d6)13.06–12.78(m，1H)，8.05–7.49(m，3H)，7.00–6.71(m，1H)，6.62(s，2H)，6.53–6.21(m，2H)，5.15–4.92(m，1H)，2.20–1.94(m，3H)，1.44–1.15(m，3H)。ES/MS 471.1(M+H+)；
(S) -2, 4-diamino-6- (((8-chloro-6-fluoro-3- (3-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydroquinazolin-2-yl) (cyclopropyl) methyl) amino) pyrimidine-5-carbonitrile (compound 220):1H NMR(400MHz，DMSO-d6)13.10–12.71(m，1H)，8.17–8.07(m，1H)，8.05–7.48(m，2H)，6.76–6.60(m，2H)，6.60–6.15(m，3H)，5.22–4.95(m，1H)，2.18–1.90(m，3H)，1.43–0.99(m，1H)，0.49–0.17(m，4H)。ES/MS481.1(M+H+)；
(S) -8-chloro-2- (cyclopropyl ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) methyl) -6-fluoro-3- (3-methyl-1H-pyrazol-4-yl) quinazolin-4 (3H) -one (compound 221):1H NMR(400MHz，DMSO-d6)13.25–12.75(m，1H)，8.18–7.58(m，3H)，6.36–5.98(m，3H)，5.85–5.48(m，2H)，5.31–4.85(m，1H)，2.16–1.90(m，3H)，1.31–0.93(m，1H)，0.44–0.15(m，4H)。ES/MS 490.1(M+H+)；
(S) -2, 4-diamino-6- ((1- (8-chloro-5-methyl-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (compound 222):1HNMR(400MHz，DMSO-d6)13.30–13.21(m，1H)，7.96(dd，J＝2.4，1.6Hz，1H)，7.87(d，J＝8.1Hz，1H)，7.32(dd，J＝8.1，1.0Hz，1H)，6.87(d，J＝7.0Hz，1H)，6.64(s，2H)，6.55(t，J＝2.2Hz，1H)，6.39(s，2H)，4.81(p，J＝6.6Hz，1H)，2.70(s，3H)，1.38(d，J＝6.6Hz，3H)。ES/MS 437.1(M+H+)；
(S) -8-chloro-2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) ethyl) -5-methyl-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (compound 223):1H NMR(400MHz，DMSO-d6)13.26(t，J＝2.0Hz，1H)，7.97(dd，J＝2.4，1.7Hz，1H)，7.88(d，J＝8.1Hz，1H)，7.39–7.21(m，1H)，6.55(t，J＝2.2Hz，1H)，6.51(d，J＝7.5Hz，1H)，6.02(s，2H)，5.62(s，2H)，4.79–4.64(m，1H)，2.69(s，3H)，1.35(d，J＝6.6Hz，3H)。ES/MS 446.1(M+H+)；
(S) -2-amino-4- ((1- (8-chloro-5-methyl-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) -6- (difluoromethyl) pyrimidine-5-carbonitrile (compound 224):1H NMR(400MHz，DMSO-d6)13.21(s，1H)，7.94–7.85(m，2H)，7.74(d，J＝6.6Hz，1H)，7.58(s，1H)，7.44–7.29(m，2H)，6.68(t，J＝53.3Hz，1H)，6.51(d，J＝2.4Hz，1H)，4.98–4.83(m，1H)，2.70(s，3H)，1.44(d，J＝6.6Hz，3H)。ES/MS 472.1(M+H+)；
(S) -2- (1- ((2-amino-5-chloro-6- (difluoromethyl) pyrimidin-4-yl) amino) ethyl) -5-chloro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (compound 225):1H NMR(400MHz，DMSO-d6)13.17(s，1H)，7.87(dd，J＝2.4，1.5Hz，1H)，7.79–7.69(m，1H)，7.61–7.52(m，2H)，7.34(d，J＝6.7Hz，1H)，6.80(t，J＝53.5Hz，1H)，6.56(t，J＝2.1Hz，1H)，6.49(br s，2H)，4.69–4.59(m，1H)，1.41(d，J＝6.7Hz，3H)。ES/MS 467.0(M+H+)；
(S) -2- (1- ((2-amino-5-chloro-6- (difluoromethyl) pyrimidin-4-yl) amino) ethyl) -8-chloro-6-fluoro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (compound 226):1H NMR(400MHz，DMSO-d6)13.27(s，1H)，8.15(dd，J＝8.5，2.9Hz，1H)，7.93(dd，J＝2.4，1.6Hz，1H)，7.84(dd，J＝8.2，2.9Hz，1H)，7.44(d，J＝6.8Hz，1H)，6.84(t，J＝53.6Hz，1H)，6.58(br s，2H)，6.54(t，J＝2.2Hz，1H)，4.91–4.78(m，1H)，1.44(d，J＝6.7Hz，3H)。ES/MS 485.0(M+H+)；
(S) -8-chloro-2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) ethyl) -5- (difluoromethyl) -3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (compound 227):1H NMR(400MHz，DMSO-d6)13.29(s，1H)，8.13(d，J＝8.3Hz，1H)，7.95(dd，J＝2.3，1.2Hz，1H)，7.79(d，J＝8.3Hz，1H)，7.78(t，J＝55.1Hz，1H)，6.55(t，J＝1.9Hz，1H)，6.40(d，J＝7.5Hz，1H)，6.00(s，2H)，5.57(s，2H)，4.71(p，J＝6.8Hz，1H)，1.35(d，J＝6.6Hz，3H)。ES/MS 482.1(M+H+)；
(S) -2, 4-diamino-6- ((1- (8-chloro-5- (difluoromethyl) -4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (compound 228):1H NMR(400MHz，DMSO-d6)13.26(s，1H)，8.14(d，J＝8.2Hz，1H)，7.96–7.89(m，1H)，7.80(d，J＝8.3Hz，1H)，7.72(t，J＝54.9Hz，1H)，6.84(d，J＝6.9Hz，1H)，6.58(s，2H)，6.53(t，J＝2.2Hz，1H)，6.33(s，1H)，4.81(p，J＝6.6Hz，1H)，1.37(d，J＝6.7Hz，3H)。ES/MS 473.1(M+H+)；
(S) -6-chloro-2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) ethyl) -5- (difluoromethyl) -3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (compound 229):1H NMR(400MHz，DMSO-d6)13.28(s，1H)，8.46(t，J＝53.6Hz，1H)，8.01(d，J＝8.8Hz，1H)，7.98–7.94(m，1H)，7.85(d，J＝8.8Hz，1H)，6.61(t，J＝2.0Hz，1H)，6.29(d，J＝7.1Hz，1H)，6.00(s，2H)，5.55(s，2H)，4.65–4.54(m，1H)，1.39(d，J＝6.8Hz，3H)。ES/MS 482.1(M+H+)；
(S) -2, 4-diamino-6- ((1- (6-chloro-5- (difluoromethyl) -4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (compound 230):1H NMR(400MHz，DMSO-d6)13.23(s，1H)，8.43(t，J＝53.6Hz，1H)，7.99(d，J＝8.8Hz，1H)，7.93–7.88(m，1H)，7.80(d，J＝8.8Hz，1H)，6.84(d，J＝6.8Hz，1H)，6.64–6.52(m，3H)，6.28(s，2H)，4.65(p，J＝6.7Hz，1H)，1.37(d，J＝6.8Hz，3H)。ES/MS 473.1(M+H+)；
(S) -2, 4-diamino-6- ((1- (7, 8-difluoro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (compound 231):1H NMR(400MHz，DMSO-d6)13.19(br s，1H)，8.00–7.89(m，2H)，7.88(d，J＝2.4Hz，1H)，7.83–7.69(m，2H)，7.62(ddd，J＝10.2，9.0，6.9Hz，1H)，7.40(br s，2H)，6.51(d，J＝2.3Hz，1H)，4.88–4.78(m，1H)，1.41(d，J＝6.8Hz，3H)。ES/MS 425.1(M+H+)；
(S) -2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) ethyl) -7, 8-difluoro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (compound 232):1H NMR(400MHz，DMSO-d6)13.23(br s，1H)，8.02–7.92(m，1H)，7.88(d，J＝2.3Hz，1H)，7.74(d，J＝6.7Hz，1H)，7.67–7.57(m，1H)，7.52(s，2H)，7.36(s，2H)，6.51(d，J＝2.2Hz，1H)，4.87–4.74(m，1H)，1.43(d，J＝6.7Hz，3H)。ES/MS434.1(M+H+)；
(S) -2- (1- ((2-amino-5-chloro-6- (difluoromethyl) pyrimidin-4-yl) amino) ethyl) -5, 7-difluoro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (compound 233):1H NMR(400MHz，DMSO-d6)13.19(s，1H)，7.87(dd，J＝2.4，1.6Hz，1H)，7.40(ddd，J＝11.5，9.5，2.5Hz，1H)，7.33(d，J＝6.5Hz，1H)，7.31–7.26(m，1H)，6.80(t，J＝53.4Hz，1H)，6.57(t，J＝2.2Hz，1H)，6.49(s，2H)，4.66–4.55(m，1H)，1.42(d，J＝6.8Hz，3H)。ES/MS 469.1(M+H+)；
(S) -2- (1- ((2-amino-5-chloro-6- (difluoromethyl) pyrimidin-4-yl) amino) ethyl) -7, 8-difluoro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (compound 234):1H NMR(400MHz，DMSO-d6)13.21(s，1H)，7.99–7.92(m，1H)，7.88(dd，J＝2.4，1.6Hz，1H)，7.65–7.55(m，1H)，7.42(d，J＝6.6Hz，1H)，6.80(t，J＝53.4Hz，1H)，6.58(t，J＝2.2Hz，1H)，6.49(s，2H)，4.73–4.63(m，1H)，1.44(d，J＝6.8Hz，3H)。ES/MS 469.1(M+H+)；
(S) -2, 4-diamino-6- ((1- (5, 7-difluoro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (compound 235):1H NMR(400MHz，DMSO-d6)13.19(s，1H)，7.89(d，J＝2.4Hz，1H)，7.39(ddd，J＝11.5，9.6，2.6Hz，1H)，7.25(dd，J＝9.6，2.5Hz，1H)，6.79(d，J＝6.6Hz，1H)，6.70–6.43(m，3H)，6.27(s，2H)，4.71–4.45(m，1H)，1.36(d，J＝6.8Hz，3H)。ES/MS 425.1(M+H+)；
(S) -2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) ethyl) -5, 7-difluoro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (compound 236):1H NMR(400MHz，DMSO-d6)13.21(s，1H)，7.91(dd，J＝2.4，1.1Hz，1H)，7.38(ddd，J＝11.7，9.5，2.5Hz，1H)，7.31–7.23(m，1H)，6.57(t，J＝1.8Hz，1H)，6.21(d，J＝7.2Hz，1H)，5.97(s，2H)，5.51(s，2H)，4.59–4.46(m，1H)，1.35(d，J＝6.8Hz，3H)。ES/MS 434.1(M+H+)；
(S) -2, 4-diamino-6- ((1- (5-chloro-7-fluoro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (compound 237):1H NMR(400MHz，DMSO-d6)13.18(s，1H)，7.89(dd，J＝2.4，1.6Hz，1H)，7.59(dd，J＝8.8，2.6Hz，1H)，7.37(dd，J＝9.3，2.6Hz，1H)，6.81(br d，J＝3.9Hz，1H)，6.59(s，2H)，6.57(t，J＝2.2Hz，1H)，6.30(br s，3H)，4.66–4.52(m，1H)，1.36(d，J＝6.8Hz，3H)。ES/MS 441.1(M+H+)；
(S) -5-chloro-2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) ethyl) -7-fluoro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (compound 238):1H NMR(400MHz，DMSO-d6)13.21(s，1H)，7.92(dd，J＝2.4，1.6Hz，1H)，7.58(dd，J＝8.8，2.6Hz，1H)，7.40(dd，J＝9.4，2.6Hz，1H)，6.58(t，J＝2.2Hz，1H)，6.23(d，J＝7.1Hz，1H)，6.00(s，2H)，5.55(s，2H)，4.58–4.48(m，1H)，1.34(d，J＝6.8Hz，3H)。ES/MS 450.0(M+H+)；
(S) -2, 4-diamino-6- (((5-chloro-7-fluoro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) (cyclopropyl) methyl) amino) pyrimidine-5-carbonitrile (compound 239):1H NMR(400MHz，DMSO-d6)13.18(s，1H)，7.86(dd，J＝2.4，1.6Hz，1H)，7.61(dd，J＝8.8，2.6Hz，1H)，7.41(dd，J＝9.2，2.6Hz，1H)，6.61(s，2H)，6.42(t，J＝2.2Hz，1H)，6.35(d，J＝7.4Hz，1H)，6.29(s，2H)，4.62(t，J＝7.3Hz，1H)，1.32–1.20(m，1H)，0.42–0.13(m，4H)。ES/MS 467.1(M+H+)；
(S) -5-chloro-2- (cyclopropyl ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) methyl) -7-fluoro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (compound 240):1H NMR(400MHz，DMSO-d6)13.23(s，1H)，7.91(dd，J＝2.4，1.6Hz，1H)，7.61(dd，J＝8.8，2.6Hz，1H)，7.47(dd，J＝9.3，2.6Hz，1H)，6.46(t，J＝2.2Hz，1H)，6.09(br s，2H)，6.01(br d，J＝8.0Hz，1H)，5.62(br s，2H)，4.61(dd，J＝7.8，6.8Hz，1H)，1.26–1.14(m，1H)，0.40–0.13(m，4H)。ES/MS 476.1(M+H+)；
(S) -2- (cyclopropyl ((2, 6-diamino-5-cyanopyrimidin-4-yl) amino) methyl) -3- (4-methyl-1H-pyrazol-3-yl) -4-oxo-3, 4-dihydroquinazoline-8-carbonitrile (compound 241):1H NMR(400MHz，DMSO-d6)13.12–12.52(m，1H)，8.64–8.24(m，2H)，8.22–6.88(m，8H)，5.26–4.59(m，1H)，1.88–1.71(m，3H)，1.66–1.16(m，1H)，0.67–0.41(m，3H)，0.30–0.06(m，1H)。ES/MS 454.2(M+H+)；
2- ((1S) - ((6-amino-3-bromo-3 aH-pyrazolo [3, 4-d)]Pyrimidin-4-yl) amino) (cyclopropyl) methyl) -5-chloro-3- (4-methyl-1H-pyrazol-3-yl) quinazolin-4 (3H) -one (compound 242):1H NMR(400MHz，DMSO-d6)13.61–12.71(m，2H)，7.89–7.71(m，3H)，7.68–7.47(m，1H)，7.46–6.45(m，2H)，5.32–5.05(m，1H)，1.92–1.71(m，3H)，1.34–0.93(m，1H)，0.47–0.26(m，3H)，0.24–0.02(m，1H)。ES/MS541.0(M+H+)；
(S) -5-chloro-2- (cyclopropyl ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) methyl) -3- (4-methyl-1H-pyrazol-3-yl) quinazolin-4 (3H) -one (compound 248):1H NMR(400MHz，DMSO-d6)13.11–12.43(m，1H)，7.86–7.74(m，2H)，7.74–7.57(m，2H)，7.57–7.44(m，2H)，7.44–7.21(m，3H)，4.92–4.67(m，1H)，1.86–1.66(m，3H)，1.43–1.18(m，1H)，0.58–0.29(m，3H)，0.22–0.03(m，1H)。ES/MS472.1(M+H+)；
(S) -2-amino-4-chloro-6- (((5-chloro-3- (4-methyl-1H-pyrazol-3-yl) -4-oxo-3, 4-dihydroquinazolin-2-yl) (cyclopropyl) methyl) amino) pyrimidine-5-carbonitrile (compound 243):1H NMR(400MHz，DMSO-d6)13.02–12.39(m，1H)，7.87–7.75(m，2H)，7.74–7.44(m，4H)，7.43–7.36(m，1H)，7.31–7.03(m，1H)，4.97–4.66(m，1H)，1.86–1.69(m，3H)，1.39(ddd，J＝69.9，12.6，7.4Hz，1H)，0.60–0.32(m，3H)，0.22–0.02(m，1H)。ES/MS 482.1(M+H+)；
(S) -2-amino-4- (((5-chloro-3- (4-methyl-1H-pyrazol-3-yl) -4-oxo-3, 4-dihydroquinazolin-2-yl) (cyclopropyl) methyl) amino) -6-methylpyrimidine-5-carbonitrile (compound 244):1H NMR(400MHz，DMSO-d6)12.68(br s，1H)，8.39–7.89(m，1H)，7.85–7.76(m，1H)，7.72–7.58(m，2H)，7.48(s，2H)，7.44–7.39(m，1H)，4.98–4.64(m，1H)，2.34–2.26(m，3H)，1.85–1.69(m，3H)，1.54–1.29(m，1H)，0.60–0.33(m，3H)，0.24–0.02(m，1H)。ES/MS 462.1(M+H+)；
(S) -2, 4-diamino-6- ((1- (5-cyclopropyl-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) propyl) amino) pyrimidine-5-carbonitrile (compound 245):1H NMR(400MHz，DMSO-d6)13.13(br s，1H)，7.88(d，J＝2.3Hz，1H)，7.85–7.72(br m，3H)，7.67(t，J＝7.9Hz，1H)，7.41(dd，J＝8.1，1.2Hz，1H)，7.26(br m，2H)，7.07(dt，J＝7.4，0.8Hz，1H)，6.54(d，J＝2.3Hz，1H)，4.74–4.63(m，1H)，3.29(tt，J＝8.5，5.5Hz，1H)，1.96(ddt，J＝14.6，11.6，7.3Hz，1H)，1.86–1.62(m，1H)，1.04–0.84(m，2H)，0.84–0.59(m，5H)。ES/MS 443.2(M+H+)；
(S) -2- (((2-amino-6-chloro-5-cyanopyrimidin-4-yl) amino) (cyclopropyl) methyl) -3- (4-methyl-1H-pyrazol-3-yl) -4-oxo-3, 4-dihydroquinazoline-8-carbonitrile (compound 246):1H NMR(400MHz，DMSO-d6)12.62(s，1H)，8.54–8.27(m，2H)，7.96–7.85(m，1H)，7.75–7.64(m，1H)，7.58–7.30(m，2H)，7.16(s，1H)，5.14–4.56(m，1H)，1.83–1.68(m，3H)，1.67–1.46(m，1H)，0.65–0.39(m，3H)，0.26–0.05(m，1H)。ES/MS 473.1(M+H+)；
(S) -2, 4-diamino-6- (((5-chloro-3- (4-methyl-1H-pyrazol-3-yl) -4-oxo-3, 4-dihydroquinazolin-2-yl) (cyclopropyl) methyl) amino) pyrimidine-5-carbonitrile (compound 247):1H NMR(400MHz，DMSO-d6)13.11–12.43(m，1H)，7.87–7.71(m，1H)，7.71–7.56(m，6H)，7.56–6.92(m，2H)，4.96–4.66(m，1H)，1.86–1.70(m，3H)，1.48–1.15(m，1H)，0.59–0.27(m，3H)，0.24–0.03(m，1H)。ES/MS 463.1(M+H+)；
(S) -2, 4-diamino-6- ((1- (8-chloro-6-fluoro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-Carbonitrile (compound 279).1H NMR(400MHz，DMSO-d6)13.23(d，J＝2.1Hz，1H)，8.09(dd，J＝8.5，2.9Hz，1H)，7.91(dd，J＝2.5，1.6Hz，1H)，7.78(dd，J＝8.2，2.9Hz，1H)，6.81(d，J＝6.9Hz，1H)，6.67–6.39(m，2H)，6.31(s，1H)，4.80(p，J＝6.6Hz，1H)，1.35(d，J＝6.6Hz，3H)。ES/MS 441.1(M+H+)；
(S) -2, 4-diamino-6- ((1- (5-chloro-4-oxo-3- (1H-pyrazol-4-yl) -3, 4-dihydroquinazolin-2-yl) butyl) amino) pyrimidine-5-carbonitrile (Compound 249).1H NMR(400MHz，DMSO-d6)13.21(s，1H)，8.20(s，1H)，7.88–7.67(m，2H)，7.67–7.42(m，2H)，6.78–6.49(m，3H)，6.35(s，1H)，4.83(ddd，J＝9.8，7.6，3.1Hz，1H)，1.86–1.57(m，2H)，1.27(dd，J＝15.3，7.7Hz，1H)，1.04(dq，J＝14.8，7.5Hz，1H)，0.61(t，J＝7.3Hz，3H)。ES/MS 451.1(M+H+)；
(S) -5-chloro-2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) butyl) -3- (1H-pyrazol-4-yl) quinazolin-4 (3H) -one (Compound 250).1H NMR(400MHz，DMSO-d6)13.21(s，1H)，8.20(d，J＝1.9Hz，1H)，7.90–7.65(m，2H)，7.59–7.36(m，2H)，6.02(d，J＝7.8Hz，3H)，5.61(s，2H)，4.79(td，J＝8.5，3.6Hz，1H)，1.81–1.53(m，2H)，1.28(dq，J＝14.6，7.2Hz，1H)，1.06(dq，J＝14.4，7.4Hz，1H)，0.61(t，J＝7.4Hz，3H)。ES/MS 460.1(M+H+)；
(S) -2, 4-diamino-6- ((1- (5, 8-dichloro-4-oxo-3- (1H-pyrazol-4-yl) -3, 4-dihydroquinazolin-2-yl) butyl) amino) pyrimidine-5-carbonitrile (Compound 251).1H NMR(400MHz，DMSO-d6)13.25(s，1H)，8.17(s，1H)，7.94(d，J＝8.5Hz，1H)，7.77(s，1H)，7.54(d，J＝8.5Hz，1H)，6.63(s，2H)，6.59–6.28(m，3H)，4.95(td，J＝8.3，3.4Hz，1H)，1.83–1.53(m，2H)，1.36–1.19(m，1H)，1.09(dq，J＝14.5，7.6Hz，1H)，0.65(t，J＝7.3Hz，3H)。ES/MS 485.1(M+H+)；
(S) -5, 8-dichloro-2- (1- ((S)2, 6-diamino-5-chloropyrimidin-4-yl) amino) butyl) -3- (1H-pyrazol-4-yl) quinazolin-4 (3H) -one (Compound 252).1H NMR(400MHz，DMSO-d6)13.25(s，1H)，8.18(d，J＝1.6Hz，1H)，8.04–7.84(m，1H)，7.82–7.67(m，1H)，7.53(d，J＝8.5Hz，1H)，6.03(t，J＝4.3Hz，3H)，5.64(s，2H)，4.90(td，J＝8.8，3.2Hz，1H)，1.83–1.46(m，2H)，1.27(dt，J＝13.9，6.1Hz，1H)，1.12(tt，J＝14.5，7.3Hz，1H)，0.65(q，J＝7.4，6.8Hz，3H)。ES/MS 494.0(M+H+)；
(S) -2, 4-diamino-6- ((1- (5-chloro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) butyl) amino) pyrimidine-5-carbonitrile (Compound 253).1H NMR(400MHz，DMSO-d6)13.23(s，1H)，7.95(d，J＝2.5Hz，1H)，7.90–7.65(m，1H)，7.58(dtd，J＝6.6，3.6，3.0，1.5Hz，1H)，6.78–6.47(m，3H)，6.24(s，2H)，4.77–4.44(m，1H)，1.98–1.59(m，2H)，1.42–1.17(m，1H)，1.08(dq，J＝14.4，7.5Hz，1H)，0.66(t，J＝7.2Hz，3H)。ES/MS 451.1(M+H+)；
(S) -2, 4-diamino-6- ((1- (5, 8-dichloro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) butyl) amino) pyrimidine-5-carbonitrile (Compound 254).1H NMR(400MHz，DMSO-d6)13.27(s，1H)，8.04–7.77(m，2H)，7.67–7.40(m，1H)，6.80–6.51(m，4H)，6.30(s，2H)，4.83(td，J＝8.1，3.6Hz，1H)，2.02–1.79(m，1H)，1.66(ddt，J＝17.4，8.8，4.5Hz，1H)，1.38–1.21(m，1H)，1.21–0.93(m，1H)，0.69(t，J＝7.3Hz，3H)。ES/MS 485.1(M+H+)；
(S) -5, 8-dichloro-2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) butyl) -3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 255).1H NMR(400MHz，DMSO-d6)13.29(s，1H)，8.04–7.86(m，1H)，7.56(dd，J＝8.5，1.3Hz，1H)，6.61(q，J＝2.6，2.0Hz，1H)，6.24–5.87(m，3H)，5.54(s，2H)，4.90–4.42(m，1H)，1.85(s，1H)，1.73–1.49(m，1H)，1.28(d，J＝11.8Hz，1H)，1.14(dq，J＝14.8，7.5Hz，1H)，0.68(t，J＝7.3Hz，3H)。ES/MS 494.0(M+H+)；
(S) -8-chloro-2- (cyclopropyl ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) methyl) -6-fluoro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 256).1H NMR(400MHz，DMSO-d6)13.32(d，J＝2.5Hz，1H)，8.14(ddd，J＝8.6，3.0，1.7Hz，1H)，7.98(t，J＝2.1Hz，1H)，7.82(ddd，J＝8.2，3.0，1.7Hz，1H)，6.52(q，J＝2.0Hz，1H)，6.24–5.89(m，3H)，5.61(s，2H)，4.92(ddd，J＝7.9，5.6，1.8Hz，1H)，1.25(qd，J＝7.3，6.6，3.8Hz，1H)，0.43–0.10(m，4H)。ES/MS 476.1(M+H+)；
(S) -8-chloro-2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) propyl) -6-fluoro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 257).1H NMR(400MHz，DMSO-d6)13.31(d，J＝25.8Hz，1H)，8.18(ddd，J＝12.4，8.5，2.9Hz，1H)，8.02–7.77(m，2H)，7.59(d，J＝30.8Hz，2H)，7.41(s，2H)，6.54(dd，J＝24.8，2.4Hz，1H)，4.86(td，J＝7.1，4.6Hz，1H)，2.18–1.65(m，2H)，0.78(dt，J＝14.4，7.3Hz，3H)。ES/MS 464.1(M+H+)；
(S) -2, 4-diamino-6- ((1- (8-chloro-6-fluoro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) propyl) amino) pyrimidine-5-carbonitrile (Compound 258).1H NMR(400MHz，DMSO-d6)13.25(s，1H)，8.15(dd，J＝8.5，2.9Hz，1H)，7.93(d，J＝2.4Hz，1H)，7.83(dd，J＝8.1，2.9Hz，1H)，7.61(s，3H)，6.51(d，J＝2.4Hz，2H)，4.88(td，J＝7.1，4.7Hz，1H)，2.03(ddd，J＝12.9，7.3，5.2Hz，1H)，1.77(dt，J＝14.1，7.2Hz，1H)，0.78(t，J＝7.3Hz，3H)。ES/MS 455.1(M+H+)；
(S) -5-chloro-2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) ethyl) -6-fluoro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 259).1H NMR(400MHz，DMSO-d6)13.25(d，J＝2.2Hz，1H)，8.10–7.77(m，2H)，7.68(dd，J＝9.0，5.0Hz，1H)，6.61(t，J＝2.2Hz，1H)，6.26(d，J＝7.3Hz，1H)，6.00(s，2H)，5.56(s，2H)，4.58(q，J＝6.9Hz，1H)，1.37(d，J＝6.7Hz，3H)。ES/MS 450.1(M+H+)；
(S) -2, 4-diamino-6- ((1- (5-chloro-6-fluoro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (Compound 260).1H NMR(400MHz，DMSO-d6)13.23(d，J＝2.1Hz，1H)，8.08–7.78(m，2H)，7.67(dd，J＝9.1，4.9Hz，1H)，6.83(d，J＝6.7Hz，1H)，6.59(d，J＝2.2Hz，3H)，6.31(s，2H)，4.66(p，J＝6.6Hz，1H)，1.38(d，J＝6.8Hz，3H)。ES/MS441.1(M+H+)；
(S) -5-chloro-2- (cyclopropyl ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) methyl) -6-fluoro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 261).1H NMR(400MHz，DMSO-d6)13.34–13.16(m，1H)，8.06–7.84(m，2H)，7.73(dd，J＝9.0，5.0Hz，1H)，6.50(t，J＝2.2Hz，1H)，6.10–5.91(m，3H)，5.66–5.52(m，2H)，4.84–4.56(m，1H)，1.23(t，J＝6.8Hz，1H)，0.47–0.12(m，4H)。ES/MS476.1(M+H+)；
(S) -2, 4-diamino-6- (((5-chloro-6-fluoro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) (cyclopropyl) methyl) amino) pyrimidine-5-carbonitrile (Compound 262).1H NMR(400MHz，DMSO-d6)13.23(d，J＝2.2Hz，1H)，8.08–7.80(m，2H)，7.70(dd，J＝9.1，4.9Hz，1H)，6.64(s，2H)，6.55–6.16(m，3H)，4.72(t，J＝7.2Hz，1H)，1.29(q，J＝6.5Hz，1H)，0.55–0.30(m，3H)，0.30–0.10(m，1H)。ES/MS 467.1(M+H+)；
(S) -5-chloro-2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) ethyl) -6-fluoro-3- (1H-pyrazol-4-yl) quinazolin-4 (3H) -one (Compound 263).1H NMR(400MHz，DMSO-d6)13.27(d，J＝21.6Hz，1H)，8.27–8.11(m，1H)，7.90(dt，J＝24.1，9.0Hz，1H)，7.80–7.55(m，2H)，6.28(s，1H)，6.07(s，2H)，5.70(s，2H)，4.80(dt，J＝24.0，6.9Hz，1H)，1.32(d，J＝6.8Hz，3H)。ES/MS 450.1(M+H+)；
(S) -2, 4-diamino-6- ((1- (5-chloro-6-fluoro-4-oxo-3- (1H-pyrazol-4-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (Compound 264).1H NMR(400MHz，DMSO-d6)13.23(s，1H)，8.25–8.06(m，1H)，7.89(t，J＝9.0Hz，1H)，7.75(d，J＝1.8Hz，1H)，7.65(dd，J＝9.0，5.0Hz，1H)，6.80(d，J＝6.8Hz，1H)，6.60(s，2H)，6.38(s，2H)，4.81(p，J＝6.7Hz，1H)，1.33(d，J＝6.7Hz，3H)。ES/MS 441.1(M+H+)。
(S) -8-chloro-2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) ethyl) -6-fluoro-3- (1H-pyrazol-4-yl) quinazolin-4 (3H) -one (Compound 265).1H NMR(400MHz，DMSO-d6)13.28(s，1H)，8.23–8.04(m，2H)，7.86–7.63(m，2H)，6.39(d，J＝7.7Hz，1H)，6.03(s，2H)，5.68(s，2H)，4.98–4.73(m，1H)，1.32(d，J＝6.7Hz，3H)。ES/MS 450.1(M+H+)；
(S) -2, 4-diamino-6- ((1- (8-chloro-6-fluoro-4-oxo-3- (1H-pyrazol-4-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (Compound 266).1H NMR(400MHz，DMSO-d6)13.26(s，1H)，8.11(d，J＝8.3Hz，2H)，7.90–7.57(m，2H)，6.82(d，J＝6.9Hz，1H)，6.61(s，2H)，6.41(s，2H)，4.94(h，J＝6.6Hz，1H)，1.34(d，J＝6.6Hz，3H)。ES/MS 441.1(M+H+)；
(S) -5-chloro-2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) butyl) -6-fluoro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (Compound 267).1H NMR(400MHz，DMSO-d6)13.26(s，1H)，7.97(dd，J＝2.4，1.6Hz，1H)，7.87(t，J＝9.0Hz，1H)，7.64(dd，J＝9.1，5.0Hz，1H)，6.66(t，J＝2.2Hz，1H)，6.26–5.85(m，3H)，5.52(s，2H)，4.82–4.49(m，1H)，1.98–1.53(m，2H)，1.30(d，J＝8.4Hz，1H)，1.09(dq，J＝14.5，7.5Hz，1H)，0.65(t，J＝7.3Hz，3H)。ES/MS 478.1(M+H+)；
(S) -2, 4-diamino-6- ((1- (5-chloro-6-fluoro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) butyl) amino) pyrimidine-5-carbonitrile (Compound 268).1H NMR(400MHz，DMSO-d6)13.25(d，J＝2.4Hz，1H)，8.04–7.77(m，2H)，7.64(dd，J＝9.1，5.0Hz，1H)，6.80–6.57(m，3H)，6.29(s，2H)，4.65(td，J＝8.5，7.4，3.3Hz，1H)，2.04–1.53(m，2H)，1.27(dd，J＝14.5，7.3Hz，1H)，1.07(tt，J＝15.2，7.7Hz，1H)，0.65(t，J＝7.3Hz，3H)。ES/MS 469.1(M+H+)；
(S) -2, 4-diamino-6- (((8-chloro-6-fluoro-4-oxo-3- (1H-pyrazol-4-yl) -3, 4-dihydroquinazolin-2-yl) (cyclopropyl) methyl) amino) pyrimidine-5-carbonitrile (Compound 269).1H NMR(400MHz，DMSO-d6)13.26(s，1H)，8.17–7.98(m，2H)，7.90–7.57(m，2H)，6.82–6.53(m，2H)，6.51–6.16(m，3H)，5.19–4.79(m，1H)，1.38–1.11(m，1H)，0.45–0.16(m，3H)，0.13(dd，J＝5.2，3.3Hz，1H)。ES/MS 467.1(M+H+)；
(S) -3- (4-bromo-1H-pyrazol-3-yl) -8-chloro-2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) ethyl) -6-fluoroquinazolin-4 (3H) -one (Compound 270).1H NMR(400MHz，DMSO-d6)13.75(s，1H)，8.83–8.08(m，3H)，8.02–7.69(m，1H)，6.58(dd，J＝9.4，6.2Hz，1H)，6.35(d，J＝8.1Hz，1H)，6.03(d，J＝4.3Hz，2H)，5.57(d，J＝59.5Hz，2H)，5.02–4.65(m，1H)，1.40–1.13(m，3H)。ES/MS530.0(M+H+)；
(S) -2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) ethyl) -6-fluoro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazoline-8-carbonitrile (compound 271).1H NMR(400MHz，DMSO-d6)13.32(t，J＝1.9Hz，1H)，8.49(dd，J＝8.3，3.0Hz，1H)，8.15(dd，J＝8.1，3.0Hz，1H)，7.98(dd，J＝2.4，1.6Hz，1H)，6.57(t，J＝2.2Hz，1H)，6.40(d，J＝7.4Hz，1H)，6.02(s，2H)，5.59(s，2H)，4.75(p，J＝6.7Hz，1H)，1.39(d，J＝6.7Hz，3H)。ES/MS 441.1(M+H+)；
(S) -2- (1- ((2, 6-diamino-5-cyanopyrimidin-4-yl) amino) ethyl) -6-fluoro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazoline-8-carbonitrile (compound 272).1H NMR(400MHz，DMSO-d6)13.23(s，1H)，8.48(ddd，J＝8.5，3.1，0.8Hz，1H)，8.23–8.08(m，1H)，7.90(ddd，J＝3.1，2.0，1.0Hz，1H)，6.85–6.66(m，1H)，6.66–6.43(m，3H)，6.28(s，2H)，4.92–4.52(m，1H)，1.65–1.26(m，3H)。ES/MS 432.1(M+H+)；
(S) -2- (cyclopropyl ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) methyl) -6-fluoro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazoline-8-carbonitrile (compound 273).1H NMR(400MHz，DMSO-d6)13.34(s，1H)，8.50(ddd，J＝8.4，2.9，0.6Hz，1H)，8.25–8.04(m，1H)，7.98(t，J＝1.9Hz，1H)，6.59–6.35(m，1H)，6.26–5.93(m，3H)，5.60(s，2H)，4.91(dd，J＝8.1，5.8Hz，1H)，1.38–1.11(m，1H)，0.45–0.30(m，3H)，0.30–0.14(m，1H)。ES/MS 467.1(M+H+)；
(S) -2, 4-diamino-6- ((1- (4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (Compound 274). 1H NMR (400MHz, DMSO-d)6)13.16(s，1H)，8.11(ddd，J＝8.0，1.6，0.6Hz，1H)，7.96–7.84(m，2H)，7.66(ddd，J＝8.1，1.2，0.6Hz，1H)，7.55(ddd，J＝8.2，7.2，1.2Hz，1H)，6.51(d，J＝2.4Hz，1H)，4.83(t，J＝6.7Hz，1H)，1.39(d，J＝6.7Hz，3H)；
(S) -2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) ethyl) -3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (compound 275). 1H NMR (400MHz, DMSO-d)6)13.18(s，1H)，8.11(ddd，J＝7.9，1.6，0.6Hz，1H)，7.93–7.79(m，2H)，7.76–7.65(m，2H)，7.56(ddd，J＝7.9，7.2，1.2Hz，1H)，7.47(s，2H)，7.33(s，2H)，6.51(d，J＝2.4Hz，1H)，4.81(t，J＝6.8Hz，1H)，1.41(d，J＝6.7Hz，3H)；
(S) -8-chloro-2- (cyclopropyl ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) methyl) -6-fluoro-3- (1H-imidazol-4-yl) quinazolin-4 (3H) -one (compound 280):1H NMR(400MHz，DMSO-d6)12.52(s，1H)，8.10(dd，J＝8.5，2.9Hz，1H)，7.86–7.68(m，2H)，7.45–7.33(m，1H)，6.17(d，J＝5.3Hz，1H)，6.04(s，2H)，5.65(s，2H)，4.96(dd，J＝8.0，5.6Hz，1H)，1.36–1.21(m，1H)，0.34–0.13(m，4H)。ES/MS476.1(M+H+)；
(S) -2, 4-diamino-6- (((8-chloro-6-fluoro-3- (1H-imidazol-4-yl) -4-oxo-3, 4-dihydroquinazolin-2-yl) (cyclopropyl) methyl) amino) pyrimidine-5-carbonitrile (compound 281):1H NMR(400MHz，DMSO-d6)12.51(s，1H)，8.10(dd，J＝8.5，2.9Hz，1H)，7.89–7.70(m，2H)，7.36(dd，J＝2.2，1.3Hz，1H)，6.62(s，2H)，6.45(d，J＝7.7Hz，1H)，6.38(s，2H)，5.01(dd，J＝7.7，6.0Hz，1H)，1.38–1.24(m，1H)，0.39–0.21(m，3H)，0.21–0.11(m，1H)。ES/MS 467.1(M+H+)；
(S) -5-chloro-2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) butyl) -3- (1H-imidazol-4-yl) quinazolin-4 (3H) -one (compound 282):1H NMR(400MHz，DMSO-d6)12.46(s，1H)，7.80(d，J＝1.3Hz，1H)，7.70(dd，J＝8.3，7.8Hz，1H)，7.57–7.48(m，3H)，6.18(s，1H)，6.10(s，2H)，5.72(s，2H)，4.73–4.64(m，1H)，1.90–1.77(m，1H)，1.72–1.59(m，1H)，1.32–1.18(m，1H)，1.13–0.99(m，1H)，0.63(t，J＝7.3Hz，3H)。ES/MS 460.1(M+H+)；
(S) -2, 4-diamino-6- ((1- (5-chloro-3- (1H-imidazol-4-yl) -4-oxo-3, 4-dihydroquinazolin-2-yl) butyl) amino) pyrimidine-5-carbonitrile (compound 283):1H NMR(400MHz，DMSO-d6)12.45(s，1H)，7.79(t，J＝1.3Hz，1H)，7.71(dd，J＝8.3，7.8Hz，1H)，7.57–7.48(m，3H)，6.67(d，J＝7.6Hz，1H)，6.56(s，2H)，6.31(s，2H)，4.74(ddd，J＝9.5，7.6，3.3Hz，1H)，1.91–1.77(m，1H)，1.70(ddp，J＝13.6，9.1，4.6Hz，1H)，1.31–1.17(m，1H)，1.11–0.96(m，1H)，0.63(t，J＝7.3Hz，3H)。ES/MS 451.2(M+H+)；
(S) -8-chloro-2- (1- ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) ethyl) -6-fluoro-3- (1H-imidazol-4-yl) quinazolin-4 (3H) -one (compound 284):1H NMR(400MHz，DMSO-d6)12.52(s，1H)，8.08(dd，J＝8.5，2.9Hz，1H)，7.81(t，J＝1.2Hz，1H)，7.77(dd，J＝8.2，2.9Hz，1H)，7.47(dd，J＝2.2，1.4Hz，1H)，6.38(d，J＝7.5Hz，1H)，5.97(s，2H)，5.61(s，2H)，4.85–4.70(m，1H)，1.34(d，J＝6.7Hz，3H)。ES/MS 450.1(M+H+)；
(S) -2, 4-diamino-6- ((1- (8-chloro-6-fluoro-3- (1H-imidazol-4-yl) -4-oxo-3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (compound 285):1H NMR(400MHz，DMSO-d6)12.51(s，1H)，8.08(dd，J＝8.5，2.9Hz，1H)，7.85–7.68(m，2H)，7.45(t，J＝1.6Hz，1H)，6.81(d，J＝6.9Hz，1H)，6.57(s，2H)，6.37(s，2H)，4.96–4.79(m，1H)，1.36(d，J＝6.7Hz，3H)。ES/MS 441.1(M+H+)；
(S) -2, 4-diamino-6- ((1- (5, 8-dichloro-3- (1H-imidazol-4-yl) -4-oxo-3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (compound 286):1H NMR(400MHz，DMSO-d6)12.51(s，1H)，7.93(d，J＝8.5Hz，1H)，7.80(d，J＝1.3Hz，1H)，7.54(d，J＝8.5Hz，1H)，7.44(d，J＝1.4Hz，1H)，6.84(br.d，J＝6.9Hz，1H)，6.63(s，2H)，6.42(s，2H)，4.89–4.77(m，1H)，1.36(d，J＝6.6Hz，3H)。ES/MS457.1(M+H+)；
(S) -2, 4-diamino-6- ((1- (5-chloro-4-oxo-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazol-4-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile. ES/MS 553.2(M + H)+)；
(S) -5-chloro-2- (cyclopropyl ((2, 6-diamino-5-chloropyrimidin-4-yl) amino) methyl) -3- (1H-imidazol-4-yl) quinazolin-4 (3H) -one (compound 287):1H NMR(400MHz，DMSO-d6)12.56(s，1H)，7.82–7.74(m，2H)，7.66(dd，J＝8.2，1.2Hz，1H)，7.59(dd，J＝7.8，1.2Hz，1H)，7.57–7.29(m，6H)，7.27(d，J＝1.3Hz，1H)，4.74(t，J＝7.7Hz，1H)，1.41–1.17(m，1H)，0.49–0.30(m，3H)，0.21–0.11(m，1H)。ES/MS 458.1(M+H+)；
(S) -2, 4-diamino-6- ((1- (5-chloro-4-oxo-3- (1H-pyrrol-2-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (Compound 289).1H NMR(400MHz，DMSO)11.27–11.12(m，1H)，7.81–7.69(m，1H)，7.60–7.48(m，2H)，6.93–6.84(m，1H)，6.26–6.09(m，1H)，1.45–1.25(m，3H)。ES/MS 422.1(M+H+)；
(S) -5-chloro-3- (1H-pyrrol-2-yl) -2- (1- (thiazolo [5, 4-d)]Pyrimidin-7-ylamino) ethyl) quinazolin-4 (3H) -one (compound 290).1H NMR(400MHz，DMSO)11.20(br s，1H)，9.29(s，1H)，8.42(s，1H)，8.38(s，1H)，7.71(dd，J＝8.3，7.7Hz，1H)，7.57–7.52(m，2H)，6.90-6.86(m，1H)，6.27–6.22(m，1H)，6.15–6.11(m，1H)，5.06(br s，1H)，1.45(br s，3H)。ES/MS 424.1(M+H+) (ii) a And
(S) -5-chloro-2- (1- (imidazo [2, 1-f)][1,2,4]Triazin-4-ylamino) ethyl) -3- (1H-pyrrol-2-yl) quinazolin-4 (3H) -one (compound 291).1H NMR(400MHz，DMSO)11.20(br s，1H)，8.93(d，J＝6.4Hz，1H)，8.12(s，1H)，8.05(d，J＝1.1Hz，1H)，7.71(dd，J＝8.3，7.7Hz，1H)，7.61(d，J＝1.1Hz，1H)，7.57–7.54(m，1H)，7.54–7.52(m，1H)，6.87(td，J＝2.8，1.7Hz，1H)，6.25–6.20(m，1H)，6.14–6.10(m，1H)，4.76(br s，1H)，1.45(br s，3H)。ES/MS 407.1(M+H+)。
C. Preparation of a Compound of formula (I) wherein X is CH, Y is N, Z is C and is the point of attachment to quinazolinone, A is CO, N is 1, R1Is Cl, m' is 0, R3Is methyl, R5Is hydrogen, and R4Is 2-aminopyrazolo [1,5-a ]]Pyrimidin-3-yl
Trifluoroacetic acid (0.5mL) was added to a suspension of tert-butyl (S) - (1- (5-chloro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) carbamate (120mg, 0.31mmol) in dichloromethane (2.0 mL). The solution was stirred at room temperature for 3 hours and concentrated in vacuo. Dichloromethane (3.5mL) was then added and the resulting solution was transferred to a solution containing 2-aminopyrazolo [1,5-a ]]Pyrimidine-3-carboxylic acid (60mg, 0.34mmol) in a flask. Diisopropylethylamine (0.32mL, 1.8mmol) and HATU (176mg, 0.46mmol) were then added and the reaction mixture was stirred at room temperature for 16 h. The reaction was concentrated and the DMSO solution of the crude mixture was then purified by HPLC eluting with 5% -95% water/acetonitrile (0.1% v/v trifluoroacetic acid). The appropriate fractions were pooled and lyophilized to give (S) -2-amino-N- (1- (5-chloro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) pyrazolo [1,5-a]Pyrimidine-3-carboxamide (compound 117).1H NMR(400MHz，DMSO)13.31(br s，1H)，8.92(dd，J＝6.7，1.7Hz，1H)，8.77(d，J＝7.6Hz，1H)，8.65(dd，J＝4.5，1.7Hz，1H)，8.00(d，J＝2.4Hz，1H)，7.87–7.75(m，1H)，7.72(dd，J＝8.2，1.3Hz，1H)，7.61(dd，J＝7.8，1.2Hz，1H)，7.02(dd，J＝6.7，4.5Hz，1H)，6.51(d，J＝2.3Hz，1H)，4.88–4.74(m，1H)，1.39(d，J＝6.7Hz，3H)。ES/MS 450.1(M+H+)。
D. The following compound of formula (I) was prepared using the procedure and reaction scheme I described in example 4C:
(S) -3-amino-N- (1- (5, 8-dichloro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) propyl) pyrazine-2-carboxamide (Compound 118).1H NMR(400MHz，DMSO)8.98(d，J＝8.4Hz，1H)，8.24(d，J＝2.4Hz，1H)，8.02–7.98(m，2H)，7.88(d，J＝2.4Hz，1H)，7.59(d，J＝8.5Hz，1H)，6.47(d，J＝2.3Hz，1H)，4.75(td，J＝8.0，4.2Hz，1H)，2.03–1.92(m，1H)，1.73–1.60(m，1H)，0.77(t，J＝7.3Hz，3H)。ES/MS 459.0(M+H+)；
(S) -N- (1- (5, 8-dichloro-4-oxo-3- (1H-pyrazole-4)-yl) -3, 4-dihydroquinazolin-2-yl) propyl) pyrazolo [1,5-a]Pyrimidine-3-carboxamide (compound 119).1H NMR(400MHz，DMSO)9.34(dd，J＝7.0，1.6Hz，1H)，8.97(d，J＝8.4Hz，1H)，8.86(dd，J＝4.2，1.7Hz，1H)，8.57(s，1H)，7.97(d，J＝8.5Hz，1H)，7.91(s，1H)，7.57(d，J＝8.5Hz，1H)，7.30(dd，J＝7.0，4.2Hz，1H)，5.06(td，J＝7.9，4.2Hz，1H)，1.99–1.87(m，1H)，1.69–1.60(m，1H)，0.81(t，J＝7.3Hz，3H)。ES/MS 483.0(M+H+)；
(S) -N- (1- (5, 8-dichloro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) propyl) pyrazolo [1,5-a]Pyrimidine-3-carboxamide (compound 120).1H NMR(400MHz，DMSO)9.34(dd，J＝7.0，1.7Hz，1H)，8.98(d，J＝8.4Hz，1H)，8.86(dd，J＝4.2，1.7Hz，1H)，8.55(s，1H)，8.03(d，J＝2.3Hz，1H)，7.99(d，J＝8.5Hz，1H)，7.59(d，J＝8.5Hz，1H)，7.30(dd，J＝7.0，4.2Hz，1H)，4.92(td，J＝8.1，4.0Hz，1H)，2.02–1.93(m，1H)，1.71–1.60(m，1H)，0.80(t，J＝7.4Hz，3H)。ES/MS 483.1(M+H+)；
(S) -3-amino-N- (1- (5-chloro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) pyrazine-2-carboxamide (Compound 121).1H NMR(400MHz，DMSO)8.94(d，J＝7.6Hz，1H)，8.25(d，J＝2.3Hz，1H)，7.98(d，J＝2.4Hz，1H)，7.88(d，J＝2.3Hz，1H)，7.84–7.77(m，1H)，7.68(dd，J＝8.2，1.2Hz，1H)，7.61(dd，J＝7.8，1.2Hz，1H)，6.48(d，J＝2.3Hz，1H)，4.79–4.68(m，1H)，1.40(d，J＝6.7Hz，3H)。ES/MS 411.1(M+H+) (ii) a And
(S) -3-amino-N- (1- (5, 8-dichloro-4-oxo-3- (1H-pyrazol-4-yl) -3, 4-dihydroquinazolin-2-yl) propyl) pyrazine-2-carboxamide (Compound 122).1H NMR(400MHz，DMSO)9.01(d，J＝8.3Hz，1H)，8.24(d，J＝2.4Hz，1H)，7.98(d，J＝8.5Hz，1H)，7.89–7.83(m，3H)，7.58(d，J＝8.5Hz，1H)，4.85(td，J＝7.9，4.5Hz，1H)，1.99–1.88(m，1H)，1.73–1.62(m，1H)，0.79(t，J＝7.3Hz，3H)。ES/MS 459.0(M+H+)。
(S) -3, 5-diamino-6-chloro-N- (1- (5-chloro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) pyrazine-2-carboxamide (compound 276): 1H NMR (400MHz, DMSO)13.25(t, J ═ 1.9Hz, 1H), 8.14(d, J ═ 7.5Hz, 1H), 7.94(dd, J ═ 2.4, 1.6Hz, 1H), 7.84-7.69 (m, 1H), 7.69-7.49 (m, 2H), 7.07(s, 3H), 6.43(t, J ═ 2.2Hz, 1H), 4.61(dd, J ═ 7.5, 6.7Hz, 1H), 1.32(d, J ═ 6.7Hz, 3H);
(S) -3, 5-diamino-6-chloro-N- (1- (5-chloro-8-fluoro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) pyrazine-2-carboxamide (compound 277):1H NMR(400MHz，DMSO-d6)13.32(s, 1H), 8.27(d, J ═ 7.5Hz, 1H), 7.98(dd, J ═ 2.4, 0.6Hz, 1H), 7.77(ddd, J ═ 9.6, 8.9, 0.7Hz, 1H), 7.67-7.53 (m, 1H), 7.11(s, 2H), 6.47(dd, J ═ 2.4, 0.6Hz, 1H), 4.75-4.57 (m, 1H), 1.44-1.30 (m, 3H); and
(S) -3, 5-diamino-6-chloro-N- (1- (5-chloro-8-fluoro-4-oxo-3- (1H-pyrazol-4-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) pyrazine-2-carboxamide (compound 278):1H NMR(400MHz，DMSO-d6)8.31(d，J＝7.3Hz，1H)，7.86(s，2H)，7.75(dd，J＝9.6，8.7Hz，1H)，7.59(dd，J＝8.8，4.4Hz，1H)，7.10(s，2H)，4.85–4.73(m，1H)，1.33(d，J＝6.7Hz，3H)，1.29–1.19(m，2H)。
E. preparation of a compound of formula (I) wherein X is CH, Y is N, Z is C and is the point of attachment to a quinazolinone, A is a single bond, N is 1, R1Is chlorine, m' is 0, R3Is CH3，R5Is hydrogen, and R4Is 2, 6-diamino-5-trifluoromethylpyrimidin-4-yl
To (S) -5-chloro-2- (1- ((2, 6-diaminopyrimidin-4-yl) amino) ethyl) -3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one at 0 deg.C(100mg, 0.251mmol) and Na2SO2CF3(118mg, 0.754mmol) to a solution of dichloromethane (1.0mL) and water (0.4mL) was added tert-butyl hydroperoxide (70% solution in water, 0.17mL, 1.25 mmol). The mixture was stirred at room temperature overnight and diluted with dichloromethane, washed with water, and dried over magnesium sulfate. The organic layer was filtered and concentrated in vacuo. The DMSO solution of the crude mixture was then purified by HPLC eluting with 5% -95% water/acetonitrile (0.1% v/v trifluoroacetic acid). The appropriate fractions were pooled and lyophilized to give (S) -5-chloro-2- (1- ((2, 6-diamino-5- (trifluoromethyl) pyrimidin-4-yl) amino) ethyl) -3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (compound 201).1HNMR(400MHz，DMSO)13.24(s，1H)，7.93(d，J＝2.4Hz，1H)，7.78(t，J＝8.0Hz，1H)，7.58(td，J＝7.8，1.2Hz，2H)，6.51(br s，1H)，4.85–4.77(m，1H)，1.35(d，J＝6.6Hz，3H)。ES/MS466.1(M+H+)；
F. Preparation of a compound of formula (I) wherein X is CH, Y is N, Z is C and is the point of attachment to a quinazolinone, A is a single bond, N is 1, R1Is chlorine, m' is 0, R3Is CH3，R5Is hydrogen, and R4Is 5-cyanothieno [2,3-d ]]Pyrimidin-4-yl
Reacting (S) -2- (1- ((5-bromothieno [2, 3-d)]Pyrimidin-4-yl) amino) ethyl) -5-chloro-3- (1H-pyrazol-3-yl) quinazolin-4 (3H) -one (55mg, 0.11mmol), zinc cyanide (15mg, 0.13mmol), and tetrakis (triphenylphosphine) palladium (0) (19mg, 0.016mmol) were mixed in NMP and degassed under argon. The resulting solution was heated to 120 ℃ in a microwave for 2 hours. The reaction was cooled to room temperature and filtered. The solution of the crude mixture was then purified by HPLC eluting with 5% to 95% water/acetonitrile (0.1% v/v trifluoroacetic acid). The appropriate fractions were pooled and lyophilized to give (S) -4- ((1- (5-chloro-4-oxo-3- (1H-pyrazol-3-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) thieno [2,3-d]Pyrimidine-5-carbonitrile (Compound 202).1H NMR(400MHz，DMSO)13.36(s，1H)，8.82(s，1H)，8.49(s，1H)，8.02(d，J＝2.4Hz，1H)，7.98(d，J＝6.6Hz，1H)，7.86(t，J＝8.0Hz，1H)，7.74(dd，J＝8.1，1.2Hz，1H)，7.63(dd，J＝7.9，1.2Hz，1H)，6.55(d，J＝2.3Hz，1H)，5.11(p，J＝6.5Hz，1H)，1.44(d，J＝6.5Hz，3H)。ES/MS 449.1(M+H+)；
G. Preparation of a compound of formula (I) wherein Y is CH, Z is N, X is C and is the point of attachment to a quinazolinone, A is a single bond, N is 1, R1Is chlorine, m' is 0, R3Is CH3，R5Is hydrogen, and R4Is 2, 6-diamino-5-cyanopyrimidin-4-yl
To a solution of (S) -2, 4-diamino-6- ((1- (5-chloro-4-oxo-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazol-4-yl) -3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (13mg, 0.024mmol) in DCM (1mL) was added a few drops of TFA. The mixture was stirred at ambient temperature for 18 hours, then concentrated in vacuo and purified by preparative LC to give (S) -2, 4-diamino-6- ((1- (5-chloro-3- (1H-imidazol-4-yl) -4-oxo-3, 4-dihydroquinazolin-2-yl) ethyl) amino) pyrimidine-5-carbonitrile (compound 288):1H NMR(400MHz，DMSO-d6)12.62(brs，1H)，7.87(s，1H)，7.81–7.72(m，1H)，7.60–7.54(m，2H)，7.47(d，J＝1.4Hz，1H)，4.86–4.76(m，1H)，1.38(d，J＝6.7Hz，3H)。ES/MS 423.1(M+H+)。