ATR inhibitors and uses thereof

Abstract

The present disclosure relates to novel compounds useful as ATR kinase inhibitors as well as pharmaceutical compositions comprising these compounds and methods of treatment by administering these compounds or the pharmaceutical compositions.

Description

Technical Field

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

[0002] ATR (also known as FRAP-associated protein 1; FRP1, MEC1, SCKL, SECKL1) protein kinase is a member of the PI3-kinase-like kinase (PIKK) protein family that is involved in the repair and maintenance of the genome and its stability. It is essential for the viability of replicating cells and is activated during the S phase to regulate the initiation of replication origins and repair damaged replication forks. Therefore, ATR inhibitors have the potential to be an effective approach for cancer treatment.

[0003] Although progress has been made in the field of ATR inhibitors, there remains a strong need in the art to develop improved drugs having inhibitory activity against ATR. Summary of the invention

[0004] The present disclosure provides compounds capable of inhibiting ATR protein kinase, including stereoisomers, pharmaceutically acceptable salts, tautomers and prodrugs thereof, and also provides methods of using such compounds to treat various diseases or conditions such as cancer.

[0005] In one aspect, the present disclosure provides a compound having formula (I):

[0006]

[0007] or a pharmaceutically acceptable salt thereof,

[0008] in

[0009] Ring A is absent or is a 3- to 6-membered cycloalkyl group, a 5- to 6-membered heterocyclyl group, or a 5- to 6-membered heteroaryl group;

[0010] V is a direct bond, a carbonyl group or optionally substituted by one or more R c Substituted alkyl;

[0011] W and L are each independently a direct bond, -O-, -S- or -N(R a )-;

[0012] R 1 is alkyl, cyano, -S(O)2CH3 or -S(O)(NH)CH3;

[0013] R 2 is hydrogen, halogen or optionally substituted by one or more R b Substituted alkyl;

[0014] Ring B is

[0015] R 5 is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, and haloalkyl;

[0016] R a is hydrogen or alkyl;

[0017] R b is hydroxyl or halogen;

[0018] R c is hydroxy, halogen or alkyl;

[0019] n is 0, 1, 2 or 3.

[0020] In some embodiments, the present disclosure provides a compound having formula (II) or formula (III):

[0021]

[0022] In some embodiments, the present disclosure provides a compound having a formula selected from the group consisting of:

[0023]

[0024] as well as

[0025]

[0026] in

[0027] U is O or NH;

[0028] V is a direct bond, a carbonyl group or optionally substituted by one or more R c Substituted alkyl;

[0029] W and L are each independently -N(R a )-;

[0030] R 1 is an alkyl group;

[0031] R 2 is hydrogen, halogen or is replaced by one or more R b Substituted alkyl;

[0032] R 5 is hydrogen or alkyl;

[0033] R a is hydrogen or alkyl;

[0034] Rb is hydroxy or halogen; and

[0035] R c is hydroxy, halogen or alkyl.

[0036] In some embodiments, the present disclosure provides a compound having formula (V):

[0037]

[0038] or a pharmaceutically acceptable salt thereof,

[0039] in

[0040] Ring A is absent or is a 3- to 6-membered cycloalkyl, a 5- to 6-membered heterocyclyl, or a 5- to 6-membered heteroaryl; Q is a direct bond or is optionally substituted by one or more R d Substituted alkyl;

[0041] L is -O-, -S- or -N(R a )-;

[0042] Ring B is

[0043] R a is hydrogen or alkyl;

[0044] R d is hydroxy, halogen or alkyl;

[0045] R 1 Selected from the group consisting of cyano, hydroxy, halogen, -H, -S(O)2CH3 and -S(O)(NH)CH3;

[0046] R 5 is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, and haloalkyl;

[0047] n is 0, 1, 2 or 3.

[0048] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0049] In another aspect, the present disclosure provides a method for treating cancer, comprising administering an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure to a subject in need thereof.

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

[0051] In a further aspect, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure for use in treating cancer.

[0052] In another aspect, the present disclosure provides a method for inhibiting ATR kinase in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. DETAILED DESCRIPTION

[0053] Reference will now be made in detail to certain embodiments of the present disclosure, examples of which are shown in the attached structures and formulas. Although the present disclosure will be described in conjunction with the enumerated embodiments, it should be understood that the embodiments are not intended to limit the present disclosure to those embodiments. On the contrary, the present disclosure is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the present disclosure as defined in the claims. Those skilled in the art will recognize many methods and materials that are similar or equivalent to the methods and materials described herein and can be used in practicing the present disclosure. The present disclosure is in no way limited to the methods and materials described. In the event that one or more of the incorporated references and similar materials (including but not limited to defined terms, term usage, described technology, etc.) are different from or contradictory to the present application, the present disclosure shall prevail. All references, patents, and patent applications cited in the present disclosure are hereby incorporated by reference in their entirety.

[0054] It should be understood that certain features of the present disclosure described in the context of separate embodiments for the sake of clarity may also be provided in combination in a single embodiment. Conversely, various features of the present disclosure described in the context of a single embodiment for the sake of brevity may also be provided separately or in any suitable sub-combination. It must be noted that, unless the context clearly indicates otherwise, as used in the specification and the appended claims, the singular forms "a or an" and "the" include their plural forms. Thus, for example, reference to "a compound" includes a plurality of compounds.

[0055] definition

[0056] The definitions of specific functional groups and chemical terms are described in more detail below. For the purposes of this disclosure, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition, inside cover, and specific functional groups are generally defined as described herein. In addition, general principles of organic chemistry as well as specific functional moieties and reactivities are described in the following references: Organic Chemistry, Thomas Sorrell, 2nd edition, University Science Books, Sausalito, 2006; Smith and March, March's Advanced Organic Chemistry, 6th edition, John Wiley & Sons, Inc., New York, 2007; Larock, Comprehensive Organic Transformations, 3rd edition, VCH Publishers, Inc., New York, 2018; Carruthers, Some Modern Methods of Organic Synthesis, 4th edition, Cambridge University Press, Cambridge, 2004; the entire contents of each of the above references are incorporated herein by reference.

[0057] Throughout this disclosure, linking substituents are described. Where a structure clearly requires a linking group, the Markush variable listed for that group is to be understood as the linking group. For example, if a structure requires a linking group and the Markush group definition for that variable lists "alkyl," it is to be understood that "alkyl" means a linking alkylene group.

[0058] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, such substituent may be bonded to any atom in the ring. When a substituent is listed without specifying the atom via which such substituent is bonded to the rest of the compound of a given formula, such substituent may be bonded to any atom in such formula. Combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0059] In any variable (e.g., R i ) occurs more than once in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is represented by 0 to 2 R i Partially substituted, the group may optionally be substituted with up to two R i Partially substituted, and R i Each occurrence is independently selected from R i Also, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0060] As used herein, the term “C i-j " indicates a range of carbon atoms, where i and j are integers, and the range of carbon atoms includes the endpoints (i.e., i and j) and every integer point therebetween, and where j is greater than i. For example, C 1-6 Indicates a range of one to six carbon atoms, including one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms, and six carbon atoms. In some embodiments, the term “C 1-12 ” indicates 1 to 12 carbon atoms, especially 1 to 10 carbon atoms, especially 1 to 8 carbon atoms, especially 1 to 6 carbon atoms, especially 1 to 5 carbon atoms, especially 1 to 4 carbon atoms, especially 1 to 3 carbon atoms or especially 1 to 2 carbon atoms.

[0061] As used herein, the term "alkyl", whether used as part of another term or by itself, refers to a saturated straight or branched chain hydrocarbon group that may be optionally substituted independently with one or more substituents as described below. i-j The term "alkyl" refers to an alkyl group having from i to j carbon atoms. In some embodiments, the alkyl group contains from 1 to 10 carbon atoms. In some embodiments, the alkyl group contains from 1 to 9 carbon atoms. In some embodiments, the alkyl group contains from 1 to 8 carbon atoms, from 1 to 7 carbon atoms, from 1 to 6 carbon atoms, from 1 to 5 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or from 1 to 2 carbon atoms. "C 1-10 Examples of "alkyl" include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. 1-6Examples of "alkyl" are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, and the like.

[0062] As used herein, the term "alkenyl", whether used as part of another term or independently, refers to a straight or branched hydrocarbon group with at least one carbon-carbon double bond that can be optionally independently substituted by one or more substituents described herein and includes groups with "cis" orientation and "trans" orientation or alternatively "E" orientation and "Z" orientation. In some embodiments, the alkenyl contains 2 to 12 carbon atoms. In some embodiments, the alkenyl contains 2 to 11 carbon atoms. In some embodiments, the alkenyl contains 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, the alkenyl contains 2 carbon atoms. Examples of alkenyl include but are not limited to vinyl (ethylenyl or vinyl), propenyl (allyl), butenyl, pentenyl, 1-methyl-2-butene-1-yl, 5-hexenyl, etc.

[0063] As used herein, the term "alkynyl", whether used as part of another term or independently, refers to a straight or branched hydrocarbon group with at least one carbon-carbon triple bond that can be optionally independently substituted by one or more substituents described herein. In some embodiments, alkenyl contains 2 to 12 carbon atoms. In some embodiments, alkynyl contains 2 to 11 carbon atoms. In some embodiments, alkynyl contains 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, alkynyl contains 2 carbon atoms. Examples of alkynyl include but are not limited to ethynyl, 1-propynyl, 2-propynyl, etc.

[0064] As used herein, the term "cycloalkyl", whether used as part of another term or independently, refers to a monovalent non-aromatic saturated or partially unsaturated monocyclic and polycyclic system, wherein all ring atoms are carbon, and the system contains at least three ring-forming carbon atoms. In some embodiments, the cycloalkyl may contain 3 to 12 ring-forming carbon atoms, 3 to 10 ring-forming carbon atoms, 3 to 9 ring-forming carbon atoms, 3 to 8 ring-forming carbon atoms, 3 to 7 ring-forming carbon atoms, 3 to 6 ring-forming carbon atoms, 3 to 5 ring-forming carbon atoms, 4 to 12 ring-forming carbon atoms, 4 to 10 ring-forming carbon atoms, 4 to 9 ring-forming carbon atoms, 4 to 8 ring-forming carbon atoms, 4 to 7 ring-forming carbon atoms, 4 to 6 ring-forming carbon atoms, 4 to 5 ring-forming carbon atoms. Cycloalkyl can be saturated or partially unsaturated. Cycloalkyl can be substituted. In some embodiments, cycloalkyl can be a saturated cyclic alkyl. In some embodiments, cycloalkyl can be a partially unsaturated cyclic alkyl containing at least one double bond or triple bond in its ring system. In some embodiments, cycloalkyl can be monocyclic or polycyclic. Examples of monocyclic cycloalkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. Examples of polycyclic cycloalkyl include but are not limited to adamantyl, norbornyl, fluorenyl, spiro-pentadienyl, spiro[3.6]-decyl, bicyclo[1,1,1]pentenyl, bicyclo[2,2,1]heptenyl, etc.

[0065] As used herein, the term "cyano" refers to -CN.

[0066] As used herein, the term "halogen" refers to an atom selected from fluorine (fluorine or fluoro), chlorine (chlorine or chloro), bromine (bromine or bromo), and iodine (iodine or iodo).

[0067] As used herein, the term "haloalkyl" refers to an alkyl group as defined above that is substituted with one or more halogens as defined above. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0068] As used herein, the term "heteroatom" refers to nitrogen, oxygen, sulfur, or phosphorus, and includes any oxidized form of the nitrogen or sulfur and any quaternized form of a basic nitrogen (including N-oxides).

[0069] As used herein, the term "heteroaryl", whether used as part of another term or independently, refers to an aryl having one or more heteroatoms in addition to a carbon atom. Heteroaryl can be monocyclic. Examples of monocyclic heteroaryl include, but are not limited to, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, benzofuranyl and pteridinyl. Heteroaryl also includes a polycyclic group to which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic or heterocyclic rings, wherein a linking group or a point of attachment is located on the heteroaromatic ring. Examples of polycyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, benzothiophenyl, benzofuranyl, benzo[1,3]dioxolyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, dihydroquinolyl, dihydroisoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, and the like.

[0070] As used herein, the term "heterocyclic group" refers to a saturated or partially unsaturated carbocyclic group, wherein one or more ring atoms are heteroatoms independently selected from oxygen, sulfur, nitrogen, phosphorus, etc., and the remaining ring atoms are carbon, wherein one or more ring atoms can be optionally substituted independently by one or more substituents. In some embodiments, the heterocyclic group is a saturated heterocyclic group. In some embodiments, the heterocyclic group is a partially unsaturated heterocyclic group with one or more double bonds in its ring system. In some embodiments, the heterocyclic group can contain any oxidized form of carbon, nitrogen or sulfur and any quaternized form of basic nitrogen. "Heterocyclic group" also includes a group in which a heterocyclic group is fused with a saturated, partially unsaturated or completely unsaturated (i.e., aromatic) carbocyclic or heterocyclic ring. Where possible, the heterocyclic group can be connected to carbon or nitrogen. In some embodiments, the heterocyclic ring is connected to carbon. In some embodiments, the heterocyclic ring is connected to nitrogen. For example, the group derived from pyrrole can be pyrrole-1-yl (nitrogen connected) or pyrrole-3-yl (carbon connected). Furthermore, the group derived from imidazole may be imidazol-1-yl (nitrogen attached) or imidazol-3-yl (carbon attached).

[0071] In some embodiments, the term "3 to 12 membered heterocyclyl" refers to a 3 to 12 membered saturated or partially unsaturated monocyclic or polycyclic heterocyclic ring system having 1 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur. Fused, spiro and bridged ring systems are also included within the scope of this definition. Examples of monocyclic heterocyclyls include, but are not limited to, oxetane, 1,1-dioxothietane pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, piperidinyl, piperazinyl, piperidinyl, morpholinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyridonyl, pyrimidonyl, pyrazinonyl, pyrimidonyl, pyridazinonyl, pyrrolidinyl, triazinonyl, etc. Examples of fused heterocyclic groups include, but are not limited to, phenyl fused rings or pyridyl fused rings, such as quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, quinoxalinyl, quinolizinyl, quinazolinyl, azaindolizinyl, pteridinyl, chromenyl, isochromenyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothiophenyl, benzothiazolyl, carbazolyl, phenazinyl, phenothiazinyl, phenanthridinyl, imidazo[1,2-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,3]triazolo[4,3-a]pyridinyl, etc. Examples of spiro heterocyclic groups include, but are not limited to, spiropyranyl, spirooxazinyl, etc. Examples of bridged heterocyclic groups include, but are not limited to, morphinyl, hexamethylenetetraminyl, 3-aza-bicyclo[3.1.0]hexane, 8-aza-bicyclo[3.2.1]octane, 1-aza-bicyclo[2.2.2]octane, 1,4-diazabicyclo[2.2.2]octane (DABCO), and the like.

[0072] As used herein, the term "hydroxy" refers to -OH.

[0073] As used herein, the term "partially unsaturated" refers to a group that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aromatic (ie, fully unsaturated) moieties.

[0074] As used herein, the term "substituted", whether or not there is the term "optionally" in front, means that one or more hydrogens of the specified part are replaced by suitable substituents. It should be understood that "substituted" or "substituted by..." includes implicit prerequisites, that is, such substitutions are consistent with the allowed valence of the substituted atom, and the substitution produces a stable or chemically feasible compound, for example, a compound that does not spontaneously undergo transformations such as rearrangement, cyclization, elimination, etc. Unless otherwise specified, the "optionally substituted" group can have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted by more than one substituent selected from a specified group, at each position, the substituent can be the same or different. It will be understood by those skilled in the art that the substituent itself can be substituted if appropriate. Unless specifically stated as "unsubstituted", the reference to the chemical part herein should be understood to include substituted variants. For example, the reference to the "aryl" group or part implicitly includes both substituted variants and unsubstituted variants.

[0075] Compound

[0076] The present disclosure provides novel compounds of formula (I) and pharmaceutically acceptable salts thereof, synthetic methods for preparing the compounds, and pharmaceutical compositions containing the same and various uses of the disclosed compounds.

[0077] In one aspect, the present disclosure provides a compound having formula (I):

[0078]

[0079] or a pharmaceutically acceptable salt thereof,

[0080] in

[0081] Ring A is absent or is a 3- to 6-membered cycloalkyl group, a 5- to 6-membered heterocyclyl group, or a 5- to 6-membered heteroaryl group;

[0082] V is a direct bond, a carbonyl group or optionally substituted by one or more R c Substituted alkyl;

[0083] W and L are each independently a direct bond, -O-, -S- or -N(R a )-;

[0084] R 1 is alkyl, cyano, -S(O)2CH3 or -S(O)(NH)CH3;

[0085] R 2 is hydrogen, halogen or optionally substituted by one or more R b Substituted alkyl;

[0086] Ring B is

[0087] R 5 is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, and haloalkyl;

[0088] R a is hydrogen or alkyl;

[0089] R b is hydroxyl or halogen;

[0090] R c is hydroxy, halogen or alkyl;

[0091] n is 0, 1, 2 or 3.

[0092] In some embodiments, V is a direct bond.

[0093] In some embodiments, V is carbonyl.

[0094] In some embodiments, V is optionally substituted with one or more R c In certain embodiments, V is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 alkyl.

[0095] In some embodiments, Ring A is absent.

[0096] In some embodiments, Ring A is a 3- to 6-membered cycloalkyl.

[0097] In certain embodiments, Ring A is cyclopropyl. In certain embodiments, Ring A is

[0098] In certain embodiments, Ring A is cyclopentyl. In certain embodiments, Ring A is

[0099] In certain embodiments, Ring A is cyclohexyl. In certain embodiments, Ring A is

[0100] In some embodiments, Ring A is a 5- to 6-membered heterocyclyl.

[0101] In certain embodiments, Ring A is a 5-membered heterocyclyl containing at least one nitrogen atom. In certain embodiments, Ring A is a 5-membered heterocyclyl containing at least two nitrogen atoms. In certain embodiments, Ring A is a 5-membered heterocyclyl containing two nitrogen atoms.

[0102] In some embodiments, Ring A is pyrazolyl.

[0103] In certain embodiments, Ring A is a 6-membered heterocyclyl.

[0104] In some embodiments, Ring A is tetrahydropyranyl.

[0105] In some embodiments, Ring A is a 5- to 6-membered heteroaryl.

[0106] In certain embodiments, Ring A is a 5- to 6-membered heteroaryl group containing at least one nitrogen atom.

[0107] In certain embodiments, Ring A is a 5-membered heteroaryl group containing at least one nitrogen atom. In certain embodiments, Ring A is a 5-membered heteroaryl group containing at least one nitrogen atom and an additional heteroatom selected from O, N or S. In certain embodiments, Ring A is thiazolyl, triazolyl or isoxazolyl.

[0108] In certain embodiments, Ring A is a 6-membered heteroaryl group containing at least one nitrogen atom. In certain embodiments, Ring A is a 6-membered heteroaryl group containing at least one nitrogen atom and an additional heteroatom selected from O, N or S. In certain embodiments, Ring A is pyridyl.

[0109] In some embodiments, W is a direct bond.

[0110] In some embodiments, W is -N(R a )-.

[0111] In certain embodiments, W is -N(R a )-, and R a For hydrogen.

[0112] In certain embodiments, W is -N(R a )-, and R a In certain embodiments, W is -N(R a )-, and R a C 1-3 In certain embodiments, W is -N(R a )-, and R a It is methyl.

[0113] In some embodiments, Ring A is 3- to 6-membered cycloalkyl, 5- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl, and W is a direct bond.

[0114] In some embodiments, Ring A is absent and W is -N(R a )-.

[0115] In some embodiments, Ring A is absent, W is -N(R a )-, and R a For hydrogen.

[0116] In certain embodiments, Ring A is absent, W is -N(R a )-, and R a In certain embodiments, Ring A is absent, and W is -N(R a )-, and R a C 1-3 In certain embodiments, Ring A is absent, W is -N(R a )-, and R a It is methyl.

[0117] In some embodiments, Ring A is absent and W is a direct bond.

[0118] In some embodiments, R 1 It is an alkyl group.

[0119] In some embodiments, R 1 C 1-3 alkyl.

[0120] In some embodiments, R 1 It is cyano.

[0121] In some embodiments, R 1 It is hydroxyl.

[0122] In some embodiments, R 1 It is -S(O)2CH3.

[0123] In some embodiments, R 1 is –S(O)(NH)CH3.

[0124] In some embodiments, Ring A is absent and R 1 It is cyano or -S(O)2CH3.

[0125] In some embodiments, Ring A is a 3- to 6-membered cycloalkyl, a 5- to 6-membered heterocyclyl, or a 5- to 6-membered heteroaryl, and R 1 It is alkyl, hydroxy, -S(O)2CH3 or -S(O)(NH)CH3.

[0126] In some embodiments, Ring A is cyclopropyl, cyclohexyl, tetrahydropyranyl, thiazolyl, pyridyl, or isoxazolyl, and R 1 It is -S(O)2CH3 or -S(O)(NH)CH3.

[0127] In some embodiments, Ring A is cyclopropyl, R 1 is -S(O)2CH3 or -S(O)(NH)CH3. In some embodiments, Ring A is R1 It is -S(O)2CH3 or -S(O)(NH)CH3.

[0128] In certain embodiments, Ring A is cyclopropyl, R 1 is -S(O)2CH3 or -S(O)(NH)CH3, and n is 1. In certain embodiments, Ring A is R 1 is -S(O)2CH3 or -S(O)(NH)CH3, and n is 1.

[0129] In certain embodiments, Ring A is cyclopropyl, W is a direct bond, R 1 is -S(O)2CH3 or -S(O)(NH)CH3, and n is 1. In certain embodiments, Ring A is W is a direct key, R 1 is -S(O)2CH3 or -S(O)(NH)CH3, and n is 1.

[0130] In some embodiments, for

[0131] In some embodiments, Ring A is cyclopentyl, and R 1 In certain embodiments, Ring A is And R 1 In certain embodiments, Ring A is R 1 is cyano, and n is 1.

[0132] In certain embodiments, Ring A is cyclopentyl, W is a direct bond, R 1 is cyano, and n is 1. In certain embodiments, Ring A is W is a direct key, R 1 is cyano, and n is 1.

[0133] In some embodiments, for

[0134] In some embodiments, Ring A is cyclohexyl, and R 1 In certain embodiments, Ring A is And R 1 In certain embodiments, Ring A is R 1 is cyano, and n is 1.

[0135] In certain embodiments, Ring A is cyclopentyl, W is a direct bond, R 1is cyano, and n is 1. In certain embodiments, Ring A is W is a direct key, R 1 is cyano, and n is 1.

[0136] In some embodiments, for

[0137] In some embodiments, Ring A is a 5-membered heterocyclyl, and R 1 It is an alkyl group.

[0138] In some embodiments, Ring A is pyrazolyl, isoxazolyl or triazolyl, and R 1 C 1-3 alkyl.

[0139] In some embodiments, Ring A is pyrazolyl, isoxazolyl or triazolyl, and R 1 In certain embodiments, Ring A is pyrazolyl, isoxazolyl or triazolyl, R 1 is methyl, and n is 2.

[0140] In some embodiments, Ring A is pyrazolyl, isoxazolyl or triazolyl, W is a direct bond, and R 1 In certain embodiments, Ring A is pyrazolyl, isoxazolyl or triazolyl, W is a direct bond, R 1 is methyl, and n is 2.

[0141] In some embodiments, for

[0142] In some embodiments, Ring A is a 5- to 6-membered heteroaryl group, and R 1 It is -S(O)2CH3.

[0143] In certain embodiments, Ring A is thiazolyl or pyridinyl, and R 1 In certain embodiments, Ring A is thiazolyl or pyridyl, R 1 is -S(O)2CH3, and n is 1.

[0144] In certain embodiments, Ring A is thiazolyl or pyridyl, W is a direct bond, and R 1 In certain embodiments, Ring A is thiazolyl or pyridyl, W is a direct bond, R 1 is -S(O)2CH3, and n is 1.

[0145] In some embodiments, for

[0146] In some embodiments, L is a bond.

[0147] In some embodiments, L is -O-.

[0148] In some embodiments, L is -S-.

[0149] In some embodiments, L is -N(R a )-.

[0150] In certain embodiments, R a For hydrogen.

[0151] In certain embodiments, R a C 1-3 alkyl.

[0152] In some embodiments, Ring B is

[0153] In some embodiments, L is -O-, -S-, or -N(R a )-, and ring B is

[0154] In certain embodiments, L is -O-, and Ring B is

[0155] In certain embodiments, L is -S-, and Ring B is

[0156] In certain embodiments, L is -N(R a )-,R a is hydrogen, and Ring B is

[0157] In certain embodiments, L is -N(R a )-,R a is hydrogen, and ring B is

[0158] In some embodiments, R 2 For hydrogen.

[0159] In some embodiments, R 2 In certain embodiments, R 2 is fluorine, chlorine or bromine. In certain embodiments, R 2 For fluorine.

[0160] In some embodiments, R 2 For one or more R b In certain embodiments, R 2 For one or more R bSubstituted C 1-3 alkyl.

[0161] In some embodiments, R 2 For one or more R b substituted alkyl, and R b is hydroxyl or fluorine. In certain embodiments, R 2 For one or more R b Substituted C 1-3 Alkyl, and R b is hydroxy or fluorine.

[0162] In some embodiments, R 2 It is -CH2OH or -CH2F.

[0163] In some embodiments, the present disclosure provides a compound having formula (II) or formula (III):

[0164]

[0165]

[0166] Among them, V, W, L, ring A, ring B, R 1 and R 2 As defined above.

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

[0168]

[0169] as well as

[0170]

[0171] or a pharmaceutically acceptable salt thereof, wherein

[0172] U is O or NH;

[0173] V is a direct bond, a carbonyl group or optionally substituted by one or more R c Substituted alkyl;

[0174] W and L are each independently -O-, -S- or -N(R a )-;

[0175] R 1 is an alkyl group;

[0176] R 2 is hydrogen, halogen or is replaced by one or more R b Substituted alkyl;

[0177] R 3 is a halogen;

[0178] R 5 is hydrogen or alkyl;

[0179] R a is hydrogen or alkyl;

[0180] R b is hydroxy or halogen; and

[0181] R c is hydroxy, halogen or alkyl.

[0182] In some embodiments, the present disclosure provides a compound having a formula selected from the group consisting of:

[0183]

[0184]

[0185]

[0186] or a pharmaceutically acceptable salt thereof.

[0187] In a further aspect, the present disclosure provides a compound having formula (V):

[0188]

[0189] or a pharmaceutically acceptable salt thereof,

[0190] in

[0191] Ring A is absent or is a 3- to 6-membered cycloalkyl group, a 5- to 6-membered heterocyclyl group, or a 5- to 6-membered heteroaryl group;

[0192] Q is a direct bond or optionally substituted by one or more R d Substituted alkyl;

[0193] L is -O-, -S- or -N(R a )-;

[0194] Ring B is

[0195] R d is hydrogen or alkyl;

[0196] R d is hydroxy, halogen or alkyl;

[0197] R 1 Selected from the group consisting of cyano, hydroxy, halogen, -S(O)2CH3 and -S(O)(NH)CH3;

[0198] R 5 is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, and haloalkyl;

[0199] n is 0, 1, 2 or 3.

[0200] In some embodiments, Q is a direct bond.

[0201] In some embodiments, Q is alkyl. In certain embodiments, Q is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 alkyl.

[0202] In some embodiments, Ring A is a 3- to 6-membered cycloalkyl. In some embodiments, Ring A is a cyclopropyl. In some embodiments, Ring A is

[0203] In some embodiments, Ring A is absent.

[0204] In some embodiments, Ring A is a 5- to 6-membered heterocyclyl. In certain embodiments, Ring A is a tetrahydropyranyl.

[0205] In certain embodiments, Ring A is

[0206] In some embodiments, Q is alkyl, and Ring A is absent.

[0207] In some embodiments, Q is a direct bond, and Ring A is a 3- to 6-membered cycloalkyl or a 5- to 6-membered heterocyclyl.

[0208] In some embodiments, R 1 It is -S(O)2CH3 or -S(O)(NH)CH3.

[0209] In some embodiments, R 1 is cyano, hydroxy or halogen.

[0210] In some embodiments, Ring A is absent or is a 3- to 6-membered cycloalkyl or a 5- to 6-membered heterocyclyl, and R 1 It is -S(O)2CH3 or -S(O)(NH)CH3.

[0211] In some embodiments, Ring A is absent or is a 3- to 6-membered cycloalkyl group, and R 1 is cyano, hydroxy or halogen.

[0212] In some embodiments, L is -O-.

[0213] In some embodiments, L is -S-.

[0214] In some embodiments, L is -N(R a )-, and R a For hydrogen.

[0215] In some embodiments, Ring B is

[0216] In some embodiments, R 5 is hydrogen or alkyl.

[0217] In some embodiments, the present disclosure provides a compound having a formula selected from the group consisting of:

[0218]

[0219]

[0220] or a pharmaceutically acceptable salt thereof.

[0221] Table 1 below sets forth exemplary compounds of the present disclosure.

[0222] Table 1

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231] The compounds provided herein are described with reference to general formulae and specific compounds. In addition, the compounds of the present disclosure may exist in a variety of different forms or derivatives, including but not limited to prodrugs, soft drugs, active metabolic derivatives (active metabolites) and pharmaceutically acceptable salts thereof, all of which are within the scope of the present disclosure.

[0232] As used herein, the term "prodrug" refers to a compound or a pharmaceutically acceptable salt thereof that produces a desired active compound when metabolized or converted by a solvolysis reaction under physiological conditions. Prodrugs include, but are not limited to, esters, amides, carbamates, carbonates, ureides, solvates or hydrates of active compounds. Typically, prodrugs are inactive or less active than active compounds, but can provide one or more favorable disposal, administration and / or metabolic properties. For example, some prodrugs are esters of active compounds; during metabolism, the ester group is cleaved to produce an active drug. In addition, some prodrugs are enzymatically activated to produce active compounds or compounds that produce active compounds after further chemical reactions. Prodrugs can be developed from prodrug forms to active forms in a single step, or can have one or more intermediate forms that can be active or inactive themselves. The preparation and use of prodrugs are discussed in the following references: T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems", Volume 14 of the ACS Symposium Series, "Bioreversible Carriers in Drug Design", ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987; "Prodrugs: Challenges and Rewards", ed. V. Stella, R. Borchardt, M. Hageman, R. Oliyai, H. Maag, J. Tilley, Springer-Verlag New York, 2007, which are hereby incorporated by reference in their entirety.

[0233] As used herein, the term "soft drug" refers to a compound that exerts a pharmacological effect but decomposes into inactive metabolites and degradation products, resulting in a limited active time. See, for example, "Soft drugs: Principles and methods for the design of safe drugs", Nicholas Bodor, "Medicinal Research Reviews", Vol. 4, No. 4, 449-469, 1984, which is hereby incorporated by reference in its entirety.

[0234] As used herein, the term "metabolite", such as an active metabolite, overlaps with a prodrug as described above. Therefore, such metabolites are pharmacologically active compounds or compounds that are further metabolized to pharmacologically active compounds, which are derivatives produced by metabolic processes in the subject. For example, such metabolites can be produced by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound or salt or prodrug. Among them, active metabolites are such pharmacologically active derivative compounds. For prodrugs, prodrug compounds are generally inactive or less active than metabolites. For active metabolites, the parent compound can be an active compound or can be an inactive prodrug.

[0235] Prodrugs and active metabolites can be identified using conventional techniques known in the art. See, for example, Bertolini et al., 1997, J Med Chem 40:2011-2016; Shan et al., JP Harm Sci 86:756-757; Bagshawe, 1995, Drug Dev Res 34:220-230; Wermuth, supra.

[0236] As used herein, the term "pharmaceutically acceptable" indicates that a substance or composition is chemically and / or toxicologically compatible with the other ingredients making up the formulation and / or the subject being treated.

[0237] As used herein, unless otherwise indicated, the term "pharmaceutically acceptable salt" includes salts that retain the biological effectiveness of the free acids and bases of the specified compound and are not biologically or otherwise undesirable. Pharmaceutically acceptable salt forms contemplated include, but are not limited to, monosalts, disalts, trisalts, tetrasalts, etc. Pharmaceutically acceptable salts are nontoxic in the amount and concentration in which they are administered. The preparation of such salts can promote pharmacological use by changing the physical properties of the compound without hindering it from exerting its physiological effects. Useful changes in physical properties include lowering the melting point to facilitate transmucosal administration and increasing solubility to facilitate administration of higher concentrations of drugs.

[0238] Pharmaceutically acceptable salts include acid addition salts, such as those containing the following acid addition salts: sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate. Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamate, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamate, fumaric acid and quinic acid.

[0239] When an acidic functional group such as carboxylic acid or phenol is present, pharmaceutically acceptable salts also include base addition salts, such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, tert-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamines, and zinc. For example, see Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Co., Easton, PA, Vol. 2, p. 1457, 1995; Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Stahl and Wermuth, Wiley-VCH, Weinheim, Germany, 2002. Such salts can be prepared using the appropriate corresponding bases.

[0240] Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the free base form of the compound can be dissolved in a suitable solvent (such as an aqueous or aqueous-alcoholic solution containing an appropriate acid) and then separated by evaporating the solution. Therefore, if the particular compound is a base, the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art, for example, by treating the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; or an organic acid such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid; pyranosyl acids such as glucuronic acid or galacturonic acid; α-hydroxy acids such as citric acid or tartaric acid; amino acids such as aspartic acid or glutamic acid; aromatic acids such as benzoic acid or cinnamic acid; sulfonic acids such as p-toluenesulfonic acid or ethanesulfonic acid; and the like.

[0241] Similarly, if the particular compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, by treating the free acid with an inorganic or organic base such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or an alkaline earth metal hydroxide, etc. Illustrative examples of suitable salts include organic salts derived from amino acids such as L-glycine, L-lysine and L-arginine, ammonia, primary, secondary and tertiary amines, and cyclic amines such as hydroxyethylpyrrolidine, piperidine, morpholine or piperazine; and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

[0242] It will also be understood that the compounds of the present disclosure may exist in unsolvated forms, solvated forms (eg, hydrated forms), and solid forms (eg, crystalline forms or polymorphic forms), and that the present disclosure is intended to encompass all such forms.

[0243] As used herein, the term "solvate" or "solvated form" refers to a solvent addition form containing a stoichiometric or non-stoichiometric amount of a solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thereby forming a solvate. If the solvent is water, the solvate formed is a hydrate, and if the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by combining one or more water molecules with a molecule of a substance while maintaining their molecular state as H2O. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

[0244] As used herein, the terms "crystal form", "crystalline form", "polymorphic form" and "polymorph" are used interchangeably and refer to crystal structures in which a compound (or its salt or solvate) can be crystallized in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvents, crystallization rates, storage temperatures and other factors may cause one crystal form to dominate. Polymorphs of a compound can be prepared by crystallization under different conditions.

[0245] Depending on the substituent selection, the compounds of the present disclosure may include one or more asymmetric centers, and therefore may exist in various stereoisomeric forms, for example, enantiomers and / or diastereomers. For example, the compounds provided herein may have an asymmetric carbon center, and therefore the compounds provided herein may have (R) or (S) stereo configuration at the carbon asymmetric center. Therefore, the compounds of the present disclosure may be in the form of a single enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers.

[0246] As used herein, the term "enantiomer" refers to two stereoisomers of a compound that are non-superimposable mirror images of each other. The term "diastereomer" refers to a pair of optical isomers that are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity.

[0247] When a particular enantiomer is preferred, it can be provided in some embodiments as being substantially free of the relative enantiomer, and can also be referred to as "optically enriched". As used herein, "optically enriched" means that the compound is composed of a significantly larger proportion of one enantiomer. In certain embodiments, the compound is composed of at least about 90% by weight of the preferred enantiomer. In other embodiments, the compound is composed of at least about 95%, 98%, or 99% by weight of the preferred enantiomer. The preferred enantiomer can be separated from the racemic mixture by any method known to those skilled in the art, such as by chromatography or crystallization, by synthesizing using stereochemically uniform starting materials, or by stereoselective synthesis. Optionally, derivatization can be performed before separating stereoisomers. The separation of a mixture of stereoisomers can be performed during the synthesis of the compounds provided herein at an intermediate step or it can be performed on the final racemic product. Absolute stereochemistry can be determined by X-ray crystallography of a crystalline product or a crystalline intermediate, which, if necessary, is derivatized with a reagent containing a stereocenter of a known configuration. Alternatively, absolute stereochemistry can be determined by vibrational circular dichroism (VCD) spectral analysis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, SH et al., Tetrahedron 33:2725 (1977); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolutions, p. 268 (ELiel, ed., Univ. of Notre Dame Press, IN, 1972).

[0248] In some embodiments, a mixture of diastereomers is provided, such as a mixture of diastereomers enriched in 51% or more of one of the diastereomers, including, for example, 60% or more, 70% or more, 80% or more, or 90% or more of one of the diastereomers.

[0249] In some embodiments, unless otherwise indicated, the compounds provided herein may have one or more double bonds that exist as Z or E isomers. In addition, the disclosure encompasses compounds in the form of individual isomers that are substantially free of other isomers and, alternatively, in the form of mixtures of multiple isomers (e.g., racemic mixtures of enantiomers).

[0250] Compounds of the present disclosure may also exist in different tautomeric forms, and all such forms are encompassed within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can be mutually converted by low energy barriers. For example, proton tautomers (also referred to as prototropic tautomers) include mutual conversions by proton migration, such as keto-enol, amide-imidic acid, lactam-lactim, imine-enamine isomerization, and protons can occupy two or more positions of heterocyclic systems in cyclic forms (e.g., 1H- and 3H-imidazoles, 1H-, 2H- and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, and 1H- and 2H-pyrazoles). Valence tautomers include mutual conversions by the reorganization of some bonding electrons. Tautomers can be in equilibrium or spatially locked into a form by appropriate substitution. Unless otherwise stated, compounds disclosed herein identified by name or structure as one particular tautomeric form are intended to include the other tautomeric forms.

[0251] The present disclosure is also intended to include all isotopes of atoms in the compounds. Isotopes of atoms include atoms having the same atomic number but different mass numbers. For example, unless otherwise specified, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, or iodine in the compounds of the present disclosure are intended to also include their isotopes, such as but not limited to 1 H. 2 H. 3 H. 11 C. 12 C. 13 C. 14 C. 14 N. 15 N. 16 O. 17 O. 18 O. 31 P. 32 P. 32 S. 33 S. 34 S. 36 S. 17 F. 18 F. 19 F. 35 Cl, 37 Cl, 79 Br, 81Br, 124 I. 127 I and 131 I. In some embodiments, hydrogen includes protium, deuterium, and tritium. In some embodiments, carbon includes 12 C and 13 C.

[0252] Synthesis of compounds

[0253] The synthesis of the compounds provided herein including pharmaceutically acceptable salts thereof is described in the synthetic schemes of the embodiments. The compounds provided herein can be prepared using any known organic synthesis techniques and can be synthesized according to any synthetic route in a variety of possible synthetic routes, and therefore these schemes are only illustrative and are not intended to limit other possible methods that can be used to prepare the compounds provided herein. In addition, the steps in these schemes are for better illustration and can be changed as required. The embodiments of the compounds in the embodiments are synthesized for the purpose of research and possible submission to regulatory agencies.

[0254] The reaction for preparing the disclosed compound can be carried out in a suitable solvent that can be easily selected by a technician in the field of organic synthesis. Suitable solvents can be substantially non-reactive with starting materials (reactants), intermediates or products at a temperature (e.g., a range from the freezing temperature of the solvent to the boiling temperature of the solvent) for the reaction. A given reaction can be carried out in a solvent or a mixture of more than one solvent. According to a specific reaction step, a suitable solvent for a specific reaction step can be selected by a person skilled in the art.

[0255] The preparation of compounds disclosed herein may involve the protection and deprotection of various chemical groups. The demand for protection and deprotection and the selection of appropriate protecting groups can be easily determined by a person skilled in the art. The chemistry of protecting groups can be found in, for example, the following references: TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons Publishing Company, New York, (1999); P. Kocienski, Protecting Groups, Georg Thieme Verlag, 2003; and Peter GMW Wuts, Greene's Protective Groups in Organic Synthesis, 5th edition, Wiley, 2014, the references are incorporated herein by reference in their entirety.

[0256] The reaction can be monitored by any suitable method known in the art. For example, the reaction can be monitored by methods such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible light), mass spectrometry or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS) or thin layer chromatography (TLC) to monitor product formation. Those skilled in the art can purify the compound by various methods, including high performance liquid chromatography (HPLC) ("Preparative LC-MS Purification: Improved Compound Specific Method Optimization" Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs "Journal of Combinatorial Chemistry (J. Combi. Chem.) 2004, 6 (6), 874-883, the reference is incorporated herein by reference in its entirety) and normal phase silica gel chromatography.

[0257] Known starting materials of the present disclosure can be used or synthesized according to methods known in the art, or can be purchased from commercial suppliers. Unless otherwise stated, analytical grade solvents and commercially available reagents were used without further purification.

[0258] Unless otherwise stated, the reactions of the present disclosure were carried out under a positive pressure of nitrogen or argon or in anhydrous solvents using a drying tube, and the reaction flasks were typically equipped with rubber septa for the introduction of substrates and reagents by syringe. Glassware was oven dried and / or heat dried.

[0259] For illustrative purposes, the following examples partially illustrate the synthetic routes for preparing compounds of the present disclosure and key intermediates. It will be appreciated by those skilled in the art that other synthetic routes may be used to synthesize compounds of the present invention. Although specific starting materials and reagents are depicted, other starting materials and reagents may also be easily substituted to provide a variety of derivatives and / or reaction conditions. In addition, according to the present disclosure, conventional chemical methods well known to those skilled in the art may be used to further modify many compounds prepared by the following methods.

[0260] Pharmaceutical composition

[0261] In additional aspects, pharmaceutical compositions are provided comprising one or more molecules or compounds of the present disclosure, or pharmaceutically acceptable salts thereof.

[0262] In another aspect, a pharmaceutical composition is provided, comprising one or more molecules or compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0263] As used herein, the term "pharmaceutical composition" refers to a formulation containing a molecule or compound of the present disclosure in a form suitable for administration to a subject.

[0264] As used herein, the term "pharmaceutically acceptable excipient" means an excipient that can be used to prepare a pharmaceutical composition that is generally safe, non-toxic, and biologically and otherwise desirable, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use. As used herein, a "pharmaceutically acceptable excipient" includes one and more than one such excipient. The term "pharmaceutically acceptable excipient" also encompasses "pharmaceutically acceptable carriers" and "pharmaceutically acceptable diluents."

[0265] The specific excipient used will depend on the means and purpose for which the compounds of the present disclosure are to be applied. Solvents are typically selected based on solvents considered safe by those skilled in the art to be administered to mammals, including humans. Typically, safe solvents are non-toxic aqueous solvents, such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG 400, PEG 300), etc., and mixtures thereof.

[0266] In some embodiments, suitable excipients may include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl alcohol or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins , such as serum albumin, gelatin or immunoglobulin; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates, including glucose, mannose or dextran; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn protein complexes); and / or nonionic surfactants such as TWEEN TM 、PLURONICS TM or polyethylene glycol (PEG).

[0267] In some embodiments, suitable excipients may include one or more stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, aromatics, flavoring agents and other known additives to provide the best presentation of the drug (i.e., the compound of the present disclosure or its pharmaceutical composition) or to help manufacture the drug product (i.e., the drug). The active pharmaceutical ingredient may also be embedded in a microcapsule prepared, for example, by coacervation technology or by interfacial polymerization, such as hydroxymethylcellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in a crude emulsion. Such technology is disclosed in Remington's Pharmaceutical Sciences, 16th edition, Osol, A. Editor (1980). "Liposomes" are small vesicles including various types of lipids, phospholipids and / or surfactants that can be used to deliver drugs (such as compounds disclosed herein and optionally chemotherapeutic agents) to mammals including humans. The components of liposomes are typically arranged in a bilayer formation, similar to the lipid arrangement of biological membranes.

[0268] The pharmaceutical compositions provided herein may be in any form that permits administration of the composition to a subject, including but not limited to humans, and allows formulation of the composition to be compatible with the intended route of administration.

[0269] A variety of approaches have been considered for the pharmaceutical compositions provided herein, and therefore the pharmaceutical compositions provided herein can be supplied in bulk or unit dosage forms depending on the expected route of administration. For example, for oral, buccal and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, soft capsules and caplets can be acceptable as solid dosage forms, and emulsions, syrups, elixirs, suspensions and solutions can be acceptable as liquid dosage forms. For injection administration, emulsions and suspensions can be acceptable as liquid dosage forms, and powders suitable for reconstitution with suitable solutions can be acceptable as solid dosage forms. For inhalation administration, solutions, sprays, dry powders and aerosols can be acceptable dosage forms. For topical (including buccal and sublingual) or transdermal administration, powders, sprays, ointments, pastes, creams, lotions, gels, solutions and patches can be acceptable dosage forms. For vaginal administration, vaginal suppositories, tampons, creams, gels, pastes, foams and sprays can be acceptable dosage forms.

[0270] The amount of active ingredient in the unit dosage form of the composition is a therapeutically effective amount and varies according to the specific treatment involved. As used herein, the term "therapeutically effective amount" refers to the amount of a molecule, compound, or composition comprising the molecule or compound that treats, improves, or prevents an identified disease or condition or shows a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount of the subject will depend on the subject's weight, size, and health; the nature and extent of the condition; the rate of administration; the treatment or therapeutic combination selected for administration; and the judgment of the prescribing physician. The therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician.

[0271] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of oral administration preparations.

[0272] In certain embodiments, the pharmaceutical composition of the present disclosure may be in the form of a tablet formulation. Pharmaceutically acceptable excipients suitable for tablet formulations include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate; granulating agents and disintegrants such as corn starch or alginic acid; binders such as starch; lubricants such as magnesium stearate, stearic acid or talc; preservatives such as ethyl paraben or propyl paraben; and antioxidants such as ascorbic acid. Tablet formulations may be uncoated or coated to regulate their disintegration and subsequent absorption of active ingredients in the gastrointestinal tract, or to improve their stability and / or appearance, in either case, using conventional coating agents and procedures well known in the art.

[0273] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin; or in the form of soft gelatin capsules in which the active ingredient is mixed with water or an oil, such as peanut oil, liquid paraffin or olive oil.

[0274] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of an aqueous suspension, which typically contains the active ingredient in fine powder form and one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum arabic; a dispersant or wetting agent, such as lecithin or a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate); or a condensation product of ethylene oxide with a long chain fatty alcohol, such as heptadecaethyleneoxycetanol; or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, such as polyoxyethylene sorbitan monooleate; or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, such as polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (for example, ethyl or propyl p-hydroxybenzoate), antioxidants (for example, ascorbic acid), coloring agents, flavoring agents and / or sweetening agents (for example, sucrose, saccharin or aspartame).

[0275] In certain embodiments, the pharmaceutical composition of the present disclosure can be in the form of an oily suspension, which generally contains a suspended active ingredient in a vegetable oil (such as peanut oil, castor oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). The oily suspension can also contain a thickener, such as beeswax, hard paraffin or cetyl alcohol. Sweeteners, such as those stated above, and flavorings can be added to provide a palatable oral formulation. These compositions can be preserved by adding an antioxidant (such as ascorbic acid).

[0276] In certain embodiments, the pharmaceutical composition of the present disclosure may be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, such as olive oil or peanut oil; or a mineral oil, such as liquid paraffin; or a mixture of any of these oils. Suitable emulsifiers may be, for example, naturally occurring gums, such as gum arabic or gum tragacanth; naturally occurring phospholipids, such as soybeans, lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate) and condensation products of the partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners, flavorings, and preservatives.

[0277] In certain embodiments, the pharmaceutical compositions provided herein may be in the form of syrups and elixirs, which may contain sweeteners, such as glycerol, propylene glycol, sorbitol, aspartame or sucrose; demulcents; preservatives; flavoring agents and / or coloring agents.

[0278] In some embodiments, the pharmaceutical composition of the present disclosure may be in the form of an injectable formulation.

[0279] In certain embodiments, the pharmaceutical composition of the present disclosure can be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oily suspension. This suspension can be formulated using those suitable dispersants or wetting agents and suspending agents mentioned above according to known techniques. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenteral acceptable diluent or solvent, such as a solution in 1,3-butanediol or prepared as a lyophilized powder. The acceptable vehicles and solvents that can be used include water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils can be used as solvents or suspension media conventionally. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can also be used to prepare injectables.

[0280] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of inhalation administration formulations.

[0281] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of aqueous and non-aqueous (e.g., in fluorocarbon propellants) aerosols containing any suitable solvent and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH adjusters, surfactants, bioavailability modifiers, and combinations thereof. Carriers and stabilizers vary with the requirements of the specific compound, but typically include nonionic surfactants (Tween, Pluronic, or polyethylene glycol), innocuous proteinaceous serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars, or sugar alcohols.

[0282] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of topical or transdermal formulations.

[0283] In certain embodiments, the pharmaceutical compositions provided herein may be in the form of creams, ointments, gels, and aqueous or oily solutions or suspensions, which are generally obtained by formulating the active ingredient with conventional topically acceptable excipients, such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0284] In certain embodiments, the pharmaceutical compositions provided herein may be formulated in the form of transdermal skin patches well known to those of ordinary skill in the art.

[0285] In addition to those representative dosage forms described above, pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are therefore included in the present disclosure. Such excipients and carriers are described in, for example, Remington's Pharmaceutical Sciences, Mark Publishing Company, New Jersey (1991); Remington: The Science and Practice of Pharmacy, ed. University of the Sciences in Philadelphia, 21st ed., LWW (2005), which are incorporated herein by reference.

[0286] In some embodiments, the pharmaceutical compositions of the present disclosure can be formulated into a single dosage form. The amount of the compound provided herein in a single dosage form will vary depending on the subject being treated and the particular mode of administration.

[0287] In some embodiments, the pharmaceutical composition of the present disclosure can be formulated so that 0.001 mg / kg body weight / day to 1000 mg / kg body weight / day, for example, 0.01 mg / kg body weight / day to 800 mg / kg body weight / day, 0.01 mg / kg body weight / day to 700 mg / kg body weight / day, 0.01 mg / kg body weight / day to 600 mg / kg body weight / day, 0.01 mg / kg body weight / day to 500 mg / kg body weight / day, 0.01 mg / kg body weight / day to 400 mg / kg body weight / day, 0.01 mg / kg body weight / day to 300 mg / kg body weight / day, 0.1 mg / kg body weight / day to 200 mg / kg body weight / day, 0.1 mg / kg body weight / day to 150 mg / kg body weight / day, 0.1 mg / kg body weight / day to 200 mg / kg body weight / day kg body weight / day to 100 mg / kg body weight / day, 0.5 mg / kg body weight / day to 100 mg / kg body weight / day, 0.5 mg / kg body weight / day to 80 mg / kg body weight / day, 0.5 mg / kg body weight / day to 60 mg / kg body weight / day, 0.5 mg / kg body weight / day to 50 mg / kg body weight / day, 1 mg / kg body weight / day to 50 mg / kg body weight / day, 1 mg / kg body weight / day to 45 mg / kg body weight / day, 1 mg / kg body weight / day to 40 mg / kg body weight / day, 1 mg / kg body weight / day to 35 mg / kg body weight / day, 1 mg / kg body weight / day to 30 mg / kg body weight / day, 1 mg / kg body weight / day to 25 mg / kg body weight / day of a compound or a pharmaceutically acceptable salt thereof provided herein. In some cases, dosage levels below the lower limit of the aforementioned range may be more than adequate, while in other cases, larger doses may be used without causing any harmful side effects, provided that the larger dose is first divided into several small doses for administration throughout the day. For more information on routes of administration and dosage regimens, see Comprehensive Medicinal Chemistry, Vol. 5, Chapter 25.3 (Corwin Hansch; Chairman of the Editorial Board), Pergamon Press 1990, which reference is specifically incorporated herein by reference.

[0288] In some embodiments, the pharmaceutical compositions of the present disclosure can be formulated into short-acting, fast-release, long-acting and sustained-release forms. Therefore, the pharmaceutical preparations of the present disclosure can also be formulated for controlled release or slow release.

[0289] In a further aspect, a veterinary composition is also provided, comprising one or more molecules or compounds of the present disclosure or a pharmaceutically acceptable salt thereof and a veterinary carrier. A veterinary carrier is a substance that can be used for the purpose of administering the composition, and can be a solid, liquid or gaseous substance that is originally inert or acceptable in the field of veterinary medicine and is compatible with the active ingredient. These veterinary compositions can be administered parenterally, orally or by any other desired route.

[0290] Pharmaceutical compositions or veterinary compositions can be packaged in various ways depending on the method for administering the drug. For example, the article for distribution can include a container in which the composition in appropriate form is stored. Suitable containers are well known to those skilled in the art, and include materials such as bottles (plastic and glass), medicine capsules, ampoules, plastic bags, metal cylinders, etc. The container can also include an anti-disassembly assembly to prevent easy access to the contents of the package. In addition, the container has a label of the contents of the description container placed thereon. The label can also include appropriate warnings. The composition can also be packaged in unit dose or multi-dose containers, such as sealed ampoules and vials, and can be stored under conditions of freeze drying (freeze drying) of water for injection, which only requires the addition of a sterile liquid carrier immediately before use. Extemporaneous injection solutions and suspensions are prepared by sterile powders, granules and tablets of the types described previously.

[0291] In a further aspect, a pharmaceutical composition is also provided, comprising one or more compounds of the present disclosure or a pharmaceutically acceptable salt thereof as a first active ingredient and a second active ingredient.

[0292] In some embodiments, the second active ingredient has complementary activities to the compounds provided herein such that they do not adversely affect each other. Such ingredients are suitably present in combination in amounts effective for the intended purpose.

[0293] In some embodiments, the second active ingredient may include:

[0294] (i) antiproliferative / antineoplastic drugs as used in medical oncology, and combinations thereof, such as alkylating agents (e.g., cis-platin, carboplatin, cyclophosphamide, mechlorethamine, melphalan, chlorambucil, busulphan, and nitrosoureas); antimetabolites (e.g., antifolates, such as fluoropyrimidines (such as 5-fluorouracil and tegafur), raltitrexed, methotrexate, cytarabine, hydroxyurea, and gemcitabine); antitumor antibiotics (e.g., anthracyclines, such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, and sirolimus); antimitotic agents (e.g., vinca alkaloids, such as vincristine, vinblastine, vindesine, and vinorelbine) and taxanes (such as paclitaxel and taxotere); and topoisomerase inhibitors (e.g., epipodophyllotoxins, such as etoposide and teniposide, amsacrine, topotecan, and camptothecins);

[0295] (ii) Cytostatics, such as antiestrogens (e.g., tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), estrogen receptor downregulators (e.g., fulvestrant), antiandrogens (e.g., bicalutamide, flutamide, nilutamide and acetylcholine), cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprorelin, and buserelin), progestins (e.g., megestrol acetate), aromatase inhibitors (e.g., such as anastrozole, letrozole, vorazole, and exemestane), and 5a-reductase inhibitors (e.g., finasteride);

[0296] (iii) anti-invasive agents (e.g., inhibitors of the c-Src kinase family, such as 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (AZD0530) and N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxamide (dasatinib, BMS-354825)) and metalloproteinase inhibitors, such as marimastat and urokinase plasminogen activator receptor function inhibitor);

[0297] (iv) Inhibitors of growth factor function: For example, such inhibitors include growth factor antibodies and growth factor receptor antibodies (e.g., the anti-erbB2 antibody trastuzumab [Herceptin TM] and the anti-erbB1 antibody cetuximab [C225]); such inhibitors also include, for example, tyrosine kinase inhibitors, such as epidermal growth factor family inhibitors (e.g., EGFR family tyrosine kinase inhibitors, such as N-(3-fluoro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD 1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-fluoro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI 1033) and erbB2 tyrosine kinase inhibitors, such as lapatinib), hepatocyte growth factor family inhibitors, platelet-derived growth factor family inhibitors, such as imatinib, serine / threonine kinase inhibitors (e.g., Ras / Raf signaling inhibitors, such as farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006)), and inhibitors of cell signaling through MEK and / or Akt kinases;

[0298] (v) anti-angiogenic agents, such as anti-angiogenic agents that inhibit the action of vascular endothelial growth factor [e.g., the anti-vascular endothelial growth factor antibody bevacizumab (Avastin TM ) and VEGF receptor tyrosine kinase inhibitors, such as 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (ZD6474; Example 2 in WO 01 / 32651), 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (AZD2171; Example 240 in WO 00 / 47212), vatalanib (PTK787; WO 98 / 35985) and SU11248 (sunitinib; WO 01 / 60814), as well as compounds acting by other mechanisms (e.g., linomide, inhibitors of integrin αvβ3 function and angiostatin)];

[0299] (vi) vascular damaging agents, such as combretastatin A4 and compounds disclosed in International Patent Applications WO 99 / 02166, WO 00 / 40529, WO 00 / 41669, WO 01 / 92224, WO 02 / 04434 and WO 02 / 08213;

[0300] (vii) antisense therapy, such as ISIS2503, an anti-ras antisense agent;

[0301] (viii) gene therapy approaches, including, for example, approaches to replace abnormal genes, such as abnormal p53 or abnormal BRCA1 or BRCA2, GDEPT (gene directed enzyme prodrug therapy) approaches, such as those using cytosine deaminase, thymidine kinase or bacterial nitroreductase, and approaches to increase patient tolerance to chemotherapy or radiation therapy, such as multidrug resistance gene therapy; and

[0302] (ix) Immunotherapeutic methods, including ex vivo and in vivo methods to increase the immunogenicity of a patient's tumor cells (e.g., transfection with cytokines (e.g., interleukin 2, interleukin 4, or granulocyte-macrophage colony stimulating factor)), methods to reduce T-cell anergy, methods using transfected immune cells (e.g., cytokine-transfected dendritic cells), methods using cytokine-transfected tumor cell lines, and methods using anti-idiotypic antibodies.

[0303] Methods of treating diseases

[0304] In one aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is capable of inhibiting ATR kinase. The inhibitory properties of the compound of formula (I) can be demonstrated using the test procedures described herein.

[0305] Thus, the compounds of formula (I) may be used to treat (therapeutically or prophylactically) a condition or disease mediated by ATR kinase in a subject.

[0306] As used herein, "subject" refers to humans and non-human animals. Examples of non-human animals include all vertebrates, for example, mammals, such as non-human primates (especially higher primates), dogs, rodents (e.g., mice or rats), guinea pigs, cats; and non-mammals, such as birds, amphibians, reptiles, etc. In a preferred embodiment, the subject is a human. In another embodiment, the subject is an experimental animal or an animal suitable as a disease model.

[0307] In some embodiments, the compounds of formula (I) can be used as anti-tumor agents. In some embodiments, the compounds of formula (I) can be used as antiproliferative agents, apoptotic agents and / or anti-invasive agents to inhibit and / or treat solid and / or liquid tumor diseases. In certain embodiments, the compounds of formula (I) can be used to prevent or treat those tumors that are sensitive to inhibition of ATR. In certain embodiments, the compounds of formula (I) can be used to prevent or treat those tumors mediated alone or in part by ATR.

[0308] In some embodiments, the compounds of formula (I) can be used to treat proliferative diseases, including malignant diseases (such as cancer) and non-malignant diseases, such as inflammatory diseases, obstructive airway diseases, immune diseases or cardiovascular diseases.

[0309] In some embodiments, the compounds of formula (I) can be used to treat cancers, such as, but not limited to, hematological malignancies (e.g., leukemias, multiple myeloma), lymphomas (e.g., Hodgkin's disease, non-Hodgkin's lymphomas (including mantle cell lymphoma)) and myelodysplastic syndrome, as well as solid tumors and their metastases (e.g., breast cancer, lung cancer (non-small cell lung cancer (NSCL), small cell lung cancer (SCLC), squamous cell carcinoma), endometrial carcinoma), central nervous system tumors (e.g., gliomas, dysembryoplastic neuroepithelial tumors, glioblastoma multiforme, mixed gliomas, medulloblastomas, retinoblastomas, neuroblastomas, germ cell tumors and teratomas), Gastrointestinal cancers (e.g., stomach cancer, esophageal cancer, hepatocellular (liver) cancer, bile duct cancer, colon and rectal cancer, small intestine cancer, pancreatic cancer), skin cancers (e.g., melanoma (especially metastatic melanoma)), thyroid cancer, head and neck cancer, and salivary gland cancer, prostate cancer, testicular cancer, ovarian cancer, cervical cancer, uterine cancer, vaginal cancer, bladder cancer, kidney cancer (including renal cell carcinoma, clear cell and renal oncocytoma)), squamous cell carcinoma, sarcomas (e.g., osteosarcoma, chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, Ewing's sarcoma, gastrointestinal stromal tumor (GIST), Kaposi's sarcoma) and pediatric cancers (e.g., rhabdomyosarcoma and neuroblastoma).

[0310] In some embodiments, the compounds of formula (I) can be used to treat autoimmune and / or inflammatory diseases, such as, but not limited to, allergies, Alzheimer's disease, acute disseminated encephalomyelitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome, asthma, atherosclerosis, autoimmune hemolytic anemia, autoimmune hemolytic and thrombocytopenic states, autoimmune hepatitis, autoimmune inner ear disease, bullous pemphigoid, celiac disease, chagas disease, chronic obstructive pulmonary disease, chronic idiopathic thrombocytopenic purpura (ITP), churg-strauss syndrome, Crohn's disease, dermatomyositis, type 1 diabetes, endometriosis, Goodpasture's syndrome, syndrome (and associated glomerulonephritis and pulmonary hemorrhage), Graves' disease, Guillain-Barré syndrome, Hashimoto's disease, hidradenitis suppurativa, idiopathic thrombocytopenic purpura, interstitial cystitis, irritable bowel syndrome, lupus erythematosus, morphea, multiple sclerosis, myasthenia gravis, narcolepsy, neuromyotonia, Parkinson's disease, pemphigus vulgaris, pernicious anemia, polymyositis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, schizophrenia, septic shock, scleroderma, Sjogren's disease disease), systemic lupus erythematosus (and related glomerulonephritis), temporal arteritis, tissue transplant rejection and hyperacute rejection of transplanted organs, vasculitis (ANCA-associated vasculitis and other vasculitis), vitiligo, and Wegener's granulomatosis.

[0311] As used herein, the term "therapy" is intended to have its normal meaning, that is, to treat a disease so as to fully or partially alleviate one, some or all of its symptoms, or to correct or compensate for potential pathology, thereby achieving a beneficial or desired clinical outcome. For the purposes of this disclosure, beneficial or desired clinical outcomes include, but are not limited to, relief of symptoms, alleviation of disease extent, stabilization of disease state (i.e., no deterioration), delay or slowing of disease progression, improvement or alleviation of disease state, and relief (whether partial or complete), whether detectable or undetectable. "Therapy" can also mean that the survival period is extended compared to the expected survival period in the case of not receiving therapy. The situation in which therapy is needed includes the situation in which a condition or illness has been suffered from, as well as the situation in which a condition or illness is prone to be suffered from, or the situation in which a condition or illness is to be prevented. Unless there is a specific indication to the contrary, the term "therapy" also covers prevention. The terms "therapeutic" and "therapeutically" should be interpreted in a corresponding manner.

[0312] As used herein, the terms "prophylaxis" or "prophylactic" are intended to have their normal meaning and include primary prevention, which is used to prevent the development of a disease, and secondary prevention, which is used after a disease has developed and to temporarily or permanently protect a patient from an exacerbation or worsening of the disease or the development of new symptoms associated with the disease.

[0313] The term "treat" is used synonymously with "therapy." Similarly, the term "treatment" can be viewed as "applying therapy," where "therapy" is as defined herein.

[0314] In a further aspect, the present disclosure provides a use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure for use in therapy, for example, for therapy related to the ATR protein.

[0315] In another aspect, the present disclosure provides a use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure in the preparation of a medicament for treating cancer.

[0316] In another aspect, the present disclosure provides a use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure in the preparation of a medicament for treating cancer.

[0317] In another aspect, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure for use in treating cancer.

[0318] In some embodiments, the compound of formula (I) can be further used in combination with other biologically active ingredients (such as but not limited to a second and different anti-neoplastic agent) and non-drug therapy (such as but not limited to surgery or radiotherapy). For example, the compound of formula (I) can be used in combination with other pharmaceutically active compounds or non-drug therapy, preferably compounds that can enhance the effect of the compound of formula (I). The compound of formula (I) can be used simultaneously with other therapies (as a single preparation or a separate preparation) or in sequence. Generally, combination therapy envisions the administration of two or more drugs / treatments during a single cycle or course of treatment.

[0319] In some embodiments, the compound of formula (I) is used in combination with one or more conventional chemotherapeutic agents, which cover a wide range of therapeutic treatments in the field of oncology. These agents are administered at various stages of the disease to shrink tumors, destroy remaining cancer cells left after surgery, induce remission, maintain remission, and / or alleviate symptoms associated with cancer or its treatment.

[0320] In some embodiments, the compounds of Formula (I) are used in combination with one or more targeted anti-cancer agents that modulate protein kinases involved in various disease states.

[0321] In some embodiments, the compounds of Formula (I) are used in combination with one or more targeted anticancer agents that modulate non-kinase biological targets, pathways or processes.

[0322] In some embodiments, the compound of formula (I) is used in combination with one or more other anticancer agents, including but not limited to gene therapy, RNAi cancer therapy, chemoprotectants (e.g., amfostine, mesna, dexrazoxane), antibody conjugates (e.g., brentuximab vedotin, ibritumomab tioxetan), cancer immunotherapy (such as interleukin-2), cancer vaccines (e.g., sipuleucel-T) or monoclonal antibodies (e.g., bevacizumab, alemtuzumab, rituximab, trastuzumab, etc.).

[0323] In some embodiments, the compounds of formula (I) are used in combination with one or more anti-inflammatory agents, including but not limited to NSAIDs, nonspecific and COX-2 specific cyclooxygenase inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor receptor (TNF) receptor antagonists, immunosuppressants and methotrexate.

[0324] In some embodiments, the compound of formula (I) is used in combination with radiotherapy or surgery. Radiation is usually delivered from the body (radioactive material is implanted near the cancer site), or from the outside by a machine using photons (x-rays or gamma rays) or particle radiation. When the combination therapy further includes radiotherapy, radiotherapy can be performed at any appropriate time, as long as a beneficial effect is achieved from the combined effect of the therapeutic agent and the radiotherapy.

[0325] Therefore, in another aspect, the present disclosure provides a method for treating a disease associated with ATR kinase in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure.

[0326] Example

[0327] The following examples are included for illustrative purposes. However, it should be understood that these examples do not limit the present disclosure and are intended only to show methods of practicing the present disclosure. Those skilled in the art will recognize that the described chemical reactions can be easily adapted to prepare a variety of other compounds of the present disclosure, and alternative methods for preparing compounds of the present disclosure are considered to be within the scope of the present disclosure. For example, non-exemplary compounds according to the present disclosure can be successfully synthesized by modifications apparent to those skilled in the art, such as by appropriately protecting interfering groups, by utilizing other suitable reagents and building blocks other than the described reagents and building blocks, and / or by making conventional modifications to reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be considered to be applicable to preparing other compounds of the present disclosure.

[0328] Example 1

[0329]

[0330] Step 1: (R)-2-chloro-6-(3-methylmorpholino)isonicotinic acid methyl ester (1-3)

[0331]

[0332] To a solution of methyl 2,6-dichloropyridine-4-carboxylate (2.5 g, 12.13 mmol) and (3R)-3-methylmorpholine (1.35 g, 13.35 mmol) in dioxane (50 mL) was added Cs2CO3 (7.91 g, 24.27 mmol) and Pd(dppf)Cl2 (0.44 g, 0.61 mmol). N2 was injected twice into the mixture and then stirred at 100 °C overnight. LC-MS showed that the reaction was complete. After cooling to room temperature, the reaction mixture was diluted with EA (80 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0-15% ethyl acetate / petroleum ether) to obtain the desired product (1.01 g, yield: 31%). LC-MS (ESI): m / z 271 [M+H] + . 1 H NMR (400MHz, DMSO) δ7.11(d,J=0.7Hz,1H),7.00(d,J=0.7Hz,1H),4.32(dd,J=6.7,2.6Hz,1H),3.96–3.88(m,2H),3.87(s,3H),3.72 (d,J=11.4Hz,1H),3.61(dd,J=11.5,3.0Hz,1H),3.46(td,J=11.9,3.1Hz,1H),3.13(td,J=12.7,3.9Hz,1H),1.15(d,J=6.7Hz,3H).

[0333] Step 2. (R)-(2-Chloro-6-(3-methylmorpholino)pyridin-4-yl)methanol (1-4)

[0334]

[0335] At 0 ° C, LiBH4 solution (2.0M in THF, 15.0mL, 30.0mmol) was added to a solution of 2-chloro-6-[(3R)-3-methylmorpholine-4-yl]pyridine-4-carboxylic acid methyl ester (4.5g, 16.62mmol) in THF (40mL). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. LC-MS showed that the reaction was complete. The reaction mixture was quenched with saturated NaHCO3 aqueous solution and extracted with EA (60mL×2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-50% ethyl acetate / petroleum ether) to obtain the title product (3.87g, 96%). LC-MS (ESI): m / z 243[M+H] + . 1H NMR (400MHz, CDCl3) δ6.58(s,1H),6.46(s,1H),4.62(s,2H),4.31–4.23(m,1H),3.99(dd,J=11.4,3.8Hz,1H),3.86(dd,J=13.1,2.9Hz,1H) ,3.78(d,J=11.3Hz,1H),3.72(dd,J=11.4,2.9Hz,1H),3.61–3.54(m,1H),3.21(td,J=12.7,3.8Hz,1H),1.89(s,1H),1.24(d,J=6.7Hz,3H).

[0336] Step 3. (R)-4-(6-Chloro-4-(chloromethyl)pyridin-2-yl)-3-methylmorpholine (1-5)

[0337]

[0338] At 0 ° C, to a solution of {2-chloro-6-[(3R)-3-methylmorpholine-4-yl]pyridin-4-yl}methanol (4.0 g, 16.48 mmol) and DMF (0.05 mL, 0.65 mmol) in DCM (40 mL) was added dropwise SOCl2 (10 mL, 137.8 mmol). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. LC-MS showed that the reaction was complete. The reaction mixture was concentrated to dryness under vacuum. The residue was dissolved in DCM (50 mL), then washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous Na2SO4, filtered and concentrated to give the desired product (4.08 g, yield: 95%). LC-MS (ESI): m / z 261 [M+H] + . 1 H NMR (400MHz, CDCl3) δ6.62(s,1H),6.43(s,1H),4.41(s,2H),4.26(dd,J=6.7,2.6Hz,1H),4.00(dd,J=11.4,3.8Hz,1H),3.86(dd,J=13. 1,3.0Hz,1H),3.80–3.76(m,1H),3.73(dd,J=11.4,2.9Hz,1H),3.61–3.54(m,1H),3.22(td,J=12.7,3.9Hz,1H),1.26(d,J=6.7Hz,3H).

[0339] Step 4. (R)-4-(6-Chloro-4-((methylsulfonyl)methyl)pyridin-2-yl)-3-methylmorpholine (1-6)

[0340]

[0341] At room temperature, under a nitrogen atmosphere, a mixture of (3R)-4-[6-chloro-4-(chloromethyl)pyridin-2-yl]-3-methylmorpholine (1.50 g, 5.74 mmol) and sodium methanesulfonate (1.17 g, 11.49 mmol) in DMF (20 mL) was stirred overnight. LC-MS shows that the reaction is complete. The reaction mixture is diluted with H2O and extracted with EA (60 mL×2). The combined organic layers are washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue is purified by flash column chromatography (silica gel, 0-50% ethyl acetate / petroleum ether) to obtain the desired product (1.55 g, yield: 89%). LC-MS (ESI): m / z 305 [M+H] + . 1 H NMR (400MHz, CDCl3) δ6.60(s,1H),6.49(s,1H),4.28–4.22(m,1H),4.10(s,2H),4.00(dd,J=11.5,3.8Hz,1H),3.90(dd,J=13.2,2.8Hz,1 H),3.80–3.76(m,1H),3.72(dd,J=11.4,3.0Hz,1H),3.61–3.54(m,1H),3.23(td,J=12.7,3.9Hz,1H),2.85(s,3H),1.26(d,J=6.7Hz,3H).

[0342] Step 5. (R)-4-(6-chloro-4-(1-(methylsulfonyl)cyclopropyl)pyridin-2-yl)-3-methylmorpholine (1-7)

[0343]

[0344] At 60 ° C, under a nitrogen atmosphere, a mixture of (3R)-4-[6-chloro-4-(methylsulfonylmethyl)pyridin-2-yl]-3-methylmorpholine (1.55g, 5.09mmol), 1,2-dibromoethane (0.88mL, 10.17mmol), NaOH solution (10.0M, 5.09mL, 50.85mmol) and TBAB (330mg, 1.02mmol) in toluene (50mL) was stirred overnight. LC-MS shows that the reaction is complete. The reaction mixture is diluted with H2O and extracted with EA (60mL×2). The combined organic layers are washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue is purified by flash column chromatography (silica gel, 0-50% ethyl acetate / petroleum ether) to obtain the desired product (652mg, yield: 39%). LC-MS(ESI):m / z 331[M+H]+ . 1 H NMR (400MHz, CDCl3) δ6.70(s,1H),6.67(d,J=0.9Hz,1H),4.26(d,J=6.9Hz,1 H), 4.00 (dd, J=11.4, 3.8Hz, 1H), 3.89 (dd, J=13.2, 2.8Hz, 1H), 3.78 (d, J=11. 4Hz,1H),3.72(dd,J=11.4,3.0Hz,1H),3.58(td,J=11.9,3.1Hz,1H),3.22(t d,J=12.7,3.9Hz,1H),2.83(s,3H),1.88–1.76(m,2H),1.26(d,J=6.6Hz,5H).

[0345] Step 6. (R)-tert-Butyl 5-((6-(3-methylmorpholino)-4-(1-(methylsulfonyl)cyclopropyl)pyridin-2-yl)amino)-1H-pyrazole-1-carboxylate (1-9)

[0346]

[0347] To a solution of (3R)-4-[6-chloro-4-(1-methylsulfonylcyclopropyl)pyridin-2-yl]-3-methylmorpholine (100 mg, 0.30 mmol) and tert-butyl 5-amino-1H-pyrazole-1-carboxylate (83 mg, 0.45 mmol) in dioxane (10 mL) was added BrettPhos-Pd-G3 catalyst (27 mg, 0.030 mmol) and Cs2CO3 (197 mg, 0.060 mmol). The mixture was injected with N2 twice and then stirred at 100°C for 4 hours. LC-MS showed that the reaction was complete. The reaction mixture was diluted with EA (50 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel, 0-60% ethyl acetate / petroleum ether) to give the title product (59 mg, yield: 41%). LC-MS(ESI):m / z 478[M+H] + 。

[0348] Step 7. (R)-6-(3-methylmorpholino)-4-(1-(methylsulfonyl)cyclopropyl)-N-(1H-pyrazol-5-yl)pyridin-2-amine (1)

[0349]

[0350] A mixture of tert-butyl 5-{[4-(1-methylsulfonylcyclopropyl)-6-[(3R)-3-methylmorpholin-4-yl]pyridin-2-yl]amino}-1H-pyrazole-1-carboxylate (59 mg, 0.12 mol) and HCl solution (4M in dioxane, 2 mL) in DCM (2 mL) was stirred for 2 hours at room temperature. LC-MS showed that the reaction was complete. The reaction mixture was concentrated to dryness under vacuum. The residue was purified by preparative HPLC (C18, 20-95%, acetonitrile in H2O containing 0.1% HCOOH) to obtain the desired product (14.2 mg, yield: 30%). LC-MS (ESI): m / z 378 [M+H] + . 1 H NMR (400MHz, DMSO) δ9.14(s,1H),7.57(d,J=2.2Hz,1H),6.60(s,1H),6.28(d,J=2.2Hz,1 H),6.23(s,1H),4.26(d,J=6.6Hz,1H),3.94(dd,J=11.3,3.3Hz,1H),3.81(d,J=13.0Hz, 1H),3.73(d,J=11.2Hz,1H),3.65–3.61(m,1H),3.51(s,1H),3.08(d,J=3.6Hz,1H),2.95 (s, 3H), 1.57 (dd, J = 5.8, 4.0 Hz, 2H), 1.26 ( dd, J = 6.3, 4.7 Hz, 2H), 1.14 ( d, J = 6.6 Hz, 3H).

[0351] Example 2

[0352]

[0353] Step 1. (2,6-Dichloro-3-methylpyridin-4-yl)methanol (2-2)

[0354]

[0355] At 0 ° C, under N2 atmosphere, LiBH4 solution (2.0M in THF, 0.68mL, 1.37mmol) was added dropwise to a solution of 2,6-dichloro-3-methylpyridine-4-carboxylic acid ethyl ester (290mg, 1.24mmol) in anhydrous THF (5mL). The resulting mixture was stirred at 0 ° C for 1 hour. LC-MS shows that the reaction is complete. The reaction mixture is quenched with saturated NH4Cl aqueous solution and extracted with EA (50mL). The organic layer is dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue is purified by silica gel column chromatography (PE: EA = 5: 1, V / V) to obtain the desired product (220mg, yield: 92%). LC / MS (ESI): m / z 192 [M + H] + .

[0356] Step 2. 2,6-Dichloro-4-(chloromethyl)-3-methylpyridine (2-3)

[0357]

[0358] To a solution of (2,6-dichloro-3-methylpyridin-4-yl)methanol (220 mg, 1.14 mmol) and DMF (0.01 mL) in anhydrous DCM (5 mL) was added SOCl2 (408 mg, 3.44 mmol) dropwise at 0 ° C. The resulting mixture was stirred at room temperature for 1 hour. LC-MS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EA (40 mL), then washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was used in the next step without further purification (230 mg, yield: 95%). LC / MS (ESI): m / z 210 / 212 [M+H] + .

[0359] Step 3. 2,6-Dichloro-3-methyl-4-((methylsulfonyl)methyl)pyridinemorpholine (2-4)

[0360]

[0361] At room temperature, a mixture of 2,6-dichloro-4-(chloromethyl)-3-methylpyridine (259 mg, 1.23 mmol) and CH3SO2Na (253 mg, 2.48 mmol) in DMF (5 mL) was stirred for 4 hours. LC-MS shows that the reaction is complete. The reaction mixture is diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue is purified by silica gel column chromatography (PE: EA = 1: 1, V / V) to obtain the desired product (270 mg, yield: 86%). LC / MS (ESI): m / z 254 [M + H] + .

[0362] Step 4. (R)-4-(6-chloro-5-methyl-4-((methylsulfonyl)methyl)pyridin-2-yl)-3-methylmorpholine (2-6)

[0363]

[0364] At 180 ° C, under microwave irradiation, a mixture of 2,6-dichloro-4-(methylsulfonylmethyl)-3-methylpyridine (250 mg, 0.98 mmol), (3R)-3-methylmorpholine (399 mg, 3.94 mmol) and DIPEA (509 mg, 3.94 mmol) in NMP (3 mL) was stirred for 1 hour. LC-MS shows that the reaction is complete. The reaction mixture is diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue is purified by silica gel column chromatography (PE: EA = 1: 1, V / V) to obtain the desired product (97 mg, yield: 30%) as a white solid. LC / MS (ESI): m / z 319 [M + H] + .

[0365] Step 5. (R)-4-(6-chloro-5-methyl-4-(1-(methylsulfonyl)cyclopropyl)pyridin-2-yl)-3-methylmorpholine (2-7)

[0366]

[0367] A mixture of (3R)-4-[6-chloro-4-(methylsulfonylmethyl)-5-methylpyridin-2-yl]-3-methylmorpholine (97 mg, 0.30 mmol), 1,2-dibromoethane (113 mg, 0.60 mmol), NaOH (10.0 M in H2O, 0.3 mL, 3.05 mmol) and TBAB (19 mg, 0.06 mmol) in toluene (4 mL) was stirred at 60 ° C for 3 hours. LC-MS showed that the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA=1:1, V / V) to obtain the desired product (29 mg, yield: 27%). LC / MS(ESI):m / z 345[M+H] + .

[0368] Step 6. (R)-3-Methyl-6-(3-methylmorpholino)-4-(1-(methylsulfonyl)cyclopropyl)-N-(1H-pyrazol-5-yl)pyridin-2-amine (2)

[0369]

[0370] To a solution of (3R)-4-[6-chloro-4-(1-methylsulfonylcyclopropyl)-5-methylpyridin-2-yl]-3-methylmorpholine (30 mg, 0.08 mmol) and 1H-pyrazole-5-amine (14 mg, 0.16 mmol) in dioxane (1.5 mL) was added BrettPhosPd G3 (8 mg, 0.01 mmol) and Cs2CO3 (85 mg, 0.26 mmol). Under N2 atmosphere, the mixture was stirred at 110 °C for 10 hours. LC-MS showed that the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (C 18 The residue was purified by HPLC (10-95% MeOH in H2O containing 0.1% HCOOH) to give the desired product (17 mg, yield: 49%). LC / MS (ESI): m / z 392 [M+H] + . 1H NMR(400MHz,DMSO)δ12.09(s,1H),7.94(s,1H),7.52(s,1H),6.40(s,1H),6.24(s, 1H),4.20(d,J=5.0Hz,1H),3.92(dd,J=11.2,3.1Hz,1H),3.71(d,J=11.4Hz,2H),3 .62(dd,J=11.2,2.7Hz,1H),3.47(td,J=11.8,2.9Hz,1H),3.06–2.98(m,1H),2.95 (s,3H),2.17(s,3H),1.87(s,1H),1.52(s,1H),1.24(s,2H),1.09(d,J=6.1Hz,3H).

[0371] Example 3

[0372]

[0373] Step 1. (R)-3-methyl-N-(3-methyl-1H-pyrazol-5-yl)-6-(3-methylmorpholino)-4-(1-(methylsulfonyl)cyclopropyl)pyridin-2-amine (3)

[0374]

[0375] To a solution of (3R)-4-[6-chloro-4-(1-methylsulfonylcyclopropyl)-5-methylpyridin-2-yl]-3-methylmorpholine (50 mg, 0.14 mmol) and 3-methyl-1H-pyrazol-5-amine (28 mg, 0.28 mmol) in dioxane (2 mL) was added BrettPhos-Pd-G3 (13 mg, 0.01 mmol) and Cs2CO3 (142 mg, 0.43 mmol). Under N2 atmosphere, at 110°C, the mixture was stirred for 10 hours. LC-MS showed that the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (C 18 The residue was purified by HPLC (10-95% MeOH in H2O containing 0.1% HCOOH) to give the desired product (54 mg, yield: 91%). LC / MS (ESI): m / z 406 [M+H] + . 1H NMR (400MHz, DMSO) δ11.75(s,1H),7.69(s,1H),6.21(s,2H),4.20(s,1H),3.92(d,J=8.2Hz,1H),3.71(d,J=11.3Hz,2H),3.62(d,J=8.8Hz,1H),3.47 (dd,J=11.4,8.9Hz,1H),3.01(t,J=10.9Hz,1H),2.94(s,3H),2.17(d,J=1 5.2Hz, 6H), 1.86 (s, 1H), 1.51 (s, 1H), 1.23 (s, 2H), 1.10 (d, J = 5.9Hz, 3H).

[0376] Example 4

[0377]

[0378] Step 1. 2,6-Dichloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)pyridine (4-3)

[0379]

[0380] To a solution of 2,6-dichloro-4-iodopyridine (300 mg, 1.10 mmol) and 1,4-dimethyl-5-(tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrazole (267.6 mg, 1.21 mmol) in DME (10 mL) was added Na2CO3 (232.2 mg, 2.19 mmol) and Pd(dppf)Cl2 (80.2 mg, 0.11 mmol). N2 was injected twice into the mixture and then stirred at 90 ° C for 4 hours. LC-MS showed that the reaction was complete. The reaction mixture was diluted with water (30 mL) and extracted with EA (40 mL×2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC (PE:EA=3:1, V / V) to obtain the desired product (230 mg, yield: 86%). LC / MS(ESI)m / z:243[M+H] + .

[0381] Step 2. (R)-4-(6-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)-3-methylmorpholine (4-5)

[0382]

[0383] (3R)-3-methylmorpholine (384.4 mg, 3.80 mmol) was added to a solution of 2,6-dichloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)pyridine (230 mg, 0.95 mmol) in NMP (3 mL). The reaction was stirred for 1 hour at 150 ° C under microwave irradiation. LC-MS showed that the reaction was complete. The mixture was diluted with water (30 mL) and extracted with EA (40 mL×2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel, 0-10% ethyl acetate / petroleum ether) to obtain the desired product (150 mg, yield: 51%). LC / MS(ESI)m / z:307[M+H] + .

[0384] Step 3. (R)-tert-Butyl 5-((4-(1,4-dimethyl-1H-pyrazol-5-yl)-6-(3-methylmorpholino)pyridin-2-yl)amino)-1H-pyrazole-1-carboxylate (4-7)

[0385]

[0386] To a solution of (R)-4-(6-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)-3-methylmorpholine (120 mg, 0.39 mmol) and tert-butyl 5-amino-1H-pyrazole-1-carboxylate (107.49 mg, 0.587 mmol) in dioxane (10 mL) was added CS2CO3 (637.2 mg, 1.96 mmol) and BrettPhos Pd G3 (35.46 mg, 0.04 mmol). The mixture was injected with N2 twice and then stirred at 90 °C overnight. LC-MS showed that the reaction was complete. The reaction was diluted with water (30 mL) and extracted with EA (40 mL×2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC (PE:EA=2:1, V / V) to give the desired product (80 mg, yield: 45%). LC / MS (ESI) m / z: 454 [M+H] + .

[0387] Step 4. (R)-4-(1,4-Dimethyl-1H-pyrazol-5-yl)-6-(3-methylmorpholino)-N-(1H-pyrazol-5-yl)pyridin-2-amine (4)

[0388]

[0389] A mixture of (R)-tert-butyl 5-((4-(1,4-dimethyl-1H-pyrazol-5-yl)-6-(3-methylmorpholino)pyridin-2-yl)amino)-1H-pyrazole-1-carboxylate (80 mg, 0.18 mmol) in HCl solution (4M in dioxane, 2 mL) was stirred overnight at room temperature. LC-MS showed that the reaction was complete. The reaction mixture was concentrated to dryness under vacuum. The residue was purified by preparative HPLC (C18, 20-95% acetonitrile in H2O, containing 0.1% TFA) to give the desired product (20 mg, yield: 32%). LC / MS(ESI)m / z:354[M+H] + . 1 H NMR (400MHz, DMSO) δ9.05(s,1H),7.55(d,J=2.2Hz,1H),7.31(s,1H),6.41(s,1H),6.35(d,J=1.9Hz,1H),6.00(s,1H),4.30(d,J=6.8Hz,1H),3.9 7–3.84(m,2H),3.74(s,3H),3.71(s,1H),3.63(dd,J=11.3,2.8Hz,1H),3 .52–3.45(m,1H),3.11–3.03(m,1H),1.99(s,3H),1.15(d,J=6.6Hz,3H).

[0390] Example 5

[0391]

[0392] Step 1. (R)-2-chloro-6-(3-methylmorpholino)pyrimidine-4-carboxylic acid methyl ester (5-3)

[0393]

[0394] At room temperature, a mixture of methyl 2,6-dichloropyrimidine-4-carboxylate (1.5 g, 7.24 mmol), (3R)-3-methylmorpholine (732 mg, 7.24 mmol) and TEA (1.47 g, 14.52 mmol) in DCM (30 mL) was stirred for 16 hours. LC-MS shows that the reaction is complete. The reaction mixture is diluted with DCM (20 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue is purified by silica gel column chromatography (PE: EA = 3: 1, V / V) to obtain the desired product (1.55 g, yield: 78%). LC / MS (ESI): m / z 272 [M + H] + .

[0395] Step 2. (R)-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methanol (5-4)

[0396]

[0397] At 0 ° C, under N2 atmosphere, LiBH4 solution (2.0M in THF, 3.7mL, 7.34mmol) was added dropwise to a solution of 2-chloro-6-[(3R)-3-methylmorpholine-4-yl]pyrimidine-4-carboxylic acid methyl ester (1g, 3.67mmol) in anhydrous THF (20mL) at 0 ° C. The resulting mixture was stirred at 0 ° C for 1 hour. LC-MS shows that the reaction is complete. The reaction mixture is quenched with saturated NH4Cl aqueous solution and extracted with EA (50mL). The combined organic layers are dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue is purified by silica gel column chromatography (PE:EA=1:1, V / V) to obtain the desired product (800mg, yield: 89%). LC / MS(ESI):m / z 244[M+H] + .

[0398] Step 3. (R)-4-(2-chloro-6-(chloromethyl)pyrimidin-4-yl)-3-methylmorpholine (5-5)

[0399]

[0400] To a solution of {2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}methanol (800 mg, 3.28 mmol) and DMF (0.01 mL) in anhydrous DCM (20 mL) was added SOCl2 (1.17 g, 9.84 mmol) dropwise at 0 ° C. The resulting mixture was stirred at room temperature for 1 hour. LC-MS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EA (40 mL), then washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was used in the next step without further purification (800 mg, yield: 93%). LC / MS (ESI): m / z 262 / 264 [M+H] + .

[0401] Step 4. (R)-4-(2-chloro-6-((methylsulfonyl)methyl)pyrimidin-4-yl)-3-methylmorpholine (5-6)

[0402]

[0403] A mixture of (3R)-4-[2-chloro-6-(chloromethyl)pyrimidin-4-yl]-3-methylmorpholine (535 mg, 2.04 mmol) and CH3SO2Na (418 mg, 4.10 mmol) in DMF (10 mL) was stirred at room temperature for 16 hours. LC-MS showed that the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA=2:1, V / V) to obtain the desired product (560 mg, yield: 90%). LC / MS (ESI): m / z 306[M+H] + .

[0404] Step 5. (R)-4-(2-chloro-6-(1-(methylsulfonyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholine (5-7)

[0405]

[0406] A mixture of (3R)-4-[2-chloro-6-(methylsulfonylmethyl)pyrimidin-4-yl]-3-methylmorpholine (125 mg, 0.41 mmol), 1,2-dibromoethane (154 mg, 0.82 mmol), NaOH (10.0 M in H2O, 0.4 mL, 4.0 mmol) and TBAB (26 mg, 0.08 mmol) in toluene (4 mL) was stirred at 60 °C for 3 hours. LC-MS showed that the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA=1:1, V / V) to obtain the desired product (110 mg, yield: 81%). LC / MS(ESI):m / z 332[M+H] + .

[0407] Step 6. (R)-tert-Butyl 5-((4-(3-methylmorpholino)-6-(1-(methylsulfonyl)cyclopropyl)pyrimidin-2-yl)amino)-1H-pyrazole-1-carboxylate (5-9)

[0408]

[0409] To a solution of (3R)-4-[2-chloro-6-(1-methylsulfonylcyclopropyl)pyrimidin-4-yl]-3-methylmorpholine (200 mg, 0.60 mmol) and tert-butyl 5-amino-1H-pyrazole-1-carboxylate (166 mg, 0.90 mmol) in dioxane (10 mL) was added Pd2(dba)3(55 mg, 0.06 mmol), Xant-Phos (34 mg, 0.06 mmol) and Cs2CO3(394 mg, 1.21 mmol). Under N2 atmosphere, at 100 °C, the mixture was stirred for 6 hours. LC-MS showed that the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA=1:2, V / V) to obtain the desired product (129 mg, yield: 44%). LC / MS(ESI):m / z 479[M+H] + .

[0410] Step 7. (R)-4-(3-methylmorpholino)-6-(1-(methylsulfonyl)cyclopropyl)-N-(1H-pyrazol-5-yl)pyrimidin-2-amine (5)

[0411]

[0412] A mixture of tert-butyl 5-{[4-(1-methylsulfonylcyclopropyl)-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl]amino}-1H-pyrazole-1-carboxylate (60 mg, 0.12 mmol) in HCl solution (4.0 M in dioxane, 3.0 mL) was stirred at room temperature for 10 hours. LC-MS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (C 18 The residue was purified by HPLC (HPLC-MS / MS): m / z 379 [M+H] + . 1H NMR (400MHz, DMSO) δ12.29(s,1H),9.51(s,1H),7.58(s,1H),6.38(s,2H),4.44(s,1H),4.05(d,J=12.8Hz,1H),3.94(dd,J=11.4,3.4Hz,1H),3.74 (d,J=11.4Hz,1H),3.59(dd,J=11.5,2.9Hz,1H),3.46(s,1H),3.25(s,3H ), 3.18 (s, 1H), 1.60 (t, J = 5.7Hz, 2H), 1.50 (s, 2H), 1.21 (d, J = 6.7Hz, 3H).

[0413] Example 6

[0414]

[0415] Step 1. tert-Butyl 5-{[4-(1-methylsulfonylcyclopropyl)-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl]amino}-3-methyl-1H-pyrazole-1-carboxylate (6-2)

[0416]

[0417] To a solution of (3R)-4-[2-chloro-6-(1-methylsulfonylcyclopropyl)pyrimidin-4-yl]-3-methylmorpholine (100 mg, 0.30 mmol) and tert-butyl 5-amino-3-methyl-1H-pyrazole-1-carboxylate (89.2 mg, 0.45 mmol) in dioxane (5 mL) was added CsCO (196.4 mg, 0.60 mmol), Xant-Phos (17.4 mg, 0.03 mmol) and Pd(dba) (24.4 mg, 0.03 mmol). The mixture was stirred at 100° C. under nitrogen atmosphere for 6 hours.

[0418] LC-MS shows that the reaction is complete. The reaction mixture is diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue is purified by silica gel column chromatography (PE: EA = 1: 1, V / V) to obtain the desired product (130 mg, yield: 87%). LC / MS (ESI): m / z 493 [M+H] + .

[0419] Step 2. 4-(1-methylsulfonylcyclopropyl)-N-(3-methyl-1H-pyrazol-5-yl)-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-amine (6)

[0420]

[0421] To a solution of tert-butyl 5-{[4-(1-methylsulfonylcyclopropyl)-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl]amino}-3-methyl-1H-pyrazole-1-carboxylate (120 mg, 0.24 mmol) in DCM (2 mL) was added HCl solution (4 M in dioxane, 2 mL). The mixture was stirred at room temperature for 2 hours. LC-MS showed that the reaction was complete. The reaction mixture was concentrated under vacuum. The residue was purified by preparative HPLC (C18, 10-95% MeCN in H2O, containing 0.1% ammonia) to give the desired product (32.6 mg, yield: 34%). LC / MS(ESI)m / z:393[M+H] + . 1 H NMR (400MHz, DMSO) δ9.21(s,1H),6.31(s,1H),6.15(s,1H),4.40(s,1H),4.02(d,J=11.7Hz,1H),3.93(d,J=8.1Hz,1H),3.73(d,J=11.3H z,1H),3.58(dd,J=11.6,2.9Hz,2H),3.25(s,3H),3.16(d,J=10.8Hz,1H),2.19(s,3H),1.58(s,2H),1.47(s,2H),1.20(d,J=6.7Hz,3H).

[0422] Compound 6 can be prepared using the following scheme:

[0423]

[0424]

[0425] Step 1. tert-Butyl 3-amino-5-methyl-1H-pyrazole-1-carboxylate (6-3)

[0426]

[0427] At 0 ° C, NaH (60%, 10.81 g, 270.28 mmol) was added to a solution of 3-methyl-1H-pyrazole-5-amine (25 g, 257.41 mmol) in THF (800 mL) in batches. After stirring at 0 ° C for 30 minutes, (Boc) O (58.99 g, 270.28 mmol) was added once. The mixture was stirred at room temperature for 1 hour. TLC shows that the reaction is complete. The reaction mixture is poured into a saturated NH4Cl aqueous solution and extracted twice with DCM (600 mL × 2). The combined organic layer is separated, then washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue is purified by silica gel column chromatography (PE: EA = 2: 1, V / V) to obtain the desired product (19 g, yield: 37.42%). 1 HNMR (400MHz, CDCl3) δ5.59 (d, J = 0.9 Hz, 1H), 3.89 (s, 2H), 2.44 (d, J = 0.9 Hz, 3H), 1.62 (s, 9H).

[0428] Step 2. (R)-tert-butyl 5-methyl-3-((4-(3-methylmorpholino)-6-(1-(methylsulfonyl)cyclopropyl)pyrimidin-2-yl)amino)-1H-pyrazole-1-carboxylate (6-4)

[0429]

[0430] To a solution of (3R)-4-[2-chloro-6-(1-methylsulfonylcyclopropyl)pyrimidin-4-yl]-3-methylmorpholine (15.0 g, 45.20 mmol) and tert-butyl 3-amino-5-methyl-1H-pyrazole-1-carboxylate (10.7 g, 54.24 mmol) in dioxane (600 mL) was added BrettPhos-Pd-G3 (906 mg, 4.41 mmol) and Cs2CO3 (29.45 g, 90.4 mmol). Under N2 atmosphere, at 100°C, the mixture was stirred overnight. The reaction mixture was diluted with EA (1.0 L), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH=20:1, V / V) to give the desired product (17 g, yield: 76%). LC / MS(ESI):m / z 493[M+H] + .

[0431] Step 3. (R)-N-(3-methyl-1H-pyrazol-5-yl)-4-(3-methylmorpholino)-6-(1-(methylsulfonyl)cyclopropyl)pyrimidin-2-amine (6)

[0432]

[0433] At room temperature, a mixture of (R)-5-methyl-3-((4-(3-methylmorpholino)-6-(1-(methylsulfonyl)cyclopropyl)pyrimidin-2-yl)amino)-1H-pyrazole-1-carboxylic acid tert-butyl ester (17.0 g, 34.51 mmol) in HCl solution (4.0 M in dioxane, 100.0 mL) was stirred for 12 hours. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was diluted with EA (200 mL) and saturated NaHCO3 aqueous solution (200 mL). The resulting mixture was stirred at room temperature overnight. The organic layer was separated, then washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. By preparative HPLC (C 18 The residue was purified by HPLC (10-95% MeOH in H2O containing 0.1% HCOOH) to give the desired product (10 g, yield: 73%). LC / MS (ESI): m / z 393 [M+H] + . 1 H NMR (400MHz, DMSO) δ11.78(s,1H),9.10(s,1H),6.23(d,J=29.9Hz,2H),4.38(s,1H),4.07–3.87(m,2H),3.73(d,J=11.4Hz,1H),3.58 (dd,J=11.5,2.9Hz,1H),3.43(td,J=11.8,2.9Hz,1H),3.26(s,3H),3.13(td,J=12.9,3.7Hz,1H),2.19(s,3H),1.19(d,J=6.7Hz,3H).

[0434] Example 7

[0435]

[0436] Step 1. (R)-4-(2-chloro-6-(2-(methylsulfonyl)propan-2-yl)pyrimidin-4-yl)-3-methylmorpholine (7-1)

[0437]

[0438] At 0 ° C, to a solution of (3R)-4-[2-chloro-6-(methylsulfonylmethyl)pyrimidin-4-yl]-3-methylmorpholine (900 mg, 2.94 mmol) and t-BuONa (849 mg, 8.82 mmol) in anhydrous DMF (16 mL) was added dropwise a solution of CH3I (1.26 g, 8.85 mmol) in anhydrous DMF (1 mL). After addition, the resulting mixture was stirred at room temperature for 3 hours. LC-MS shows that the reaction is complete. The reaction mixture is diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue is purified by silica gel column chromatography (PE: EA = 10: 1, V / V) to obtain the desired product (870 mg, yield: 88%). LC / MS (ESI): m / z 334 [M + H] + .

[0439] Step 2. (R)-4-(3-methylmorpholino)-6-(2-(methylsulfonyl)propan-2-yl)-N-(1H-pyrazol-5-yl)pyrimidin-2-amine (7)

[0440]

[0441] At 110 ° C, under N2 atmosphere, a mixture of (3R)-4-[2-chloro-6-(2-methylsulfonylpropane-2-yl)pyrimidin-4-yl]-3-methylmorpholine (100 mg, 0.30 mmol), 1H-pyrazole-5-amine (37 mg, 0.44 mmol), BrettPhos Pd G3 (27 mg, 0.03 mmol) and Cs2CO3 (293 mg, 0.90 mmol) in dioxane (5 mL) was stirred for 10 hours. LC-MS showed that the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The product was purified by preparative HPLC (C 18 The residue was purified by HPLC (HPLC-MS / MS): m / z 381 [M+H] + . 1H NMR(400MHz,DMSO)δ12.18(s,1H),9.26(s,1H),7.52(s,1H),6.41(s,1H),6.30 (s,1H),4.42(s,1H),4.03(d,J=12.9Hz,1H),3.94(dd,J=11.4,3.3Hz,1H),3.7 3(d,J=11.4Hz,1H),3.59(dd,J=11.5,3.0Hz,1H),3.44(dd,J=11.8,9.0Hz,1H) ,3.14(td,J=12.9,3.7Hz,1H),3.01(s,3H),1.67(s,6H),1.19(d,J=6.7Hz,3H).

[0442] Example 8

[0443]

[0444] Step 1. (R)-N-(3-methyl-1H-pyrazol-5-yl)-4-(3-methylmorpholino)-6-(2-(methylsulfonyl)propan-2-yl)pyrimidin-2-amine (8)

[0445]

[0446] At 110 ° C, under N2 atmosphere, a mixture of (3R)-4-[6-chloro-4-(2-methylsulfonylpropane-2-yl)pyridin-2-yl]-3-methylmorpholine (100 mg, 0.30 mmol), 3-methyl-1H-pyrazol-5-amine (58 mg, 0.60 mmol), BrettPhos Pd G3 (27 mg, 0.03 mmol) and Cs2CO3 (293 mg, 0.90 mmol) in dioxane (4 mL) was stirred for 10 hours. LC-MS showed that the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The product was purified by preparative HPLC (C 18 The residue was purified by HPLC-MS / MS (ESI): m / z 395 [M+H] + . 1H NMR(400MHz,DMSO)δ11.98(s,1H),9.08(s,1H),8.13(s,1H),6.28(s,1H),6.16(s, 1H), 4.40 (s, 1H), 4.02 (d, J=13.0Hz, 1H), 3.93 (dd, J=11.4, 3.4Hz, 1H), 3.73 (d, J= 11.4Hz,1H),3.59(dd,J=11.5,2.9Hz,1H),3.44(td,J=11.8,2.8Hz,1H),3.13(td, J=13.0,3.7Hz,1H),3.01(s,3H),2.18(s,3H),1.66(s,6H),1.19(d,J=6.7Hz,3H).

[0447] Example 9

[0448]

[0449] Step 1. (R)-methyl (2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methanesulfonate (9-1)

[0450]

[0451] At 0 ° C, to a solution of (R)-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methanol (1 g, 4.10 mmol) and TEA (623 mg, 6.15 mmol) in DCM (30 mL) was added dropwise a solution of MsCl (564 mg, 4.92 mmol) in DCM (2 mL). The resulting mixture was stirred at room temperature for 3 hours. LC-MS showed that the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE: EA = 10: 1, V / V) to obtain the desired product (1.06 mg, yield: 80%). LC / MS (ESI): m / z 322 [M + H] + .

[0452] Step 2. (R)-2-(2-Chloro-6-(3-methylmorpholino)pyrimidin-4-yl)acetonitrile (9-2)

[0453]

[0454] To a solution of NaCN (184 mg, 3.75 mmol) in DMSO (20 mL) was added dropwise a solution of (R)-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methanesulfonic acid methyl ester (1 g, 3.10 mmol). The resulting mixture was stirred at room temperature for 1 hour. LC-MS showed that the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with ice water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA=3:1, V / V) to obtain the desired product (300 mg, yield: 38%). LC / MS(ESI):m / z 253[M+H] + .

[0455] Step 3. (R)-1-(2-Chloro-6-(3-methylmorpholino)pyrimidin-4-yl)cyclopropanecarbonitrile (9-3)

[0456]

[0457] To a solution of (R)-2-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)acetonitrile (100 mg, 0.40 mmol), 1,2-dibromoethane (338 mg, 1.79 mmol) and TBAB (32.2 mg, 0.1 mmol) in 2-MeTHF (15 mL) was added a solution of KOH (1.57 g, 28.0 mmol) in H2O (15 mL). The resulting mixture was stirred at room temperature for 12 hours. LC-MS showed that the reaction was complete. The reaction mixture was diluted with EA (50 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA=5:1, V / V) to obtain the desired product (50 mg, yield: 46%). LC / MS(ESI):m / z 279[M+H] + .

[0458] Step 4. (R)-1-(2-((3-methyl-1H-pyrazol-5-yl)amino)-6-(3-methylmorpholino)pyrimidin-4-yl)cyclopropanecarbonitrile (9)

[0459]

[0460] To a solution of (R)-1-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)cyclopropanecarbonitrile (50 mg, 0.18 mmol), 3-methyl-1H-pyrazol-5-amine (35 mg, 0.36 mmol) and Cs2CO3 (117.3 mg, 0.36 mmol) in dioxane (5 mL) was added BrettPhos Pd G3 (16 mg, 0.018 mmol). The mixture was stirred at 100 °C for 16 hours. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative HPLC (C 18 The residue was purified by HPLC (HPLC-MS / MS): m / z 340 [M+H] + . 1 H NMR (400MHz, DMSO) δ8.97(s,1H),6.17(s,2H),4.35(s,1H),4.04–3.87(m,2H),3.72(d,J=11.4Hz,1H),3.58(dd,J= 11.5,2.9Hz,1H),3.47–3.39(m,4H),3.13(td,J=12.9,3.7Hz,2H),2.17(s,3H),1.70(s,4H),1.19(d,J=6.7Hz,3H).

[0461] Example 10

[0462]

[0463] Step 1. (R)-2-(2-Chloro-6-(3-methylmorpholino)pyrimidin-4-yl)-2-methylpropionitrile (10-1)

[0464]

[0465] At 0 ° C, to a solution of (R)-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methyl methanesulfonate (360 mg, 1.42 mmol) and t-BuONa (274 mg, 2.85 mmol) in anhydrous THF (15 mL) was added dropwise a solution of CH3I (605 mg, 4.26 mmol) in anhydrous THF (1 mL). After addition, the resulting mixture was stirred at room temperature for 12 hours. LC-MS shows that the reaction is complete. The reaction mixture is diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue is purified by silica gel column chromatography (PE: EA = 5: 1, V / V) to obtain the desired product (300 mg, yield: 75%). LC / MS (ESI): m / z 281 [M + H] + .

[0466] Step 2. (R)-2-Methyl-2-(2-((3-methyl-1H-pyrazol-5-yl)amino)-6-(3-methylmorpholino)pyrimidin-4-yl)propanenitrile (10)

[0467]

[0468] To a solution of (R)-2-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)-2-methylpropionitrile (50 mg, 0.18 mmol), tert-butyl 5-amino-3-methyl-1H-pyrazole-1-carboxylate (70 mg, 0.36 mmol) and Cs2CO3 (174 mg, 0.53 mmol) in dioxane (5 mL) was added BrettPhos Pd G3 (16 mg, 0.018 mmol). The mixture was stirred at 100 °C for 16 hours. LC-MS showed that the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was dissolved in DCM (4 mL), and HCl solution (4 M in dioxane, 2 mL) was added. The mixture was stirred at room temperature for 2 hours. LC-MS showed that the reaction was complete. The reaction mixture was concentrated under vacuum. The product was purified by preparative HPLC (C 18 The residue was purified by HPLC (10-95% MeOH in H2O containing 0.1% HCOOH) to give the desired product (8 mg, yield: 13%). LC / MS (ESI): m / z 342 [M+H] + . 1H NMR (400MHz, DMSO) δ11.78(s,1H),9.07(s,1H),6.26(d,J=17.8Hz,2H),4.40(dd,J=13.5,7.2Hz,1H),4.01(d,J=13.2Hz,1H),3.93(dd,J=11.3,3.3H z,1H),3.72(d,J=11.4Hz,1H),3.58(dd,J=11.4,2.9Hz,1H),3.45–3.42(m ,1H),3.17–3.10(m,1H),2.17(s,3H),1.64(s,6H),1.19(d,J=6.7Hz,3H).

[0469] Embodiment 11

[0470]

[0471] Step 1. (R)-4-(2-chloro-6-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-3-methylmorpholine (11-1)

[0472]

[0473] A mixture of (3R)-4-[2-chloro-6-(methylsulfonylmethyl)pyrimidin-4-yl]-3-methylmorpholine (400 mg, 1.31 mmol), 1-bromo-2-(2-bromoethoxy)ethane (905 mg, 3.93 mmol), TBAB (42 mg, 0.13 mmol) and NaOH (10.0 M in H2O, 1.31 mL, 13.1 mmol) in DCM (20 mL) was stirred at room temperature for 24 hours. LC-MS showed that the reaction was complete. The reaction mixture was diluted with DCM (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EA=3:1, V / V) to obtain the desired product (147 mg, yield: 30%). LC / MS(ESI):m / z 376[M+H] + .

[0474] Step 2. (R)-4-(3-methylmorpholino)-6-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)-N-(1H-pyrazol-5-yl)pyrimidin-2-amine (11)

[0475]

[0476] At 110 ° C, under N2 atmosphere, a mixture of (3R)-4-[2-chloro-6-(4-methylsulfonyltetrahydropyran-4-yl)pyrimidin-4-yl]-3-methylmorpholine (70 mg, 0.19 mmol), 1H-pyrazole-5-amine (31 mg, 0.37 mmol), BrettPhos Pd G3 (17 mg, 0.02 mmol) and Cs2CO3 (182 mg, 0.56 mmol) in dioxane (3 mL) was stirred for 10 hours. LC-MS showed that the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The product was purified by preparative HPLC (C 18 The residue was purified by HPLC (HPLC-MS / MS): m / z 423 [M+H] + . 1 H NMR (400MHz, DMSO) δ12.09(s,1H),9.19(s,1H),7.53(s,1H),6.40(s,2H),4.41(d,J=4.6H z,1H),4.08(d,J=12.8Hz,1H),3.91(ddd,J=16.0,10.8,4.0Hz,3H),3.73(d,J=11.5Hz,1H) ,3.61(dd,J=11.5,2.9Hz,1H),3.46(td,J=11.9,2.9Hz,1H),3.17(ddd,J=19.1,16.3,8.1H z, 3H), 2.85 (s, 3H), 2.64 (d, J = 13.1Hz, 2H), 2.13 (t, J = 11.8Hz, 2H), 1.19 (d, J = 6.7Hz, 3H).

[0477] Example 12

[0478]

[0479] Step 1. (R)-N-(3-methyl-1H-pyrazol-5-yl)-4-(3-methylmorpholino)-6-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine (12)

[0480]

[0481] At 110 ° C, under N2 atmosphere, a mixture of (3R)-4-[2-chloro-6-(4-methylsulfonyltetrahydropyran-4-yl)pyrimidin-4-yl]-3-methylmorpholine (70 mg, 0.18 mmol), 3-methyl-1H-pyrazole-5-amine (36 mg, 0.37 mmol), BrettPhosPd G3 (17 mg, 0.02 mmol) and Cs2CO3 (182 mg, 0.56 mmol) in dioxane (3 mL) was stirred for 10 hours. LC-MS showed that the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The product was purified by preparative HPLC (C 18 The residue was purified by HPLC (HPLC-MS / MS): m / z 437 [M+H] + . 1 H NMR(400MHz,DMSO)δ11.78(s,1H),9.03(s,1H),8.16(s,1H),6.38(s,1H),6.16(s,1H ),4.39(s,1H),4.08(d,J=13.0Hz,1H),3.98–3.84(m,3H),3.72(d,J=11.4Hz,1H),3.6 1(dd,J=11.4,2.9Hz,1H),3.46(td,J=11.9,2.8Hz,1H),3.16(ddd,J=19.2,16.3,8.1H z, 3H), 2.85 (s, 3H), 2.63 (d, J = 13.0Hz, 2H), 2.24–2.02 (m, 5H), 1.19 (d, J = 6.7Hz, 3H).

[0482] Example 13

[0483]

[0484] Step 1. (R)-N-(2-chloro-6-(3-methylmorpholino)pyridin-4-yl)methanesulfonamide (13-2)

[0485]

[0486] (3R) -3- methylmorpholine (629mg, 6.22mmol) was added to a solution of N- (2,6- dichloropyridin-4-yl) methanesulfonamide (500mg, 2.07mmol) in NMP (15mL). Under microwave irradiation, the mixture was stirred for 1 hour at 170°C. LC-MS shows that the reaction is complete. The mixture was diluted with water (60mL) and extracted three times with EA (30mL × 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (PE: EA = 1: 1, V / V) to obtain the desired product (425mg, yield: 67.02%). LC / MS (ESI): m / z 306 [M + H] + .

[0487] Step 2. (R)-N-(2-Chloro-6-(3-methylmorpholino)pyridin-4-yl)-N-methylmethanesulfonamide (13-3)

[0488]

[0489] To a mixture of (R)-N-(2-chloro-6-(3-methylmorpholino)pyridin-4-yl)methanesulfonamide (250 mg, 0.82 mmol) and KCO (339 mg, 2.45 mmol) in DMF (8 mL) was added MeI (174 mg, 1.23 mmol). The mixture was stirred at room temperature for 2 hours. LC-MS showed that the reaction was complete. The reaction mixture was poured into HO (30 mL) and extracted three times with EA (30 mL × 3). The combined organic phases were washed with brine, dried over anhydrous NaSO, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (PE: EA = 1: 1, V / V) to obtain the desired product (218 mg, yield: 83.4%). LC / MS (ESI): m / z 320 [M + H] + .

[0490] Step 3. (R)-N-methyl-N-(2-(3-methylmorpholino)-6-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)amino)pyridin-4-yl)methanesulfonamide (13-5)

[0491]

[0492] To a solution of (R)-N-(2-chloro-6-(3-methylmorpholino)pyridin-4-yl)-N-methylmethanesulfonamide (100 mg, 0.31 mmol), 1-({[2-(trimethylsilyl)ethoxy]methyl}-λ^-chloroformyl)-1H-pyrazol-5-amine (100 mg, 0.47 mmol) and CsCO (306 mg, 0.94 mmol) in dioxane (5 mL) was added Pd(dba) (29 mg, 0.031 mmol) and XantPhos (36 mg, 0.06 mmol). Under N atmosphere, at 100 °C, the mixture was stirred for 16 hours. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (60 mL), then washed with water and brine, dried over anhydrous NaSO, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (PE:EA=1:1, V / V) to obtain the desired product (118 mg, yield: 76%). LC / MS (ESI): m / z 497 [M+H] + .

[0493] Step 4. (R)-N-(2-((1H-pyrazol-5-yl)amino)-6-(3-methylmorpholino)pyridin-4-yl)-N-methylmethanesulfonamide (13)

[0494]

[0495] A mixture of (R)-N-methyl-N-(2-(3-methylmorpholino)-6-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)amino)pyridin-4-yl)methanesulfonamide (118 mg, 0.24 mmol) in TBAF solution (1M in THF, 2 mL) was stirred at 60 ° C for 2 hours. LC-MS showed that the reaction was complete. The mixture was diluted with H2O and extracted three times with EA (30 mL×3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The product was purified by preparative HPLC (C 18 The residue was purified by HPLC (10-95% MeOH in H2O containing 0.1% HCOOH) to give the desired product (20 mg, yield: 23%). LC / MS (ESI): m / z 367 [M+H] + . 1H NMR (400MHz, DMSO) δ8.96(s,1H),7.53(d,J=2.2Hz,1H),6.47(s,1H),6.30(d,J=2.1Hz,1H),6.05(d,J=1.2Hz,1H),4.29–4.23(m,1H),3.93(dd,J=11. 2,3.2Hz,1H),3.77–3.71(m,2H),3.64–3.61(m,1H),3.50–3.49(m,1H),3.1 9(s,3H),3.07(dd,J=12.6,3.7Hz,1H),3.01(s,3H),1.13(d,J=6.6Hz,3H).

[0496] Embodiment 14

[0497]

[0498] Step 1. (R)-6-(3-methylmorpholino)-4-(1-(methylsulfonyl)cyclopropyl)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridin-2-amine (14-1)

[0499]

[0500] To a solution of (R)-4-(6-chloro-4-(1-(methylsulfonyl)cyclopropyl)pyridin-2-yl)-3-methylmorpholine (356.0 mg, 1.08 mmol) and 1-({[2-(trimethylsilyl)ethoxy]methyl}-λ^-chloroformyl)-1H-pyrazol-5-amine (343.8 mg, 1.61 mmol) in dioxane (15 mL) was added Pd2(dba)3 (98.5 mg, 0.11 mmol), BrettPhos-Pd-G3 (13.7 mg, 0.015 mmol) and Cs2CO3 (701.2 mg, 2.15 mmol). The mixture was stirred overnight at 100 °C under nitrogen atmosphere. LC-MS showed the reaction was complete. The reaction was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA=3:1, V / V) to obtain the desired product (490 mg, yield: 89%). LC / MS (ESI) m / z: 508 [M+H] + .

[0501] Step 2. (R)-N-methyl-6-(3-methylmorpholino)-4-(1-(methylsulfonyl)cyclopropyl)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridin-2-amine (14-2)

[0502]

[0503] At 0 ° C, to a solution of (R)-6-(3-methylmorpholino)-4-(1-(methylsulfonyl)cyclopropyl)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridine-2-amine (200 mg, 0.39 mmol) in THF (5 mL) was added NaH (60%, 14.2 mg, 0.59 mmol) in batches. The mixture was stirred at 0 ° C for 30 minutes, and then a solution of CHI (84.0 mg, 0.59 mmol) in THF (1 mL) was added dropwise. The resulting mixture was stirred at room temperature for another 1 hour. LC-MS shows that the reaction is complete. The reaction mixture is quenched with saturated NH4Cl aqueous solution and extracted with EA (30 mL×2). The combined organic layer is washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (DCM: MeOH = 50: 1, V / V) to obtain the desired product (110 mg, yield: 53%). LC / MS (ESI) (m / z): 522 [M + H] + .

[0504] Step 3. (R)-N-methyl-6-(3-methylmorpholino)-4-(1-(methylsulfonyl)cyclopropyl)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridin-2-amine (14)

[0505]

[0506] A mixture of (R)-N-methyl-6-(3-methylmorpholino)-4-(1-(methylsulfonyl)cyclopropyl)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridin-2-amine (110 mg, 0.21 mmol) in HCl solution (4M in dioxane, 2 mL) was stirred for 2 hours at room temperature. LC-MS showed that the reaction was complete. The reaction mixture was concentrated under vacuum. The residue was purified by preparative HPLC (C18, 10-95% MeCN in H2O, containing 0.1% HCOOH) to give the desired product (14 mg, yield: 17%). LC / MS(ESI)m / z:392[M+H] + . 1H NMR(400MHz,DMSO)δ12.40(s,1H),8.37(s,1H),7.66(s,1H),6.48(s,1H),6.24(s,1H ),6.21(d,J=1.9Hz,1H),4.27(d,J=4.9Hz,1H),3.97–3.80(m,3H),3.72(d,J=11.2Hz, 1H),3.62(dd,J=11.3,2.8Hz,2H),3.53–3.42(m,3H),3.05(td,J=12.6,3.6Hz,2H),2 .91 (s, 4H), 1.53 (dd, J = 6.2, 4.1Hz, 3H), 1.22 (t, J = 5.1Hz, 3H), 1.14 (d, J = 6.6Hz, 4H).

[0507] Embodiment 15

[0508]

[0509] Step 1. 2,6-Dichloro-4-iodonicotinaldehyde (15-2)

[0510]

[0511] At -78 ° C, to a solution of 2,6-dichloro-4-iodopyridine (1 g, 3.65 mmol) in THF (10 ml), LDA solution (2M in THF, 2.74 mL, 5.48 mmol) was added dropwise. The mixture was stirred at -78 ° C for 1 hour, followed by dropwise addition of THF (1 ml) containing ethyl formate (0.44 mL, 5.48 mmol). The resulting mixture was stirred for another 2 hours at -78 ° C. LC-MS shows that the reaction is complete. The reaction mixture was quenched with saturated NH4Cl aqueous solution and extracted twice with EA (40 mL × 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE: EA = 30: 1, V / V) to obtain the desired product (553 mg, yield: 50%). LC / MS (ESI): m / z 302 [M + H] + .

[0512] Step 2. 2,6-Dichloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)nicotinaldehyde (15-3)

[0513]

[0514] Pd(dppf)Cl2 (360 mg, 0.50 mmol) and Na2CO3 (2.0 M in H2O, 6 mL, 12.0 mmol) were added to a solution of 2,6-dichloro-4-iodopyridine-3-carboxaldehyde (1.5 g, 4.97 mmol) and 1,4-dimethyl-5-(tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrazole (1.32 g, 5.96 mmol) in DME (90 mL). N2 was injected twice into the mixture, and then stirred overnight at 100 ° C under N2 atmosphere. LC-MS showed that the reaction was complete. The reaction mixture was diluted with H2O (100 mL) and extracted twice with EA (100 mL×2). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA=10:1, V / V) to obtain the desired product (548 mg, yield: 41%). LC / MS (ESI): m / z 270 [M+H] + . 1 H NMR (400MHz, DMSO) δ9.98(s,1H),7.79(s,1H),7.37(s,1H),3.59(s,3H),1.79(s,3H).

[0515] Step 3. (R)-2-Chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-6-(3-methylmorpholino)nicotinaldehyde (15-4)

[0516]

[0517] At 130 ° C, under microwave irradiation, a solution of 2,6-dichloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)pyridine-3-carboxaldehyde (330 mg, 1.22 mmol) and (3R)-3-methylmorpholine (185 mg, 1.83 mmol) in NMP (14 mL) was stirred for 1 hour. LC-MS shows that the reaction is complete. The reaction mixture is quenched with H2O (40 mL) and extracted twice with EA (50 mL × 2). The combined organic layer is washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue is purified by silica gel column chromatography (PE: EA = 5: 1, V / V) to obtain the desired product (142 mg, yield: 35%). LC / MS (ESI): m / z 335 [M + H] + .

[0518] Step 4. (R)-(2-Chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-6-(3-methylmorpholino)pyridin-3-yl)methanol (15-5)

[0519]

[0520] To a solution of 2-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-6-[(3R)-3-methylmorpholine-4-yl]pyridine-3-carbaldehyde (140 mg, 0.42 mmol) in THF (4 mL) was added NaBH4 (14 mg, 0.42 mmol). The resulting mixture was stirred at 0 ° C for 0.5 hours. LC-MS showed that the reaction was complete. The reaction mixture was quenched with H2O and extracted twice with EA (40 mL×2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA=3:1, V / V) to obtain the desired product (140 mg, yield: 99%). LC / MS(ESI):m / z 337[M+H] + .

[0521] Step 5. (R)-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-6-(3-methylmorpholino)-2-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)amino)pyridin-3-yl)methanol (15-6)

[0522]

[0523] A mixture of [2-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-6-[(3R)-3-methylmorpholin-4-yl]pyridin-3-yl]methanol (135 mg, 0.40 mmol), 1-({[2-(trimethylsilyl)ethoxy]methyl}-λ^2-chloroformyl)-1H-pyrazol-5-amine (128 mg, 0.60 mmol), BrettPhos-Pd-G3 (36 mg, 0.04 mmol) and Cs2CO3 (392 mg, 1.20 mmol) in dioxane (6 mL) was stirred overnight at 100° C. under a nitrogen atmosphere. LC-MS showed that the reaction was complete. The mixture was diluted with EA (60 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA=1:1, V / V) to obtain the desired product (46 mg, yield: 22%). LC / MS (ESI): m / z 514 [M+H] + .

[0524] Step 6. (R)-(2-((1H-pyrazol-5-yl)amino)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-6-(3-methylmorpholino)pyridin-3-yl)methanol (15)

[0525]

[0526] A mixture of [4-(1,4-dimethyl-1H-pyrazol-5-yl)-6-[(3R)-3-methylmorpholin-4-yl]-2-{[1-({[2-(trimethylsilyl)ethoxy]methyl}-λ^2-chloralyl)-1H-pyrazol-5-yl]amino}pyridin-3-yl]methanol (46 mg, 0.09 mmol) in TBAF solution (1.0 M in THF, 5 mL, 5.0 mmol) was stirred overnight at 40 °C. LC-MS showed that the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (C18, 10-95% acetonitrile in H2O, containing 0.1% ammonia) to give the desired product (13.2 mg, 38%). LC / MS(ESI)m / z:384[M+H] + . 1 H NMR(400MHz,DMSO)δ12.16(s,1H),8.51(s,1H),7.59(s,1H),7.32(s,1H),6.55(s,1 H),5.89(s,1H),5.38(s,1H),4.26(s,1H),4.22–4.14(m,2H),3.96–3.90(m,1H),3.8 5–3.78(m,1H),3.72(d,J=11.3Hz,1H),3.64(d,J=2.6Hz,1H),3.61(d,J=2.9Hz,1H) ,3.58(d,J=1.6Hz,3H),3.10–3.03(m,1H),1.85(s,3H),1.14(dd,J=6.6,3.0Hz,3H).

[0527] Example 16

[0528]

[0529] Step 1. Methyl 2,6-dichloro-4-methylpyridine-3-carboxylate (17-2)

[0530]

[0531] To a solution of 2,6-dichloro-4-methylpyridine-3-carboxylic acid (500mg, 2.43mmol) in DMF (10mL) was added CH3I (0.3mL, 4.85mmol) and K2CO3 (503mg, 3.64mmol). The mixture was stirred at room temperature overnight. LC-MS shows that the reaction is complete. The reaction mixture was diluted with EA (60mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (PE:EA=10:1, V / V) to obtain the desired product (525mg, yield: 98%). LC / MS(ESI):m / z 220[M+H] + .

[0532] Step 2. Methyl 4-(bromomethyl)-2,6-dichloropyridine-3-carboxylate (17-3)

[0533]

[0534] NBS (0.97 g, 5.45 mmol) and AIBN (74 mg, 0.45 mmol) were added to a solution of 2,6-dichloro-4-methylpyridine-3-formic acid methyl ester (1 g, 4.54 mmol) in CCl4 (40 mL). The mixture was stirred at 80 ° C overnight. LC-MS shows that the reaction is complete. The reaction mixture was diluted with EA (60 mL), then washed with saturated Na2S2O3 aqueous solution and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (PE: EA = 10: 1, V / V) to obtain the desired product (1.04 g, yield: 76%). LC / MS (ESI): m / z 300 [M + H] + .

[0535] Step 3. Methyl 2,6-dichloro-4-(methylsulfonylmethyl)pyridine-3-carboxylate (17-4)

[0536]

[0537] Sodium methanesulfonate (410 mg, 4.01 mmol) was added to a solution of 4-(bromomethyl)-2,6-dichloropyridine-3-formic acid methyl ester (600 mg, 2.00 mmol) in DMF (20 mL). The mixture was stirred at room temperature for 2 hours. LC-MS shows that the reaction is complete. The reaction mixture was diluted with EA (60 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (PE: EA = 5: 1, V / V) to obtain the desired product (510 mg, yield: 85%). LC / MS (ESI): m / z 298 [M + H] + .

[0538] Step 4. Methyl 2-chloro-4-(methylsulfonylmethyl)-6-[(3R)-3-methylmorpholin-4-yl]pyridine-3-carboxylate (17-6)

[0539]

[0540] (3R) -3- methylmorpholine (204mg, 2.01mmol) was added to a solution of 2,6- dichloro-4- (methylsulfonylmethyl) pyridine-3-formic acid methyl ester (300mg, 1.01mmol) in NMP (9mL). The mixture was stirred for 1 hour at 120°C under microwave irradiation. LC-MS shows that the reaction is complete. The reaction mixture was diluted with EA (60mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (PE: EA = 3: 1, V / V) to obtain the desired product (150mg, yield: 41%). LC / MS (ESI): m / z 363 [M + H] + .

[0541] Step 5. Methyl 2-chloro-4-(1-methylsulfonylcyclopropyl)-6-[(3R)-3-methylmorpholin-4-yl]pyridine-3-carboxylate (17-7)

[0542]

[0543] To a solution of 2-chloro-4-(methylsulfonylmethyl)-6-[(3R)-3-methylmorpholin-4-yl]pyridine-3-carboxylic acid methyl ester (150 mg, 0.41 mmol) in toluene (20 mL) was added TBAB (27 mg, 0.08 mmol), 1,2-dibromoethane (233 mg, 1.24 mmol) and NaOH aqueous solution (10 M, 0.41 mL, 4.13 mmol). The mixture was stirred at 60 ° C for 6 hours. LC-MS showed that the reaction was complete. The reaction mixture was diluted with EA (60 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (PE: EA = 3: 1, V / V) to obtain the desired product (100 mg, yield: 62%). LC / MS (ESI): m / z 389 [M + H] + .

[0544] Step 6. [2-Chloro-4-(1-methylsulfonylcyclopropyl)-6-[(3R)-3-methylmorpholin-4-yl]pyridin-3-yl]methanol (17-8)

[0545]

[0546] To a solution of methyl 2-chloro-4-(1-methylsulfonylcyclopropyl)-6-[(3R)-3-methylmorpholin-4-yl]pyridine-3-carboxylate (200 mg, 0.51 mmol) in THF (10 mL) was added LiBH4 (2M in THF, 1.03 mL, 2.06 mmol). The mixture was stirred at room temperature overnight. LC-MS showed that the reaction was complete. The reaction mixture was diluted with EA (60 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (PE:EA=1:1, V / V) to give the desired product (150 mg, yield: 80%). LC / MS(ESI):m / z361[M+H] + .

[0547] Step 7. (R)-(2-((1H-pyrazol-5-yl)amino)-6-(3-methylmorpholino)-4-(1-(methylsulfonyl)cyclopropyl)pyridin-3-yl)methanol (17)

[0548]

[0549] To a solution of (R)-(2-chloro-6-(3-methylmorpholino)-4-(1-(methylsulfonyl)cyclopropyl)pyridin-3-yl)methanol (50 mg, 0.14 mmol) and 1H-pyrazol-5-amine (23 mg, 0.28 mmol) in dioxane (2 mL) was added Brettphos-Pd-G3 (12.5 mmol, 0.014 mmol) and Cs2CO3 (135 mg, 0.41 mmol). Under N2 atmosphere, at 110 °C, the mixture was stirred overnight. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by preparative HPLC (C 18 The residue was purified by HPLC (HPLC-MS / MS): m / z 408 [M+H] + . 1 H NMR (400MHz, DMSO) δ12.11(s,1H),8.52(d,J=4.3Hz,1H),7.56(d,J=1.6Hz,1H),6.50(s,1H ),6.25(s,1H),5.30(s,1H),4.89(d,J=13.3Hz,1H),4.35(d,J=12.8Hz,1H),4.29(s,1H),3 .94(d,J=8.4Hz,1H),3.77(dd,J=25.7,11.3Hz,2H),3.65(s,2H),3.08(d,J=11.5Hz,1H),2 .96(s,3H),1.84(s,1H),1.49(d,J=28.1Hz,2H),1.33(s,1H),1.13(dd,J=18.8,5.4Hz,3H).

[0550] Embodiment 17

[0551]

[0552] Step 1. tert-Butyl 5-{[4-(1-methylsulfonylcyclopropyl)-6-[(3R)-3-methylmorpholin-4-yl]pyridin-2-yl]amino}-3-methyl-1H-pyrazole-1-carboxylate (19-2)

[0553]

[0554] At 100 ° C, under a nitrogen atmosphere, a mixture of (3R)-4-[6-chloro-4-(1-methylsulfonylcyclopropyl)pyridin-2-yl]-3-methylmorpholine (450 mg, 1.36 mmol), 5-amino-3-methyl-1H-pyrazole-1-carboxylic acid tert-butyl ester (402 mg, 2.04 mmol), BrettPhos-Pd-G3 (27 mg, 0.03 mmol) and Cs2CO3 (1.1 g, 3.40 mmol) in dioxane (40 mL) was stirred overnight. LC-MS showed that the reaction was complete. The mixture was diluted with EA (50 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA=1:1, V / V) to give the desired product (526 mg, yield: 79%). LC / MS ESI(m / z):492[M+H] + .

[0555] Step 2. 4-(1-methylsulfonylcyclopropyl)-N-(3-methyl-1H-pyrazol-5-yl)-6-[(3R)-3-methylmorpholin-4-yl]pyridin-2-amine (19)

[0556]

[0557] A mixture of tert-butyl 5-{[4-(1-methylsulfonylcyclopropyl)-6-[(3R)-3-methylmorpholin-4-yl]pyridin-2-yl]amino}-3-methyl-1H-pyrazole-1-carboxylate (526 mg, 1.07 mmol) in HCl solution (4M in dioxane, 8 mL) was stirred overnight at room temperature. LC-MS showed that the reaction was complete. The mixture was concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (C 18 The residue was purified by HPLC (10-95% MeOH in H2O containing 0.1% HCOOH) to give the desired product (213 mg, yield: 51%). LC / MS ESI (m / z): 392 [M+H] + . 1H NMR(400MHz,DMSO)δ11.69(s,1H),8.79(s,1H),6.66(s,1H),6.18(s,1H),6.00(s,1H),4.26(d, J=6.6Hz,1H),3.93(dd,J=11.2,3.2Hz,1H),3.81(d,J=11.1Hz,1H),3.72(d,J=11.2Hz,1H),3.6 1(dd,J=11.3,2.8Hz,1H),3.47(dd,J=11.6,8.9Hz,1H),3.04(td,J=12.5,3.6Hz,1H),2.93(s,3 H), 2.17 (s, 3H), 1.56 (dd, J = 5.7, 3.9Hz, 2H), 1.24 (dd, J = 6.2, 4.7Hz, 2H), 1.13 (d, J = 6.6Hz, 3H).

[0558] Embodiment 18

[0559]

[0560] Step 1. 2,6-Dichloro-4-iodo-3-methylpyridine (20-2)

[0561]

[0562] At -60 ° C, LDA (2M in THF, 5.48 mL, 10.95 mmol) was added dropwise to a solution of 2,6-dichloro-3-iodopyridine (2 g, 7.30 mmol) in DMF (40 mL) at -60 ° C. The mixture was stirred at -60 ° C for 1 hour, and then iodomethane (0.68 mL, 10.95 mmol) was added dropwise. The resulting mixture was stirred for another 1 hour at -60 ° C. LC-MS shows that the reaction is complete. The reaction is quenched with saturated NH4Cl aqueous solution and extracted with EA (50 mL). The organic layer is separated, then washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue is purified by flash chromatography on silica gel (PE: EA = 10: 1, V / V) to obtain the desired product (1.7 g, yield: 81%). LC / MS (ESI): m / z 288 [M + H] + .

[0563] Step 2. (R)-4-(6-Chloro-4-iodo-5-methylpyridin-2-yl)-3-methylmorpholine (20-4)

[0564]

[0565] (R) -3-methylmorpholine (1.79 g, 17.71 mmol) and N, N- diisopropylethylamine (2.93 mL, 17.71 mmol) were added to a solution of 2,6- dichloro-4-iodo-3-methylpyridine (1.7 g, 5.90 mmol) in NMP (17.0 mL). The mixture was stirred for 1 hour at 180 ° C under microwave irradiation. LC-MS shows that the reaction is complete. The mixture was diluted with EA (60 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (PE: EA = 3: 1, V / V) to obtain the desired product (750 mg, yield: 36%). LC / MS (ESI): m / z 353 [M + H] + .

[0566] Step 3. (R)-4-(6-chloro-4-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-methylpyridin-2-yl)-3-methylmorpholine (20-6)

[0567]

[0568] 1,4-dimethyl-1H-1,2,3-triazole (182 mg, 1.87 mmol), tetramethylammonium acetate (272 mg, 2.04 mmol) and bis(triphenylphosphine)palladium(II) chloride (132 mg, 0.17 mmol) were added to a solution of (R)-4-(6-chloro-4-iodo-5-methylpyridin-2-yl)-3-methylmorpholine (600 mg, 1.70 mmol) in DMF (6 mL). The mixture was stirred for 5 hours at 140 ° C under a nitrogen atmosphere. LC-MS showed that the reaction was complete. The mixture was diluted with EA (60 mL), washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (PE:EA=1:1, V / V) to obtain the desired product (400 mg, yield: 73%). LC / MS(ESI):m / z 322[M+H] + .

[0569] Step 4. (R)-4-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-3-methyl-6-(3-methylmorpholino)-N-(1H-pyrazol-5-yl)pyridin-2-amine (20)

[0570]

[0571] To a solution of (R)-4-(6-chloro-4-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-methylpyridin-2-yl)-3-methylmorpholine (100 mg, 0.31 mmol) in dioxane (2 mL) was added tert-butyl 5-amino-1H-pyrazole-1-carboxylate (85 mg, 0.47 mmol), Cs2CO3 (203 mg, 0.62 mmol) and BrettPhos-Pd-G3 (28 mg, 0.03 mmol). Under nitrogen atmosphere, at 100 °C, the mixture was stirred overnight. LC-MS showed the reaction was complete. The mixture was diluted with EA (60 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was dissolved in DCM (5 mL), and HCl solution (4 M in dioxane, 2 mL) was added. The resulting mixture was stirred at room temperature for 12 hours. LC-MS showed that the reaction was complete. The mixture was concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (C18, 10-95% MeOH in H2O, containing 0.1% HCOOH) to give the desired product (10 mg, yield: 8.7%). LC / MS (ESI): m / z 369 [M+H] + . 1 HNMR(400MHz,DMSO)δ8.13(s,1H),7.56(s,1H),6.46(s,1H),5.97(s,1H),4. 24–4.14(m,1H),3.90(dd,J=11.2,3.1Hz,1H),3.79(s,3H),3.77–3.71(m,1H) ,3.69(d,J=11.5Hz,1H),3.61(d,J=10.8Hz,1H),3.46(d,J=2.6Hz,1H),3.02 (t,J=12.5Hz,1H),2.10(s,3H),1.82(d,J=0.8Hz,3H),1.11(d,J=6.6Hz,3H).

[0572] Embodiment 19

[0573]

[0574] Step 1. (R)-4-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-3-methyl-N-(3-methyl-1H-pyrazol-5-yl)-6-(3-methylmorpholino)pyridin-2-amine (21)

[0575]

[0576] To a solution of (R)-4-(6-chloro-4-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-methylpyridin-2-yl)-3-methylmorpholine (100 mg, 0.31 mmol) in dioxane (2 mL) was added 3-methyl-1H-pyrazol-5-amine (45 mg, 0.47 mmol), Cs2CO3 (203 mg, 0.62 mmol) and BrettPhos-Pd-G3 (28 mg, 0.03 mmol). Under nitrogen atmosphere, at 100 °C, the mixture was stirred overnight. LC-MS showed that the reaction was complete. The mixture was diluted with EA (60 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was dissolved in DCM (5 mL), and HCl solution (4 M in dioxane, 2 mL) was added. The resulting mixture was stirred at room temperature for 12 hours. LC-MS showed that the reaction was complete. The mixture was concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (C18, 10-95% MeOH in H2O, containing 0.1% HCOOH) to give the desired product (15 mg, yield: 12.6%). LC / MS (ESI) m / z: 383 [M+H] + . 1 HNMR (400MHz, DMSO) δ8.00(s,1H),6.22(s,1H),5.96(s,1H),4.20(s,1H),3.91(dd,J=11.2,3.1Hz,1H),3.78(s,3H),3.77–3.72(m,1H),3.70(d,J= 11.8Hz,1H),3.61(d,J=10.8Hz,1H),3.50–3.43(m,1H),3.06–2.98(m,1H ), 2.20 (s, 3H), 2.09 (s, 3H), 1.80 (d, J = 0.7Hz, 3H), 1.12 (d, J = 6.6Hz, 3H).

[0577] Embodiment 20

[0578]

[0579] Step 1: (R)-4-(4,6-dichloropyridin-2-yl)-3-methylmorpholine (22-2)

[0580]

[0581] DIEA (755 mg, 5.84 mmol) was added to a solution of 2,6-dichloro-4-iodopyridine (800 mg, 2.92 mmol) and (R)-3-methylmorpholine (325 mg, 3.21 mmol) in DMA (8 mL). N2 was injected twice into the mixture, and then stirred at 120 ° C for 12 hours. The reaction mixture was diluted with water (30 mL) and extracted with EA (30 mL × 2). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting mixture was purified by flash chromatography using PE / EtOAc (20: 1, 8: 1) elution to obtain the desired product (500 mg, yield: 68.9%).

[0582] Step 2: (R)-4-(6-chloro-4-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)-3-methylmorpholine (22-3)

[0583]

[0584] To a solution of (R)-4-(6-chloro-4-iodopyridin-2-yl)-3-methylmorpholine (300 mg, 1.21 mmol) and 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (270.8 mg, 1.21 mmol) in dioxane (10 mL) was added Na2CO3 (320 mg, 3.03 mmol) and Pd(dppf)Cl2 (88 mg, 0.12 mmol). N2 was injected twice into the mixture and then stirred at 90 ° C for 12 hours. The reaction mixture was diluted with water (30 mL) and extracted with EA (30 mL×2). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting mixture was purified by flash chromatography eluting with PE / EtOAc (3:1, 1:1) to afford the desired product (320 mg, yield: 86.02%).

[0585] Step 3: (R)-4-(3,5-dimethylisoxazol-4-yl)-6-(3-methylmorpholino)-N-(1H-pyrazol-5-yl)pyridin-2-amine (22)

[0586]

[0587] Cs2CO3 (400 mg, 1.23 mmol) and BrettPhos Pd G3 (45 mg, 0.049 mmol) were added to dioxane (8 mL) containing (R)-4-(6-chloro-4-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)-3-methylmorpholine (150 mg, 0.49 mmol) and tert-butyl 5-amino-1H-pyrazole-1-carboxylate (108 mg, 0.59 mmol). N2 was injected into the mixture twice and then stirred at 90 ° C overnight. The reaction was diluted with water and extracted with EtOAc (30 mL×2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative TLC (DCM / MeOH=10 / 1) to give the desired product (20 mg, yield: 11.49%). LC / MS(ESI)m / z:355.0[M+H] + .

[0588] 1 H NMR (400MHz, DMSO-d6) δppm 12.03 (br s, 1H) 8.98 (br s, 1H) 7.55 (br s, 1H) 6.33-6.47 (m, 2H) 5.99 (s, 1H) 4.30 (br d, J=5.16Hz, 1H) 3.94 (br dd,J=11.12,3.20Hz,1H)3.84(br d,J=11.68Hz,1H)3.71-3.75(m,1H)3.61-3.66(m,1H)3.45-3.52(m,1H)3.03-3.10(m,1H)2.44(s,3H)2.25(s,3H)1.15(d,J=6.64Hz,3H).

[0589] Embodiment 21

[0590]

[0591] Step 1. (3R)-4-(6-Chloro-4-iodopyridin-2-yl)-3-methylmorpholine (23-3)

[0592]

[0593] (3R) -3-methylmorpholine (554.1 mg, 5.48 mmol) was added to a solution of 2,6- dichloro-4-iodopyridine (500 mg, 1.83 mmol) in NMP (10 mL). The mixture was stirred for 1 hour at 150 ° C under microwave irradiation. The reaction mixture was diluted with EA (60 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (PE: EA = 10: 1, V / V) to obtain the desired product (250 mg, yield: 40%). LC / MS (ESI): m / z 339 [M + H] + .

[0594] Step 2. (3R)-4-[6-Chloro-4-(dimethyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl]-3-methylmorpholine (23-5)

[0595]

[0596] Pd(PPh3)2Cl2(62.2mg, 0.09mmol) and tetramethylammonium acetate (141.6mg, 1.06mmol) were added to a solution of (3R)-4-(6-chloro-4-iodopyridin-2-yl)-3-methylmorpholine (300mg, 0.88mmol) and 1,4-dimethyl-1H-1,2,3-triazole (103.3mg, 1.06mmol) in DMF (15mL). Under a nitrogen atmosphere, at 100°C, the mixture was stirred overnight. LC-MS shows that the reaction is complete. The reaction mixture was diluted with DCM (60mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (PE:EA=3:1, V / V) to obtain the desired product (210mg, yield: 77%). LC / MS(ESI):m / z 309[M+H] + .

[0597] Step 3. 4-(Dimethyl-1H-1,2,3-triazol-5-yl)-N-(3-methyl-1H-pyrazol-5-yl)-6-[(3R)-3-methylmorpholin-4-yl]pyridin-2-amine (23)

[0598]

[0599] To a solution of (3R)-4-[6-chloro-4-(dimethyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl]-3-methylmorpholine (90 mg, 0.29 mmol) in dioxane (2 mL) was added tert-butyl 5-amino-3-methyl-1H-pyrazole-1-carboxylate (86.51 mg, 0.439 mmol), BrettPhos-Pd-G3 (26.5 mg, 0.03 mmol) and Cs2CO3 (190.5 mg, 0.59 mmol). The mixture was stirred overnight at 100 °C under nitrogen atmosphere. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by preparative HPLC (C18, 10-95% MeCN in H2O, containing 0.1% ammonia) to give the desired product (35 mg, yield: 32%). LC / MS (ESI): m / z 369 [M+H] + . 1 H NMR (400MHz, DMSO) δ11.71(s,1H),8.92(s,1H),6.55(s,1H),6.07(d,J=6.1Hz ,2H),4.31(d,J=5.9Hz,1H),3.96(s,3H),3.90(dd,J=14.1,8.1Hz,2H),3.72( d,J=11.2Hz,1H),3.63(dd,J=11.2,2.9Hz,1H),3.48(td,J=11.8,2.8Hz,1H), 3.07(td,J=12.5,3.5Hz,1H),2.25(s,3H),2.18(s,3H),1.16(d,J=6.6Hz,3H).

[0600] Embodiment 22

[0601]

[0602] Step 1. (R)-2-(2-((1H-pyrazol-5-yl)amino)-6-(3-methylmorpholino)pyridin-4-yl)-2-methylpropionitrile (24)

[0603]

[0604] To a solution of 2-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyridin-4-yl}-2-methylpropionitrile (60 mg, 0.21 mmol) and 1H-pyrazol-5-amine (35 mg, 0.42 mmol) in dioxane (3 mL) was added BrettPhos-Pd-G3 (19 mg, 0.21 mmol) and Cs2CO3 (210 mg, 0.64 mmol). Under N2 atmosphere, the mixture was stirred at 110 °C for 10 hours. LC-MS showed that the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (C 18 The residue was purified by HPLC (HPLC-MS / MS): m / z 327 [M+H] + . 1 H NMR (400MHz, DMSO) δ12.10 (s, 1H), 9.02 (s, 1H), 7.53 (d, J = 2.2Hz, 1H), 6.59 (s, 1H), 6.30 (d,J=1.9Hz,1H),6.08(d,J=1.0Hz,1H),4.32(d,J=6.5Hz,1H),3.93(dd,J=11.2,3.3Hz, 1H),3.79(d,J=12.8Hz,1H),3.73(d,J=11.2Hz,1H),3.62(dd,J=11.3,2.9Hz,1H),3.47( td,J=11.8,3.0Hz,1H),3.06(td,J=12.6,3.7Hz,1H),1.63(s,6H),1.13(d,J=6.6Hz,3H).

[0605] Embodiment 23

[0606]

[0607] Step 1. 2-{2-Chloro-6-[(3R)-3-methylmorpholin-4-yl]pyridin-4-yl}-2-methylpropionitrile (25-2)

[0608]

[0609] At 0 ° C, sodium tert-butoxide (198 mg, 2.06 mmol) and iodomethane (0.13 mL, 2.06 mmol) were added to a solution of 2-{2-chloro-6-[(3R)-3-methylmorpholine-4-yl]pyridin-4-yl}acetonitrile (173 mg, 0.69 mmol) in THF (6 mL). The mixture was stirred overnight at ambient temperature. LC-MS showed that the reaction was complete. The mixture was diluted with EA (50 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE: EA = 3: 1, V / V) to obtain the desired product (154 mg, yield: 80%). LC / MS ESI (m / z): 280 [M + H] + .

[0610] Step 2. tert-Butyl 5-{[4-(1-cyano-1-methylethyl)-6-[(3R)-3-methylmorpholin-4-yl]pyridin-2-yl]amino}-3-methyl-1H-pyrazole-1-carboxylate (25-3)

[0611]

[0612] To a solution of 2-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyridin-4-yl}-2-methylpropionitrile (154 mg, 0.55 mmol) and tert-butyl 5-amino-3-methyl-1H-pyrazole-1-carboxylate (163 mg, 0.83 mmol) in dioxane (10 mL) was added BrettPhos-Pd-G3 (50 mg, 0.06 mmol) and Cs2CO3 (538 mg, 1.65 mmol). Under a nitrogen atmosphere, the mixture was stirred overnight at 100 ° C. LC-MS showed that the reaction was complete. The mixture was diluted with EA (50 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA=1:1, V / V) to give the desired product (156 mg, yield: 64%). LC / MS ESI(m / z):441[M+H] + .

[0613] Step 3. 2-Methyl-2-{2-[(3-methyl-1H-pyrazol-5-yl)amino]-6-[(3R)-3-methylmorpholin-4-yl]pyridin-4-yl}propanenitrile (25)

[0614]

[0615] A mixture of tert-butyl 5-{[4-(1-cyano-1-methylethyl)-6-[(3R)-3-methylmorpholin-4-yl]pyridin-2-yl]amino}-3-methyl-1H-pyrazole-1-carboxylate (156 mg, 0.35 mmol) in HCl solution (4M in dioxane, 4 mL) was stirred overnight at room temperature. LC-MS showed that the reaction was complete. The mixture was concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (C 18 The residue was purified by HPLC (10-95% MeOH in H2O containing 0.1% HCOOH) to give the desired product (88.5 mg, yield: 73%). LC / MS ESI (m / z): 341 [M+H] + . 1 H NMR(400MHz,DMSO)δ9.43(s,1H),6.60(s,1H),6.18(s,1H),6.04(s,1H),4.30(d d,J=6.6,1.9Hz,1H),3.95(dd,J=11.3,3.4Hz,1H),3.80(dd,J=13.1,2.0Hz,1H), 3.74(d,J=11.3Hz,1H),3.64(dd,J=11.3,2.8Hz,1H),3.49(td,J=11.8,3.0Hz,1H ), 3.11(td,J=12.6,3.8Hz,1H),2.21(s,3H),1.64(s,6H),1.15(d,J=6.6Hz,3H).

[0616] Embodiment 24

[0617]

[0618] Step 1. (R)-4-(6-chloro-4-(2-(methylsulfonyl)propan-2-yl)pyridin-2-yl)-3-methylmorpholine (26-1)

[0619]

[0620] To a solution of (3R)-4-[6-chloro-4-(methylsulfonylmethyl)pyridin-2-yl]-3-methylmorpholine (5.8 g, 19.03 mmol) in THF (100 mL) was added CH3I (4.7 mL, 76.11 mmol) and t-BuONa (7.31 g, 76.11 mmol). The reaction was stirred at room temperature overnight. The reaction was diluted with EA (100 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA=1:1, V / V) to obtain the desired product (5.3 g, yield: 83.7%). LC / MS (ESI): m / z 333 [M+H] + .

[0621] Step 2. 6-((R)-3-methylmorpholino)-4-(2-(methylsulfonyl)propan-2-yl)-N-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-2-amine (26-3)

[0622]

[0623] To a solution of (3R)-4-[6-chloro-4-(2-methylsulfonylpropane-2-yl)pyridin-2-yl]-3-methylmorpholine (4.0 g, 12.02 mmol) in dioxane (80 mL) was added 1-(tetrahydropyran-2-yl)-1H-pyrazole-5-amine (3.0 g, 18.03 mmol), Brettphos Pd G3 (1.09 g, 1.20 mmol) and Cs2CO3 (11.8 g, 36.05 mmol). Under a nitrogen atmosphere, the mixture was stirred overnight at 100 ° C. The reaction was diluted with DCM (100 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (DCM: MeOH = 30: 1, V / V) to give the desired product (4.45 g, yield: 80%). LC / MS(ESI):m / z 464[M+H] + .

[0624] Step 3. (R)-6-(3-methylmorpholino)-4-(2-(methylsulfonyl)propan-2-yl)-N-(1H-pyrazol-5-yl)pyridin-2-amine (26)

[0625]

[0626] To a solution of 4-(2-methylsulfonylpropane-2-yl)-6-[(3R)-3-methylmorpholine-4-yl]-N-[1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]pyridine-2-amine (4.45 g, 9.60 mmol) in DCM (50 mL) was added HCl / dioxane (50 mL). The reaction was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum. The residue was diluted with DCM (50 mL), then washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous Na2SO4, filtered and concentrated. By preparative HPLC (C 18 The residue was purified by HPLC (HPLC-MS / MS): m / z 380 [M+H] + . 1 H NMR(400MHz,DMSO)δ12.02(s,1H),8.95(s,1H),7.53(s,1H),6.65(s,1H),6.27(d, J=60.7Hz,1H),6.19(s,1H),4.28(d,J=6.2Hz,1H),3.94(dd,J=11.1,3.2Hz,1H),3. 76(dd,J=22.8,11.2Hz,2H),3.63(dd,J=11.2,2.8Hz,1H),3.48(td,J=11.7,2.9Hz, 1H), 3.05 (td, J = 12.6, 3.7Hz, 1H), 2.76 (s, 3H), 1.66 (s, 6H), 1.12 (d, J = 6.6Hz, 3H).

[0627] Embodiment 25

[0628]

[0629] Step 1. tert-Butyl 5-{[4-(2-methylsulfonylpropan-2-yl)-6-[(3R)-3-methylmorpholin-4-yl]pyridin-2-yl]amino}-3-methyl-1H-pyrazole-1-carboxylate (27-1)

[0630]

[0631] At 100 ° C, under a nitrogen atmosphere, a mixture of (3R)-4-[6-chloro-4-(2-methylsulfonylpropane-2-yl)pyridin-2-yl]-3-methylmorpholine (580 mg, 1.74 mmol), 5-amino-3-methyl-1H-pyrazole-1-carboxylic acid tert-butyl ester (516 mg, 2.61 mmol), BrettPhos-Pd-G3 (157.9 mg, 0.17 mmol) and Cs2CO3 (1.42 g, 4.36 mmol) in dioxane (20 mL) was stirred overnight. LC-MS showed that the reaction was complete. The mixture was diluted with EA (50 mL), washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA=1:1, V / V) to give the desired product (758 mg, yield: 88%). LC / MS ESI(m / z):494[M+H] + .

[0632] Step 2. 4-(2-methylsulfonylpropan-2-yl)-N-(3-methyl-1H-pyrazol-5-yl)-6-[(3R)-3-methylmorpholin-4-yl]pyridin-2-amine (27)

[0633]

[0634] A mixture of tert-butyl 5-{[4-(2-methylsulfonylpropan-2-yl)-6-[(3R)-3-methylmorpholin-4-yl]pyridin-2-yl]amino}-3-methyl-1H-pyrazole-1-carboxylate (758 mg, 1.54 mmol) in HCl solution (4M in dioxane, 8 mL) was stirred overnight at ambient temperature. LC-MS showed that the reaction was complete. The mixture was concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (C 18 The residue was purified by HPLC (10-95% MeOH in H2O containing 0.1% HCOOH) to give the desired product (215 mg, yield: 35%). LC / MS ESI (m / z): 394 [M+H] + . 1H NMR(400MHz,DMSO)δ11.67(s,1H),8.79(s,1H),6.70(s,1H),6.19(s,1H),6.03(s,1H ),4.27(d,J=6.6Hz,1H),3.94(dd,J=11.2,3.2Hz,1H),3.79(d,J=13.1Hz,1H),3.73( d,J=11.2Hz,1H),3.63(dd,J=11.2,2.8Hz,1H),3.48(td,J=11.8,2.9Hz,1H),3.04(t d,J=12.6,3.7Hz,1H),2.75(s,3H),2.17(s,3H),1.66(s,6H),1.12(d,J=6.6Hz,3H).

[0635] Embodiment 26

[0636]

[0637] Step 1. (R)-2-(2-((1H-pyrazol-5-yl)amino)-6-(3-methylmorpholino)pyrimidin-4-yl)-2-methylpropionitrile (28)

[0638]

[0639] At 110 ° C, under N2 atmosphere, a mixture of 2-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}-2-methylpropionitrile (100 mg, 0.35 mmol), 1H-pyrazole-5-amine (59 mg, 0.71 mmol), BrettPhos Pd G3 (32 mg, 0.03 mmol) and Cs2CO3 (349 mg, 1.07 mmol) in dioxane (4 mL) was stirred for 16 hours. LC-MS showed that the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The product was purified by preparative HPLC (C 18 The residue was purified by HPLC (HPLC-MS / MS): m / z 328 [M+H] + . 1H NMR(400MHz,DMSO)δ12.08(s,1H),9.20(s,1H),8.13(s,1H),7.51(s,1H),6.52 (s,1H),6.25(s,1H),4.41(s,1H),4.01(d,J=12.8Hz,1H),3.93(dd,J=11.3,3. 4Hz, 1H), 3.72 (d, J = 11.4Hz, 1H), 3.58 (dd, J = 11.4, 3.0Hz, 1H), 3.43 (td, J = 11. 8, 2.9Hz, 1H), 3.14 (td, J = 13.0, 3.8Hz, 1H), 1.65 (s, 6H), 1.19 (d, J = 6.7Hz, 3H).

[0640] Embodiment 27

[0641]

[0642] Step 1. 2,6-Dichloro-3-fluoro-4-iodopyridine (33-2)

[0643]

[0644] At -78 ° C, under N2 atmosphere, LDA (2.0M in THF, 6.6 mL, 13.2 mmol) was added dropwise to a solution of 2,6-dichloro-3-fluoropyridine (2.0 g, 12.05 mmol) in anhydrous THF (30 mL). The mixture was stirred at -78 ° C for 1 hour, and then a solution of I2 (4.0 g, 15.74 mmol) in anhydrous THF (10 mL) was added dropwise. The resulting mixture was stirred for another 1 hour at -78 ° C. LC-MS shows that the reaction is complete. The reaction mixture is quenched with saturated NH4Cl aqueous solution and diluted with EA (30 mL × 3). The combined organic layer is washed with saturated Na2S2O3 aqueous solution and brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue is purified by silica gel column chromatography (PE) to obtain the desired product (2.79 g, yield: 79%). 1 H NMR (400MHz, DMSO) δ8.16 (d, J=3.5Hz, 1H).

[0645] Step 2. 2,6-Dichloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-3-fluoropyridine (33-4)

[0646]

[0647] At 90 ° C, under N2 atmosphere, a mixture of 2,6-dichloro-3-fluoro-4-iodopyridine (1.0 g, 3.42 mmol), (1,4-dimethyl-1H-pyrazol-5-yl) boronic acid (0.76 g, 3.43 mmol), PdCl2(dppf) (251 mg, 0.34 mmol) and Na2CO3 (2.0 M in H2O, 3.4 mL) in DME (35 mL) was stirred for 15 hours. LC-MS showed that the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA=10:1, V / V) to obtain the desired product (744 mg, yield: 83%). LC / MS(ESI):m / z 260[M+H] + .

[0648] Step 3. 6-Chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-3-fluoro-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridin-2-amine (33-6)

[0649]

[0650] At 100 ° C, under N2 atmosphere, a mixture of 2,6-dichloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-3-fluoropyridine (400 mg, 1.53 mmol), 1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-amine (329 mg, 1.54 mmol), Pd2(dba)3 (141 mg, 0.15 mmol), XantPhos (89 mg, 0.15 mmol) and Cs2CO3 (1.0 g, 3.06 mmol) in dioxane (25 mL) was stirred for 6 hours. LC-MS showed that the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA=2:1, V / V) to obtain the desired product (419 mg, yield: 62%). LC / MS (ESI): m / z 437 [M+H] + .

[0651] Step 4. (R)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-3-fluoro-6-(3-methylmorpholino)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridin-2-amine (33-8)

[0652]

[0653] A mixture of 6-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-3-fluoro-N-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-yl)pyridin-2-amine (400 mg, 0.91 mmol), (3R)-3-methylmorpholine (278 mg, 2.74 mmol), Pd(dba) (168 mg, 0.18 mmol), RuPhos (171 mg, 0.36 mmol) and CsCO (1.19 g, 3.65 mmol) in dioxane (40 mL) was stirred at 100 °C under N atmosphere for 6 hours. LC-MS showed that the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous NaSO, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA=2:1, V / V) to obtain the desired product (437 mg, yield: 95%). LC / MS (ESI): m / z 502 [M+H] + .

[0654] Step 5. (R)-4-(1,4-Dimethyl-1H-pyrazol-5-yl)-3-fluoro-6-(3-methylmorpholino)-N-(1H-pyrazol-5-yl)pyridin-2-amine (33)

[0655]

[0656] At 70 ° C, a mixture of 4-(1,4-dimethyl-1H-pyrazol-5-yl)-3-fluoro-6-[(3R)-3-methylmorpholine-4-yl]-N-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-yl)pyridine-2-amine (417 mg, 0.83 mmol) in TBAF solution (1.0 M in THF, 8 mL, 8 mmol) was stirred for 5 hours. LC-MS shows that the reaction is complete. The reaction mixture was diluted with EA (40 mL), then washed with water (20 mL×2) and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA=1:1, V / V) to obtain a brown solid (252 mg), which can be obtained by preparative HPLC (C 18 , 10-95% MeOH in H2O, containing 0.1% HCOOH) was further purified to give the desired product (66.9 mg, yield: 21%). LC / MS (ESI): m / z 372 [M+H] + . 1H NMR (400MHz, DMSO) δ12.18(s,1H),8.89(s,1H),7.59(s,1H),7.37(s,1H),6.51(s,1H),5.94(s,1H),4.20(d,J=4.8Hz,1H),3.97–3.89( m,1H),3.77–3.69(m,5H),3.63(dd,J=11.2,2.7Hz,1H),3.51(s,1H),3.05(td,J=12.6,3.7Hz,1H),1.96(s,3H),1.13(d,J=6.6Hz,3H).

[0657] Embodiment 28

[0658]

[0659] Step 1. 2,6-Dichloro-3-fluoroisonicotinaldehyde (34-3)

[0660]

[0661] At -78 ° C, LDA (2.5M in THF, 9.4 mL, 23.50 mmol) was added dropwise to a solution of 2,6-dichloro-3-fluoropyridine (3 g, 18.07 mmol) in THF (50 mL) at -78 ° C. The mixture was stirred at -78 ° C for 1 hour, and then a solution of ethyl formate (2.2 mL, 27.11 mmol) in THF (2 mL) was added dropwise. The mixture was stirred for another 1 hour at -78 ° C. LC-MS shows that the reaction is complete. The mixture is quenched with saturated NH4Cl aqueous solution and extracted with EA (50 mL × 3). The combined organic phases are washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue is purified by silica gel column chromatography (PE: EA = 10: 1, V / V) to obtain the desired product (1.7 g, yield: 48%). 1 H NMR (400MHz, DMSO) δ 10.11 (s, 1H), 7.91 (d, J = 4.0Hz, 1H).

[0662] Step 2. (2,6-Dichloro-3-fluoropyridin-4-yl)methanol (34-4)

[0663]

[0664] At 0 ° C, NaBH4 (590 mg, 17.53 mmol) was added to a solution of 2,6-dichloro-3-fluoroisonicotinaldehyde (1.7 g, 8.76 mmol) in THF (30 mL) in batches. After addition, the mixture was stirred at 0 ° C for 1 hour. LC-MS shows that the reaction is complete. The reaction mixture is quenched with saturated NH4Cl aqueous solution and extracted with EA (40 mL × 3). The combined organic phases are washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue is purified by silica gel column chromatography (PE: EA = 5: 1, V / V) to obtain the desired product (1.62 g, yield: 95%). LC / MS (ESI): m / z 196 [M + H] + .

[0665] Step 3. 2,6-Dichloro-4-(chloromethyl)-3-fluoropyridine (34-5)

[0666]

[0667] To a solution of (2,6-dichloro-3-fluoropyridin-4-yl)methanol (1.6 g, 8.16 mmol) and DMF (0.05 mL, 0.68 mmol) in DCM (30 mL) was added SOCl2 (1.2 mL, 16.33 mmol) dropwise at 0 ° C. The mixture was stirred at room temperature for 16 hours. LC-MS showed that the reaction was complete. The reaction mixture was concentrated to give the desired product (1.7 g, yield: 97%). LC / MS (ESI) m / z: 214 [M+H] + .

[0668] Step 4. 2,6-Dichloro-3-fluoro-4-((methylsulfonyl)methyl)pyridine (34-6)

[0669]

[0670] At 0 ° C, CH3SO2Na (1.21 g, 11.89 mmol) was added in batches to a solution of 2,6-dichloro-4-(chloromethyl)-3-fluoropyridine (1.7 g, 7.93 mmol) in DMF (30 mL). The mixture was stirred at room temperature for 4 hours. LC-MS showed that the reaction was complete. The reaction mixture was poured into H2O (20 mL) and extracted with EA (30 mL × 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel flash column chromatography (PE: EA = 3: 1, V / V) to obtain the desired product (1.76 g, yield: 86%). LC / MS (ESI): m / z 258 [M + H] + .

[0671] Step 5. 2,6-Dichloro-3-fluoro-4-(1-(methylsulfonyl)cyclopropyl)pyridine (34-7)

[0672]

[0673] To a solution of 2,6-dichloro-3-fluoro-4-((methylsulfonyl)methyl)pyridine (1.76 g, 6.82 mmol), 1,2-dibromoethane (1.5 mL, 17.05 mmol) and TBAB (440 mg, 1.36 mmol) in toluene (60 mL) was added NaOH (10 M in H2O, 6.82 mL, 68.19 mmol). The mixture was stirred at 60 ° C for 3 hours. LC-MS showed that the reaction was complete. The reaction mixture was poured into H2O (30 mL) and extracted with EA (30 mL×3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA=2:1, V / V) to obtain the desired product (1.6 g, yield: 83%). LC / MS(ESI):m / z 284[M+H] + .

[0674] Step 6. 6-Chloro-3-fluoro-4-(1-(methylsulfonyl)cyclopropyl)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridin-2-amine (34-9)

[0675]

[0676] To a solution of 2,6-dichloro-3-fluoro-4-(1-(methylsulfonyl)cyclopropyl)pyridine (600 mg, 2.11 mmol), 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-amine (450 mg, 2.11 mmol), and XantPhos (244 mg, 0.42 mmol) in dioxane (15 mL) was added Pd2(dba)3 (193 mg, 0.21 mmol) and C S2 CO3 (1.38 g, 4.22 mmol). Under N2 atmosphere, at 100 ° C, the mixture was stirred for 6 hours. LC-MS showed that the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE: EA = 1: 1, V / V) to obtain the desired product (715 mg, yield: 73.5%). LC / MS (ESI): m / z 461 [M + H] + .

[0677] Step 7. (R)-3-Fluoro-6-(3-methylmorpholino)-4-(1-(methylsulfonyl)cyclopropyl)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridin-2-amine (34-11)

[0678]

[0679] To a solution of 6-chloro-3-fluoro-4-(1-(methylsulfonyl)cyclopropyl)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridin-2-amine (640 mg, 1.39 mmol), (3R)-3-methylmorpholine (281 mg, 2.78 mmol) and RuPhos (130 mg, 0.28 mmol) in dioxane (15 mL) was added Pd2(dba)3 (127 mg, 0.14 mmol) and C S2 CO3 (1.36 g, 4.16 mmol). Under N2 atmosphere, at 100 ° C, the mixture was stirred for 16 hours. LC-MS showed that the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel flash column chromatography (DCM: MeOH = 50: 1, V / V) to obtain the desired product (450 mg, yield: 62%). LC / MS (ESI): m / z 527 [M + H] + .

[0680] Step 8. (R)-3-Fluoro-6-(3-methylmorpholino)-4-(1-(methylsulfonyl)cyclopropyl)-N-(1H-pyrazol-5-yl)pyridin-2-amine (34)

[0681]

[0682] A mixture of (R)-3-fluoro-6-(3-methylmorpholino)-4-(1-(methylsulfonyl)cyclopropyl)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridin-2-amine (450 mg, 0.86 mmol) in HCl solution (4M in dioxane, 5 mL) was stirred at 60 °C for 1.5 hours. LC-MS showed that the reaction was complete. The mixture was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (DCM:MeOH=30:1, V / V) to give a light yellow oil which could be obtained by preparative HPLC (C 18, 10-95% MeOH in H2O, containing 0.1% HCOOH) was further purified to give the desired product (45 mg, yield: 13%). LC / MS (ESI): m / z 396 [M+H] + . 1 H NMR (400MHz, DMSO) δ12.17(s,1H),8.80(s,1H),7.58(s,1H),6.47(s,1H),6. 11(s,1H),4.22–4.15(m,1H),3.93(dd,J=11.2,3.1Hz,1H),3.74–3.66(m,2H) ,3.61(dd,J=11.3,2.7Hz,1H),3.48–3.46(m,1H),3.04(dd,J=12.5,3.7Hz,1 H), 2.98 (s, 3H), 1.70–1.62 (m, 2H), 1.37–1.30 (m, 2H), 1.11 (d, J = 6.6Hz, 3H).

[0683] Embodiment 29

[0684]

[0685] Step 1. 2-{2-Chloro-6-[(3R)-3-methylmorpholin-4-yl]pyridin-4-yl}acetonitrile (35-1)

[0686]

[0687] To a solution of (3R)-4-[6-chloro-4-(chloromethyl)pyridin-2-yl]-3-methylmorpholine (778 mg, 2.98 mmol) in DMSO (15 mL) was added NaCN (219 mg, 4.47 mmol) in batches. The mixture was stirred overnight at ambient temperature. LC-MS showed that the reaction was complete. The mixture was diluted with EA (50 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA=3:1, V / V) to give the desired product (253 mg, yield: 34%). LC / MS ESI (m / z): 252 [M+H] + .

[0688] Step 2. 1-{2-Chloro-6-[(3R)-3-methylmorpholin-4-yl]pyridin-4-yl}cyclopropane-1-carbonitrile (35-2)

[0689]

[0690] At 60 ° C, under a nitrogen atmosphere, a mixture of 2-{2-chloro-6-[(3R)-3-methylmorpholine-4-yl]pyridin-4-yl}acetonitrile (80 mg, 0.32 mmol), 1,2-dibromoethane (0.06 mL, 0.64 mmol), KOH (500 mg, 8.91 mmol) and TBAB (21 mg, 0.06 mmol) in 2-methyltetrahydrofuran (2 mL) and H2O (0.5 mL) was stirred overnight. LC-MS showed that the reaction was complete. The mixture was diluted with EA (50 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA=2:1, V / V) to obtain the desired product (64 mg, yield: 73%). LC / MS ESI (m / z): 278 [M+H] + .

[0691] Step 3. tert-Butyl 5-{[4-(1-cyanocyclopropyl)-6-[(3R)-3-methylmorpholin-4-yl]pyridin-2-yl]amino}-3-methyl-1H-pyrazole-1-carboxylate (35-3)

[0692]

[0693] At 100 ° C, under a nitrogen atmosphere, a mixture of 1-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyridin-4-yl}cyclopropane-1-carbonitrile (64 mg, 0.23 mmol), 5-amino-3-methyl-1H-pyrazole-1-carboxylic acid tert-butyl ester (68 mg, 0.35 mmol), BrettPhos-Pd-G3 (20 mg, 0.02 mmol) and Cs2CO3 (225 mg, 0.69 mmol) in dioxane (6 mL) was stirred overnight. LC-MS showed that the reaction was complete. The mixture was diluted with EA (50 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA=1:1, V / V) to give the desired product (62 mg, yield: 61%). LC / MS ESI(m / z):439[M+H] + .

[0694] Step 4. 1-{2-[(3-methyl-1H-pyrazol-5-yl)amino]-6-[(3R)-3-methylmorpholin-4-yl]pyridin-4-yl}cyclopropane-1-carbonitrile (35)

[0695]

[0696] A solution of tert-butyl 5-{[4-(1-cyanocyclopropyl)-6-[(3R)-3-methylmorpholin-4-yl]pyridin-2-yl]amino}-3-methyl-1H-pyrazole-1-carboxylate (62 mg, 0.14 mmol) in HCl solution (4M in dioxane, 4 mL) was stirred overnight at ambient temperature. LC-MS showed that the reaction was complete. The mixture was concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (C 18 The residue was purified by HPLC (10-95% MeOH in H2O containing 0.1% HCOOH) to give the desired product (15.4 mg, yield: 32%). LC / MS ESI (m / z): 339 [M+H] + . 1 H NMR(400MHz,DMSO)δ11.72(br,1H),8.81(s,1H),6.57(s,1H),5.99(s,1H),5.77(s,1H),4 .30(d,J=6.5Hz,1H),3.92(dd,J=11.2,3.2Hz,1H),3.76(d,J=12.7Hz,1H),3.71(d,J=11.2 Hz,1H),3.60(dd,J=11.2,2.8Hz,1H),3.47–3.44(m,1H),3.03(dd,J=12.6,9.0Hz,1H),2. 17 (s, 3H), 1.71 (dd, J = 7.5, 4.4Hz, 2H), 1.50 (dd, J = 7.7, 4.4Hz, 2H), 1.11 (d, J = 6.6Hz, 3H).

[0697] Embodiment 30

[0698]

[0699] Step 1. (R)-N-(3-methyl-1H-pyrazol-5-yl)-6-(3-methylmorpholino)-4-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)pyridin-2-amine (36)

[0700]

[0701] To a solution of (R)-4-(6-chloro-4-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-3-methylmorpholine (100 mg, 0.27 mmol), tert-butyl 5-amino-3-methyl-1H-pyrazole-1-carboxylate (105 mg, 0.53 mmol) and Cs2CO3 (261 mg, 0.80 mmol) in dioxane (8 mL) was added BrettPhos-Pd-G3 (24 mg, 0.027 mmol). The mixture was stirred at 100 °C under N2 atmosphere for 16 hours. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (60 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The product was purified by preparative HPLC (C 18 The residue was purified by HPLC (HPLC-MS / MS): m / z 436 [M+H] + . 1 H NMR(400MHz,DMSO)δ11.69(s,1H),8.82(s,1H),6.70(s,1H),6.17(s,1H),6.05(s,1 H),4.31–4.23(m,1H),3.96–3.83(m,4H),3.72(d,J=11.2Hz,1H),3.64(dd,J=11.2,2 .7Hz,1H),3.49(td,J=11.7,2.8Hz,1H),3.26–3.18(m,2H),3.05(td,J=12.7,3.6Hz ,1H),2.71(s,3H),2.43(d,J=13.7Hz,2H),2.24–2.16(m,5H),1.12(d,J=6.6Hz,3H).

[0702] Embodiment 31

[0703]

[0704] Step 1. 1-{2-Chloro-6-[(3R)-3-methylmorpholin-4-yl]pyridin-4-yl}cyclopentane-1-carbonitrile (37-1)

[0705]

[0706] A mixture of 2-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyridin-4-yl}acetonitrile (210 mg, 0.83 mmol), 1,4-dibromobutane (1 mL, 8.34 mmol), KOH (3 g, 53.47 mmol) and TBAB (54 mg, 0.17 mmol) in a co-solvent of 2-methyltetrahydrofuran (15 mL) and H2O (3 mL) was stirred overnight at 70 °C. LC-MS showed that the reaction was complete. The mixture was diluted with EA (50 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA=3:1, V / V) to obtain the desired product (192 mg, yield: 75%). LC / MSESI (m / z): 306 [M+H] + .

[0707] Step 2. tert-Butyl 5-{[4-(1-cyanocyclopentyl)-6-[(3R)-3-methylmorpholin-4-yl]pyridin-2-yl]amino}-1H-pyrazole-1-carboxylate (37-2)

[0708]

[0709] To a solution of 1-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyridin-4-yl}cyclopentane-1-carbonitrile (100 mg, 0.33 mmol) and tert-butyl 5-amino-1H-pyrazole-1-carboxylate (90 mg, 0.49 mmol) in dioxane (10 mL) was added BrettPhos-Pd-G3 (29.6 mg, 0.03 mmol) and Cs2CO3 (319.6 mg, 0.98 mmol). Under a nitrogen atmosphere, the mixture was stirred overnight at 100 ° C. LC-MS showed that the reaction was complete. The mixture was diluted with EA (50 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA=1:1, V / V) to give the desired product (104 mg, yield: 70%). LC / MS ESI(m / z):453[M+H] + .

[0710] Step 3. 1-{2-[(3R)-3-methylmorpholin-4-yl]-6-[(1H-pyrazol-5-yl)amino]pyridin-4-yl}cyclopentane-1-carbonitrile (37)

[0711]

[0712] A mixture of tert-butyl 5-{[4-(1-cyanocyclopentyl)-6-[(3R)-3-methylmorpholin-4-yl]pyridin-2-yl]amino}-1H-pyrazole-1-carboxylate (104 mg, 0.23 mmol) in HCl solution (4M in dioxane, 4 mL) was stirred overnight at ambient temperature. LC-MS showed that the reaction was complete. The mixture was concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (C 18 The residue was purified by HPLC (10-95% MeOH in H2O containing 0.1% HCOOH) to give the desired product (42.5 mg, yield: 52%). LC / MS ESI (m / z): 353 [M+H] + . 1 H NMR (400MHz, DMSO) δ12.14(s,1H),9.01(s,1H),7.54(d,J=2.2Hz,1H),6.59(s,1H),6.30(d,J=2 .2Hz,1H),6.07(d,J=0.9Hz,1H),4.35–4.29(m,1H),3.93(dd,J=11.2,3.3Hz,1H),3.79(d,J=13. 0Hz,1H),3.73(d,J=11.2Hz,1H),3.62(dd,J=11.3,2.8Hz,1H),3.48(dd,J=11.8,2.9Hz,1H),3. 09–3.02(m,1H),2.34–2.28(m,2H),2.10–2.03(m,2H),1.90–1.85(m,4H),1.13(d,J=6.6Hz,3H).

[0713] Embodiment 32

[0714]

[0715] Step 1. 1-{2-Chloro-6-[(3R)-3-methylmorpholin-4-yl]pyridin-4-yl}cyclohexane-1-carbonitrile (38-1)

[0716]

[0717] At 70 ° C, a mixture of 2-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyridin-4-yl}acetonitrile (210 mg, 0.83 mmol), 1,5-dibromopentane (1.2 mL, 8.34 mmol), KOH (3 g, 53.47 mmol) and TBAB (54 mg, 0.17 mmol) in a co-solvent of 2-methyltetrahydrofuran (15 mL) and H2O (3 mL) was stirred overnight. LC-MS showed that the reaction was complete. The mixture was diluted with EA (50 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA=3:1, V / V) to obtain the desired product (194 mg, yield: 73%). LC / MS ESI (m / z): 320 [M+H] + .

[0718] Step 2. tert-Butyl 5-{[4-(1-cyanocyclohexyl)-6-[(3R)-3-methylmorpholin-4-yl]pyridin-2-yl]amino}-1H-pyrazole-1-carboxylate (38-2)

[0719]

[0720] To a solution of 1-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyridin-4-yl}cyclohexane-1-carbonitrile (100 mg, 0.31 mmol) and tert-butyl 5-amino-1H-pyrazole-1-carboxylate (86 mg, 0.47 mmol) in dioxane (10 mL) was added BrettPhos-Pd-G3 (28 mg, 0.03 mmol) and Cs2CO3 (306 mg, 0.94 mmol). Under a nitrogen atmosphere, the mixture was stirred overnight at 100 ° C. LC-MS showed that the reaction was complete. The mixture was diluted with EA (50 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA=1:1, V / V) to give the desired product (102 mg, yield: 70%). LC / MS ESI(m / z):467[M+H] + .

[0721] Step 3. 1-{2-[(3R)-3-methylmorpholin-4-yl]-6-[(1H-pyrazol-5-yl)amino]pyridin-4-yl}cyclohexane-1-carbonitrile (38)

[0722]

[0723] A mixture of tert-butyl 5-{[4-(1-cyanocyclohexyl)-6-[(3R)-3-methylmorpholin-4-yl]pyridin-2-yl]amino}-1H-pyrazole-1-carboxylate (102 mg, 0.22 mmol) in HCl solution (4M in dioxane, 4 mL) was stirred overnight at ambient temperature. LC-MS showed that the reaction was complete. The mixture was concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (C 18 The residue was purified by HPLC (10-95% MeOH in H2O containing 0.1% HCOOH) to give the desired product (36.6 mg, yield: 46%). LC / MS ESI (m / z): 367 [M+H] + . 1 H NMR (400MHz, DMSO) δ12.17(s,1H),9.00(s,1H),7.53(d,J=2.2Hz,1H),6.63(s,1H),6.29(d,J=2.1Hz,1H),6.11(d ,J=0.8Hz,1H),4.32(d,J=6.6Hz,1H),3.93(dd,J=11.2,3.3Hz,1H),3.80(d,J=11.3Hz,1H),3.73(d,J=11.1Hz,1H) ,3.62(dd,J=11.3,2.8Hz,1H),3.47(td,J=11.8,3.0Hz,1H),3.05(td,J=12.6,3.7Hz,1H),2.00(d,J=12.4Hz,2H), 1.81(dd,J=16.4,6.6Hz,4H), 1.73(d,J=13.6Hz,1H), 1.66–1.56(m,2H), 1.34–1.24(m,1H), 1.12(d,J=6.6Hz,3H).

[0724] Embodiment 33

[0725]

[0726] Step 1. (R)-4-(2-Chloro-6-(3-methylmorpholino)pyridin-4-yl)tetrahydro-2H-pyran-4-carbonitrile (39-1)

[0727]

[0728] At 60 ° C, 2-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyridin-4-yl}acetonitrile (180 mg, 0.72 mmol), 1-bromo-2-(2-bromoethoxy)ethane (660 mg, 2.85 mmol), TBAB (46 mg, 0.14 mmol) and NaOH (10.0 M in H2O, 14.0 mmol, 1.4 mL) were stirred in a mixture in toluene (10 mL) for 2 hours. LC-MS showed that the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE: EA = 2: 1, V / V) to obtain the desired product (157 mg, yield: 68%). LC / MS (ESI): m / z 322 [M + H] + .

[0729] Step 2. (R)-4-(2-((1H-pyrazol-5-yl)amino)-6-(3-methylmorpholino)pyridin-4-yl)tetrahydro-2H-pyran-4-carbonitrile (39)

[0730]

[0731] At 110 ° C, under N2 atmosphere, a mixture of 4-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyridin-4-yl}tetrahydropyran-4-carbonitrile (80 mg, 0.25 mmol), 1H-pyrazole-5-amine (41 mg, 0.49 mmol), BrettPhos-Pd-G3 (22 mg, 0.02 mmol) and Cs2CO3 (244 mg, 0.75 mmol) in dioxane (4 mL) was stirred for 16 hours. LC-MS showed that the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The product was purified by preparative HPLC (C 18 The residue was purified by HPLC (HPLC-MS / MS): m / z 369 [M+H] + . 1H NMR (400MHz, DMSO) δ12.06(s,1H),9.04(s,1H),7.54(d,J=1.9Hz,1H),6.64(s,1H),6.29( s,1H),6.13(s,1H),4.34(d,J=6.9Hz,1H),4.00(dd,J=11.2,3.0Hz,2H),3.93(dd,J=11.3, 3.3Hz,1H),3.82(d,J=12.8Hz,1H),3.73(d,J=11.2Hz,1H),3.68–3.59(m,3H),3.47(td,J =11.8,2.9Hz,1H),3.06(td,J=12.6,3.7Hz,1H),2.13–1.95(m,4H),1.13(d,J=6.6Hz,3H).

[0732] Embodiment 34

[0733]

[0734] Step 1. (R)-1-(2-Chloro-6-(3-methylmorpholino)pyrimidin-4-yl)cyclopentane-1-carbonitrile (40-1)

[0735]

[0736] To a solution of (R)-2-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)acetonitrile (200 mg, 0.79 mmol), 1,4-dibromobutane (0.95 mL, 7.91 mmol) and TBAB (26 mg, 0.08 mmol) in 2-MeTHF (15 mL) was added KOH aqueous solution (10 M, 1.58 mL, 15.8 mmol). The mixture was stirred at 70 ° C overnight. LC-MS showed that the reaction was complete. The reaction mixture was diluted with EA (60 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (PE:EA=10:1, V / V) to obtain the desired product (220 mg, yield: 91%). LC / MS(ESI):m / z 307[M+H] + .

[0737] Step 2. (R)-1-(2-((1H-pyrazol-5-yl)amino)-6-(3-methylmorpholino)pyrimidin-4-yl)cyclopentane-1-carbonitrile (40)

[0738]

[0739] To a suspension of (R)-1-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)cyclopentane-1-carbonitrile (100 mg, 0.33 mmol), 1H-pyrazole-5-amine (41 mg, 0.49 mmol) and Cs2CO3 (319 mg, 0.98 mmol) in dioxane (8 mL) was added BrettPhos-Pd-G3 (29 mg, 0.03 mmol). The mixture was stirred at 100 °C for 16 hours. LC-MS showed the reaction was complete. The reaction mixture was diluted with DCM (50 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The product was purified by preparative HPLC (C 18 The residue was purified by HPLC (HPLC-MS / MS): m / z 354.4 [M+H] + . 1 H NMR(400MHz,DMSO)δ12.09(s,1H),9.19(s,1H),7.52(s,1H),6.49(s,1H),6.28(s ,1H),4.40(d,J=5.4Hz,1H),4.00(d,J=12.9Hz,1H),3.93(dd,J=11.3,3.3Hz,1H), 3.72(d,J=11.4Hz,1H),3.59(dd,J=11.4,2.9Hz,1H),3.46–3.40(m,1H),3.14(td ,J=12.9,3.7Hz,1H),2.31–2.22(m,4H),1.89–1.82(m,4H),1.19(d,J=6.7Hz,3H).

[0740] Embodiment 35

[0741]

[0742] Step 1. (R)-1-(2-Chloro-6-(3-methylmorpholino)pyrimidin-4-yl)cyclohexane-1-carbonitrile (41-1)

[0743]

[0744] To a suspension of (R)-2-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)acetonitrile (200 mg, 0.79 mmol), 1,5-dibromopentane (1.08 mL, 7.91 mmol) and TBAB (26 mg, 0.08 mmol) in 2-MeTHF (15 mL) was added KOH aqueous solution (10 M, 1.58 mL, 15.8 mmol). The mixture was stirred at 70 ° C for 16 hours. LC-MS showed that the reaction was complete. The reaction mixture was diluted with EA (60 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (PE: EA = 10: 1, V / V) to give the desired product (210 mg, yield: 83%). LC / MS (ESI): m / z 321 [M + H] + .

[0745] Step 2. (R)-1-(2-((1H-pyrazol-5-yl)amino)-6-(3-methylmorpholino)pyrimidin-4-yl)cyclohexane-1-carbonitrile (41)

[0746]

[0747] To a suspension of (R)-1-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)cyclohexane-1-carbonitrile (100 mg, 0.31 mmol), 1H-pyrazole-5-amine (39 mg, 0.47 mmol) and Cs2CO3 (305 mg, 0.94 mmol) in dioxane (8 mL) was added BrettPhos-Pd-G3 (28 mg, 0.03 mmol). The mixture was stirred at 100 °C for 16 hours. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (50 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The product was purified by preparative HPLC (C 18 The residue was purified by HPLC (HPLC-MS / MS): m / z 368.5 [M+H] + . 1H NMR(400MHz,DMSO)δ12.09(s,1H),9.18(s,1H),7.51(s,1H),6.52(s,1H),6.26(s,1H),4.46–4.34(m,1 H),4.01(d,J=13.3Hz,1H),3.93(dd,J=11.4,3.3Hz,1H),3.72(d,J=11.4Hz,1H),3.58(dd,J=11.4,3.0 Hz,1H),3.43(td,J=11.9,2.9Hz,1H),3.14(td,J=12.8,3.6Hz,1H),2.09–2.02(m,2H),1.95–1.86(m,2 H),1.85–1.78(m,2H),1.77–1.70(m,1H),1.65–1.53(m,2H),1.32–1.22(m,1H),1.19(d,J=6.7Hz,3H).

[0748] Embodiment 36

[0749]

[0750] Step 1. (R)-4-(2-Chloro-6-(3-methylmorpholino)pyrimidin-4-yl)tetrahydro-2H-pyran-4-carbonitrile (42-1)

[0751]

[0752] To a solution of (R)-2-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)acetonitrile (200 mg, 0.79 mmol) in toluene (10 mL) was added 1-bromo-2-(2-bromoethoxy)ethane (367 mg, 1.58 mmol), sodium hydroxide (10 M in H2O, 0.79 mL, 7.91 mmol) and TBAB (52 mg, 0.16 mmol). The reaction was stirred at 60 °C overnight. LC-MS showed that the reaction was complete. The mixture was diluted with EA (60 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (PE:EA=3:1, V / V) to give the desired product (180 mg, yield: 70%). LC / MS(ESI):m / z 323[M+H] + .

[0753] Step 2. (R)-4-(2-((1H-pyrazol-5-yl)amino)-6-(3-methylmorpholino)pyrimidin-4-yl)tetrahydro-2H-pyran-4-carbonitrile (42)

[0754]

[0755] To a solution of (R)-4-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)tetrahydro-2H-pyran-4-carbonitrile (80 mg, 0.25 mmol) in dioxane (8 mL) was added 1H-pyrazole-5-amine (31 mg, 0.37 mmol), Cs2CO3 (162 mg, 0.50 mmol) and BrettPhos-Pd-G3 (45 mg, 0.05 mmol). The mixture was stirred overnight at 100°C under nitrogen atmosphere. LC-MS showed the reaction was complete. The mixture was diluted with EA (60 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (C18, 10-95% MeOH in H2O, containing 0.1% HCOOH) to give the desired product (15 mg, yield: 16%). LC / MS(ESI):m / z 370[M+H] + . 1 HNMR(400MHz,DMSO)δ12.10(s,1H),9.14(s,1H),7.54(s,1H),6.60(s,1H),6.29(s,1H), 4.43(s,1H),4.07–3.96(m,3H),3.93(dd,J=11.4,3.4Hz,1H),3.72(d,J=11.4Hz,1H),3. 63(dd,J=12.0,10.3Hz,2H),3.57(d,J=3.0Hz,1H),3.43(td,J=11.9,2.9Hz,1H),3.15(t d,J=12.9,3.6Hz,1H),2.20–2.12(m,2H),2.03(d,J=12.3Hz,2H),1.20(d,J=6.7Hz,3H).

[0756] Embodiment 37

[0757]

[0758] Step 1. 1-(2,6-Dichloropyridin-4-yl)cyclohexan-1-ol (43-3)

[0759]

[0760] At -78 ° C, n-BuLi solution (2.5M in THF, 0.74 mL, 1.85 mmol) was added dropwise to a solution of 4-bromo-2,6-dichloropyridine (300 mg, 1.32 mmol) and cyclohexanone (156 mg, 1.59 mmol) in THF (8 mL) at -78 ° C. The mixture was stirred for 1 hour at -78 ° C. LC-MS shows that the reaction is complete. The mixture is quenched with saturated NH4Cl aqueous solution and extracted three times with EA (30 mL × 3). The combined organic phases are washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue is purified by silica gel column chromatography (PE: EA = 10: 1, V / V) to obtain the desired product (252 mg, yield: 77%). LC / MS (ESI): m / z 246 [M + H] + .

[0761] Step 2. (R)-1-(2-Chloro-6-(3-methylmorpholino)pyridin-4-yl)cyclohexan-1-ol (43-5)

[0762]

[0763] (3R)-3-methylmorpholine (308 mg, 3.05 mmol) was added to a solution of 1-(2,6-dichloropyridin-4-yl)cyclohexan-1-ol (250 mg, 1.02 mmol) in NMP (5 mL). The mixture was stirred at 150 ° C for 16 hours. LC-MS showed that the reaction was complete. The reaction mixture was diluted with EA (60 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (PE: EA = 5: 1, V / V) to obtain the desired product (42 mg, yield: 13.3%). LC / MS (ESI): m / z 311 [M + H] + .

[0764] Step 3. (R)-1-(2-((1H-pyrazol-5-yl)amino)-6-(3-methylmorpholino)pyridin-4-yl)cyclohexan-1-ol (43)

[0765]

[0766] To a suspension of (R)-1-(2-chloro-6-(3-methylmorpholino)pyridin-4-yl)cyclohexan-1-ol (42 mg, 0.135 mmol), 1H-pyrazole-5-amine (23 mg, 0.270 mmol) and Cs2CO3 (132 mg, 0.405 mmol) in dioxane (6 mL) was added BrettPhos-Pd-G3 (12 mg, 0.01 mmol). The mixture was stirred at 100 °C for 16 hours under N2 atmosphere. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by preparative HPLC (C 18 The residue was purified by HPLC (10-95% MeOH in H2O containing 0.1% HCOOH) to give the desired product (10 mg, yield: 21%). LC / MS (ESI): m / z 358 [M+H] + . 1 H NMR (400MHz, DMSO) δ12.17(s,1H),8.74(s,1H),7.50(d,J=2.2Hz,1H),6.54(s,1H),6.28(d, J=2.0Hz,1H),6.15(s,1H),4.60(s,1H),4.32–4.23(m,1H),3.93(dd,J=11.1,3.1Hz,1H),3.7 7–3.68(m,2H),3.62(dd,J=11.2,2.8Hz,1H),3.47(td,J=11.7,2.9Hz,1H),3.03(td,J=12.5 ,3.6Hz,1H),1.73–1.53(m,7H),1.51–1.43(m,2H),1.27–1.17(m,1H),1.11(d,J=6.6Hz,3H).

[0767] Embodiment 38

[0768]

[0769] Step 1. 4-Bromo-2,6-dichloropyrimidine (44-3)

[0770]

[0771] At -60 ° C, 2,4-dichloropyrimidine (1g, 6.71mmol) was added dropwise to a solution of tetramethylpiperidinium lithium solution (1.0M in THF, 8.0mL, 8.05mmol) in THF (50mL) at -60 ° C. The mixture was stirred at -60 ° C for 1 hour, and then a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (3.28g, 10.07mmol) in THF (5mL) was added dropwise. The resulting mixture was stirred for another 2 hours at -60 ° C. LC-MS shows that the reaction is complete. The reaction mixture was quenched with saturated NH4Cl aqueous solution and extracted with EA (60mL). The organic layer was separated, then washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (PE:EA=50:1, V / V) to obtain the desired product (600mg, yield: 39%). LC / MS(ESI):m / z 228[M+H] + .

[0772] Step 2. 1-(2,6-Dichloropyrimidin-4-yl)cyclohexan-1-ol (44-5)

[0773]

[0774] At -60 ° C, n-butyl lithium (2.5M in THF, 1.5 mL, 3.69 mmol) was added dropwise to a solution of 4-bromo-2,6-dichloropyrimidine (600 mg, 2.63 mmol) and cyclohexanone (0.32 mL, 3.16 mmol) in THF (15 mL). The mixture was stirred at -60 ° C for 30 minutes. LC-MS shows that the reaction is complete. The reaction mixture is quenched with saturated NH4Cl aqueous solution and extracted with EA (60 mL). The organic layer is separated, then washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue is purified by flash chromatography on silica gel (PE: EA = 20: 1, V / V) to obtain the desired product (200 mg, yield: 30%). LC / MS (ESI): m / z 248 [M + H] + .

[0775] Step 3. (R)-1-(2-Chloro-6-(3-methylmorpholino)pyrimidin-4-yl)cyclohexan-1-ol (44-7)

[0776]

[0777] (R)-3-methylmorpholine (246 mg, 2.43 mmol) was added to a solution of 1-(2,6-dichloropyrimidin-4-yl)cyclohexan-1-ol (200 mg, 0.81 mmol) in NMP (5 mL). The mixture was stirred for 1 hour at 120 ° C under microwave irradiation. LC-MS shows that the reaction is complete. The mixture was diluted with EA (60 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (PE:EA=10:1, V / V) to obtain the desired product (200 mg, yield: 79%). LC / MS(ESI):m / z 312[M+H] + .

[0778] Step 4. (R)-1-(2-((1H-pyrazol-5-yl)amino)-6-(2-methylpiperidin-1-yl)pyrimidin-4-yl)cyclohexan-1-ol (44)

[0779]

[0780] To a solution of (R)-1-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)cyclohexan-1-ol (80 mg, 0.26 mmol) in dioxane (2 mL) was added 1H-pyrazole-5-amine (32 mg, 0.39 mmol), Cs2CO3 (167 mg, 0.51 mmol) and BrettPhos-Pd-G3 (23 mg, 0.03 mmol). The mixture was stirred overnight at 80°C under nitrogen atmosphere. LC-MS showed the reaction was complete. The mixture was diluted with EA (50 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (C18, 10-95% MeOH in H2O, containing 0.1% HCOOH) to give the desired product (20 mg, yield: 21%). LC / MS(ESI)m / z:317[M+H] + . 1H NMR (400MHz, DMSO) δ8.99 (s, 1H), 7.50 (d, J = 2.0Hz, 1H), 6.41 (d, J = 1.7Hz, 1H), 6.38 (s, 1H), 4. 86(s,1H),4.35(d,J=4.7Hz,1H),3.94(dd,J=19.7,8.5Hz,2H),3.73(d,J=11.3Hz,1H),3.58(d ,J=8.5Hz,1H),3.43(d,J=2.9Hz,1H),3.12(dd,J=12.6,9.2Hz,1H),1.85(dt,J=12.2,7.2Hz,2 H), 1.69 (dd, J = 24.2, 11.5Hz, 3H), 1.49 (t, J = 13.8Hz, 4H), 1.24 (s, 1H), 1.18 (d, J = 6.7Hz, 3H).

[0781] Embodiment 39

[0782]

[0783] Step 1. (R)-4-(6-Chloro-4-((methylsulfonyl)methyl)pyridin-2-yl)-3-methylmorpholine (45-1)

[0784]

[0785] To a solution of (3R)-4-[6-chloro-4-(chloromethyl)pyridin-2-yl]-3-methylmorpholine (2 g, 7.66 mmol) in DMF (40 mL) was added CH3SO2Na (1.56 g, 15.32 mmol). The mixture was stirred at room temperature for 16 hours. LC-MS showed that the reaction was complete. The reaction mixture was diluted with EA (100 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (PE:EA=10:1, V / V) to obtain the desired product (1.6 g, yield: 68%). LC / MS(ESI):m / z 305[M+H] + .

[0786] Step 2. (R)-4-(6-chloro-4-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-3-methylmorpholine (45-2)

[0787]

[0788] To a solution of (R)-4-(6-chloro-4-((methylsulfonyl)methyl)pyridin-2-yl)-3-methylmorpholine (800 mg, 2.62 mmol), 1-bromo-2-(2-bromoethoxy)ethane (1.83 g, 7.87 mmol) and TBAB (170 mg, 0.53 mmol) in toluene (26 mL) was added an aqueous solution of NaOH (10 M, 2.63 mL, 26.25 mmol). The mixture was stirred at 60 ° C for 16 hours. LC-MS showed that the reaction was complete. The reaction mixture was diluted with EA (60 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (PE:EA=10:1, V / V) to obtain the desired product (550 mg, yield: 56%). LC / MS(ESI):m / z 375[M+H] + .

[0789] Step 3. (R)-6-(3-methylmorpholino)-4-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)-N-(1H-pyrazol-5-yl)pyridin-2-amine (45)

[0790]

[0791] To a solution of (R)-4-(6-chloro-4-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-3-methylmorpholine (100 mg, 0.27 mmol), 1H-pyrazole-5 (44 mg, 0.53 mmol) and Cs2CO3 (261 mg, 0.80 mmol) in dioxane (8 mL) was added BrettPhos-Pd-G3 (24 mg, 0.03 mmol). The mixture was stirred at 100 °C for 5 hours. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (60 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by preparative HPLC (C 18 The residue was purified by HPLC (HPLC-MS / MS): m / z 422 [M+H] + . 1H NMR (400MHz, DMSO) δ11.94(s,1H),8.98(s,1H),7.54(d,J=2.2Hz,1H),6.61(s,1H),6.35( d,J=2.1Hz,1H),6.18(s,1H),4.32–4.23(m,1H),3.97–3.83(m,4H),3.73(d,J=11.1Hz,1H ),3.64(dd,J=11.2,2.8Hz,1H),3.52–3.46(m,1H),3.26–3.20(m,2H),3.06(td,J=12.7,3 .7Hz,1H),2.71(s,3H),2.44(d,J=13.7Hz,2H),2.25–2.14(m,2H),1.12(d,J=6.6Hz,3H).

[0792] Embodiment 40

[0793]

[0794] Step 1: (R)-4-(6-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)-3-methylmorpholine (46-2)

[0795]

[0796] To a solution of (R)-4-(6-chloro-4-iodopyridin-2-yl)-3-methylmorpholine (150 mg, 0.44 mmol) and 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (108.24 mg, 0.49 mmol) in dioxane (5 mL) was added K2CO3 (121.44 mg, 0.89 mmol) and Pd(dppf)Cl2 (32.20 mg, 0.04 mmol). N2 was injected twice into the mixture and then stirred at 90 ° C for 12 hours. The reaction mixture was diluted with water (10 mL) and extracted with EA (15 mL×2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting mixture was purified by flash chromatography eluting with PE / EtOAc (3:1, V / V) to afford the desired product (110 mg, yield: 80.93%).

[0797] Step 2: (R)-tert-butyl 5-((4-(1,4-dimethyl-1H-pyrazol-5-yl)-6-(3-methylmorpholino)pyridin-2-yl)amino)-3-methyl-1H-pyrazole-1-carboxylate (46-3)

[0798]

[0799] To a solution of (R)-4-(6-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)-3-methylmorpholine (110 mg, 0.36 mmol) and tert-butyl 5-amino-3-methyl-1H-pyrazole-1-carboxylate (84.86 mg, 0.43 mmol) in dioxane (5 mL) was added CS2CO3 (350.47 mg, 1.08 mmol) and BrettPhos Pd G3 (32.67 mg, 0.036 mmol). The mixture was injected with N2 twice and then stirred at 90 °C overnight. The reaction was diluted with water and extracted with EtOAc (10 mL×2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting mixture was purified by flash chromatography eluting with PE / EtOAc (2:1, V / V) to afford the desired product (120 mg, yield: 71.58%).

[0800] Step 3: (R)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-(3-methyl-1H-pyrazol-5-yl)-6-(3-methylmorpholino)pyridin-2-amine (46)

[0801]

[0802] To a mixture of (R)-tert-butyl 5-((4-(1,4-dimethyl-1H-pyrazol-5-yl)-6-(3-methylmorpholino)pyridin-2-yl)amino)-1H-pyrazole-1-carboxylate (50 mg, 0.11 mmol) in DCM (3 mL) was added TFA (1 mL), and the mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated in vacuo. A saturated solution of NaHCO3 was added to the mixture until pH = 7-8, and extracted with DCM (10 mL×2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative TLC (DCM / MeOH=10 / 1, V / V) to give the desired product (10 mg, yield: 25.45%). LC / MS(ESI)m / z:368.1[M+H] + . 1HNMR(400MHz,DMSO-d6)δppm 11.69(br s,1H)8.88(br s,1H)7.31(s,1H)6.49(br s,1H)6.05(br s,1H)5.98-6.01(m,1H)4.29(br d,J=6.16Hz,1H)3.86-3.96(m,2H)3.73(s,3H)3.69-3.72(m,1H)3.61-3.66(m,1H)3.45-3 .52(m,1H)3.07(td,J=12.58,3.34Hz,1H)2.18(s,3H)1.98(s,3H)1.15(d,J=6.54Hz,3H).

[0803] Embodiment 41

[0804]

[0805] Step 1. (R)-4-(3,5-Dimethylisoxazol-4-yl)-N-(3-methyl-1H-pyrazol-5-yl)-6-(3-methylmorpholino)pyridin-2-amine (47)

[0806] Cs2CO3 (400 mg, 1.23 mmol) and BrettPhos Pd G3 (45 mg, 0.049 mmol) were added to dioxane (8 mL) containing (R)-4-(6-chloro-4-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)-3-methylmorpholine (150 mg, 0.49 mmol) and tert-butyl 5-amino-1H-pyrazole-1-carboxylate (116 mg, 0.59 mmol). N2 was injected into the mixture twice and then stirred at 90 ° C overnight. The reaction was diluted with water and extracted with EtOAc (30 mL×2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative TLC (DCM / MeOH=10 / 1) to give the desired product (30 mg, yield: 16.67%). LC / MS(ESI)m / z:369.1[M+H] + .

[0807] 1H NMR(400MHz,DMSO-d6)δppm 11.68(br s,1H)8.80(br s,1H)6.52(br s,1H)6.05(br s,1H)5.98(s,1H)4.33-4.34(m,1H)4.29(br d,J=6.52Hz,1H)3.93(br dd,J=11.16,3.01Hz,1H)3.82-3.88(m,1H)3.70-3.74(m,1H)3.61-3.65(m,1H)3.48(td,J=11.72,2. 82Hz, 1H) 3.06 (td, J = 12.68, 3.64Hz, 1H) 2.43 (s, 3H) 2.25 (s, 3H) 2.18 (s, 3H) 1.15 (d, J = 6.64Hz, 3H).

[0808] Embodiment 42

[0809] Biochemical tests

[0810] Test 1: ATR inhibition test

[0811] The detection of ATR kinase activity uses a mobility shift assay to measure the phosphorylation of the substrate protein FAM-RAD17 (GL, catalog number: 514318, batch number: P19042-MJ524315). The assay was developed and performed by Chempartner. All test compounds were dissolved in 100% DMSO at a concentration of 20 mM, and then the compounds were prepared and assayed as follows:

[0812] 1) Transfer 80 μl of 20 mM compound into 40 μl 100% DMSO in a 96-well plate.

[0813] 2) Serially dilute the compound by transferring 20 μl to 60 μl of 100% DMSO in the next well, and so on, for a total of 10 dilution concentrations.

[0814] 3) Add 100 μl of 100% DMSO to two empty wells in the same 96-well plate for no compound control and no enzyme control. Label the plate as the source plate.

[0815] 4) Transfer 40 μl of compound from the source plate to a new 384-well plate as an intermediate plate.

[0816] 5) Transfer 60 nl of compound to the assay plate via Echo.

[0817] 6) ATR kinase (Eurofins, catalog number: 14-953, lot number: D14JP007N) was added to kinase base buffer (50 mM HEPES, pH 7.5; 0.0015% Brij-35; 0.01% Triton) to prepare a 2x enzyme solution, and then 10 μl of the 2x enzyme solution was added to each well of a 384-well plate and incubated at room temperature for 10 minutes.

[0818] 7) Add FAM-RAD17 and ATP (Sigma, Catalog No: A7699-1G, CAS No: 987-65-5) to the kinase base buffer to prepare a 2x peptide solution, then add 10 μl to the assay plate.

[0819] 8) Incubate at 28°C for the indicated time periods. Add 40 μl of stop buffer (100 mM HEPES, pH 7.5; 0.015% Brij-35; 0.2% coating reagent #3; 50 mM EDTA) to stop the reaction.

[0820] 9) Collect the data on the caliper. Convert the transformation value to the inhibition value.

[0821] Inhibition percentage = (maximum conversion rate) / (max-min)*100

[0822] Where "max" represents the DMSO control; "min" represents the low control.

[0823] The data in XLFit excel add-in version 5.4.0.8 were fitted to obtain IC50 values. The formula used was:

[0824] Y = bottom + (top - bottom) / (1 + (IC50 / X)^Hill slope)

[0825] Where X means the concentration which is not converted into logarithmic form.

[0826] Table 2 below lists the IC50 values ​​of exemplary compounds of formula (I).

[0827] Table 2

[0828]

[0829]

[0830] Test 2: Tumor cell antiproliferation test (CTG test)

[0831] Human colorectal cancer cells HT-29 (HTB-38) and LoVo (CCL-229) were selected for CTG determination, and these two cell lines were originally obtained from the American Type Culture Collection (ATCC). FBS and appropriate additives were added to the basal medium to prepare complete medium, and then the cell layer was briefly rinsed with 0.25% (w / v) trypsin-0.038% (w / v) EDTA solution to remove all traces of serum containing trypsin inhibitors, and then an appropriate volume of trypsin-EDTA solution was added to the flask, and the cells were observed under an inverted microscope until the cell layer was dispersed, and finally an appropriate volume of complete growth medium was added, and the cells were gently pipetted. Cells were collected with Vi-cell XR and the cells were counted and the cell density was adjusted, and the cells were inoculated into 96-well opaque wall transparent bottom tissue culture treated plates in a CO2 incubator for 20-24 hours. The concentration of all test compounds in DMSO will be 10mM. The compound was then added to the cell culture medium in 3-fold serial dilutions with a final DMSO concentration of 0.5%. The plate was incubated at 37°C for 96 hours at 5% CO2. Prior to measurement, an appropriate volume of CellTiter-Glo buffer was transferred to an amber bottle containing CellTiter-Glo substrate to reconstitute the lyophilized enzyme / substrate mixture and gently mixed, which formed the CellTiter-Glo reagent (Promega catalog number: G7573). The plate and its contents were equilibrated to room temperature for approximately 30 minutes, and then 100 μL of CellTiter-Glo reagent was added to the assay plate, the contents were mixed on a gyratory shaker for 2 minutes to induce cell lysis, incubated at room temperature for 10 minutes to stabilize the luminescent signal, and finally the transparent bottom was affixed with a white back sealant and the luminescence was recorded with Enspire. IC was calculated using the 4-parameter logistic model Y=bottom+(top-bottom) / (1+(IC50 / X)^Hill slope) by XLFit curve fitting software. 50 Value and GI 50 value.

[0832] Table 3 below provides IC50 (Y=50%) values ​​for exemplary compounds of Formula (I).

[0833] Table 3

[0834]

[0835]

[0836] The foregoing description is considered to be only an illustration of the basic principles of the present disclosure. Further, since many modifications and variations will be apparent to those skilled in the art, it is not desirable to limit the present invention to the exact configuration and process shown as described above. Therefore, all suitable modifications and equivalents may be considered to fall within the scope of the present invention as defined by the appended claims.

Claims

1. A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

3. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 2 in the preparation of a medicament for treating colon and rectal cancer.

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