WO2022188735A1

WO2022188735A1 - Heterocyclic compounds as hpk1 inhibitors

Info

Publication number: WO2022188735A1
Application number: PCT/CN2022/079503
Authority: WO
Inventors: Zhaoyin Wang; Yanqiang SHAO; Lintong Li; Nanxin LI
Original assignee: Guangdong Newopp Biopharmaceuticals Co., Ltd.
Priority date: 2021-03-08
Filing date: 2022-03-07
Publication date: 2022-09-15

Abstract

Provided are heterocyclics as inhibitors of HPK1, in particular a compound of Formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising said compound that is useful for treatment of HPK1 mediated diseases and conditions such as cancer.

Description

HETEROCYCLIC COMPOUNDS AS HPK1 INHIBITORS

Technical field

The present invention relates to heterocyclic compounds as inhibitors of HPK1 that are useful for treatment of HPK1 mediated diseases and conditions such as cancer.

Background

Enhancing anti-tumor immunity is emerging as a new cancer treatment method. The hematopoietic progenitor kinase 1 (HPK1) , also known as Mitogen-Activated Protein Kinase Kinase Kinase Kinase 1 (MAP4K1) , negatively regulates T cell activation, thus contributing the escape of tumor cells from the immune system. Kinase inhibitors of HPK1 may be useful to enhance T cell activity and restore anti-tumor immunity.

Description of the Invention

The present invention describes inhibitors of HPK1. The present invention further describes pharmaceutical formulations that include an inhibitor of HPK1.

In the first aspect of the invention, the invention provided a compound of Formula I, or a pharmaceutically acceptable salt thereof:

Wherein

is

X is N or CH;

Y and Z are independently N, CR ⁴;

Z ¹ is N or CR ³;

R ¹ is selected from the group consisting of CO ₂H, CO ₂ (C _1-6alkyl) , cyano, C _1-6alkyl, C _3-6cycloalkyl, C _1-6alkoxy, -SC _1-6alkylC _3- ₆cycloalkyloxy, -C≡C-R ⁹, -CH=CHR ⁹, -C (O) NR ^aR ^b, S (O) ₂R ^a, -S (O) (NCN) R ^a, -P (O) R ^aR ^b, -P (O) (OR ^a) (OR ^b) , -NR ^cC (O) NR ^a ₂, -NR ^cS (O) ₂NR ^a ₂, -NR ^cS (O) ₂R ^a, -NR ^aR ^b, -NR ^aC (O) OR ^a, -S (O) ₂NR ^aR ^b, -NR ^cS (O) ₂NR ^aR ^b, -C (O) R ^a, C (O) NHNH ₂, -C (O) NHNHC (O) R ^a, -C (O) NHNHC (=NCH ₂CH ₃ (NH (CH ₂) _2-4N (CH ₃) ₂) , 1, 8-dioxa-3-azaspiro [4.5] dec-2-enyl, -C _1-6heteroalkyl, 5-10-membered heteroaryl, 3-10-membered heterocyclyl, or heterocyclylalkyl; each R ¹ is substituted with zero to 3 R ¹⁰; R ² is -C _1-6alkyl, -C _2-6alkenyl, -C _2-6alkynyl, -C _0-10alkylene-C ₃- ₁₀cycloalkyl, -C _4-10cycloalkenyl, -C _0-10alkylene-3-10-membered heterocyclyl, -C _0-10alkylene-C _6-10aryl, -C _0-10alkylene-5-10-membered heteroaryl, -CHR ^d (CH ₂) _nR ^e, -CHR ^dC (OH) (R ^c) ₂, - CHR ^dC (NR ^aR ^b) (R ^c) ₂, -CHR ^d (CH ₂) _nC (OH) (R ^c) ₂, -CHR ^d (CH ₂) _nC (NR ^aR ^b) (R ^c) ₂, - (CH ₂) _mNR ^c (CH ₂) _mNR ^aR ^b, - (CH ₂) _nC (O) R ^c, -(CH ₂) _nNR ^aR ^b , - (CH ₂) _nC (O) NR ^aR ^b; R ² is substituted with zero to 3 R ¹⁰;

n is 0, 1, 2 or 3;

m is independently 0, 1, 2 or 3;

R ^a, R ^b and R ^c are independently hydrogen, -C _1-6alkyl, -C _1-6haloalkyl, -C _2-6alkenyl, -C _2-6alkynyl, -C ₃- ₁₀cycloalkyl, -C _4- ₁₀cycloalkenyl, -3-10-membered heterocyclyl, -C _6-10aryl, -5-10-membered heteroaryl, R ^a and R ^b or R ^b and R ^c are taken together with the atom (s) to which they are attached to form an optionally substituted 4-10 membered carbocyclyl, or heterocyclyl which contains 0-3 heteroatoms and is optionally substitute with 0-5 occurrences of R ¹⁰; R ^a, R ^b and R ^c are independently substituted with 0-5 occurrences of R ¹⁰;

R ^d is -C _3-6cycloalkyl, oxadiazolyl, oxazolyl, oxetanyl, phenyl, pyrazolyl, pyrazolo [l, 5-a] pyridinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, tetrahydropyrido [3, 4-d] pyrimidinyl, or thiazolyl; R ^d is substituted with zero to three R ¹⁰;

R ^e is independently selected from H, -OH, -CN, -C _1-6alkyl, -C _1-6haloalkyl, -C _1-3hydroxyalkyl, -CH ₂OCH ₃, -CH ₂OCF ₃, -CH ₂NR ^aR ^b, -CH ₂S (C _1-3alkyl) , or -CH ₂C (O) NR ^aR ^b;

R ³ and R ⁴ are independently selected from H, CH _3, CF ₃, CN or halo;

R ⁹ is H, -C _1-6alkyl, -C _2-6haloalkyl, -CO ₂R ^a, -C (O) NR ^aR ^b, -C _0-10alkylene-C _6-10aryl, -C _0-10alkylene-5-10-membered heteroaryl; R ⁹ is substituted with zero to three R ¹⁰;

R ¹⁰ is independently selected from C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxyl, C _1-6alkoxy, halo, hydroxy, oxo, amino, C _0- ₆alkylene-R ^c, C _0-6alkylene-NR ^bR ^c, C _0-6alkylene-NR ^bR ^c, C _0-6alkylene-C (O) NR ^aR ^b, C _0-6alkylene-NR ^cC (O) R ^b, C _0-6alkylene-S (O) ₂R ^b, C _0-6alkylene-S (O) ₂NR ^aR ^b, C _0-6alkylene-NR ^cS (O) ₂R ^b, C _0-6alkylene-NR ^cS (O) ₂NR ^aR ^b, C _0-6alkylene-P (O) R ^aR ^b, C _0- ₆alkylene-P (O) (OR ^a) (OR ^b) , C _0-6alkylene-cyano, C _0-6alkylene-C _3-8 cycloalkyl, C _0-6alkylene-5-10 membered heterocyclyl, C _0- ₆alkylene-C _6-10aryl, C _0-6alkylene-5-10 membered heteroaryl, C _2-6hydroxyalkyl, C _2-4hydroxy-fluoroalkyl, -S (C _1-2 alkyl) , azabicyclo [2.2.2] octanyl, fluoroazabicyclo [2.2.2] octanyl, aminobicyclo [l . 1.1] pentanyl, dimethylaminobicyclo [l . 1.1] pentanyl, acetamidobicyclo [l . 1. l] pentanyl and (methoxycarbonyl) aminobicyclo [l . 1. l] pentanyl; R ¹⁰ is substituted with zero to two substituents independently selected halogen, -CN, CF ₃, C (C _0-6alkyl) ₂OH; two adjacent R ¹⁰ are taken together with the atom (s) to which they are attached to form an optionally substituted 5-10 membered carbocyclyl or 5-10 membered heterocyclyl;

is selected from the following moieties:

R ⁵ and R ⁶ are independently selected from H, -C _1-6alkyl or -OC _1-6alkyl; R ⁵ and R ⁶ together with the carbon atom to which they are attached may form an optionally substituted 3-10 membered carbocyclyl, or 4-10 membered heterocyclyl which contains 1-3 heteroatoms and is optionally substitute with 0-5 occurrences of R ¹⁰;

L is O, S, NR ^c or absent

is a 4-8 membered heterocyclyl which contains a heteroatom V ^a;

V and V ^a are independently selected from O, S or NR ⁷;

W is OCR ^5aR ^6a, CR ^5aR ^6aO, NR ⁷CR ^5aR ^5b, CR ^5aR ^6aNR ⁷, (CR ^5aR ^6a) _t, SCR ^5aR ^6a or CR ^5aR ^6aS;

W ¹ is O, S or NR ⁷;

W ³-W ² may also be NR ⁷CR ⁸=CR ⁹, NR ⁷CR ⁸=N-

R ^5a and R ^6a are independently selected from H, -C _1-6alkyl or -OC _1-6alkyl; R ^5a and R ^6a together with the carbon atom to which they are attached may form an optionally substituted 3-10 membered carbocyclyl, or 4-10 membered heterocyclyl which contains 1-3 heteroatoms and is optionally substituted with 0-5 occurrences of R ¹⁰;

R ⁷, R ⁸ and R ⁹ are independently selected from H, -C _1-6alkyl, -C _1-6haloalkyl, -C _0-10alkylene-C _6-10aryl, -C _0-10alkylene-C _6- ₁₀cycloalkyl, -C _0-10alkylene-5-10-membered heteroaryl, with the proviso that R ⁷ and R ⁸ are not H or CH ₃ when L is absent;

R ⁷ and R ⁸ can be taken together with the atom (s) to which they are attached to form an optionally substituted 5-10 membered carbocyclyl or 5-10 membered heterocyclyl;

t is 2 or 3.

In an embodiment, the invention further provides a compound of Formula II or a pharmaceutically acceptable salt thereof:

R ¹, R ², R ⁵, R ⁶, X, Y, Z and Z ¹ are defined as for Formula I;

W is OCR ^5aR ^6a, CR ^5aR ^6aO, NR ⁷CR ^5aR ^6a, CR ^5aR ^6aNR ⁷, (CR ^5aR ^6a) _t, SCR ^5aR ^6a or CR ^5aR ^6aS;

R ¹⁰ is defined as in Formula I;

t is 1, 2 or 3.

In another embodiment, the invention further provides a compound of Formula III or a pharmaceutically acceptable salt thereof:

R ¹, R ², R ³, R ⁵, R ⁶, X, Y and Z are defined as for Formula I.

In another embodiment, the invention further provides a compound of Formula IV or a pharmaceutically acceptable salt thereof:

R ¹, R ², R ³, R ⁵, R ⁶, R ⁷, X, Y and Z are defined as for Formula I.

In another embodiment, the invention further provides a compound of Formula V or a pharmaceutically acceptable salt thereof:

R ¹, R ², R ³, R ⁵, R ^5a, R ^5b, R ⁶, R ⁷, X, Y and Z are defined as for Formula I.

In another embodiment, the invention further provides a compound of Formula VI or a pharmaceutically acceptable salt thereof:

R ¹, R ², R ³, R ⁷, R ⁸, X, Y and Z are defined as for Formula I; L is O, NR ^c; R ⁷ and R8 may form an optionally substituted 4-6 membered heterocyclyl.

In another embodiment, the invention further provides a compound of Formula VII or its open form Formula VIII, or a pharmaceutically acceptable salt thereof:

R ¹, R ², R ³, R ⁷, X, Y and Z are defined as for Formula I.

In another embodiment, the invention further provides a compound of Formula IX or a pharmaceutically acceptable salt thereof:

R ¹, R ², R ³, R ⁷, R ⁸, X, Y and Z are defined as for Formula I.

In another embodiment, the invention further provides a compound of Formula X or a pharmaceutically acceptable salt thereof:

R ¹, R ², R ³, R ⁷, R ⁸, X, Y and Z are defined as for Formula I.

In another embodiment, the invention further provides a compound of Formula XI or a pharmaceutically acceptable salt thereof:

R ¹, R ², R ³, X, Y and Z are defined as for Formula I; j and k are independently 1 or 2.

In another embodiment, the invention further provides a compound of Formula XII or a pharmaceutically acceptable salt thereof:

R ¹, R ², R ³, R ⁵, R ⁶, R ⁷, X, Y and Z are defined as for Formula I;

R ⁵, R ⁶, R ^5a and R ^6a are independently selected from H, -C _1-6alkyl or -OC _1-6alkyl; R ^5a and R ^6a, or R ⁵ and R ⁶ together with the carbon atom to which they are attached may form an optionally substituted 3-10 membered carbocyclyl, or 4-10 membered heterocyclyl which contains 1-3 heteroatoms and is optionally substituted with 0-5 occurrences of R ¹⁰;

R ¹⁰ is defined as in Formula I;

W ^2a is O, CR ^5aR ^6a, S or NR ⁷.

In another embodiment, the invention further provides a compound of Formula XIII or a pharmaceutically acceptable salt thereof:

R ¹, R ², R ³, R ⁵, R ⁶, R ⁷, X, Y, Z ¹ and Z are defined as for Formula I;

R ¹⁰ is defined as in Formula I;

W ¹ is O, CR ^5aR ^6a, S or NR ⁷.

In another embodiment, the invention further provides a compound of Formula XIV or a pharmaceutically acceptable salt thereof:

R ¹⁰ is defined as in Formula I;

W ¹ is O, CR ^5aR ^6a, S or NR ⁷.

In another embodiment, the invention further provides a compound of Formula XV or a pharmaceutically acceptable salt thereof:

R ¹, R ², R ³, R ⁷, R ⁸, R ⁹, X, Y, Z ¹ and Z are defined as for Formula I. R ⁷ and R ⁸ can be taken together with the atoms to which they are attached to form an optionally substituted 5-10 membered carbocyclyl or 5-10 membered heterocyclyl; R ⁸ and R ⁹ can be taken together with the atoms to which they are attached to form an optionally substituted 5-10 membered carbocyclyl or 5-10 membered heterocyclyl.

In another embodiment, the invention further provides a compound of Formula XVI or a pharmaceutically acceptable salt thereof:

R ¹, R ², R ³, R ⁷, R ⁸, R ⁹, X, Y, Z ¹ and Z are defined as for Formula I. R ⁷ and R ⁸ can be taken together with the atom (s) to which they are attached to form an optionally substituted 5-10 membered carbocyclyl or 5-10 membered heterocyclyl;

In one embodiment, R ¹ is selected from:

The attachment for R ¹ is at any position of R ¹ provided the bond valence is permitted. R ¹ is substituted with zero to 3 R ¹⁰.

In a preferred embodiment, R ¹ is selected from oxadiazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, thiadiazolyl, pyrazinyl, imidazolyl, triazolyl, isoxazolyl, and dihydrooxazolyl, each substituted with zero to two R ¹⁰.

In some preferred embodiment, each of R ¹, R ², R ³, R ⁴, R ⁵, R ^5a, R ^5b, R ⁶, R ⁷, R ¹⁰, R ^a, R ^b, R ^c, R ^d, L, V, W, W ¹, W ², X, Y, Z, Z ¹ and Ring A are the corresponding groups in specific compounds disclosed hereinafter or the compounds as prepared in the Examples.

In some embodiments, a compound of Formula I to Formula VI is selected from the group consisting of the following compounds, or a pharmaceutically acceptable salt thereof:

In the second aspect of the invention, the invention provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula I to XVI or a compound disclosed herein.

In some embodiments, the invention provided a pharmaceutical composition comprising the compound of Formula I to XVI or a pharmaceutically acceptable salt, stereoisomer or tautomer, or prodrug thereof and a pharmaceutically acceptable carrier and/or an antineoplastic agent, such as IDO inhibitors, EP2 and/or EP4 antagonists, angiogenesis inhibitors, cell proliferation and survival inhibitors, target therapies, apoptosis agents, immunotherapies such as CTLA4, PD-1/PD-L1, LAG-3, TIGIT, TIM-3 antibody, for the treatment of cancer.

In the third aspect of the invention, the invention provided a method for treating a condition mediated by HPK1 or overexpressed HPK1, comprising administering a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof according to the first aspect of the invention or a pharmaceutical composition according to the second aspect of the invention.

In the fourth aspect of the invention, the invention provided a method of treating cancer, wherein the method comprising administering to a subject a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof according to the first aspect of the invention or the pharmaceutical composition according to the second aspect of the invention, wherein the cancer is selected from, but not limited to, lung cancer, breast cancer, ovarian cancer, prostate cancer, liver cancer, gastric cancer, esophageal cancer, pancreatic cancer, colon cancer, kidney cancer, head and neck cancer, bladder cancer, or a sarcoma.

In the fifth aspect of the invention, the invention provided a method of conditioning adoptive cell transfer therapy, wherein the method comprising treating engineered (such as CAR-T cells) or non-engineered T cells or immune cells with the compound or pharmaceutically acceptable salt thereof according to the first aspect of the invention in adoptive cell transfer therapy before the cells are given back to patients.

The invention includes all possible combinations of the embodiments described above and below. It should be understood that, within the scope of the present invention, each technical feature of the present invention described above and, in the following, (as examples) may be combined with each other to form a new or preferred technical solution, which is not listed here due to space limitations.

Definitions

The term "alkyl, " by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e. unbranched) or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono-or polyunsaturated and can include di-and multivalent radicals, having the number of carbon atoms designated (i.e. C ₁- ₁₀ means one to ten carbons, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms) . Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl) methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl) , 2, 4-pentadienyl, 3- (1, 4-pentadienyl) , ethynyl, 1-and 3-propynyl, 3-butynyl, and the higher homologs and isomers. Alkyl groups which are limited to hydrocarbon groups are termed "homoalkyl" . The alkyl is optionally substituted with one or more halogen atom (s) .

The term “halogenated alkyl” means alkyl as defined above wherein one or more hydrogen atoms have been replaced by halogen atoms.

The term “alkenyl” means carbon chains which contain at least one carbon-carbon double bond, which may be linear or branched, Z-or E-, or combinations thereof. Examples of alkenyl are CH ₃CH=CH-, CH ₂=CHCH ₂-and CH (CH ₃) ₂CH=CH-.

The term "alkylene" by itself or as part of another substituent means a divalent radical derived from an alkyl, as exemplified, but not limited, by -CH ₂CH ₂CH ₂CH ₂-, -CH=CH-, -CH ₂CH=CHCH ₂-, -CH ₂C≡CCH ₂-, -CH ₂CH ₂CH (CH ₂CH ₂CH ₃) CH ₂-. The alkylene radical may be optionally substituted independently with one or more substituents described herein, and includes radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations. Typically, an alkyl (or alkylene) group has from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms. The alkylene is optionally substituted with one or more halogen atom (s) .

The term "alkynyl" means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like. The alkynyl is optionally substituted with one or more halogen atom (s) .

The term “alkylamino” refers to an amino substituent which is further substituted with one or two alkyl groups. The term “aminoalkyl” refers to an alkyl substituent which is further substituted with one or more amino groups. The term “hydroxyalkyl” refers to an alkyl substituent which is further substituted with one or more hydroxyl groups. The alkyl or aryl portion of alkylamino, aminoalkyl, mercaptoalkyl, hydroxyalkyl, mercaptoalkoxy, sulfonylalkyl, sulfonylaryl, alkylcarbonyl, and alkylcarbonylalkyl may be optionally substituted with one or more substituents.

The term "cycloalkyl" or “carbococyclyl” means mono-, bicyclic or spiro-bicyclic carbocyclic rings, each of which has from 3 to 10 carbon atoms. A “fused analog” of cycloalkyl means a monocyclic ring fused to an aryl or heteroaryl group in which the point of attachment is on the non-aromatic portion. Examples of cycloalkyl and fused analogs thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl, and the like. The spiro- bicyclic carbocyclic rings are bicyclic (having just two rings) or have a bicyclic portion as part of the larger ring system, in either case with the two rings connected through the defining single common carbon atom The cycloalkyl is optionally substituted with one or more halogen atom (s) .

The term “alkoxy” means alkoxy groups of a straight or branched having the indicated number of carbon atoms. C _1-6alkoxy, for example, includes methoxy, ethoxy, propoxy, isopropoxy, and the like.

The term "heteroalkyl, " by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of at least one carbon atoms and at least one heteroatom selected from the group consisting of O, N, P, Si and S, and wherein the nitrogen, phosphorus, and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom (s) O, N, P and S and Si may be placed at any interior position of the heteroalkyl group or at the position at which alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, -CH ₂-CH ₂-O-CH ₃, -CH ₂-CH ₂-NH-CH ₃, -CH ₂-CH ₂-N (CH ₃) -CH ₃, -CH ₂-S-CH ₂-CH ₃, -CH ₂-CH ₂, -S (O) -CH ₃, -CH ₂-CH ₂-S (O) ₂-CH ₃, -CH=CH-O-CH ₃, -Si (CH ₃) ₃, -CH ₂-CH=N-OCH ₃, -CH=CH-N (CH ₃) -CH ₃, -O-CH ₃, -O-CH ₂-CH ₃, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH ₂-NH-OCH ₃ and -CH ₂-O-Si (CH ₃) ₃. Similarly, the term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH ₂ -CH ₂-S-CH ₂-CH ₂-and -CH ₂-S-CH ₂-CH ₂-NH-CH ₂-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxo, alkylenedioxo, alkyleneamino, alkylenediamino, and the like) . Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C (O) OR'-represents both-C (O) OR'-and -R'OC (O) -. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C (O) R', -C (O) NR', -NR'R", -OR', -SR', and/or -SO ₂R'. Where "heteroalkyl" is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R"or the like, it will be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term "heteroalkyl" should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R"or the like.

The term “cycloalkoxy” means cycloalkyl as defined above bonded to an oxygen atom, such as cyclopropyloxy.

The term “halogenated alkoxy” means alkoxy as defined above wherein one or more hydrogen atoms have been replaced by halogen atoms.

The term "aryl" means mono-or bicyclic aromatic rings containing only carbon atoms. the aryl may contain such as 6, 7, 8, 9 or 10 carbon atoms. A “fused analog” of aryl means an aryl group fused to a monocyclic cycloalkyl or monocyclic heterocyclyl group in which the point of attachment is on the aromatic portion. Examples of aryl and fused analogs thereof include phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, 2, 3-dihydrobenzofuranyl, dihydrobenzopyranyl, 1, 4-benzodioxanyl, and the like.

The term "heteroaryl" means a mono-or bicyclic aromatic ring containing at least one heteroatom selected from N, O and S, with each ring containing 5 to 10 atoms (5, 6, 7, 8, 9 or 10 atoms) , preferably 5 to 6 atoms. A “fused analog” of heteroaryl means a heteroaryl group fused to a monocyclic cycloalkyl or monocyclic heterocyclyl group in which the point of attachment is on the aromatic portion. Examples of heteroaryl include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, pyrazolyl pyrazolo [l, 5-a] pyridinyl, pyrimidinyl, pyrrolidinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, furo (2, 3-b) pyridyl, quinolyl, indolyl, isoquinolyl, tetrahydropyrido [3, 4-d] pyrimidinyl and the like.

The representative structures of bicyclic heteroary consist of:

The alkyl groups, aryl groups and said heteroaryl groups referred to in the definitions are unsubstituted or are substituted by at least one substituent selected from the group consisting of substituents.

The substituents are selected from the group consisting of halogen atoms, alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, haloalkyl groups having from 1 to 4 carbon atoms, haloalkoxy groups having from 1 to 4 carbon atoms, cyano groups, alkynyl groups having from 2 to 6 carbon atoms, alkanoyl groups having from 1 to 5 carbon atoms, cycloalkyl groups having from 3 to 7 ring atoms, heteroaryl groups, aryl groups, aralkoxy groups having from 7 to 10 carbon atoms, arylcarbonyl groups, two adjacent-x groups are optionally joined together to form an alkylene or an alkenylene chain having 3 or 4 carbon atoms, aminocarbonyl groups, alkenyl groups having from 2 to 5 carbon atoms, alkylthio groups having from 1 to 4 carbon atoms, aminosulfinyl groups, aminosulfonyl groups, hydroxy groups, -SF ₅, -P (O) Me ₂, hydroxyalkyl groups having from 1 to 4 carbon atoms, nitro groups, amino groups, carboxy groups, alkoxycarbonyl groups having from 2 to 5 carbon atoms, alkoxyalkyl groups having from 1 to 4 carbon atoms, alkylsulfonyl groups having from 1 to 4 carbon atoms, alkanoylamino groups having from 1 to 4 carbon atoms, alkanoyl (alkyl) amino groups having from 1 to 6 carbon atoms, alkanoylaminoalkyl groups having from 1 to 6 carbon atoms in both the alkanoyl and alkyl part, alkanoyl (alkyl) aminoalkyl groups having from 1 to 6 carbon atoms in both the alkanoyl and each alkyl part, alkylsulfonylamino groups having from 1 to 4 carbon atoms, mono-or di-alkylaminocarbonyl groups having from 1 to 6 carbon atoms, mono-or di-alkylaminosulfinyl groups having from 1 to 6 carbon atoms, mono-or di alkylaminosulfonyl groups having from 1 to 6 carbon atoms, aminoalkyl groups having from 1 to 4 carbon atoms, mono-or di-alkylamino groups having from 1 to 6 carbon atoms, mono-or di-alkylaminoalkyl groups having from 1 to 6 carbon atoms in each alkyl part, aralkyl groups having from 7 to 10 carbon atoms, heteroarylalkyl groups having from 1 to 4 carbon atoms in the alkyl part, heteroarylalkoxy groups having from 1 to 4 carbon atoms in the alkoxy part and alkylsulfonylamino groups having from 1 to 4 carbon atoms.

The term "heterocyclyl" or “heterocyclic ring” means, unless otherwise defined, mono-, bicyclic saturated rings, bridged bicyclic or spirocyclic rings containing at least one (such as 1.2. or 3) heteroatom (s) selected from N, S and O, each of said ring having from 3 to 10 atoms (such as 3, 4, 5, 6, 7, 8, 9 or 10 atoms) in which the point of attachment may be carbon or nitrogen. A “fused analog” of heterocyclyl means a monocyclic heterocycle fused to an aryl or heteroaryl group in which the point of attachment is on the non-aromatic portion. Examples of "heterocyclyl" and fused analogs thereof include pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, 2, 3-dihydrofuro (2, 3-b) pyridyl, benzoxazinyl, tetrahydrohydroquinolinyl, tetrahydroisoquinolinyl, dihydroindolyl, and the like. The term also includes partially unsaturated monocyclic rings that are not aromatic, such as 2-or 4-pyridones attached through the nitrogen or N-substituted- (1H, 3H) -pyrimidine-2, 4-diones (N-substituted uracils) .

The terms "halo" or "halogen, " by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl, " or “halogenated alkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "halo (C ₁-C ₄) alkyl" is meant to include, but not be limited to, trifluoromethyl, 2, 2, 2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

A "prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrugs may also have improved solubility in pharmaceutical compositions over the parent drug. An example, without limitation, of a prodrug would be a compound of any of Formula I, which is administered as an ester (the "prodrug" ) to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility, but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial. A further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.

Optical Isomers -Diastereomers -Geometric Isomers –Tautomers:

Compounds of Formula I to VI may contain one or more asymmetric centers and may thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of the compounds of Formula I to XVI.

Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.

Some of the compounds of Formula I to XVI may contain one or more than one cyclic ring systems and may thus exist in cis-and trans-isomers. The present invention is meant to include all such cis-and trans-isomers.

Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers. Such an example may be a ketone and its enol form known as keto-enol tautomers. The individual tautomers as well as mixture thereof are encompassed with compounds of Formula I to XVI.

Compounds of the Formula I may be separated into diastereoisomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example MeOH or EtOAc or a mixture thereof. The pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active amine or acid as a resolving agent or on a chiral HPLC column.

Alternatively, any enantiomer of a compound of the general Formula I to XVI may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.

Stable Isotope-Labeled Analogs:

One or more than one of the protons in compounds of Formula I to XVI can be replaced with deuterium atom (s) , thus providing deuterated analogs that may have improved pharmacological activities.

Salts and Formulations:

The compounds described herein can be useful as the free base or as a salt.

The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N, N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydramine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

When the compound of the present invention is alkaline, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.

It will be understood that, as used herein, references to the compounds of Formula I to XVI are meant to also include the pharmaceutically acceptable salts.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients are mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethyl-cellulose, methylcellulose, hydroxypropylmethy-cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist) , or nebuliser, with or without the use of a suitable propellant, such as 1, 1, 1, 2-tetrafluoroethane or 1, 1, 1, 2, 3, 3, 3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

The pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of the compound (s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active, a propellant (s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.

Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns) .

This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

Capsules (made, for example, from gelatin or HPMC) , blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

A suitable solution formulation for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from l mg to 200 mg of the compound of the invention per actuation and the actuation volume may vary from 1 L to 100 L. A typical formulation may comprise a compound of Formula I to VI, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.

Suitable flavors, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.

Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, poly (DL-lactic-coglycolic acid (PGLA) . Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve which delivers a metered amount. Units in accordance with the invention are typically arranged to administer a metered dose or "puff" containing from 1 fig to 10 mg of the compound of Formula I to XVI. The overall daily dose will typically be in the range 1 lag to 10 mg which may be administered in a single dose or, more usually, as divided doses throughout the day.

Compounds of Formula I to XVI may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compound of Formula I to XVI are employed. (For purposes of this application, topical application shall include mouth washes and gargles. )

Dosage levels of the order of from about 0.01 mg to about 140 mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5 mg to about 7 g per patient per day. For example, a condition may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 3.5 g per patient per day, preferably 2.5 mg to 1 g per patient per day.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration of humans may contain from 0.5 mg to 5 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.

It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

Indications

Compounds of the present invention may be used for treatment of HPK1 mediated diseases and conditions such as cancer.

Combination Therapy

Administration of the HPK1 inhibitors disclosed herein can be combined with other cancer treatments. For example, the inhibitors can be administered in combination with surgical treatments, radiation, or other therapeutic agents such as antibodies, other kinase inhibitors, target therapies, chemotherapeutics, or immunotherapies. The inhibitors may also be administered in combination with RNAi therapy, antisense therapy, vaccines, or immunotherapies including adoptive cell transfer therapy such as CAR-T therapy. The HPK1 inhibitors described herein may be combined with one, two, or more other therapeutic agents. In the examples outlined below, it is understood that "second therapeutic agent" also includes more than one therapeutic agent other than the HPK1 inhibitor. For instance, the compounds disclosed herein may be combined with an agent such as a PD-1/PD-L1 antibody, a CTLA4 antibody, or any other checkpoint protein antibodies. A HPK1 inhibitor described herein may be administered with one, two, or more other therapeutic agents.

The HPK1 inhibitors disclosed herein can also be used to condition engineered (such as CAR-T cells) or non-engineered T cells or immune cells in adoptive cell transfer therapy before the cells are given back to patients.

Synthesis

The compounds of the present invention can be prepared according to the following synthetic schemes:

The following prodrugs can be prepared accordingly:

In the above-mentioned prodrugs, R ¹ is selected from the following heterocyclics:

is selected from the following moieties:

Biological Activity Evaluation

HPK1 (MAP4K1) and GLK (MAP4K3) Kinase Assay: The inhibitory activities of the compounds toward HPK1 and GLK were measured in the HPK1 and GLK ADP-Glo ^TM Assay (Promega, Madison, WI) , respectively. For HPK1 kinase assay, in wells of 384-w plates, 5 ng of recombinant human HPK1 (amino acid 1–346 with an N-terminal GST tag) was incubated with 0.1 ug/uL Myelin Basic Protein (MBP) substrate and 10 uM ATP in the presence of varying concentrations of compounds at room temperature (r.t. ) for 60 min in the reaction mixture of 7.5ul. For GLK kinase assay, in wells of 384-w plates, 10 ng of recombinant human GLK (amino acid 1-380 with an N-terminal GST tag) was incubated with 0.2 ug/uL PKA substrate and 10 uM ATP in the presence of varying concentrations of compounds at r.t. for 60 min in the reaction mixture of 7.5ul. Then 5 ul of the ADP-Glo ^TM Reagent was added to the reaction mixture, and wells were incubated at r.t. for 40 min. 10 ul of the Kinase Detection Reagent was added to the above mixture, and the wells were incubated at r.t. for 30 min. Luminescence signal was then read by CLARIOstar (BMG Labtech) .

The IC ₅₀ value was determined as the concentration for 50%inhibition of the kinase activity compared to DMSO control wells (A: IC ₅₀ < 0.1 μM; B: IC ₅₀ between 0.1 μM and 1.0 μM; C: IC ₅₀ between 1.0 μM and 10.0 μM; D: IC ₅₀ > 10.0 μM; /: not determined) .

Table 1 (IC ₅₀ for HPK1 and GLK)

Example	HPK1	GLK	Example	HPK1	GLK
1	A	B	34	A	/
2	A	B	35	B	/
3	A	/	36	C	/
4	A	/	37	A	C
5	A	/	38	A	A
6	A	/	39	A	B
7	B	/	40	A	/

8	A	/	41	A	B
9	A	A	42	A	/
10	A	/	43	B	/
11	A	B	44	A	A
12	A	/	45	C	/
13	A	/	46	A	B
14	A	/	47	B	/
15	A	/	48	A	B
16	B	/	49	C	/
17	A	/	50	A	B
18	A	/	51	A	/
19	A	/	52	B	/
20	A	/	53	C	/
21	A	/	54	B	/
22	A	/	55	A	/
23	C	/	56	A	C
24	A	/	57	A	/
25	B	/	58	A	/
26	A	/	59	A	D
27	A	B	60	A	B
28	A	/	61	A	B
29	A	A	62	C	/
31	B	/	63	A	C
32	B	/	64	A	A
33	C	/	65	B	/
66	A	C	67	B	/
68	B	/

The following abbreviations have the meanings indicated. EA means ethyl acetate; CIP means 2-chloro-1, 3-dimethylimidazolidium hexafluorophosphate; CSA means camphorsulfonic acid; DBU means l, 8-diazabicyclo [5.4.0] undec-7-ene; DIBAL means diisobutylaluminum hydride; DCM means dichloromethane; DIEA means diisopropylethylamine; DMAP means N, N-dimethylaminopyridine; DME means 1, 2-dimethoxyethane; DMF means N, N-dimethylformamide; dmpe means l, 2-bis (dimethylρhosphino) ethane; DMSO means dimethylsulfoxide; dppb means l, 4-bis (diphenylphosphino) butane; dppe means 1, 2-bis (diphenylphosphino) ethane; dppf means 1, 1’ -bis (diphenylphosphino) ferrocene; dppm means 1, 1’ -bis (diphenylphosphino) methane; DIAD means diisopropylazodicarboxylate; EA means ethyl acetate; EDCI means 1- (3-dimethylaminopropyl) -3 -ethylcarbodiimide; HATU means 2- (7-Aza-1H-benzotriazole-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate; HMPA means hexamethylphosphorarnide; IPA means isopropyl alcohol; LDA means lithium diisopropylamide; LHMDS means lithium bis (hexamethyldisilylamide) ; LAH means lithium aluminum hydride; NCS means N-chlorosuccinimide; PE means petroleum ether; PyBOP means benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate; SGC means silica gel chromatography; TDA means tris (2- (2-methoxyethoxy) ethyl) amine; DCM means dichloromethame; TEA means triethylamine; TFA means trifluoroacetic acid; THF means tetrahydrofuran; NCS means N-chlorosuccinimide; NMI means 1-methylimidazole; NMM means N-methylmorpholine; NMP means N-methylpyrrolidine; PPh ₃ means triphenylphosphine, rt or RT means room temperature; sat. means saturated; T3P means propylphosphonic anhydride; TBS means t-butyldimethylsilyl; TCFH means N, N, N’, N’-tetramethylchloroformaidinium hexafluorophosphate.

HPLC-MS analyses were performed on Waters HPLC 2790 with Waters micromass ZQ 4000 (Model MAA050) as mass detector and Waters 2487 UV as detector. Column used was Phenomemex OOB-4605-E0 (5u-XB-C18-100A, 50 x4.6mm) . The mobile phase consists of eluent A (water, 0.05%TFA) and eluent B (CH ₃CN, 0.05%TFA) , and the elution proceeded at 1 mL/min. The initial conditions were 90%A for 1 min, then 90%A to 10%A linearly decreased within 5 min, then from 10%A to 90%A within 1 min. The total run time is 7 minutes.

The present invention will be more readily understood by referring to the following examples which are given to illustrate the invention rather than to limit its scope.

Intermediate 1

Step 1 (S) -ethyl 2-chloro-4- (2-hydroxy-1-phenylethylamino) pyrimidine-5-carboxylate

To a stirred solution of ethyl 2, 4-dichloropyrimidine-5-carboxylate (20 g, 90.9 mmol) and DIEA (23.45 g, 18.18 mmol) in CH ₃CN (250 ml) was added (S) -2-amino-2-phenylethanol (12.7 g, 92.7 mmol) in small portions at 0-10℃. The mixture was stirred for 1 h at 0-10℃. Water (500 ml) was added slowly at 0-10℃. The solid was collected by filtration and dried to give 25.3 g of the product as a white solid. MS (ES+) : 322.0 [M+1] ⁺.

Step 2 (S) -2-chloro-4- (2-hydroxy-1-phenylethylamino) pyrimidine-5-carboxylic acid

A mixture of the product of Step 1 (25 g, 79 mmol) and LiOH·H ₂O (6.63 g, 158 mmol) in THF/H ₂O (1/1, 250 ml) was stirred at rt for 1 h. The solution was adjusted pH<7 with 1N HCl and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated to give 22 g of the product as a white solid. MS (ES+) : 294.0 [M+1] ⁺.

Step 3 (S) -tert-butyl 2- (2-chloro-4- (2-hydroxy-1-phenylethylamino) pyrimidine-5-carbonyl) hydrazinecarboxylate

To a stirred solution of the product of Step 2 (5 g, 17.0 mmol) , tert-butyl hydrazinecarboxylate (2.25 g, 17.0 mmol) and DIEA (6.6 g, 51.3 mmol) in DMF (50 ml) was added HATU (7.78 g, 20.4 mmol) in small portions at 0-10℃. The mixture was stirred for 1 h. The solution was quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel column chromatography (EA: PE=2: 3) to give 5.1 g of the product as a white solid. MS (ES+) : 408.0 [M+1] ⁺.

Step 4 (S) -2-chloro-4- (2-hydroxy-1-phenylethylamino) pyrimidine-5-carbohydrazide

A mixture of the product of Step 3 (5.1 g, 12.5 mmol) in 4N HCl (EA, solution, 50 ml) was stirred for 1 h at rt. The mixture was concentrated to give 4.4 g of crude product as a white solid which was used for the next step without further purification. MS (ES+) : 308.0 [M+1] ⁺.

Step 5 (S) -2- (2-chloro-5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-4-ylamino) -2-phenylethanol

A mixture of the product of Step 4 (4.4 g, 12.8 mmol) in triethoxymethane (40 ml) was stirred for 1 h at 100℃. The solution was quenched with 1N HCl, water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel column chromatography (EA: PE=2: 3) to give 990 mg of the title product as a white solid. MS (ES+) : 318.0 [M+1] ⁺.

EXAMPLE 1

(S) -5- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -3, 3-dimethyl-2, 3-dihydro-1H-inden-1-one

Step 1 6-bromo-1, 1-dimethyl-2, 3-dihydro-1H-indene

To a stirred solution of TiCl ₄ (5.4 g, 0.029 mmol) in DCM (30 ml) was added (CH ₃) ₂Zn (42.6 ml, 1M in hexane) at -40℃under Ar. The mixture was stirred for 20 min. Then 6-bromo-2, 3-dihydro-1H-inden-1-one (3 g, 0.014 mmol) which dissolved in DCM (24 ml) was added dropwise at -40℃ under Ar. The mixture was stirred at rt overnight, and water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel column chromatography (EA: PE=1: 9) to give 2.4 g of the title product as yellow oil.

Step 2 5-bromo-3, 3-dimethyl-2, 3-dihydro-1H-inden-1-one

To a stirred solution of 6-bromo-1, 1-dimethyl-2, 3-dihydro-1H-indene (2.4 g, 0.011 mmol) in acetic acid (33 ml) was added CrO ₃ (6.4 g, 0.064 mmol) which dissolved in acetic acid/H ₂O (1: 1, 33 ml) at 60℃ under Ar. The mixture was stirred at 60℃ for 3 h, then water was added. The mixture was adjusted pH>7 with NaOH (2N) , then extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel column chromatography (EA: PE=1: 9) to give 643 mg of the title product as a pink solid. MS (ES+) : 238.8 [M+1] ⁺ _.

Step 3 tert-butyl 3, 3-dimethyl-1-oxo-2, 3-dihydro-1H-inden-5-ylcarbamate

To a stirred solution of 5-bromo-3, 3-dimethyl-2, 3-dihydro-1H-inden-1-one (700 mg, 2.941 mmol) in 1, 4-Dioxane (14 ml) were added Pd ₂ (dba) ₃ (269 mg, 0.294 mmol) , Xant-phos (340 mg, 0.588 mmol) , Cs ₂CO ₃ (1.9 g, 6 mmol) and NH ₂Boc (1 g, 9 mmol) at 100℃ under Ar. The mixture was stirred at 100℃ for 2 h. The mixture was filtered through a layer of celite. The filtrate was concentrated. The residue was purified by silica gel column chromatography (EA: PE=1: 8) to give 1.1 g of crude product as a yellow solid. MS (ES+) : 276.1 [M+1] ⁺.

Step 4 5-amino-3, 3-dimethyl-2, 3-dihydro-1H-inden-1-one

A mixture of the product of Step 3 (550 mg) and TFA (6 ml) in DCM (9 ml) was stirred at rt for 2 h. The solution was then concentrated, adjusted pH>7 with Na ₂CO ₃ (aq. ) and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel column chromatography (EA: PE=1: 4) to give 220 mg of the title product as a yellow solid. MS (ES+) : 176.1 [M+1] ⁺.

Step 5 (S) -5- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -3, 3-dimethyl-2, 3-dihydro-1H-inden-1-one

A mixture of the product of Step 4 (200 mg, 1.14mmol) in 1, 4-dioxane (3.0 ml) were added Pd ₂ (dba) ₃ (105 mg, 0.11 mmol) , Xant-phos (132 mg, 0.23 mmol) , Cs ₂CO ₃ (745 mg, 2.29 mmol) and (S) -2- (2-chloro-5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-4-ylamino) -2-phenylethanol (363 mg, 1.15 mmol) . The mixture was stirred for 2 h at 100℃ under Ar. The mixture was then concentrated and purified by silica gel column chromatography (EA: PE=5: 1) to give 147.5 mg of the title product as a yellow solid. MS (ES+) : 456.8 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.18 (s, 1H) , 9.35 (s, 1H) , 8.92 (d, J = 7.8 Hz, 1H) , 8.69 (s, 1H) , 7.92 (s, 1H) , 7.62 (m, 1H) , 7.49 –7.32 (m, 5H) , 7.26 (m, 1H) , 5.48 (m, 1H) , 5.27 (m, 1H) , 3.88 –3.81 (m, 2H) , 1.34 (s, 3H) , 1.31 (s, 3H) .

EXAMPLE 2

(S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -2, 2-dimethylbenzofuran-3 (2H) -one

Step 1 1- (4-bromo-2-hydroxyphenyl) -2-chloroethanone

To a solution of 1- (4-bromo-2-hydroxyphenyl) ethan-1-one (10 g, 4.65 mmol) in a mixture of DCE (143 ml) and MeOH (57 ml) was added benzyltrimethylazanium dichloroiodanuide (32.3 g, 9.3 mmol) under nitrogen. The mixture was stirred at 70℃ for 4 h. The mixture was concentrated under reduced pressure. The residue was dissolved in DCM, washed with water, brine and NaHSO ₃ (5%aq. ) , dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel column chromatography (EA: PE=1: 3) to give 15 g of the title product as a yellow solid. MS (ES+) : 248.8 [M+1] ⁺.

Step 2 6-bromobenzofuran-3 (2H) -one

To a solution of the product of Step 6 (11.6 g, 46.5 mmol) in ACN (200 ml) was added a solution of TEA (4.71 g, 46.5 mmol) in ACN (20 ml) . The mixture was stirred for 2 h at rt, and then concentrated under reduced pressure. The residue was dissolved in EA, washed with water, brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/PE= 3/7) to afford 3.47 g of the title product as a yellow solid. MS (ES+) : 213 [M+1] ⁺. Step 3 6-bromo-2, 2-dimethylbenzofuran-3 (2H) -one

To a stirred solution of the product of Step 7 (1 g, 4.74 mmol) in DMF (10 ml) were added NaH (417 mg, 10.42 mmol) and CH ₃I (2.35 g, 16.59 mmol) at 0-10℃ under Ar. The solution was quenched with NH ₄Cl (aq. ) and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel column chromatography (DCM: PE=2: 3) to give 300 mg of the product as a yellow solid.

Step 4 (S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -2, 2-dimethylbenzofuran-3 (2H) -one

The title compound was synthesized using the same procedures as described in Example 1. MS (ES+) : 459.2 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.33 (s, 1H) , 9.38 (s, 1H) , 9.01 (d, J = 7.1 Hz, 1H) , 8.69 (s, 1H) , 7.81 (d, J = 1.7 Hz, 1H) , 7.45 (t, J = 8.2 Hz, 3H) , 7.32 (t, J = 7.5 Hz, 2H) , 7.23 (m, 2H) , 5.38 –5.27 (m, 2H) , 3.91 (m, 1H) , 3.75 (m, 1H) , 1.42 (s, 6H) .

EXAMPLE 3

(S) -5- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -3, 3-bis (hydroxymethyl) isobenzofuran-1 (3H) -one

Step 1 5-bromo-3, 3-bis (hydroxymethyl) isobenzofuran-1 (3H) -one

To a stirred solution of 5-bromoisobenzofuran-1 (3H) -one (10 g, 0.047 mol) in THF (100 mL) was added LDA (50 mL) dropwise at -78℃ under Ar. The mixture was stirred for 30 min. Then paraformaldehyde (12.7 g, 0.141mol) and HMPA (17.7 g, 0.099 mol) were added at -78℃ under Ar. The mixture was stirred at rt for another 2 h. NH ₄Cl (sat. aq., 300 mL) was added at 0℃ and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel column chromatography (EA: PE=2: 3) to give 2.7 g of the title product as a yellow solid. MS (ES+) : 272.6 [M+1] ⁺.

Step 2 (S) -5- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -3, 3-bis (hydroxymethyl) isobenzofuran-1 (3H) -one

The title compound was synthesized using the same procedures as described in Example 1. MS (ES+) : 491.0 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.26 (s, 1H) , 9.36 (s, 1H) , 8.94 (d, J = 7.9 Hz, 1H) , 8.69 (s, 1H) , 8.00 (s, 1H) , 7.77 (d, J =8.5 Hz, 1H) , 7.63 (d, J = 8.5 Hz, 1H) , 7.45 (d, J = 7.6 Hz, 2H) , 7.37 (t, J = 7.6 Hz, 2H) , 7.27 (m, 1H) , 5.48 (m, 1H) , 5.33 (t, 1H) , 3.94 –3.67 (m, 8H) .

EXAMPLE 4

(S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) benzofuran-3 (2H) -one

The title compound was synthesized using the same procedures as described in Example 1. MS (ES+) : 430.6 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.34 (s, 1H) , 9.37 (s, 1H) , 9.01 (d, J = 7.3 Hz, 1H) , 8.70 (s, 1H) , 7.82 (s, 1H) , 7.45 (dd, J =11.5, 8.0 Hz, 3H) , 7.34 (t, J = 7.6 Hz, 2H) , 7.29 –7.17 (m, 2H) , 5.36 (m, 1H) , 5.30 (t, J = 5.0 Hz, 1H) , 4.79 (s, 2H) , 3.90 (m, 1H) , 3.76 (m, 1H) .

EXAMPLE 5

(S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -3H-spiro [benzofuran-2, 1'-cyclopropan] -3-one

Step 1 methyl 4-acetamido-2- (2-oxotetrahydrofuran-3-yloxy) benzoate

To a stirred solution of methyl 4-acetamido-2-hydroxybenzoate (55 g, 0.26 mol) in acetone (122 mL) were added K ₂CO ₃ (45.4 g, 0.33 mol) and 3-bromodihydrofuran-2 (3H) -one (63 g, 0.38 mol) at rt. The mixture was stirred for 30 h at 60℃. The mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (EA: PE=3: 1) to give 66.5 g of the product as yellow oil. MS (ES+) : 294.0 [M+1] ⁺.

Step 2 N- (3-oxo-3H-spiro [benzofuran-2, 1'-cyclopropane] -6-yl) acetamide

To a mixture of DBU (1.58 g, 0.01 mol) and NaCl (12.1 g, 0.21 mol) in DMF (300 mL) stirred at 150℃under Ar, was added a solution of the product of Step 1 (30.5 g, 0.10 mol) in DMF (310 mL) was added. The mixture was stirred for 8 h at 150℃. Water was added and the mixture was extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by beating with MTBE to give 8.97 g of the product as yellow solid. MS (ES+) : 218.0 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.49 (s, 1H) , 7.77 (d, J = 1.7 Hz, 1H) , 7.62 (d, J = 8.5 Hz, 1H) , 7.22 (dd, J = 8.5, 1.7 Hz, 1H) , 2.12 (s, 3H) , 1.74 (q, J = 5.2 Hz, 2H) , 1.39 (q, J = 5.2 Hz, 2H) .

Step 3 6-amino-3H-spiro [benzofuran-2, 1'-cyclopropan] -3-one

A mixture of the product of Step 2 (8.96 g, 0.04 mol) and KOH (6.95 g, 0.12 mol) in MeOH (91 mL) was stirred for 1 h at 65℃. Water was added and the mixture was extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by beating with EA to give 4.78 g of pure product as a yellow solid. Yield: 66.5%. MS (ES+) : 176.0 [M+1] ⁺.

Step 4 (S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -3H-spiro [benzofuran-2, 1'-cyclopropan] -3-one

The title compound was synthesized using the same procedures as described in Example 1. MS (ES+) : 457.0 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.36 (s, 1H) , 9.38 (s, 1H) , 9.01 (d, J = 7.2 Hz, 1H) , 8.70 (s, 1H) , 7.88 (d, J = 1.8 Hz, 1H) , 7.52 (d, J = 8.5 Hz, 1H) , 7.47 –7.37 (m, 2H) , 7.35 –7.28 (m, 3H) , 7.24 –7.17 (m, 1H) , 5.34 (m, 1H) , 5.29 (t, J = 4.9 Hz, 1H) , 3.90 (m, 1H) , 3.75 (m, 1H) , 1.79 (q, J = 4.1 Hz, 2H) , 1.46 –1.38 (m, 2H) .

EXAMPLE 6

6- (4- ( (S) -2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -2, 2-dimethyl-2, 3-dihydrobenzofuran-3-ol

To a stirred solution of Example 2 (25 mg, 0.05 mmol) in MeOH (0.5 ml) was added NaBH ₄ (19 mg, 0.4 mmol) . The mixture was stirred at rt for 1h. The mixture was quenched with NH ₄Cl (aq. ) and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated to give 19 mg of the product as a yellow solid. MS (ES+) : 461.1 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 9.68 (s, 1H) , 9.31 (s, 1H) , 8.87 (s, 1H) , 8.59 (s, 1H) , 7.39-7.05 (m, 8H) , 5.34 -5.25 (m, 3H) , 4.63 (s, 1H) , 3.86 (m, 1H) , 3.73 (m, 1H) , 1.43 (s, 3H) , 1.38 (s, 3H) .

EXAMPLE 7

(S) -2- (2- (1-methyl-1H-indol-6-ylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-4-ylamino) -2-phenylethanol

To a stirred solution of ( (S) -2- (2-chloro-5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-4-ylamino) -2-phenylethanol (110 mg, 0.347 mmol) in 1, 4-Dioxane (4 mL) were added Pd ₂ (dba) ₃ (39 mg, 0.043 mmol ) , X-phos (40 mg, 0.274 mmol) , Cs ₂CO ₃ (227 mg, 0.697 mmol) and 1-methyl-1H-indol-6-amine (152 mg, 1.041 mmol) under Ar. The mixture was stirred at 70℃ overnight and then filtered through a layer of celite. The filtrate was concentrated. The residue was purified by Prep-TLC (EA: PE=7: 3) to give 20.6 mg of the title product as a brown solid. MS (ES+) : 428.1 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 9.71 (s, 1H) , 9.29 (s, 1H) , 8.78 (d, J = 8.0 Hz, 1H) , 8.61 (s, 1H) , 7.87 (s, 1H) , 7.41 (d, J = 9.2 Hz, 3H) , 7.34 (t, J = 7.5 Hz, 2H) , 7.27 –7.19 (m, 3H) , 6.35 (d, J = 3.1 Hz, 1H) , 5.52 (m, 1H) , 5.19 (t, J = 4.9 Hz, 1H) , 3.95 –3.81 (m, 2H) , 3.70 (s, 3H) .

EXAMPLE 8

(S) -2- (2- (1-methyl-1H-indazol-6-ylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-4-ylamino) -2-phenylethanol

The title compound was synthesized using the same procedures as described in Example 7. MS (ES+) : 429.1 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.01 (s, 1H) , 9.34 (s, 1H) , 8.90 (d, 1H) , 8.67 (s, 1H) , 8.07 (s, 1H) , 7.93 (s, 1H) , 7.61 (m, 1H) , 7.45 –7.23 (m, 7H) , 5.54 (m, 1H) , 3.95 (m, 6H) .

EXAMPLE 9

(S) -5- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -3, 3-bis (methoxymethyl) isobenzofuran-1 (3H) -one

Step 1 5-amino-3, 3-bis (methoxymethyl) isobenzofuran-1 (3H) -one

To a stirred solution of tert-butyl 3, 3-bis (hydroxymethyl) -1-oxo-1, 3-dihydroisobenzofuran-5-ylcarbamate (220 mg, 0.712 mmol) in DCM (4 mL) was added trimethyloxonium tetrafluoroborate (632 mg, 4.27 mmol) at 0-10℃ under Ar. The mixture was stirred at rt overnight and then concentrated. The residue was purified by silica gel column chromatography (EA: PE=7: 3) to give 135 mg of the title product as a yellow solid. MS (ES+) : 237.9 [M+1] ⁺.

Step 2 (S) -5- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -3, 3-bis (methoxymethyl) isobenzofuran-1 (3H) -one

The title compound was synthesized using the same procedures as described in Example 1. MS (ES+) : 518.9 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.30 (s, 1H) , 9.35 (s, 1H) , 8.93 (d, J = 7.8 Hz, 1H) , 8.70 (s, 1H) , 7.99 (d, J = 1.8 Hz, 1H) , 7.77 (dd, J = 8.5, 1.8 Hz, 1H) , 7.65 (d, J = 8.4 Hz, 1H) , 7.41 (dd, J = 19.0, 7.5 Hz, 4H) , 7.27 (t, J = 7.3 Hz, 1H) , 5.44 (dt, J = 8.9, 4.8 Hz, 1H) , 3.98 –3.84 (m, 2H) , 3.68 (m, 4H) , 3.25 (s, 3H) , 3.19 (s, 3H) .

EXAMPLE 10

(S) -5- (4- (2-amino-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -3, 3-dimethylisobenzofuran-1 (3H) -one

Step 1 (S) -2- (2-chloro-5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-4-ylamino) -2-phenylethyl 4-methylbenzenesulfonate

To a stirred solution of Intermediate 1 (1.0 g, 3.15 mmol) in DCM (10 mL) was added Et ₃N (3.2 g, 31.68 mmol) at 0℃, followed by TsCl (3.0 g, 15.74 mmol) . The mixture was stirred for 1 h at rt. Water was added and the mixture was extracted with EA.The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel column chromatography (EA: PE=3: 1) to give 1.4 g of the product as a yellow solid. MS (ES+) : 472.0 [M+1] ⁺.

Step 2 (S) -2-azido-N- (2-azido-1-phenylethyl) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-4-amine

To a stirred solution of the product of Step 1 (1.4 g, 2.97 mmol) in DMF (14 mL) was added NaN ₃ (970 mg, 14.92 mmol) . The mixture was stirred for 2 h at 50 ℃ under Ar. Water and the mixture and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated to give 860 mg of the crude product as a yellow solid. MS (ES+) : 350.0 [M+1] ⁺.

Step 3 (S) -N ⁴- (2-amino-1-phenylethyl) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidine-2, 4-diamine

To a stirred solution of the product of Step 2 (860 mg, 2.46 mmol) in MeOH (10 mL) was added 10%Pd/C (172 mg) . The mixture was stirred overnight at rt, filtered and concentrated. The residue was purified by silica gel column chromatography (MeOH: DCM=10%) to give 450 mg of pure product as yellow oil. MS (ES+) : 298.1 [M+1] ⁺.

Step 4 (S) -tert-butyl 2- (2-amino-5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-4-ylamino) -2-phenylethylcarbamate

To a stirred solution of the product of Step 3 (210 mg, 0.71 mmol) in DCM (4 mL) was added BOC ₂O (176 mg, 0.85 mmol) . The mixture was stirred for 2 h at 0-10℃ under Ar. Water was added and the mixture was extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by Prep-TLC (EA) to give 180 mg of the product as a yellow solid. MS (ES+) : 398.1 [M+1] ⁺.

Step 5 (S) -tert-butyl 2- (2- (3, 3-dimethyl-1-oxo-1, 3-dihydroisobenzofuran-5-ylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-4-ylamino) -2-phenylethylcarbamate

To a stirred solution of the product of Step 4 (80 mg, 0.20 mmol) in 1, 4-dioxane (3.0 mL) were added Pd ₂ (dba) ₃ (20 mg, 0.02 mmol) , Xant-phos (24 mg, 0.04 mmol) , Cs ₂CO ₃ (131 mg, 0.40 mmol) and 5-bromo-3, 3-dimethylisobenzofuran-1 (3H) -one (91 mg, 0.38 mmol) . The mixture was stirred for 1 h at 100℃ under Ar and then concentrated. The residue was purified by Prep-TLC (EA: PE=3: 1) to give 65 mg of the product as a yellow solid. MS (ES+) : 558.1 [M+1] ⁺.

Step 6 (S) -5- (4- (2-amino-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -3, 3-dimethylisobenzofuran-1 (3H) -one

A mixture of the product of Step 5 (65 mg, 0.12 mmol) in DCM (1.5 mL) and TFA (1.5 mL) was stirred for 1 h at rt. The solution was adjusted pH>7 with Na ₂CO ₃ (aq. ) and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by Prep-TLC (MeOH: EA=5%) to give 11.5 mg of the product as a white solid. MS (ES+) : 458.1 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.37 (s, 1H) , 9.40 (s, 1H) , 8.74 (s, 1H) , 8.62 (d, J = 8.4 Hz, 1H) , 7.86 (d, J = 8.4 Hz, 2H) , 7.72 (d, J = 4.7 Hz, 1H) , 7.50 (d, J = 7.6 Hz, 2H) , 7.43 (t, J = 7.6 Hz, 2H) , 7.35 (d, J = 7.3 Hz, 1H) , 5.74 (d, J = 13.5 Hz, 1H) , 1.60 (s, 3H) , 1.53 (s, 3H) .

EXAMPLE 11

(S) -2-acetyl-4- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) benzoic acid

Step 1 5-amino-3-hydroxy-3-methylisobenzofuran-1 (3H) -one

To a stirred solution of methyl 2-acetyl-4-aminobenzoate (200 mg, 1.036 mmol) in THF/H ₂O (4: 1, 2 mL) was added LiOH·H ₂O (131 mg, 3.108 mmol) at rt. The mixture was stirred at rt for 2 h. The mixture was adjusted pH<7 with HCl (1N) and extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was beating with DCM to give 39 mg of the title product as a white solid. MS (ES+) : 180.0 [M+1] ⁺ .

¹H NMR (400 MHz, Methanol-d ₄) δ 7.46 (d, J = 8.4 Hz, 1H) , 6.79 –6.64 (m, 2H) , 1.73 (s, 3H) .

Step 2 (S) -2-acetyl-4- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) benzoic acid

To a stirred solution of (S) -2- (2-chloro-5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-4-ylamino) -2-phenylethanol (20 mg, 0.065 mmol) in 1, 4-Dioxane (2 mL) were added Pd ₂ (dba) ₃ (6 mg, 0.006 mmol) , Xant-phos (7 mg, 0.013 mmol) , Cs ₂CO ₃ (65 mg, 0.26 mmol) and the product of Step 1 (35 mg, 0.195 mmol) at rt under Ar. The mixture was stirred at 100℃ for 3 h, and then filtered through a layer of celite. The filtrate was concentrated and the residue was purified by chromatography to give 16 mg of the title product as a yellow solid. MS (ES+) : 461.1 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.20 (s, 1H) , 9.36 (s, 1H) , 8.96 (d, J = 7.8 Hz, 1H) , 8.68 (s, 1H) , 7.81 (s, 1H) , 7.78 –7.71 (m, 1H) , 7.66 (d, J = 8.5 Hz, 1H) , 7.43 (d, J = 7.5 Hz, 2H) , 7.35 (t, J = 7.5 Hz, 2H) , 7.25 (t, J = 7.3 Hz, 1H) , 5.41 (q, J = 5.3 Hz, 1H) , 5.26 (s, 1H) , 3.90 (m, 1H) , 3.77 (m, 1H) , 1.99 (s, 3H) .

EXAMPLE 12

(S) -5- ( (4- ( (2-hydroxy-1-phenylethyl) amino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-yl) amino) -3, 3-dimethyl-2, 3-dihydrobenzo [b] thiophene 1, 1-dioxide

Step 1 1- (4-bromophenylthio) -2-methylpropan-2-ol

To a stirred solution of 4-bromobenzenethiol (10.0 g, 0.04 mol) in DMF (100 mL) were added 2, 2-dimethyloxirane (4.2 g, 0.06 mol) and K ₂CO ₃ (10.96 g, 0.08 mol) . The mixture was stirred for 2 h at rt. Water was added and the mixture was extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel column chromatography (PE: EA=5: 1) to give 12.6 g of the product as yellow oil. Yield: 91.3%.

Step 2 5-bromo-3, 3-dimethyl-2, 3-dihydrobenzo [b] thiophene

To a stirred solution of the product of Step 1 (12.5 g, 0.05 mol) in CS ₂ (250 mL) at 0℃ was added AlCl ₃ (22.3 g, 0.17 mol) . The mixture was stirred for 2 h at 75℃ under Ar and 1N HCl was added. The mixture was extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel column chromatography (PE) to give 7.2 g of the product as yellow oil. Yield: 61.6%.

Step 3 5-bromo-3, 3-dimethyl-2, 3-dihydrobenzo [b] thiophene 1, 1-dioxide

To a stirred solution of the product of Step 2 (6.75 g, 0.03 mol) in DCM (230 mL) at 0℃ was added m-CPBA (14.4 g, 0.08 mol) . The mixture was stirred overnight at 30℃. Na ₂S ₂O ₃ (aq. ) and Na ₂CO ₃ (aq. ) were added and the mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel column chromatography (PE: EA=9: 1) to give 4.1 g of the product as an off-white solid. Yield: 54%.

Step 4 (S) -5- ( (4- ( (2-hydroxy-1-phenylethyl) amino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-yl) amino) -3, 3-dimethyl-2, 3-dihydrobenzo [b] thiophene 1, 1-dioxide

The title compound was synthesized using the same procedures as described in Example 1. MS (ES+) : 493.0 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.13 (s, 1H) , 9.35 (s, 1H) , 8.92 (d, J = 7.7 Hz, 1H) , 8.69 (s, 1H) , 7.81 (d, J = 10.1 Hz, 2H) , 7.54 (d, J = 8.5 Hz, 1H) , 7.45 –7.34 (m, 4H) , 7.30 –7.19 (m, 1H) , 5.44 (dt, J = 8.8, 4.7 Hz, 1H) , 5.26 (t, J = 4.9 Hz, 1H) , 3.95 –3.72 (m, 2H) , 3.46 (s, 2H) , 1.42 (d, J = 8.6 Hz, 6H) .

EXAMPLE 13

(S) -2- (3, 3-dimethyl-1-oxo-2, 3-dihydro-1H-inden-5-ylamino) -4- (2-hydroxy-1-phenylethylamino) pyrimidine-5-carboxamide

Step 1 (S) -2-chloro-4- (2-hydroxy-1-phenylethylamino) pyrimidine-5-carboxamide

To a stirred solution of (S) -2-chloro-4- (2-hydroxy-1-phenylethylamino) pyrimidine-5-carboxylic acid (5.7 g, 19.45 mmol) , NH ₄Cl (3.02 g, 58.35 mmol) and DIEA (15.05 g, 116.7 mmol) in DMF (57 mL) was added HATU (8.86 g, 23.34 mmol) at 0-10℃. The mixture was stirred at rt overnight. The solution was adjusted with sat. NaHCO ₃ (aq. ) to pH= 9～10 and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was recrystallized in DCM/MeOH (9/1) to give 350 mg of the product as a white solid. MS (ES+) : 293.0 [M+1] ⁺.

Step 2 (S) -2- (3, 3-dimethyl-1-oxo-2, 3-dihydro-1H-inden-5-ylamino) -4- (2-hydroxy-1-phenylethylamino) pyrimidine-5-carboxamide

To a stirred solution of the product of Step 1 (110 mg, 0.376 mmol) in 1, 4-Dioxane (1 mL) were added Pd ₂ (dba) ₃ (34 mg, 0.037 mmol) , Xant-phos (43 mg, 0.075 mmol) , Cs ₂CO ₃ (245 mg, 0.752 mmol) and 5-amino-3, 3-dimethyl-2, 3-dihydro-1H-inden-1-one (98 mg, 0.564 mmol) under Ar. The mixture was stirred at 100 ℃ for 3 h. The mixture was filtered through a layer of celite. The filtrate was concentrated and purified by Prep-HPLC (EA) to give 7 mg of the title product as a yellow solid. MS (ES+) : 432.1 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 9.91 (m, 2H) , 8.62 (s, 1H) , 7.94 (m, 2H) , 7.63 (d, J = 8.5 Hz, 1H) , 7.44 –7.16 (m, 7H) , 5.33 (m, 1H) , 5.11 (t, 1H) , 3.86 –3.67 (m, 2H) , 1.39 –1.27 (m, 6H) .

EXAMPLE 14

(S) -2- (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-ylamino) -4- (2-hydroxy-1-phenylethylamino) pyrimidine-5-carboxamide

The title compound was synthesized using the same procedures as described in Example 13. MS (ES+) : 434.0 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.08 (s, 1H) , 9.95 (d, J = 7.4 Hz, 1H) , 8.61 (s, 1H) , 7.95 (s, 1H) , 7.80 (s, 1H) , 7.43 –7.15 (m, 8H) , 5.17 (m, 2H) , 3.72 (m, 2H) , 1.41 (s, 6H) .

EXAMPLE 15

(S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -4-methylphthalazin-1 (2H) -one

¹H NMR (400 MHz, DMSO-d ₆) δ 12.29 (s, 1H) , 10.35 (s, 1H) , 9.42 (s, 1H) , 9.00 (d, J = 7.7 Hz, 1H) , 8.77 (s, 1H) , 8.25 –8.04 (m, 3H) , 7.57 –7.20 (m, 5H) , 5.54 (dt, J = 8.4, 4.9 Hz, 1H) , 5.31 (t, J = 4.9 Hz, 1H) , 3.94 (m, 2H) , 2.51 (s, 3H) .

EXAMPLE 16

(S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -2, 4-dimethylphthalazin-1 (2H) -one

Step 1 (S) -methyl 2-acetyl-4- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) benzoate

To a stirred solution of Intermediate 1 (273 mg, 0.86 mmol) in 1, 4-Dioxane (4 mL) were added Pd (OAc) ₂ (19 mg, 0.09 mmol ) , BINAP (107 mg, 0.17 mmol) , Cs ₂CO ₃ (561 mg, 1.72 mmol) and methyl 2-acetyl-4-aminobenzoate (500 mg, 2.59 mmol) at rt under N ₂. The mixture was stirred at 100℃ for 4 h. The mixture was filtered through a layer of celite and the filtrate was concentrated. The residue was purified by silica gel column chromatography (EA: PE=1: 1) to obtain 180 mg of the product as a yellow solid. MS (ES+) : 475.0 [M+1] ⁺.

Step 2 (S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -2, 4-dimethylphthalazin-1 (2H) -one

To a stirred solution of the product of Step 1 (180 mg, 0.38 mmol) in MeOH (10 mL) were added DIEA (547 mg, 3.80 mmol) and methylhydrazine sulfate (1.47 g, 11.39 mmol) at rt under N ₂. The mixture was stirred at 70℃ for 5 h. The solid was collected by filtration to obtain 72.6 mg of the product as a white solid. MS (ES+) : 471.2 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.26 (s, 1H) , 9.33 (s, 1H) , 8.92 (d, J = 7.7 Hz, 1H) , 8.68 (s, 1H) , 8.10 (dd, J = 17.6, 8.9 Hz, 3H) , 7.43 (d, J = 7.7 Hz, 2H) , 7.35 (t, J = 7.5 Hz, 2H) , 7.25 (t, J = 7.3 Hz, 1H) , 5.47 (m, 1H) , 5.28 (t, 1H) , 3.96 –3.81 (m, 2H) , 3.64 (s, 3H) , 2.46 (s, 3H) .

EXAMPLE 17

5- (4- ( (S) -2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -3, 3-dimethyl-1, 3-dihydroisobenzofuran-1-carbonitrile

Step 1 tert-butyl 1-hydroxy-3, 3-dimethyl-1, 3-dihydroisobenzofuran-5-ylcarbamate

To a stirred solution of tert-butyl 3, 3-dimethyl-1-oxo-1, 3-dihydroisobenzofuran-5-ylcarbamate (200 mg, 0.722 mmol) in toluene (2 mL) was added DIBAL-H (1.1 mL, 1.083 mmol) at 0-10℃ under Ar. The mixture was stirred at 0-10℃ for 1 h. Sat. NaHCO ₃ (aq. ) was added and the mixture was extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by Prep-TLC (EA: PE=7: 3) to give 122 mg of the product as colorless oil.

Step 2 5-amino-3, 3-dimethyl-1, 3-dihydroisobenzofuran-1-carbonitrile

To a stirred solution of the product od Step 1 (122 mg, 0.437 mmol) in DCM (2 mL) were added BF ₃ ^. Et ₂O (186 mg, 1.312 mmol) and TMSCN (217 mg, 2.186 mmol) at -20℃ under Ar. The mixture was stirred at -20 ℃ for 1 h. NaOH (1N) was added and the mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by Prep-TLC (EA: PE=3: 7) to give 20 mg of the product as a yellow solid. MS (ES+) : 189.0 [M+1] ⁺.

Step 3 5- (4- ( (S) -2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -3, 3-dimethyl-1, 3-dihydroisobenzofuran-1-carbonitrile

The title compound was synthesized using the same procedures as described in Example 1. MS (ES+) : 470.1 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 9.92 (s, 1H) , 9.33 (s, 1H) , 8.86 (d, J = 4.9 Hz, 1H) , 8.64 (s, 1H) , 7.63 (d, J = 6.4 Hz, 2H) , 7.37 (t, J = 6.4 Hz, 5H) , 7.27 (d, J = 7.0 Hz, 1H) , 6.15 (s, 1H) , 5.42 (m, 1H) , 5.23 (t, J = 4.9 Hz, 1H) , 3.94 –3.78 (m, 2H) , 1.52 (d, J = 7.7 Hz, 3H) , 1.45 (d, J = 11.5 Hz, 3H) .

EXAMPLE 18

(S) -methyl 2-acetyl-4- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) benzoate

Step 1 methyl 2-acetyl-4-aminobenzoate

To a stirred solution of methyl 2-acetyl-4-nitrobenzoate (750 mg, 3.363 mmol) in MeOH (2 mL) was added 10%Pd/C (150 mg) at rt under H ₂. The mixture was stirred at rt for 3 h. The mixture was filtered through a layer of celite, and the filtrate was concentrated to give 636 mg of crude product as a yellow solid.

¹H NMR (400 MHz, Chloroform-d) δ 7.78 (d, J = 8.5 Hz, 1H) , 6.64 (dd, J = 8.5, 2.4 Hz, 1H) , 6.44 (d, J = 2.4 Hz, 1H) , 4.17 (brs, 2H) , 3.83 (s, 3H) , 2.48 (s, 3H) .

Step 2 (S) -methyl 2-formyl-4- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) benzoate

The title compound was synthesized using the same procedures as described in Example 1. MS (ES+) : 475.1 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.49 –10.15 (m, 1H) , 9.44 –9.27 (m, 1H) , 8.98 (dt, J = 13.1, 7.4 Hz, 1H) , 8.77 –8.64 (m, 1H) , 8.07 –7.68 (m, 3H) , 7.49 –7.34 (m, 4H) , 7.27 (t, J = 7.0 Hz, 1H) , 5.41 (s, 1H) , 5.26 (dq, J = 9.8, 4.9 Hz, 1H) , 3.94 –3.84 (m, 1H) , 3.78 (d, J = 5.2 Hz, 1H) , 3.01 (s, 1H) , 2.98 (s, 1H) , 2.42 (s, 1H) , 1.79 (s, 1H) , 1.71 (s, 1H) .

EXAMPLE 19

3- (fluoromethyl) -5- (4- ( (S) -2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -3- (methoxymethyl) isobenzofuran-1 (3H) -one

Step 1 (6- (tert-butoxycarbonylamino) -3-oxo-1, 3-dihydroisobenzofuran-1, 1-diyl) bis (methylene) bis (4-methylbenzenesulfonate)

To a stirred solution of tert-butyl 3, 3-bis (hydroxymethyl) -1-oxo-1, 3-dihydroisobenzofuran-5-ylcarbamate (4 g, 12.94 mmol) in DCM (40 mL) were added Et ₃N (13 g, 12.87 mmol ) and TsCl (12 g, 63.16 mmol) at 0℃under Ar. The mixture was stirred at rt for 3 h under Ar. The mixture was concentrated. The residue was purified by silica gel column chromatography (EA: PE=1: 4) to give 6.7 g of the title product as a yellow solid.

Step 2 tert-butyl 3- (fluoromethyl) -3- (hydroxymethyl) -1-oxo-1, 3-dihydroisobenzofuran-5-ylcarbamate

A mixture of 4A MS (6.4 g) in TBAF/THF (1 M, 118 mL) was stirred at rt for 0.5 h under Ar. Then the product of Step 1 (6.4 g, 10.37 mmol) was added at 50℃. The mixture was stirred at 50℃ overnight under Ar. Water was added and extracted with EA.The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel column chromatography (EA: PE=1: 4) to give 480 mg of the title product as a yellow solid.

Step 3 5-amino-3- (fluoromethyl) -3- (methoxymethyl) isobenzofuran-1 (3H) -one

To a stirred solution of tert-butyl3- (fluoromethyl) -3- (hydroxymethyl) -1-oxo-1, 3-dihydroisobenzofuran-5-ylcarbamate (480 mg, 1.543 mmol) in DCM (12 mL) was added trimethyloxonium tetrafluoroborate (1.3 g, 8.78 mmol) at 0-10℃. The mixture was stirred at rt overnight and then concentrated. The residue was purified by silica gel column chromatography (EA: PE=3: 7) to give 179 mg of the title product as a yellow solid. MS (ES+) : 226.1 [M+1] ⁺.

Step 4 3- (fluoromethyl) -5- (4- ( (S) -2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -3- (methoxymethyl) isobenzofuran-1 (3H) -one

The title compound was synthesized using the same procedures as described in Example 1. MS (ES+) : 507.1 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.36 (s, 1H) , 9.36 (d, J = 1.2 Hz, 1H) , 8.93 (t, J = 8.0 Hz, 1H) , 8.70 (s, 1H) , 8.05 (d, J = 10.0 Hz, 1H) , 7.81 (d, J = 8.1 Hz, 1H) , 7.71 (d, J = 8.5 Hz, 1H) , 7.44 –7.34 (m, 4H) , 7.27 (t, J = 7.2 Hz, 1H) , 5.43 (m, 1H) , 5.28 (q, J = 4.9 Hz, 1H) , 4.87 –4.71 (m, 2H) , 3.95 –3.73 (m, 4H) , 3.26 (d, J = 22.0 Hz, 3H) .

EXAMPLE 20

(S) -6'- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -3'H-spiro [ [1, 3] dioxane-5, 1'-isobenzofuran] -3'-one

Step 1 6'-bromo-3'H-spiro [ [1, 3] dioxane-5, 1'-isobenzofuran] -3'-one

To a stirred solution of 5-bromo-3, 3-bis (hydroxymethyl) isobenzofuran-1 (3H) -one (400 mg, 1.47 mmol) in toluene (7 mL) were added (CH ₂O) n (529 mg, 5.88 mmol) and TsOH ^. H ₂O (20 mg, 0.10 mmol) at rt. The mixture was stirred at 100℃ for 3 h. Water was added and the mixture was extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated to give 381 mg of the title product as a yellow solid. MS (ES+) : 287.0 [M+1] ⁺.

Step 2 (S) -6'- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -3'H-spiro [ [1, 3] dioxane-5, 1'-isobenzofuran] -3'-one

The title compound was synthesized using the same procedures as described in Example 1. MS (ES+) : 503.1 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.35 (s, 1H) , 9.35 (s, 1H) , 8.90 (d, J = 7.7 Hz, 1H) , 8.70 (s, 1H) , 8.12 (d, J = 1.8 Hz, 1H) , 7.81 (dd, J = 8.6, 1.8 Hz, 1H) , 7.72 (d, J = 8.5 Hz, 1H) , 7.43 (d, J = 7.5 Hz, 2H) , 7.36 (t, J = 7.6 Hz, 2H) , 7.26 (t, J = 7.3 Hz, 1H) , 5.48 (m, 1H) , 5.31 (t, J = 4.9 Hz, 1H) , 5.04 (d, J = 6.3 Hz, 1H) , 4.95 (d, J = 6.3 Hz, 1H) , 4.13 –3.83 (m, 6H) .

EXAMPLE 21

(S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -2', 3', 5', 6'-tetrahydro-3H-spiro [isobenzofuran-1, 4'-pyran] -3-one

Step 1 6-fluoro-2', 3', 5', 6'-tetrahydro-3H-spiro [isobenzofuran-1, 4'-pyran] -3-one

To a stirred solution of 2-bromo-4-fluorobenzoic acid (5 g, 22.8 mmol) in THF (150 mL) was added butyl‐lithium-solution 2.5M (18 mL, 45.6 mmol ) at -78℃. The mixture was stirred for 1h, and then treated with dihydro-2H-pyran-4 (3H) -one (2.73 g, 27.39 mmol) . The resulting mixture was stirred at -78 ℃ for 1 h and stirred at rt for 3 h. The mixture was poured into ice-water and extracted with EA. The aqueous phase was adjusted with 25%HCl to pH=1 and stirred at 100 ℃ for 1 h, then adjusted with 4M NaOH to pH=12 and extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by beating with DCM to give 1g of the product as a white solid. MS (ES+) : 223.0 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 7.91 (dd, J = 8.4, 4.9 Hz, 1H) , 7.78 (dd, J = 8.6, 2.3 Hz, 1H) , 7.45 (ddd, J = 9.2, 8.4, 2.2 Hz, 1H) , 4.01 –3.87 (m, 2H) , 3.69 (td, J = 12.1, 2.0 Hz, 2H) , 2.30 (td, J = 13.2, 5.2 Hz, 2H) , 1.60 (dd, J = 14.0, 1.9 Hz, 2H) .

Step 2 6-azido-2', 3', 5', 6'-tetrahydro-3H-spiro [isobenzofuran-1, 4'-pyran] -3-one

To a stirred solution of the product of Step 1 (870 mg, 3.91 mmol) in DMF (10 mL) was added Sodium azide (1.27 g, 19.59 mmol) at rt. The mixture was stirred at 100℃ overnight under N ₂. Water was added and the mixture was extracted with EA. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 880 mg of the title product as a yellow solid. MS (ES+) : 246.0 [M+1] ⁺.

Step 3 6-amino-2', 3', 5', 6'-tetrahydro-3H-spiro [isobenzofuran-1, 4'-pyran] -3-one

To a stirred solution of the product of Step 2 (880 mg, 3.59 mmol) in MeOH (30 mL) was added Pd/C (440 mg) . The mixture was stirred at rt for 3 h under H ₂. The mixture was filtered through a layer of celite and the filtrate was concentrated to give 350 mg of the title product as a black solid which was used in the next step without further purification. MS (ES+) : 220.0 [M+1] ⁺.

Step 4 (S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -2', 3', 5', 6'-tetrahydro-3H-spiro [isobenzofuran-1, 4'-pyran] -3-one

The title compound was synthesized using the same procedures as described in Example 1. MS (ES+) : 501.0 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.32 (s, 1H) , 9.36 (s, 1H) , 8.97 (d, J = 7.8 Hz, 1H) , 8.71 (s, 1H) , 7.96 (s, 1H) , 7.77 (dd, J =8.6, 1.8 Hz, 1H) , 7.68 (d, J = 8.5 Hz, 1H) , 7.44 (d, J = 7.2 Hz, 2H) , 7.37 (d, J = 7.7 Hz, 2H) , 7.27 (t, J = 7.2 Hz, 1H) , 5.46 (d, J = 6.6 Hz, 1H) , 5.28 (s, 1H) , 3.95 (m, 3H) , 3.83 (m, 1H) , 3.71 (t, J = 11.7 Hz, 2H) , 2.16 (m, 1H) , 2.04 (m, 1H) , 1.60 (m, 2H) .

EXAMPLE 22

(S) -6'- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -2, 4-dihydro-3'H-spiro [benzo [b] [1, 4] dioxepine-3, 1'-isobenzofuran] -3'-one

Step 1 tert-butyl 3'-oxo-2, 4-dihydro-3'H-spiro [benzo [b] [1, 4] dioxepine-3, 1'-isobenzofuran] -6'-ylcarbamate

A mixture of the product of Step 1 of Example 19 (400 mg, 0.648 mmol) , pyrocatechol (1.426 mg, 12.96 mmol) , NaI (195 mg, 1.30 mmol) and K ₂CO ₃ (3.585 mg, 25.98 mmol) in DMF (20 mL) was stirred at 100℃ overnight under Ar. After the reaction was completed, water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by Prep-TLC (EA: PE=1: 4) to give 70 mg of the title product as a yellow solid. Yield: 38.3%. MS (ES+) : 284.1 [M+1] ⁺.

Step 2 6'-amino-2H, 3'H, 4H-spiro [benzo [b] [1, 4] dioxepine-3, 1'-isobenzofuran] -3'-one

The title product was obtained by using the same conditions described as for Step 3 of Example 19.

Step 3 (S) -6'- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -2, 4-dihydro-3'H-spiro [benzo [b] [1, 4] dioxepine-3, 1'-isobenzofuran] -3'-one

The title compound was synthesized using the same procedures as described in Example 1. MS (ES+) : 565.2 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.36 (s, 1H) , 9.35 (s, 1H) , 8.96 (d, J = 7.7 Hz, 1H) , 8.69 (s, 1H) , 8.11 (d, J = 1.8 Hz, 1H) , 7.91 (d, J = 8.6 Hz, 1H) , 7.75 (d, J = 8.5 Hz, 1H) , 7.32 –7.22 (m, 5H) , 7.11 –7.01 (m, 4H) , 5.34 (m, 1H) , 5.22 (t, J = 4.9 Hz, 1H) , 4.53 –4.34 (m, 4H) , 3.74 (m, 2H) .

EXAMPLE 23

(S) -2- (2- (3, 3-bis (methoxymethyl) -1-oxo-1, 3-dihydroisobenzofuran-5-ylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-4-ylamino) -2-phenylethyl isobutyrate

Step 1 (S) -2- (2-chloro-5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-4-ylamino) -2-phenylethyl isobutyrate

To a stirred solution of Intermediate 1 (500 mg, 1.577 mmol) in DCM (4 mL) was added Et ₃N (319 mg, 1.158 mmol) at 0℃ under Ar and stirred at 0 ℃ for 0.5 h, followed by a solution of isobutyryl chloride (502 mg, 4.732 mmol) in DCM (1 mL) at 0℃. The mixture was stirred at rt for 2 h and then concentrated. The residue was purified by silica gel column chromatography (EA: PE=3: 7) to give 380 mg of the title product as yellow oil. MS (ES+) : 388.2 [M+1] ⁺.

Step 2 (S) -2- (2- (3, 3-bis (methoxymethyl) -1-oxo-1, 3-dihydroisobenzofuran-5-ylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-4-ylamino) -2-phenylethyl isobutyrate

To a stirred solution of the product of Step 1 (110 mg, 0.284 mmol) in 1, 4-dioxane (2 mL) were added Pd ₂ (dba) ₃ (34 mg, 0.037 mmol) , Xant-phos (40 mg, 0.069 mmol) , Cs ₂CO ₃ (185 mg, 0.568 mmol) and 5-amino-3, 3-bis (methoxymethyl) isobenzofuran-1 (3H) -one (202 mg, 0.852 mmol) at rt under Ar. The mixture was stirred at 100℃ for 2 h. The mixture was filtered through a layer of celite and the filtrate was concentrated. The residue was purified by Prep-TLC (EA: PE=3: 2) to give 31.3 mg of the title product as a white solid. MS (ES+) : 589.3 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.37 (s, 1H) , 9.36 (s, 1H) , 8.92 (d, J = 8.4 Hz, 1H) , 8.72 (s, 1H) , 8.01 (d, J = 1.8 Hz, 1H) , 7.79 (dd, J = 8.5, 1.8 Hz, 1H) , 7.68 (d, J = 8.4 Hz, 1H) , 7.49 (d, J = 7.3 Hz, 2H) , 7.41 (t, J = 7.5 Hz, 2H) , 7.36 –7.25 (m, 1H) , 5.81 (dt, J = 9.0, 5.0 Hz, 1H) , 4.57 (qd, J = 11.4, 5.0 Hz, 2H) , 3.78 –3.62 (m, 4H) , 3.25 (s, 3H) , 3.18 (s, 3H) , 2.47 (m, 1H) , 1.00 (dd, J = 7.0, 3.9 Hz, 6H) .

EXAMPLE 24

(S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -4-methyl-1H-benzo [d] [1, 2] oxazin-1-one

Step 1 6-amino-4-methyl-1H-benzo [d] [1, 2] oxazin-1-one

A mixture of methyl 2-acetyl-4-aminobenzoate (300 mg, 1.544 mmol) , NH ₂OH ^. HCl (429 mg, 6.218 mmol) and KOH (522 mg, 9.326 mmol) in EtOH/H ₂O (12: 5, 6 mL) was stirred at 70℃ for 2 h. Additional NH ₂OH ^. HCl (429 mg, 6.218 mmol) was added and stirred at 70℃ for 1 h. The mixture was cooled to rt and filtered to give 240 mg of the title product as a white solid. MS (ES+) : 177.2 [M+1] ⁺.

Step 2 (S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -4-methyl-1H-benzo [d] [1, 2] oxazin-1-one

A mixture of Intermediate 1 (95 mg, 0.300 mmol) , the product of Step 1 (58 mg, 0.330 mmol) and TsOH ^. H ₂O (63 mg, 0.332 mmol) in 1.4-dioxane (3 mL) was stirred at 100℃ for 1 h. Water was added and the mixture was extracted with EA. The organic layer was washed with brined, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by Prep-TLC (EA: PE=7: 3) to give 12.3 mg of the title product as a yellow solid. (ES+) : 458.1 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.49 (s, 1H) , 9.37 (s, 1H) , 8.98 (d, J = 7.6 Hz, 1H) , 8.73 (s, 1H) , 8.27 (dd, J = 8.8, 2.1 Hz, 1H) , 8.15 –8.04 (m, 2H) , 7.45 (d, J = 7.1 Hz, 2H) , 7.37 (t, J = 7.6 Hz, 2H) , 7.26 (t, J = 7.3 Hz, 1H) , 5.46 –5.25 (m, 2H) , 3.92 -3.83 (m, 2H) , 2.40 (s, 3H) .

EXAMPLE 25

(S) -4-cyclopropyl-7- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -1H-benzo [d] [1, 2] oxazin-1-one

Step 1 5-bromo-2- (cyclopropanecarbonyl) benzoic acid or 4-bromo-2- (cyclopropanecarbonyl) benzoic acid

To a stirred solution of 5-bromoisobenzofuran-1, 3-dione (11 g, 0.049 mol) and CuI (925 mg, 4.868 mmol) in THF (110 mL) was added cyclopropylmagnesium bromide (1M, 58.3 mL) drop wise at 0-10℃ under Ar. The mixture was stirred at 0-10℃for 1 h and rt for 3 h. The mixture was adjusted to pH<7 with HCl (1N) and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel column chromatography (EA: PE=1: 3) to give 6 g of a mixture of products as yellow oil which was used in the next step without further purification. MS (ES+) : 269.1 [M+1] ⁺.

Step 2 7-bromo-4-cyclopropyl-1H-benzo [d] [1, 2] oxazin-1-one &6-bromo-4-cyclopropyl-1H-benzo [d] [1, 2] oxazin-1-one

A mixture of the product of step 1 (6 g, 0.022 mol) , NH ₂OH·HCl (12.3 g, 0.178 mol) and KOH (7.5 g, 0.134 mol) in EtOH/H ₂O (12: 5, 55 mL) was stirred at 70℃ for 1 h under Ar. Water was added and the mixture was extracted with EA. The organic layer was washed with brined, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel column chromatography (EA/PE=2%) to give 1.2 g of 7-bromo-4-cyclopropyl-1H-benzo [d] [1, 2] oxazin-1-one and 364 mg of 6-bromo-4-cyclopropyl-1H-benzo [d] [1, 2] oxazin-1-one. MS (ES+) : 266.1 [M+1] ⁺.

Step 3 tert-butyl 4-cyclopropyl-1-oxo-1H-benzo [d] [1, 2] oxazin-6-ylcarbamate

To a stirred solution of 6-bromo-4-cyclopropyl-1H-benzo [d] [1, 2] oxazin-1-one (300 mg, 1.132 mmol) in 1, 4-Dioxane (3 mL) were added Pd ₂ (dba) ₃ (110 mg, 0.120 mmol) , Xant-phos (137 mg, 0.237 mmol) , Cs ₂CO ₃ (738 mg, 2.265 mmol) and NH ₂Boc (397 mg, 3.393 mmol) at rt under Ar. The mixture was stirred at 100℃ for 2 h. The mixture was filtered through a layer of celite and the filtrate was concentrated. The residue was purified by silica gel column chromatography (EA: PE=1: 9) to give 110 mg of the title product as a yellow solid. MS (ES+) : 303.0 [M+1] ⁺.

Step 4 6-amino-4-cyclopropyl-1H-benzo [d] [1, 2] oxazin-1-one

The mixture of the product of Step 3 (110 mg, 0.364 mol) in TFA/DCM (4: 1, 2 mL) was stirred at rt for 1 h under Ar. Na ₂CO ₃ (aq. ) was added and extracted with EA. The organic layer was washed with brined, dried over anhydrous Na ₂SO ₄, filtered and concentrated to give 77 mg of the title product as a yellow solid. MS (ES+) : 203.0 [M+1] ⁺.

Step 5 (S) -4-cyclopropyl-6- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -1H-benzo [d] [1, 2] oxazin-1-one

A mixture of Intermediate 1 (90 mg, 0.284 mmol) , the product of Step 4 (63 mg, 0.312 mmol) and TsOH ^. H ₂O (59 mg, 0.310 mmol) in 1, 4-Dioxane (3 mL) was stirred at 100℃ for 1.5 h under Ar. Water was added and extracted with EA. The organic layer was washed with brined, dried over anhydrous Na ₂SO _4, filtered and concentrated. The residue was purified by Prep-TLC (EA: PE=7: 3) to give 8.7 mg of the product as a yellow solid. MS (ES+) : 484.0 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.51 (s, 1H) , 9.38 (s, 1H) , 9.02 (d, J = 7.7 Hz, 1H) , 8.76 (d, J = 2.3 Hz, 1H) , 8.72 (s, 1H) , 8.24 (dd, J = 8.7, 2.3 Hz, 1H) , 8.08 (d, J = 8.8 Hz, 1H) , 7.48 (d, J = 7.6 Hz, 2H) , 7.34 (t, J = 7.5 Hz, 2H) , 7.23 (t, J = 7.3 Hz, 1H) , 5.51 (d, J = 6.6 Hz, 1H) , 5.29 (t, J = 4.9 Hz, 1H) , 4.01 –3.74 (m, 2H) , 2.42 (m, 1H) , 1.13 –0.94 (m, 4H) .

EXAMPLE 26

(S) -7- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) quinazolin-4 (3H) -one

Step 1 7-aminoquinazolin-4 (3H) -one

The mixture of 7-nitroquinazolin-4 (1H) -one (600 mg, 3.14 mmol) , Fe (879 mg, 15.69 mmol) and NH ₄Cl (1 g, 18.84 mmol) in EtOH/H ₂O (2 /0.5 mL) was stirred at 70℃ for 3 h. The mixture was filtered and slurred with EtOH to give 570 mg of the title product as a yellow solid. MS (ES+) : 162.0 [M+1] ⁺.

Step 2 (S) -7- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) quinazolin-4 (3H) -one

The title compound was synthesized using the same procedures as described in Example 1. The crude product was further purified by Prep-HPLC (Column: Green ODS-A, 21.2 x 250mm, 10um; Mobile A: water with 0.05%TFA, Mobile B: CH ₃CN; Gradient: 40%B over 2 min, 55%B over 15 min; Flow: 35 mL/min) to give 7.6 mg of the title product as a yellow solid. MS (ES+) : 443.0 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 12.11 (s, 1H) , 10.29 (d, J = 11.5 Hz, 1H) , 9.40 (s, 1H) , 9.08 –8.96 (m, 1H) , 8.74 (s, 1H) , 8.22 (dd, J = 6.6, 2.1 Hz, 1H) , 8.14 (d, J = 7.6 Hz, 1H) , 8.01 (d, J = 8.5 Hz, 1H) , 7.81 –7.70 (m, 1H) , 7.60 (m, 2H) , 7.47 –7.41 (m, 2H) , 7.27 (m, 1H) , 5.48 (m, 1H) , 5.37 (t, 1H) , 3.96 (m, 1H) , 3.90 –3.78 (m, 1H) .

EXAMPLE 27

(S) -7- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -2, 2-dimethylchroman-4-one

Step 1 tert-butyl 2, 2-dimethyl-4-oxochroman-7-ylcarbamate

To a stirred solution of 7-bromo-2, 2-dimethylchroman-4-one (1 g, 4 mmol) in 1, 4-dioxane (10 mL) were added Pd ₂ (dba) ₃ (360 mg, 0.393 mmol) , Xant-phos (456 mg, 0.789 mmol) , Cs ₂CO ₃ (2.6 g, 0.008 mol) and NH ₂Boc (1.3 g, 0.011 mol) at rt under Ar.The mixture was stirred at 100℃ for 2 h. The mixture was filtered through a layer of celite and the filtrate was concentrated. The residue was purified by silica gel column chromatography (EA: PE=1: 9) to give 1.3 g of the title product as a yellow solid. MS (ES+) : 292.0 [M+1] ⁺.

Step 2 7-amino-2, 2-dimethylchroman-4-one

The mixture of the product of Step 1 (1.3 g) in TFA/DCM (1: 4, 12 mL) was stirred at rt for 1 h under Ar. Sat. Na ₂CO ₃ (aq. ) was added and the mixture was extracted with EA. The organic layer was washed with brined, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel column chromatography (EA/PE=15%) to give 659 mg of the title product as a yellow solid. MS (ES+) : 192.1 [M+1] ⁺.

Step 3 (S) -7- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -2, 2-dimethylchroman-4-one

The title compound was synthesized using the same procedures as described in Example 1. MS (ES+) : 473.1 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.13 (s, 1H) , 9.34 (s, 1H) , 8.98 (d, J = 7.5 Hz, 1H) , 8.66 (s, 1H) , 7.58 (d, J = 8.6 Hz, 1H) , 7.52 (d, J = 2.0 Hz, 1H) , 7.46 (d, J = 7.5 Hz, 2H) , 7.34 (t, J = 7.5 Hz, 2H) , 7.25 (t, J = 7.3 Hz, 1H) , 7.17 (dd, J = 8.8, 2.0 Hz, 1H) , 5.43 –5.35 (m, 1H) , 5.30 (t, J = 4.9 Hz, 1H) , 3.94 –3.70 (m, 2H) , 2.72 (d, J = 6.0 Hz, 2H) , 1.46 (s, 3H) , 1.42 (s, 3H) .

EXAMPLE 28

(S) -5- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -2, 2-dimethyl-2, 3-dihydro-1H-inden-1-one

Step 1 5-bromo-2, 2-dimethyl-2, 3-dihydro-1H-inden-1-one

To a stirred solution of 5-bromo-2, 3-dihydro-1H-inden-1-one (5 g, 23.7 mmol) in THF (50 mL) were added Cs ₂CO ₃ (38.5 g, 118.5 mmol) and CH ₃I (16.7 g, 118.5 mmol) at rt under Ar. The mixture was stirred at 65℃ overnight. The mixture was cool to rt, poured into water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel column chromatography (EA: PE=1: 20) to give 4 g of the title product as yellow oil.

Step 2 (S) -5- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -2, 2-dimethyl-2, 3-dihydro-1H-inden-1-one

The title compound was synthesized using the same procedures as described in Example 1. MS (ES+) : 457.1 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.19 (s, 1H) , 9.34 (s, 1H) , 8.97 (d, J = 7.3 Hz, 1H) , 8.68 (s, 1H) , 7.89 (s, 1H) , 7.56 (d, J =8.5 Hz, 1H) , 7.49 (d, J = 8.4 Hz, 1H) , 7.43 (d, J = 7.6 Hz, 2H) , 7.36 (t, J = 7.5 Hz, 2H) , 7.25 (t, J = 7.4 Hz, 1H) , 5.40 (m, 1H) , 5.28 (t, J = 4.9 Hz, 1H) , 3.85 (m, 2H) , 3.09 –2.83 (m, 2H) , 1.14 (d, J = 4.0 Hz, 6H) .

EXAMPLE 29

5- ( (4- ( ( (S) -2-hydroxy-1-phenylethyl) amino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-yl) amino) -3, 3-dimethyl-3H-benzo [c] [1, 2] oxathiole 1-oxide

Step 1 2- (2-bromo-5-fluorophenyl) propan-2-ol

To a stirred solution of methyl 2-bromo-5-fluorobenzoate (15 g, 64.4 mmol) in THF (150 mL) was added drop wise MeMgCl (86 mL, 257.5 mmol) at 0℃ under Ar. The mixture was stirred at rt for 4 h. Sat. NH ₄Cl (aq. ) was added dropwise and the mixture was extract with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel column chromatography (PE: EA=4: 1) to get 9.8 g of the title product as colorless oil. MS (ES+) : 214.9 [M-18] ⁺.

Step 2 5-fluoro-3, 3-dimethyl-3H-benzo [c] [1, 2] oxathiole 1-oxide

To a stirred solution of the product of Step 1 (8.3 g, 35.6 mmol) in THF (83 mL) was added dropwise n-BuLi (32 mL, 78.3 mmol) at -78℃ under Ar. After mixture was stirred at -78℃ for 0.5 h, the mixture was bubbled with SO ₂ at -78℃ for 30 min. The mixture was stirred for 15 min at -78℃ and stirred for 30 min at rt. The mixture was concentrated and treated with HCl (6N, 70mL) . The resulting mixture was stirred for 30 min at rt and then extracted with EA. The organic layer was washed with sat. NaHCO ₃ (aq. ) , dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel column chromatography (PE: EA=4: 1) to get 3.4 g of the title product as yellow oil. MS (ES+) : 201.0 [M+1] ⁺.

Step 3 5-azido-3, 3-dimethyl-3H-benzo [c] [1, 2] oxathiole 1-oxide

To a stirred solution of the product of Step 2 (3.4 g, 16.98 mmol) in DMF (68 mL) was added NaN ₃ (5.519 g, 84.9 mmol) . The mixture was stirred at 100℃ for 3 h and at 120℃ overnight. Water was added and the mixture was extracted with DCM. The organic layer was dried over anhydrous Na ₂SO ₄, filtered and concentrated under vacuum to get 4.2 g of crude product as black oil which was used in the next step without further purification. MS (ES+) : 224.0 [M+1] ⁺.

Step 4 5-amino-3, 3-dimethyl-3H-benzo [c] [1, 2] oxathiole 1-oxide

To a stirred solution of the product of Step 3 (4.2 g, 18.8 mmol) in MeOH (20 mL) was added 10%Pd/C (800 mg) at rt. The mixture was stirred at rt for 1 h under H ₂. Upon completion, the mixture was filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE: EA=4: 1) to get 535 mg of the title product as a yellow solid. MS (ES+) : 198.0 [M+1] ⁺.

Step 5 5- ( (4- ( ( (S) -2-hydroxy-1-phenylethyl) amino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-yl) amino) -3, 3-dimethyl-3H-benzo [c] [1, 2] oxathiole 1-oxide

The title compound was synthesized using the same procedures as described in Example 1. MS (ES+) : 479.0 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.16 (s, 1H) , 9.35 (s, 1H) , 8.91 (d, J = 7.7 Hz, 1H) , 8.69 (s, 1H) , 7.78 (m, 3H) , 7.45 –7.33 (m, 4H) , 7.26 (m, 1H) , 5.43 (m, 1H) , 5.26 (td, J = 4.9, 1.7 Hz, 1H) , 3.87 (m, 2H) , 1.73 (d, J = 8.7 Hz, 3H) , 1.58 (d, J = 16.4 Hz, 3H) .

EXAMPLE 31

(S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -2, 2-dimethylbenzo [b] thiophen-3 (2H) -one

Step 1 tert-butyl 2- (3-bromophenylthio) acetate

A mixture of 3-bromobenzenethiol (5 g) , tert-butyl2-bromoacetate (7.7 g) and pyridine (6 g) in DMSO (50 mL) was stirred at rt overnight under Ar, and was then treated with water, extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica-gel column chromatography (EA/PE=5%) to give 6.73 g of the title compound as a colorless oil.

Step 2 2- (3-bromophenylthio) acetic acid

A mixture of tert-butyl 2- (3-bromophenylthio) acetate (5.73 g) in TFA/DCM (1: 1, 33 ml) was stirred at rt for 2 h. The mixture was concentrated, and was then treated with water, extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica-gel column chromatography (EA: PE=1: 9) to give 4 g of the title compound as a white solid.

Step 3 6-bromobenzo [b] thiophen-3 (2H) -one

The mixture of 2- (3-bromophenylthio) acetic acid (4 g) in SOCl ₂ (12 mL) was stirred for 2 h at 80℃ under Ar, and was then concentrated. To a stirred solution of the residue in DCE (20 mL) was added AlCl ₃ (2.8 g) at 0-10℃ under Ar, and was then stirred at rt for 3 h. After adjusting the pH to <7 with 1N HCl (aq. ) , the mixture was extracted with EA. The residue was purified by silica-gel column chromatography (EA/PE=1%) to give 755 mg of the title compound as a yellow solid.

Step 4 6-bromo-2, 2-dimethylbenzo [b] thiophen-3 (2H) -one

To a stirred solution of 6-bromobenzo [b] thiophen-3 (2H) -one (340 mg) and Cs ₂CO ₃ (2408 mg) in 1, 4-Dioxane (14 mL) was added CH ₃I (1.4 mL) at 100℃ under Ar. The mixture was stirred at 100℃ for 1 h, and was then treated with ice-water, extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by Prep-TLC (EA/PE=1%) to give 110 mg of the title compound as a yellow oil.

Step 5 (S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -2, 2-dimethylbenzo [b] thiophen-3 (2H) -one

The title compound was synthesized using the same procedures as described in step 3 to step 5 in Example 1. MS (ES+) : 475.0 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.32 (s, 1H) , 9.38 (s, 1H) , 9.02 (d, J = 7.4 Hz, 1H) , 8.70 (s, 1H) , 7.97 (d, J = 1.8 Hz, 1H) , 7.57 (d, J = 8.6 Hz, 1H) , 7.48 –7.32 (m, 5H) , 7.28 –7.19 (m, 1H) , 5.36 (q, J = 5.6 Hz, 1H) , 5.29 (t, J = 4.9 Hz, 1H) , 3.91 (dt, J = 10.9, 4.4 Hz, 1H) , 3.77 (dt, J = 10.8, 5.4 Hz, 1H) , 1.55 –1.46 (s, 6H) .

EXAMPLE 32

6- (4- ( (S) -2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -2, 2-dimethyl-2, 3-dihydrobenzo [b] thiophen-3-ol

To a stirred solution of (S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -2, 2-dimethylbenzo [b] thiophen-3 (2H) -one (16 mg) in MeOH (2 mL) was added NaBH ₄ (7.6 mg) at 0-10℃ under Ar. The mixture was stirred at 0-10℃ for 1 h, and was then treated with water, extracted with EA. The organic layer was washed with brined, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by Prep-TLC (EA: PE=7: 3) to give 3.5 mg of the title compound as a yellow solid. MS (ES+) : 477.0 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 9.72 (s, 1H) , 9.31 (s, 1H) , 8.89 (d, J = 7.6 Hz, 1H) , 8.60 (s, 1H) , 7.54 (dd, J = 6.5, 1.9 Hz, 1H) , 7.40 (d, J = 7.1 Hz, 2H) , 7.34 (t, J = 7.5 Hz, 2H) , 7.27 –7.19 (m, 2H) , 7.10 (d, J = 8.1 Hz, 1H) , 5.67 (dd, J = 6.3, 5.4 Hz, 1H) , 5.38 –5.29 (m, 1H) , 5.28 –5.19 (m, 1H) , 4.69 (t, J = 6.0 Hz, 1H) , 3.90 –3.84 (m, 1H) , 3.73 (m, 1H) , 1.49 (d, J = 2.0 Hz, 3H) , 1.34 –1.29 (s, 3H) .

EXAMPLE 33

(S) -2- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -7, 7-dimethyl-7, 8-dihydro-5H-pyrano [4, 3-b] pyridin-5-one

Step 1 7, 7-dimethyl-7, 8-dihydro-1H-pyrano [4, 3-b] pyridin-2 (5H) -one

To a stirred solution of 2, 2-dimethyldihydro-2H-pyran-4 (3H) -one (22 g) in toluene (220 mL) was added pyrrolidine (14.6 g) at rt under Ar. The mixture was stirred at 145℃ for 2h., and was then cooled to rt. Propiolamide (23.5 g) was added and then the mixture was heat to 150℃ for 4 h. The mixture was cooled to rt, filtered and concentrated. The residue was purified by silica-gel column chromatography (MeOH: DCM=2%) to give 12 g of the title compound as a yellow solid. MS (ES+) : 180.0 [M+1] ⁺.

Step 2 2-chloro-7, 7-dimethyl-7, 8-dihydro-5H-pyrano [4, 3-b] pyridine

A mixture of 7, 7-dimethyl-7, 8-dihydro-1H-pyrano [4, 3-b] pyridin-2 (5H) -one (6 g) in POCl ₃ (30 mL) was stirred at 100℃for 2 h under Ar, and was then treated with ice-water, extract with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel column chromatography (EA: PE=1: 9) to give 2.6 g of the title compound as a gray solid. MS (ES+) : 198.0 [M+1] ⁺.

Step 3 2-chloro-7, 7-dimethyl-7, 8-dihydro-5H-pyrano [4, 3-b] pyridin-5-one

To a stirred solution of 2-chloro-7, 7-dimethyl-7, 8-dihydro-5H-pyrano [4, 3-b] pyridine (2.6 g) in ACN/CCl ₄ (8.8 mL/88 mL) were added RuCl ₃ (0.19 g) and a solution of NaIO ₄ (8.6 g) in water (44 mL) . The mixture was stirred overnight at rt, and was then treated with Na ₂SO ₃ (aq. ) , extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica-gel column chromatography (EA: PE=1: 9) to give 1.8 g of the title compound as a yellow solid. MS (ES+) : 212.0 [M+1] ⁺.

Step 4 2- (2, 4-dimethoxybenzylamino) -7, 7-dimethyl-7, 8-dihydro-5H-pyrano [4, 3-b] pyridin-5-one

To a stirred solution of 2-chloro-7, 7-dimethyl-7, 8-dihydro-5H-pyrano [4, 3-b] pyridin-5-one (1.6 g) and DIEA (2 g) in NMP (16 mL) was added DMB-NH ₂ (1.9 g) at rt under Ar. The mixture was stirred at 140℃for 2 h, and was then treated with ice-water, extracted with EA. The organic layer was washed with water and brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by Prep-TLC (EA: PE=1: 1) to give 2.8 g of the title compound as yellow oil. MS (ES+) : 343.0 [M+1] ⁺.

Step 5 2-amino-7, 7-dimethyl-7, 8-dihydro-5H-pyrano [4, 3-b] pyridin-5-one

The mixture of 2- (2, 4-dimethoxybenzylamino) -7, 7-dimethyl-7, 8-dihydro-5H-pyrano [4, 3-b] pyridin-5-one (2.7 g) in HCl/1.4-dioxane (54 mL) was stirred at 60℃ for 2 h, and was then treated with sat. NaHCO ₃ (aq. ) , extracted with EA. The organic layer was washed with water and brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by Prep-TLC (EA: PE=2: 1) to give 1.5 g of the title compound as a yellow solid. MS (ES+) : 193.0 [M+1] ⁺.

Step 6 (S) -2- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -7, 7-dimethyl-7, 8-dihydro-5H-pyrano [4, 3-b] pyridin-5-one

The title compound was synthesized using the same procedures as described in step 5 in Example 1. MS (ES+) : 474.0 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.50 (s, 1H) , 9.38 (s, 1H) , 8.99 (d, J = 6.9 Hz, 1H) , 8.72 (s, 1H) , 8.04 (d, J = 8.7 Hz, 1H) , 7.93 (d, J = 8.8 Hz, 1H) , 7.45 (d, J = 7.1 Hz, 2H) , 7.36 (t, J = 7.5 Hz, 2H) , 7.25 (t, J = 7.3 Hz, 1H) , 5.33 (d, J = 5.8 Hz, 1H) , 5.29 (q, J = 4.9 Hz, 1H) , 3.91 (m, 1H) , 3.77 (m, 1H) , 3.08 (s, 2H) , 1.41 (d, J = 4.6 Hz, 6H) .

EXAMPLE 34

(S) -2, 2-diethyl-6- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) benzofuran-3 (2H) -one

Step 1 6-bromo-2, 2-diethylbenzofuran-3 (2H) -one

To a solution of 6-bromo-2, 3-dihydro-1-benzofuran-3-one (1 g) and CH ₃I (15 mL) in THF (10 mL) was added sodium hydride (480 mg) at 70℃ under Ar. The mixture was stirred at 70 ℃ for 0.5 h, and was then quenched with ice-water, extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica-gel column chromatography (PE) to give 260 mg of title compound as a yellow solid.

Step 2 (S) -2, 2-diethyl-6- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) benzofuran-3 (2H) -one

The title compound was synthesized using the same procedures as described in step 3 to step 5 in Example 1. MS (ES+) : 487.1 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.34 (s, 1H) , 9.36 (s, 1H) , 9.02 (d, J = 7.1 Hz, 1H) , 8.70 (s, 1H) , 7.85 (d, J = 1.7 Hz, 1H) , 7.45 –7.41 (m, 3H) , 7.31 (t, J = 7.5 Hz, 2H) , 7.23 (t, J = 7.3 Hz, 1H) , 7.18 –7.13 (m, 1H) , 5.33 (m, 2H) , 3.91 (m, 1H) , 3.75 (m, 1H) , 1.88 –1.75 (m, 4H) , 0.79 –0.67 (m, 6H) .

EXAMPLE 35

(S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -2, 2-dimethylfuro [3, 2-b] pyridin-3 (2H) -one

Step 1 5-chloro-2-iodopyridin-3-ol

To a stirred solution of 5-chloropyridin-3-ol (5 g) in water (50 mL) were added Iodine (9.83 g) and sodium carbonate (8.21 g) at rt under Ar. The mixture was stirred at rt overnight, and was then acidified by 1N HCl, extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated to give 9.4 g of the title compound as a yellow solid. MS (ES+) : 255.8 [M+1] ⁺.

Step 2 ethyl 2- (5-chloro-2-iodopyridin-3-yloxy) -2-methylpropanoate

To a stirred solution of methyl2-bromo-2-methylpropanoate (7.2 g) and K ₂CO ₃ (6.4 g) in EtOH (184 mL) was added 5-chloro-2-iodopyridin-3-ol (9.6 g) at rt under Ar. The mixture was stirred at 80℃ overnight; and was then treated with water, extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica-gel column chromatography (EA: PE=1: 19) to give 4 g of title compound as a yellow oil which was used in the next step without further purification. MS (ES+) : 369.9 [M+1] ⁺.

Step 3 6-chloro-2, 2-dimethylfuro [3, 2-b] pyridin-3 (2H) -one

To a stirred solution of ethyl2- (5-chloro-2-iodopyridin-3-yloxy) -2-methylpropanoate (2.3 g) in THF (26 mL) was added n-BuLi (3.8 mL) at -65℃ under Ar. The mixture was stirred at -65℃ for 2 h, and was then treated with water, extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica-gel column chromatography (EA: PE=1: 19) to give 450 mg of title compound as a yellow solid. MS (ES+) : 198.0 [M+1] ⁺. Step 4 (S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -2, 2-dimethylfuro [3, 2-b] pyridine-3 (2H) -one

The title compound was synthesized using the same procedures as described in step 3 to step 5 in Example 1. MS (ES+) : 460.0 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.62 (s, 1H) , 9.40 (s, 1H) , 9.06 (d, J = 7.1 Hz, 1H) , 8.73 (s, 1H) , 8.53 (d, J = 2.1 Hz, 1H) , 8.24 (d, J = 2.0 Hz, 1H) , 7.46 –7.39 (m, 2H) , 7.31 (t, J = 7.5 Hz, 2H) , 7.24 –7.19 (m, 1H) , 5.32 (m, 2H) , 3.91 (m, 1H) , 3.76 (m, 1H) , 1.47 (d, J = 2.8 Hz, 6H) .

EXAMPLE 36

(S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -2, 2-dimethylfuro [3, 2-c] pyridin-3 (2H) -one

Step1 4, 6-dichloronicotinaldehyde

To a stirred solution of methyl 4, 6-dichloronicotinate (5 g) in DCM (50 mL) was added DIBALH (24 mL) at -70℃ under Ar.The mixture was stirred at -70℃ for 0.5 h, and was then quenched by potassium sodium tartrate tetrahydrate (aq. ) , extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica-gel column chromatography (PE: EA=20: 1～9: 1) to get 2.1 g of title compound as a white solid. MS (ES+) : 175.9 [M+1] ⁺.

Step 2 1- (4, 6-dichloropyridin-3-yl) -2-methylpropan-1-ol

To a stirred solution of 4, 6-dichloronicotinaldehyde (1.9 g) in THF (20 mL) was added isopropylmagnesium chloride lithium chloride complex (25 mL) at -10～0℃ under Ar. The mixture was stirred at -10～0℃ for 2 h, and was then quenched by sat. NH ₄Cl (aq. ) , extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica-gel column chromatography (PE: EA=20: 1～6: 1) to give 950 mg of the title compound as a yellow oil. MS (ES+) : 220 [M+1] ⁺.

Step 3 1- (4, 6-dichloropyridin-3-yl) -2-methylpropan-1-one

To a stirred solution of 1- (4, 6-dichloropyridin-3-yl) -2-methylpropan-1-ol (950 mg) in DCM (10 mL) was added PCC (1.87 g) at rt. The mixture was stirred at rt for 2 h, and was then treated with water. After adjusting the pH to >7 with NaHCO ₃ (aq. ) , the mixture was filtered through a layer of celite and extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica-gel column chromatography (PE: EA=20: 1～9: 1) to give 700 mg of the title compound as a yellow oil. MS (ES+) : 218.0 [M+1] ⁺.

Step 4 1- (4, 6-dichloropyridin-3-yl) -2-hydroxy-2-methylpropan-1-one

To a stirred solution of 1- (4, 6-dichloropyridin-3-yl) -2-methylpropan-1-one (580 mg) in DMSO (8 mL) was added NBS (95 mg) at rt. The mixture was stirred at 100℃ for 16 h, and was then treated with water, extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica-gel column chromatography (PE: EA=20: 1～4: 1) to give 269 mg of the title compound as a yellow oil. MS (ES+) : 234 [M+1] ⁺.

Step 5 6-chloro-2, 2-dimethylfuro [3, 2-c] pyridin-3 (2H) -one

To a stirred solution of 1- (4, 6-dichloropyridin-3-yl) -2-hydroxy-2-methylpropan-1-one (280 mg) in 1, 4-Dioxane (10 mL) was added t-BuOK (201 mg) at rt. The mixture was stirred at rt for 2 h, and was then treated with water, extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by Prep-TLC (PE: EA=9: 1) to give 91 mg of the title compound as a white solid. MS (ES+) : 198 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 8.73 (d, J = 0.7 Hz, 1H) , 7.58 (d, J = 0.7 Hz, 1H) , 1.45 (s, 6H) .

Step 6 (S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -2, 2-dimethylfuro [3, 2-c] pyridine-3 (2H) -one

¹H NMR (400 MHz, DMSO-d ₆) δ 10.58 (s, 1H) , 9.40 (s, 1H) , 9.04 (d, J = 7.0 Hz, 1H) , 8.73 (s, 1H) , 8.58 (s, 1H) , 7.96 (s, 1H) , 7.43 (d, J = 7.6 Hz, 2H) , 7.31 (t, J = 7.5 Hz, 2H) , 7.22 (t, J = 7.3 Hz, 1H) , 5.32 (m, 2H) , 3.93 –3.84 (m, 1H) , 3.76 (m, 1H) , 1.49 (d, J = 4.5 Hz, 6H) .

EXAMPLE 37

(S) -7- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -1-methylquinolin-4 (1H) -one

Step 1 7-bromo-1-methylquinolin-4 (1H) -one

To a stirred solution of 7-bromoquinolin-4-ol (2 g) in THF (20 mL) were added DBU (2 g) and CH ₃I (2.5 g) at rt under Ar.The mixture was stirred at rt overnight, and was then treated with water, extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica-gel column chromatography (MeOH/DCM) , and then slurred with EA and MTBE to give the title compound as a yellow solid (970 mg) . MS (ES+) : 239.9 [M+1] ⁺.

Step 2 (S) -7- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -1-methylquinolin-4 (1H) -one

The title compound was synthesized using the same procedures as described in step 3 to step 5 in Example 1. MS (ES+) : 456.0 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.13 (s, 1H) , 9.35 (s, 1H) , 8.90 (d, J = 7.9 Hz, 1H) , 8.70 (s, 1H) , 8.02 (d, J = 8.8 Hz, 1H) , 7.94 –7.82 (m, 2H) , 7.77 –7.67 (m, 1H) , 7.43 (d, J = 7.6 Hz, 2H) , 7.36 (t, J = 7.5 Hz, 2H) , 7.27 (d, J = 7.2 Hz, 1H) , 5.94 (d, J = 7.7 Hz, 1H) , 5.50 (d, J = 6.9 Hz, 1H) , 5.23 (t, J = 4.9 Hz, 1H) , 3.95 –3.79 (m, 2H) , 3.71 (s, 3H) .

EXAMPLE 38

(S) -2- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyridin-2-ylamino) -7, 7-dimethyl-7, 8-dihydro-5H-pyrano [4, 3-b] pyridin-5-one

Step 1 (S) -methyl 6-chloro-4- (2-hydroxy-1-phenylethylamino) nicotinate

To a stirred solution of methyl 4, 6-dichloronicotinate (6 g) in ACN (60 mL) were added (S) -2-amino-2-phenylethanol (4.02 g) and DIEA (4.92 g) at rt under the Ar. The mixture was stirred at 50 ℃ for 14 h, and was then treated with water, extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica-gel column chromatography (PE: EA=9: 1～3: 1) to give 3.8 of the title compound as a yellow solid. MS (ES+) : 307.0 [M+1] ⁺.

Step 2 (S) -6-chloro-4- (2-hydroxy-1-phenylethylamino) nicotinic acid

To a stirred solution of (S) -methyl6-chloro-4- (2-hydroxy-1-phenylethylamino) nicotinate (1 g) in THF/H ₂O (1: 1, 10 mL) was added lithium hydroxide hydrate (0.27 g) at rt. The mixture was stirred for 1 h at rt, and was then treated with water. After adjusting the pH to 5～6 with 1N HCl (aq. ) , the mixture was extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated to give 1 g of the title compound as a yellow solid. MS (ES+) : 293.0 [M+1] ⁺. Step 3 (S) -2- (2-chloro-5- (1, 3, 4-oxadiazol-2-yl) pyridin-4-ylamino) -2-phenylethanol

To a stirred solution of (S) -6-chloro-4- (2-hydroxy-1-phenylethylamino) nicotinic acid (500 mg) in DCE (15 mL) was added (isocyanoimino) triphenylphosphorane (1.55 g) . The mixture was stirred at 80℃ for 2 h, and was then treated with water, extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica-gel column chromatography (PE: EA=3: 1～1: 2) to give 1.1 g of title compound as a yellow solid. MS (ES+) : 317.0 [M+1] ⁺.

Step 4 (S) -2- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyridin-2-ylamino) -7, 7-dimethyl-7, 8-dihydro-5H-pyrano [4, 3-b] pyridin-5-one

To a solution of (S) -2- (2-chloro-5- (1, 3, 4-oxadiazol-2-yl) pyridin-4-ylamino) -2-phenylethanol (200 mg) in 1, 4-dioxane (8 mL) were added 2-amino-7, 7-dimethyl-7, 8-dihydro-5H-pyrano [4, 3-b] pyridin-5-one (120 mg) , Cs ₂CO ₃ (600 mg) , X-phos (184 mg) and Pd ₂ (dba) ₃ (144 mg) at rt. The mixture was stirred at 100℃ for 2 h under Ar, and was then treated with water, extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by Prep-TLC (PE: EA=1: 1) to give 10.9 mg of the title compound as a yellow solid. MS (ES+) : 473.1 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.31 (s, 1H) , 9.35 (s, 1H) , 8.63 –8.49 (m, 2H) , 8.00 (d, J = 8.7 Hz, 1H) , 7.46 (s, 1H) , 7.44 –7.31 (m, 5H) , 7.25 (t, J = 7.2 Hz, 1H) , 5.29 (t, J = 4.8 Hz, 1H) , 4.75 (d, J = 5.2 Hz, 1H) , 4.02 –3.88 (m, 1H) , 3.72 (m, 1H) , 3.11 (d, J = 16.9 Hz, 1H) , 2.87 (d, J = 16.9 Hz, 1H) , 1.47 (s, 3H) , 1.40 (s, 3H) .

EXAMPLE 39

(S) -2- ( (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-yl) amino) -4- ( (2-hydroxy-1-phenylethyl) amino) -N-methylpyrimidine-5-carboxamide

Step 1 ethyl (S) -2- ( (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-yl) amino) -4- ( (2-hydroxy-1-phenylethyl) amino) pyrimidine-5-carboxylate

To a stirred solution of ethyl (S) -2-chloro-4- ( (2-hydroxy-1-phenylethyl) amino) pyrimidine-5-carboxylate (61 mg) in 1, 4-Dioxane (14 mL) were added Pd ₂ (dba) ₃ (33 mg) , Xant-phos (36 mg) , Cs ₂CO ₃ (124 mg) and 6-amino-2, 2-dimethylbenzofuran-3 (2H) -one (91 mg) at rt under Ar. The mixture was stirred at 100℃ for 2 h, and was then filtered through a layer of celite. The filtrate was concentrated and the residue was purified by Prep-TLC (EA: PE=1: 2) to give 73 mg of the title compound as a yellow solid. MS (ES+) : 463.0 [M+1] ⁺.

Step 2 (S) -2- ( (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-yl) amino) -4- ( (2-hydroxy-1-phenylethyl) amino) pyrimidine-5-carboxylic acid

To a stirred solution of ethyl (S) -2- ( (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-yl) amino) -4- ( (2-hydroxy-1-phenylethyl) amino) pyrimidine-5-carboxylate (60 mg) in THF/H ₂O (4: 1, 3 mL) was added LiOH·H ₂O (16.3 mg) . The mixture was stirred overnight at rt, and was then treated with water, extracted with MTBE. After adjusting the pH to 5 with 1N HCl (aq. ) , the aqueous layer was extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated to give 32 mg of the title compound as a white solid. MS (ES+) : 435.0 [M+1] ⁺.

Step 3 (S) -2- ( (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-yl) amino) -4- ( (2-hydroxy-1-phenylethyl) amino) -N-methylpyrimidine-5-carboxamide

To a stirred solution of (S) -2- ( (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-yl) amino) -4- ( (2-hydroxy-1-phenylethyl) amino) pyrimidine-5-carboxylic acid (32 mg) and methylamine hydrochloride (14 mg) in DMF (4 mL) were added DIEA (66 mg) and HATU (23 mg) at rt. The mixture was stirred for 2 h under Ar, and was then treated with water, extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by Prep-TLC (MeOH: DCM=8%) to give 12.2 mg of the title compound as a white solid. MS (ES+) : 448.1 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.08 (s, 1H) , 9.86 (d, J = 7.4 Hz, 1H) , 8.55 (s, 1H) , 8.42 (d, J = 4.6 Hz, 1H) , 7.79 (d, J = 1.7 Hz, 1H) , 7.40 (m, 3H) , 7.30 (m, 2H) , 7.24 –7.11 (m, 2H) , 5.16 (m, 2H) , 3.79 (m, 1H) , 3.64 (m, 1H) , 2.79 (d, J = 4.4 Hz, 3H) , 1.40 (s, 6H) .

EXAMPLE 40

(S) -2- (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-ylamino) -4- (2-hydroxy-1-phenylethylamino) -N-propylpyrimidine-5-carboxamide

The title compound was synthesized using the same procedures as described in in Example 39. MS (ES+) : 476.1 [M+1] ⁺ .

¹H NMR (400 MHz, Chloroform-d) δ 10.50 (d, J = 7.2 Hz, 1H) , 9.49 (s, 1H) , 8.87 –8.50 (m, 1H) , 7.54 –7.21 (m, 8H) , 6.81 (d, J = 8.3 Hz, 1H) , 5.26 (dt, J = 10.1, 5.1 Hz, 2H) , 4.03 –3.82 (m, 2H) , 3.28 (m, 2H) , 1.43 (s, 6H) , 0.91 (t, J = 7.4 Hz, 3H) .

EXAMPLE 41

(S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyridin-2-ylamino) -2, 2-dimethylbenzofuran-3 (2H) -one

The title compound was synthesized using the same procedures as described in step 4 in Example 38. MS (ES+) : 458.0 [M+1] ⁺.

¹H NMR (400 MHz, Methanol-d ₄) δ 8.95 (s, 1H) , 8.60 (s, 1H) , 7.68 –7.59 (m, 3H) , 7.55 (m, 2H) , 7.48 (d, J = 1.8 Hz, 1H) , 7.42 –7.33 (m, 5H) , 7.29 (t, J = 7.0 Hz, 1H) , 6.84 (dd, J = 8.6, 1.8 Hz, 1H) , 6.06 (s, 1H) , 4.71 (dd, J = 7.4, 4.1 Hz, 1H) , 3.96 (dd, J =11.3, 4.2 Hz, 1H) , 3.84 (dd, J = 11.2, 7.2 Hz, 1H) , 1.40 (s, 6H) .

EXAMPLE 42

(S) -7- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -3, 3-dimethylchroman-4-one

Step 1 7-bromo-3, 3-dimethylchroman-4-one

To a stirred solution of 7-bromochroman-4-one (1 g) in THF (10 mL) were added CH ₃I (1.9 g) and t-BuOK (2.5 g) at -65℃. The mixture was stirred at rt for 2 h, and was then treated with ice-water, extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel-column chromatography (EA: PE=1: 19) to give 353 mg of the title compound as a yellow solid.

Step 2 (S) -7- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -3, 3-dimethylchroman-4-one

The title compound was synthesized using the same procedures as described in step 3 to step 5 in Example 1. MS (ES+) : 473.1 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.15 (s, 1H) , 9.36 (s, 1H) , 8.97 (d, J = 7.3 Hz, 1H) , 8.67 (s, 1H) , 7.66 –7.54 (m, 2H) , 7.44 (d, J = 7.2 Hz, 2H) , 7.33 (t, J = 7.5 Hz, 2H) , 7.24 (dd, J = 8.4, 2.0 Hz, 2H) , 5.36 (d, J = 6.1 Hz, 1H) , 5.29 (t, J = 5.0 Hz, 1H) , 4.24 (s, 2H) , 3.90 (m, 1H) , 3.76 (m, 1H) , 1.12 (d, J = 2.0 Hz, 6H) .

EXAMPLE 43

(S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -2, 2-dimethyl-3, 4-dihydronaphthalen-1 (2H) -one

Step 1 6-chloro-2, 2-dimethyl-3, 4-dihydronaphthalen-1 (2H) -one

To a stirred solution of 6-chloro-3, 4-dihydronaphthalen-1 (2H) -one (1 g) in THF (10 mL) was added NaH (556 mg) at rt under Ar. The mixture was stirred at rt for 15 min. To this solution was added CH ₃I (2.4 g) . The mixture was stirred at rt for 2 h, and was then treated with ice-water, extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated to give 1.3 g of the title compound as yellow oil. MS (ES+) : 209.0 [M+1] ⁺.

Step 2 (S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -2, 2-dimethyl-3, 4-dihydronaphthalen-1 (2H) -one

The title compound was synthesized using the same procedures as described in step 3 to step 5 in Example 1. MS (ES+) : 471.1 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.08 (s, 1H) , 9.35 (s, 1H) , 8.94 (d, J = 7.5 Hz, 1H) , 8.67 (s, 1H) , 7.75 (d, J = 8.6 Hz, 1H) , 7.65 –7.49 (m, 2H) , 7.42 (d, J = 7.3 Hz, 2H) , 7.35 (t, J = 7.6 Hz, 2H) , 7.25 (t, J = 7.2 Hz, 1H) , 5.41 (m, 1H) , 3.91 (m, 1H) , 3.81 (dd, J = 10.9, 5.3 Hz, 1H) , 3.01 –2.79 (m, 2H) , 1.91 (t, J = 6.4 Hz, 2H) , 1.12 (s, 6H) .

EXAMPLE 44

(S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -3, 3-dimethylisochroman-1-one

Step 1 methyl 2-bromo-4-fluorobenzoate

To a stirred solution of 2-bromo-4-fluorobenzoic acid (5 g) in MeOH (50 mL) was added H ₂SO ₄ (3.35 g) at rt. The mixture was stirred at 60 ℃ for 14 h, and was then treated with ice-water. After adjusting the pH to 7 with NaHCO ₃, the mixture was extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica-gel column chromatography (PE: EA=20: 1～9: 1) to give 5.2 g of the title compound as a yellow oil. MS (ES+) : 232.9 [M+1] ⁺.

Step 2 methyl 4-fluoro-2- (2-methylprop-1-enyl) benzoate

To a stirred solution of methyl 2-bromo-4-fluorobenzoate (4.5 g) in 1, 4-Dioxane/H ₂O (4: 1, 50 mL) were added 4, 4, 5, 5-tetramethyl-2- (2-methylprop-1-enyl) -1, 3, 2-dioxaborolane (4.57 g) , Pd (dppf) Cl ₂ (1.41 g) and K ₂CO ₃ (5.3 g) at rt. The mixture was stirred for 3 h at 100℃ under Ar, and was then treated with water, extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica-gel column chromatography (PE: EA=20: 1～9: 1) to give 4.3 g of the title compound as a yellow oil. MS (ES+) : 209.0 [M+1] ⁺.

Step 3 6-fluoro-3, 3-dimethylisochroman-1-one

A mixture of methyl 4-fluoro-2- (2-methylprop-1-enyl) benzoate (3.9 g) in H ₂SO ₄ (16 mL) was stirred at 0～5℃ for 2 h, and was then treated with ice-water. After adjusting the pH to 7 with NaHCO ₃, the mixture was extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica-gel column chromatography (PE: EA=20: 1～9: 1) to give 2.9 g of the title compound as a white solid. MS (ES+) : 195.0 [M+1] ⁺.

Step 4 6-azido-3, 3-dimethylisochroman-1-one

To a solution of 6-fluoro-3, 3-dimethylisochroman-1-one (1.9 g) in DMF (20 mL) was added NaN ₃ (3.2 g) at rt. The mixture was stirred at 100 ℃ for 12 h under Ar, and was then treated with water, extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated to give 2 g of title compound as a yellow solid. MS (ES+) : 218.0 [M+1] ⁺.

Step 5 6-amino-3, 3-dimethylisochroman-1-one

To a solution of 6-azido-3, 3-dimethylisochroman-1-one (2 g) in MeOH (20 mL) was added Pd/C (200 mg) . The mixture was stirred at rt for 2 h, and was then filtered through a layer of celite. The filtrate was concentrated and the residue was purified by silica-gel column chromatography (PE: EA=9: 1～3: 7) to give 1.4 of the title compound as a yellow solid. MS (ES+) : 192.0 [M+1] ⁺.

Step 6 (S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -3, 3-dimethylisochroman-1-one

The title compound was synthesized using the same procedures as described in step 5 Example 1. MS (ES+) : 473.1 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.17 (s, 1H) , 9.36 (s, 1H) , 8.95 (d, J = 7.4 Hz, 1H) , 8.68 (s, 1H) , 7.76 (d, J = 8.6 Hz, 1H) , 7.62 (d, J = 8.1 Hz, 2H) , 7.42 (d, J = 7.6 Hz, 2H) , 7.35 (t, J = 7.5 Hz, 2H) , 7.25 (t, J = 7.3 Hz, 1H) , 5.39 (m, 1H) , 5.25 (m, 1H) , 3.92 (m, 1H) , 3.81 (m, 1H) , 3.08 –2.85 (m, 2H) , 1.37 (d, J = 9.7 Hz, 6H) .

EXAMPLE 45

(S) -2- (2- (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-ylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-4-ylamino) -2-phenylethyl isobutyrate

To a stirred solution of isobutyric acid (28 mg) in DCM (12 mL) were added DCC (165 mg) and DMAP (16 mg) at rt. The mixture was stirred for 10 min at rt, and was then added (S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -2, 2-dimethylbenzofuran-3 (2H) -one (60 mg) . The mixture was stirred for 1 h at rt, and was then filtered. The filtrate was concentrated and the residue was purified by Prep-HPLC (Column: Green ODS-A, 21.2*250mm, 10um; Mobile A:water with 0.05%CHOOH, Mobile B: CH ₃CN; Gradient: 95%B over 15.2 min, 95%B over 18 min; Flow: 35 mL/min) to give 9.8 mg of the title compound as a white solid. MS (ES+) : 529.1 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.39 (s, 1H) , 9.37 (s, 1H) , 8.99 (d, J = 7.7 Hz, 1H) , 8.72 (s, 1H) , 7.76 (d, J = 1.7 Hz, 1H) , 7.55 –7.44 (m, 3H) , 7.37 (t, J = 7.5 Hz, 2H) , 7.31 –7.22 (m, 2H) , 5.70 (q, J = 5.3 Hz, 1H) , 4.51 (m, 2H) , 2.56 (m, 1H) , 1.41 (s, 6H) , 1.06 (dd, J = 10.4, 7.0 Hz, 6H) .

EXAMPLE 46

(S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyridin-2-ylamino) -3, 3-dimethylisochroman-1-one

The title compound was synthesized using the same procedures as described in step 4 in Example 38. MS (ES+) : 472.1 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 9.55 (s, 1H) , 9.33 (s, 1H) , 8.56 (s, 1H) , 8.48 (d, J = 6.2 Hz, 1H) , 7.73 (d, J = 8.6 Hz, 1H) , 7.56 (d, J = 2.2 Hz, 1H) , 7.44 (dd, J = 8.6, 2.1 Hz, 1H) , 7.41 –7.34 (m, 4H) , 7.29 (dt, J = 7.0, 3.8 Hz, 1H) , 6.02 (s, 1H) , 5.28 (t, J =4.9 Hz, 1H) , 4.66 (d, J = 5.4 Hz, 1H) , 3.87 (m, 1H) , 3.69 (m, 1H) , 2.97 (s, 2H) , 1.35 (s, 6H) .

EXAMPLE 47

(S) -2- (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-ylamino) -4- (2-hydroxy-1-phenylethylamino) -N-phenylpyrimidine-5-carboxamide

The title compound was synthesized using the same procedures as described in in Example 39. MS (ES+) : 510.1 [M+1] ⁺.

¹H NMR (400 MHz, Methanol-d ₄) δ 8.64 (s, 1H) , 7.80 (d, J = 1.8 Hz, 1H) , 7.71 –7.61 (m, 2H) , 7.45 (m, 3H) , 7.39 –7.30 (m, 4H) , 7.25 –7.20 (m, 1H) , 7.13 (tt, J = 7.4, 1.2 Hz, 1H) , 7.05 (dd, J = 8.6, 1.8 Hz, 1H) , 5.34 (dd, J = 6.8, 4.3 Hz, 1H) , 3.94 (dd, J = 11.3, 4.3 Hz, 1H) , 3.83 (dd, J = 11.3, 6.8 Hz, 1H) , 1.47 (s, 6H) .

EXAMPLE 48

(S) -7- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -1-methylquinazolin-4 (1H) -one

Step 1 2- (methylamino) -4-nitrobenzoic acid

A mixture of 2-fluoro-4-nitrobenzoic acid (10 g) in CH ₃NH ₂ (solution, 38 mL) was stirred at 80℃ overnight. After adjusting the pH to 6 with 2N HCl (aq. ) , the mixture was filtered. The filter cake was washed with water, dried and slurred with DCM to give 1.49 g of the title compound as an orange solid. MS (ES+) : 197.0 [M+1] ⁺.

Step 2 1-methyl-7-nitroquinazolin-4 (1H) -one

The mixture of 2- (methylamino) -4-nitrobenzoic acid (760 mg) and NH ₄OAc (1.79 g) in triethyl orthoformate (10 mL) was stirred at 90℃ overnight. After adjusting the pH to <7 with 1N HCl (aq. ) , the mixture was extracted with EA. The aqueous layer was concentrated to give 458 mg of title compound as a yellow solid. MS (ES+) : 206.0 [M+1] ⁺.

Step 3 7-amino-1-methylquinazolin-4 (1H) -one

To a stirred solution of 1-methyl-7-nitroquinazolin-4 (1H) -one (378 mg) in EtOH (5 mL) and water (1 mL) were added NH ₄Cl (1.46 g) and Fe (1.03 g) . The mixture was stirred at 70℃ for 3 h, and was then filtered. The filtrate was concentrated to give 403 mg of title compound as a yellow solid. MS (ES+) : 176.0 [M+1] ⁺.

Step 4 (S) -7- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-yl-amino) -1-methylquinazolin-4 (1H) -one

The title compound was synthesized using the same procedures as described in step 4 in Example 38. MS (ES+) : 457.0 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.27 (s, 1H) , 9.37 (s, 1H) , 8.93 (d, J = 7.7 Hz, 1H) , 8.71 (s, 1H) , 8.40 (s, 1H) , 7.97 –7.76 (m, 3H) , 7.36 (m, 5H) , 5.49 (m, 1H) , 5.25 (s, 1H) , 3.87 (m, 2H) , 3.65 (s, 3H) .

EXAMPLE 49

(S) -2- (2- (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-ylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-4-ylamino) -2-phenylethyl acetate

The title compound was synthesized using the same procedures as described in in Example 45. MS (ES+) : 501.0 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.39 (s, 1H) , 9.39 (s, 1H) , 8.92 (d, J = 7.6 Hz, 1H) , 8.72 (s, 1H) , 7.77 (d, J = 1.7 Hz, 1H) , 7.49 (t, J = 8.4 Hz, 3H) , 7.38 (t, J = 7.6 Hz, 2H) , 7.32 –7.23 (m, 2H) , 5.66 (m, 1H) , 4.67 –4.34 (m, 2H) , 2.03 (s, 3H) , 1.41 (s, 6H) .

EXAMPLE 50

(S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -2, 2-dimethylbenzofuran-3 (2H) -one

Step 1 (S) -tert-butyl2- (2- (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-ylamino) -4- (2-hydroxy-1-phenylethylamino) pyrimidine-5-carbonyl) hydrazinecarboxylate

To a stirred solution of (S) -2- (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-ylamino) -4- (2-hydroxy-1-phenylethylamino) pyrimidine-5-carboxylic acid (910 mg) and tert-butyl hydrazinecarboxylate (335 mg) in DCM (36 mL) was added EDCI (513 mg) at rt under Ar. The mixture was stirred at rt for 1 h, and was then treated with water, extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica-gel column chromatography (EA: PE=2: 3) to give 745 mg of the title compound as a white solid. MS (ES+) : 549.1 [M+1] ⁺.

Step 2 (S) -2- (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-ylamino) -4- (2-hydroxy-1-phenylethylamino) pyrimidine-5-carbohydrazide

A mixture of (S) -tert-butyl2- (2- (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-ylamino) -4- (2-hydroxy-1-phenylethylamino) pyrimidine-5-carbonyl) hydrazinecarboxylate (50 mg) in HCl/EA (4N, 1 mL) was stirred at rt for 1 h under Ar, and was then concentrated to give 41 mg of the title compound as a yellow solid.

Step 3 (S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -2, 2-dimethylbenzofuran-3 (2H) -one

A mixture of (S) -2- (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-ylamino) -4- (2-hydroxy-1-phenylethylamino) pyrimidine-5-carbohydrazide (41 mg) in 1, 1, 1-triethoxyethane (1 mL) was stirred at 100 ℃ for 3 h under Ar. After adjusting the pH to <7 with 0.5N HCl (aq. ) , the mixture was extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by Prep-HPLC (Column: Green ODS-A, 21.2*250 mm, 10um; Mobile A: water with 0.05%TFA, Mobile B: CH ₃CN; Gradient: 60%B over 2 min, 75%B over 15 min; Flow: 35 mL/min) to give 4.4 mg of the title compound as a white solid. MS (ES+) : 473.1 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.31 (s, 1H) , 8.97 (d, J = 7.2 Hz, 1H) , 8.62 (s, 1H) , 7.81 (d, J = 1.7 Hz, 1H) , 7.44 (dd, J =12.4, 7.8 Hz, 3H) , 7.32 (t, J = 7.5 Hz, 2H) , 7.25 –7.16 (m, 2H) , 5.38 –5.24 (m, 2H) , 3.89 (m, 1H) , 3.74 (m, 1H) , 2.61 (s, 3H) , 1.42 (s, 6H) .

EXAMPLE 51

(S) -6- (5- (5-cyclopropyl-1, 3, 4-oxadiazol-2-yl) -4- (2-hydroxy-1-phenylethylamino) pyrimidin-2-ylamino) -2, 2-dimethylbenzofuran-3 (2H) -one

Step 1 (S) -N'- (cyclopropanecarbonyl) -2- (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-ylamino) -4- (2-hydroxy-1-phenylethylamino) pyrimidine-5-carbohydrazide

To a stirred solution of (S) -2- (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-ylamino) -4- (2-hydroxy-1-phenylethylamino) pyrimidine-5-carbohydrazide (41 mg) and cyclopropanecarboxylic acid (8 mg) in DMF (2 mL) were added DIEA (36 mg) and HATU (31 mg) at rt under Ar. The mixture was stirred at rt for 1 h under Ar, and was then treated with water, extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by Prep-TLC (EA: PE=4: 1) to give 30 mg of the title compound as a yellow solid. MS (ES+) : 517.1 [M+1] ⁺.

Step 2 (S) -6- (5- (5-cyclopropyl-1, 3, 4-oxadiazol-2-yl) -4- (2-hydroxy-1-phenylethylamino) pyrimidin-2-ylamino) -2, 2-dimethylbenzofuran-3 (2H) -one

To a stirred solution of (S) -N'- (cyclopropanecarbonyl) -2- (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-ylamino) -4- (2-hydroxy-1-phenylethylamino) pyrimidine-5-carbohydrazide (30 mg) in ACN (2 mL) were added TsCl (22 mg) and Et ₃N (18 mg) at rt under Ar. The mixture was stirred at 50℃ for 2 h under Ar, and was then treated with water, extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by Prep-TLC (EA: PE=3: 2) to give 8.5 mg of the title compound as a white solid. MS (ES+) : 499.1 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.32 (s, 1H) , 8.94 (d, J = 7.2 Hz, 1H) , 8.63 (s, 1H) , 7.80 (d, J = 1.7 Hz, 1H) , 7.44 (dd, J =11.8, 8.0 Hz, 3H) , 7.32 (d, J = 7.5 Hz, 2H) , 7.27 –7.16 (m, 2H) , 5.32 (m, 1H) , 3.88 (m, 1H) , 3.78 –3.71 (m, 1H) , 2.32 (m, 1H) , 1.42 (s, 6H) , 1.27 –1.11 (m, 4H) .

EXAMPLE 52

(S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyridin-2-ylamino) -2, 2-dimethylfuro [3, 2-b] pyridin-3 (2H) -one

The title compound was synthesized using the same procedures as described in step 4 in Example 38. MS (ES+) : 459.0 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.08 (s, 1H) , 9.36 (s, 1H) , 8.63 (s, 1H) , 8.58 (d, J = 6.3 Hz, 1H) , 8.34 (d, J = 2.2 Hz, 1H) , 8.31 (d, J = 2.1 Hz, 1H) , 7.38 (m, 4H) , 7.28 (m, 1H) , 6.09 (s, 1H) , 5.30 (t, J = 4.9 Hz, 1H) , 4.69 (q, J = 5.7 Hz, 1H) , 3.88 (m, 1H) , 3.70 (m, 1H) , 1.39 (s, 6H) .

EXAMPLE 53

(S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (5- (pyridin-4-yl) -1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -2, 2-dimethylbenzofuran-3 (2H) -one

Step 1 (S) -2- (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-ylamino) -4- (2-hydroxy-1-phenylethylamino) -N'-isonicotinoylpyrimidine-5-carbohydrazide

To a stirred solution of (S) -2- (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-ylamino) -4- (2-hydroxy-1-phenylethylamino) pyrimidine-5-carbohydrazide (65 mg) and isonicotinic acid (22 mg) in DMF (5 mL) were added DIEA (56 mg) and HATU (48 mg) at rt under Ar. The mixture was stirred at rt for 1 h under Ar, and was then treated with water, extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was slurred with DCM to give 40 mg of the title compound as a white solid. MS (ES+) : 554.1 [M+1] ⁺.

Step 2 (S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (5- (pyridin-4-yl) -1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -2, 2-dimethylbenzofuran-3 (2H) -one

To a stirred solution of (S) -2- (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-ylamino) -4- (2-hydroxy-1-phenylethylamino) -N'-isonicotinoylpyrimidine-5-carbohydrazide (40 mg) in ACN (4 mL) were added TsCl (28 mg) and Et ₃N (20 mg) at rt under Ar. The mixture was stirred at 50℃ for 1 h under Ar, and was then treated with water, extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by Prep-TLC (EA) to give 28.8 mg of the title compound as a yellow solid. MS (ES+) : 536.1 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.42 (s, 1H) , 9.01 (d, J = 7.1 Hz, 1H) , 8.95 (s, 1H) , 8.91 –8.83 (m, 2H) , 8.19 –8.06 (m, 2H) , 7.82 (s, 1H) , 7.46 (dd, J = 8.1, 4.5 Hz, 3H) , 7.33 (t, J = 7.5 Hz, 2H) , 7.23 (t, J = 7.8 Hz, 2H) , 5.34 (m, 2H) , 3.98 –3.87 (m, 1H) , 3.83 –3.73 (m, 1H) , 1.43 (s, 6H) .

EXAMPLE 54

(S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (5- (trifluoromethyl) -1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -2, 2-dimethylbenzofuran-3 (2H) -one

Step 1 (S) -2- (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-ylamino) -4- (2-hydroxy -1-phenylethylamino) -N'- (2, 2, 2-trifluoroacetyl) pyrimidine-5-carbohydrazide

To a stirred solution of (S) -2- (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-ylamino) -4- (2-hydroxy-1-phenylethylamino) pyrimidine-5-carbohydrazide (50 mg) in THF (2 mL) were added Et ₃N (34 mg) and TFAA (47 mg) at rt under Ar. The mixture was stirred at rt for 2 h under Ar, and was then treated with water, extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by Prep-TLC (EA: PE=3: 2) to give 37 mg of the title compound as a yellow solid. MS (ES+) : 545.0 [M+1] ⁺.

Step 2 (S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (5- (trifluoromethyl) -1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -2, 2-dimethylbenzofuran-3 (2H) -one

To a stirred solution of (S) -2- (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-ylamino) -4- (2-hydroxy-1-phenylethylamino) -N'- (2, 2, 2-trifluoroacetyl) pyrimidine-5-carbohydrazide (37 mg) in ACN (4 mL) were added TsCl (27 mg) and Et ₃N (22 mg) at rt under Ar. The mixture was stirred at 50℃ for 1 h under Ar, and was then treated with water, extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by Prep-TLC (EA: PE=1: 1) to give 10.3 mg of the title compound as a yellow solid. MS (ES+) : 527.0 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.49 (s, 1H) , 8.84 (d, J = 7.0 Hz, 1H) , 8.75 (s, 1H) , 7.79 (d, J = 1.6 Hz, 1H) , 7.46 (dd, J =10.5, 7.9 Hz, 3H) , 7.32 (t, J = 7.5 Hz, 2H) , 7.27 –7.19 (m, 2H) , 5.43 –5.20 (m, 2H) , 3.91 (m, 1H) , 3.76 (m, 1H) , 1.43 (s, 6H) .

EXAMPLE 55

(S) -6- (5- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) -4- (2-hydroxy-1-phenylethylamino) pyrimidin-2-ylamino) -2, 2-dimethylbenzofuran-3 (2H) -one

Step 1 (S) -N- (2- (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-ylamino) -4- (2-hydroxy -1-phenylethylamino) pyrimidine-5-carbonyloxy) cyclopropanecarboximidamide

To a stirred solution of (S) -2- (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-ylamino) -4- (2-hydroxy-1-phenylethylamino) pyrimidine-5-carboxylic acid (20 mg) in DMF (2 mL) were added HOBT (19 mg) and EDCI (27 mg) at rt under Ar. The mixture was stirred at rt for 0.5 h under Ar, and then N-hydroxycyclopropanecarboximidamide (14 mg) was added at rt. The mixture was stirred for another 2 h at rt, and was then treated with water, filtered and the solid was dried to give 11 mg of the title compound as a white solid. MS (ES+) : 517.1 [M+1] ⁺.

Step2 (S) -6- (5- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) -4- (2-hydroxy-1-phenylethylamino) pyrimidin-2-ylamino) -2, 2-dimethylbenzofuran-3 (2H) -one

To a stirred solution of (S) -N- (2- (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-ylamino) -4- (2-hydroxy-1-phenylethylamino) pyrimidine-5-carbonyloxy) cyclopropanecarboximidamide (11 mg) in 1, 4-dioxane (1 mL) was added TsOH·H ₂O (5 mg) at rt under Ar. The mixture was stirred at 100℃ for 2 h under Ar, and was then concentrated. The residue was purified by Prep-TLC (EA: PE=1: 1) to give 8.1 mg of the title compound as a white solid. MS (ES+) : 499.1 [M+1] ⁺.

¹H NMR (400 MHz, Methanol-d ₄) δ 9.28 (d, J = 7.1 Hz, 1H) , 8.64 (s, 1H) , 7.75 (d, J = 1.8 Hz, 1H) , 7.49 –7.41 (m, 3H) , 7.34 (t, J = 7.6 Hz, 2H) , 7.29 –7.20 (m, 1H) , 7.02 (dd, J = 8.6, 1.8 Hz, 1H) , 5.40 –5.29 (m, 1H) , 4.03 (m, 1H) , 3.88 –3.81 (m, 1H) , 2.17 (m, 1H) , 1.47 (s, 6H) , 1.14 (m, 4H) .

EXAMPLE 56

(S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-2-ylamino) -2, 2-dimethylbenzofuran-3 (2H) -one

The title compound was synthesized using the same procedures as described in Example 55. MS (ES+) : 473.1 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.41 (s, 1H) , 9.10 (d, J = 7.1 Hz, 1H) , 8.81 (s, 1H) , 7.78 (s, 1H) , 7.44 (m, 3H) , 7.32 (t, J =7.5 Hz, 2H) , 7.22 (m, 2H) , 5.30 (m, 2H) , 3.90 (m, 1H) , 3.74 (m, 1H) , 2.47 (s, 3H) , 1.42 (s, 6H) .

EXAMPLE 57

(S) -7- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyridin-2-ylamino) -2, 2-dimethylchroman-4-one

The title compound was synthesized using the same procedures as described in step 3 to step 5 in Example 1. MS (ES+) : 472.1 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 9.58 (s, 1H) , 9.34 (s, 1H) , 8.58 (s, 1H) , 8.49 (d, J = 6.3 Hz, 1H) , 7.55 (m, 2H) , 7.43 –7.32 (m, 4H) , 7.28 (m, 1H) , 6.91 (m, 1H) , 6.04 (s, 1H) , 5.29 (t, J = 4.9 Hz, 1H) , 4.66 (q, J = 5.7 Hz, 1H) , 3.77 (m, 2H) , 2.68 (d, J = 11.2 Hz, 2H) , 1.38 (s, 6H) .

EXAMPLE 58

(S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (3- (pyridin-4-yl) -1, 2, 4-oxadiazol-5-yl) pyrimidin-2-ylamino) -2, 2-dimethylbenzofuran-3 (2H) -one

The title compound was synthesized using the same procedures as described in Example 55. MS (ES+) : 536.1 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.49 (s, 1H) , 9.47 (d, J = 7.9 Hz, 1H) , 8.88 (m, 3H) , 8.09 (m, 2H) , 7.77 (s, 1H) , 7.52 –7.19 (m, 7H) , 5.50 (m, 1H) , 5.31 (m, 1H) , 1.42 (s, 6H) .

EXAMPLE 59

(S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 2, 4-oxadiazol-5-yl) pyrimidin-2-ylamino) -2, 2-dimethylbenzofuran-3 (2H) -one

Step 1 (S) -2- (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-ylamino) -4- (2-hydroxy-1-phenylethylamino) pyrimidine-5-carboxamide

To a stirred solution of (S) -2- (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-ylamino) -4- (2-hydroxy-1-phenylethylamino) pyrimidine-5-carboxylic acid (250 mg) and NH ₄Cl (305 mg) in DMF (10 mL) were added DIEA (743 mg) and HATU (531 mg) at rt under Ar. The mixture was stirred at rt overnight, and was then treated with water, extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by Prep-TLC (MeOH/DCM=10%) to give 130 mg of the title compound as a white solid. MS (ES+) : 434.1 [M+1] ⁺.

Step 2 (S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 2, 4-oxadiazol-5-yl) pyrimidin-2-ylamino) -2, 2-dimethylbenzofuran-3 (2H) -one

A mixture of (S) -2- (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-ylamino) -4- (2-hydroxy-1-phenylethylamino) pyrimidine-5-carboxamide (130 mg) in DMF-DMA (13 mL) was stirred at 80℃ for 1 h under Ar. Then the mixture was concentrated and the residue was added to a stirred solution of NH ₂OH ^. HCl (42 mg) in 1, 4-Dioxane (6.5 mL) , NaOH (5N, 1.3 mL) and AcOH (13 mL) . The mixture was stirred for 10 min at rt and 80℃overnight under Ar, and was then treated with NaHCO ₃ (aq. ) , extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by Prep-TLC (MeOH/DCM=5%) to give 8.6 mg of the title compound as a white solid. MS (ES+) : 459.1 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.46 (s, 1H) , 9.22 (s, 1H) , 9.13 (d, J = 7.1 Hz, 1H) , 8.87 (s, 1H) , 7.80 (s, 1H) , 7.45 (m, 3H) , 7.32 (t, J = 7.5 Hz, 2H) , 7.23 (d, J = 7.8 Hz, 2H) , 5.31 (m, 2H) , 3.81 (m, 2H) , 1.42 (s, 6H) .

EXAMPLE 60

(S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyridin-2-ylamino) -2, 2-dimethylfuro [2, 3-b] pyridin-3 (2H) -one

Step 1 1- (2, 6-dichloropyridin-3-yl) -2-methylpropan-1-ol

To a stirred solution of 2, 6-dichloronicotinaldehyde (9.6 g) in THF (96 mL) was added isopropylmagnesium chloride lithium chloride complex (63 mL) dropwise at -10～0℃ under Ar. The mixture was stirred at -10～0℃ for 2 h, and was then treated with sat. NH ₄Cl (aq. ) , extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica-gel column chromatography (PE: EA=9: 1) to give 4.2 g of the titlecompound as a yellow solid. MS (ES+) : 220 [M+1] ⁺.

Step 2 1- (2, 6-dichloropyridin-3-yl) -2-methylpropan-1-one

To a stirred solution of 1- (2, 6-dichloropyridin-3-yl) -2-methylpropan-1-ol (3.2 g) in DCM (30 mL) was added PCC (6.2 g) at rt. The mixture was stirred at rt for 2 h, and was then treated with water. After adjusting the pH to >7 with sat. NaHCO ₃ (aq. ) , the mixture was filtered through diatomite and extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica-gel column chromatography (PE: EA=9: 1) to give 3.2 g of the title compound as yellow oil. MS (ES+) : 218 [M+1] ⁺.

Step 3 1- (2, 6-dichloropyridin-3-yl) -2-hydroxy-2-methylpropan-1-one

To a stirred solution of 1- (2, 6-dichloropyridin-3-yl) -2-methylpropan-1-one (2 g) in DMSO (20 mL) was added NBS (660 mg) at rt. The mixture was stirred at 100℃ for 16 h, and was then treated with water, extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica-gel column chromatography (PE: EA=9: 1) to give 1.29 g of the title compound as yellow oil. MS (ES+) : 234 [M+1] ⁺.

Step 4 6-chloro-2, 2-dimethylfuro [2, 3-b] pyridin-3 (2H) -one

To a stirred solution of 1- (2, 6-dichloropyridin-3-yl) -2-hydroxy-2-methylpropan-1-one (680 mg) in DMF (136 mL) were added CsF (680 mg) at rt and then t-BuOK (323 mg) at 0-10℃ under Ar. The mixture was stirred at 0-10 ℃ for 3.5 h, and was then treated with water, extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by Prep-TLC (PE: EA=3: 1) to give 160 mg of title compound as a white solid. MS (ES+) : 198 [M+1] ⁺.

Step 5 tert-butyl 2, 2-dimethyl-3-oxo-2, 3-dihydrofuro [2, 3-b] pyridin-6-ylcarbamate

To a stirred solution of 6-chloro-2, 2-dimethylfuro [2, 3-b] pyridin-3 (2H) -one (150 mg) in 1, 4-Dioxane (15 mL) were added Pd ₂ (dba) ₃ (70 mg) , Xant-phos (88 mg) , Cs ₂CO ₃ (496 mg) and tert-butyl carbamate (267 mg) at rt under Ar. The mixture was stirred at 100℃ for 2 h, and was then treated with water, extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by Prep-TLC (PE: EA=3: 1) to give 130 mg of the title compound as a yellow solid. MS (ES+) : 223 [M-55] ⁺.

Step 6 6-amino-2, 2-dimethylfuro [2, 3-b] pyridin-3 (2H) -one

The mixture of tert-butyl 2, 2-dimethyl-3-oxo-2, 3-dihydrofuro [2, 3-b] pyridin-6-ylcarbamate (130 mg) in TFA/DCM (1: 1, 12 mL) was stirred at rt for 1 h, and was then treated with sat. Na ₂CO ₃ (aq. ) , extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by Prep-TLC (PE: EA=1: 1) to give 60 mg of the titlecompound as a yellow solid. MS (ES+) : 179.0 [M+1] ⁺.

Step 7 (S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyridin-2-ylamino) -2, 2-dimethylfuro [2, 3-b] pyridine-3 (2H) -one

The title compound was synthesized using the same procedures as described in step 4 in Example 38. MS (ES+) : 459.1 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.64 (s, 1H) , 9.36 (s, 1H) , 8.63 (d, J = 5.9 Hz, 1H) , 8.57 (s, 1H) , 7.85 (d, J = 8.5 Hz, 1H) , 7.78 (s, 1H) , 7.53 –7.44 (m, 2H) , 7.30 (t, J = 7.5 Hz, 2H) , 7.27 –7.19 (m, 1H) , 7.07 (d, J = 8.5 Hz, 1H) , 5.33 (m, 1H) , 4.68 (m, 1H) , 3.86 (m, 1H) , 3.73 (m, 1H) , 1.51 (d, J = 9.7 Hz, 6H) .

EXAMPLE 61

(S) -2- ( (4- ( (2-hydroxy-1-phenylethyl) amino) -5- (1, 3, 4-oxadiazol-2-yl) pyridin-2-yl) amino) -7, 7-dimethyl-7, 8-dihydroquinolin-5 (6H) -one

Step1 7, 7-dimethyl-7, 8-dihydroquinoline-2, 5 (1H, 6H) -dione

The mixture of 3-amino-5, 5-dimethylcyclohex-2-en-1-one (1 g) in ethyl propiolate (2.5 mL) was stirred at 70℃ for 1 h and 90℃ for 2 h, and was then cooled to rt. MTBE was added and the mixture was stirred for 0.5 h. The resulting precipitate was filtered and then purified by Prep-TLC (EA) to give 275 mg of the title compound as a yellow solid. MS (ES+) : 192.1 [M+1] ⁺. Step 2 2-chloro-7, 7-dimethyl-7, 8-dihydroquinolin-5 (6H) -one

A mixture of 7, 7-dimethyl-7, 8-dihydroquinoline-2, 5 (1H, 6H) -dione (270 mg) in phosphoryl trichloride (2.7 mL) was stirred at 100℃ for 2 h, and was then treated with water, extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by Prep-TLC (PE: EA=1: 9) to give 86 mg of the title compound as yellow oil. MS (ES+) : 210 [M+1] ⁺.

Step 3 2- ( (2, 4-dimethoxybenzyl) amino) -7, 7-dimethyl-7, 8-dihydroquinolin-5 (6H) -one

To a stirred solution of 2-chloro-7, 7-dimethyl-7, 8-dihydrophosphinolin-5 (6H) -one (80 mg) and DIEA (198 mg) in NMP (8 mL) was added (2, 4-dimethoxyphenyl) methanamine (96 mg) at rt. The mixture was stirred at 140℃ for 2 h under Ar, and was then treated with water, extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by Prep-TLC (PE: EA=1: 1) to give 80 mg of title compound as yellow oil. MS (ES+) : 341.1 [M+1] ⁺.

Step 4 2-amino-7, 7-dimethyl-7, 8-dihydroquinolin-5 (6H) -one

A mixture of 2- ( (2, 4-dimethoxybenzyl) amino) -7, 7-dimethyl-7, 8-dihydroquinolin-5 (6H) -one (80 mg) in HCl/1.4-dioxane (3.5 mL) was stirred at 60℃ for 2 h. After adjusting the pH to 8 with sat. NaHCO ₃ (aq. ) , the mixture was extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by Prep-TLC (EA: PE=2: 1) to give 35 mg of title compound as a white solid. MS (ES+) : 191 [M+1] ⁺.

Step 5 (S) -2- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyridin-2-ylamino) -7, 7-dimethyl-7, 8-dihydroquinolin-5 (6H) -one

The title compound was synthesized using the same procedures as described in step 4 in Example 38. MS (ES+) : 471.1 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.23 (s, 1H) , 9.33 (s, 1H) , 8.64 –8.46 (m, 2H) , 7.94 (d, J = 8.6 Hz, 1H) , 7.55 (s, 1H) , 7.33 (m, 6H) , 5.29 (t, J = 4.9 Hz, 1H) , 4.76 (m, 1H) , 3.91 (m, 1H) , 3.73 (m, 1H) , 2.89 (m, 1H) , 2.72 –2.64 (m, 1H) , 2.45 (s, 2H) , 1.10 (s, 3H) , 1.03 (s, 3H) .

EXAMPLE 62

(S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyridin-2-ylamino) -2, 2-dimethylfuro [3, 2-c] pyridin-3 (2H) -one

The title compound was synthesized using the same procedures as described in Example 38. MS (ES+) : 459.1 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.34 (s, 1H) , 9.35 (s, 1H) , 8.58 (s, 1H) , 8.55 (d, J = 6.2 Hz, 1H) , 8.52 (s, 1H) , 7.47 (s, 1H) , 7.41 (d, J = 7.6 Hz, 2H) , 7.35 (t, J = 7.5 Hz, 2H) , 7.26 (t, J = 7.2 Hz, 1H) , 7.04 (s, 1H) , 5.31 (m, 1H) , 4.65 (m, 1H) , 3.85 (m, 1H) , 3.70 (m, 1H) , 1.40 (d, J = 3.1 Hz, 6H) .

EXAMPLE 63

(S) -7- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -1, 2-dimethylquinazolin-4 (1H) -one

Step1 2- (methylamino) -4-nitrobenzoic acid

The mixture of 2-fluoro-4-nitrobenzoic acid (10 g) in methylamine aqueous solution (38 mL) was stirred at 80℃ under the pressure tank for 6 h. After adjusting the pH to 5 with 2 N HCl (aq. ) , the mixture was filtered. The filter cake was dried to give 1.5 g of the title compound as a yellow solid. MS (ES+) : 197 [M+1] ⁺.

Step 2 2- (methylamino) -4-nitrobenzamide

To a stirred solution of 2- (methylamino) -4-nitrobenzoic acid (1.5 g) in DMF (10 mL) were added NH ₄Cl (4 g) , HATU (3.2 g) and DIEA (9.9 g) at rt. The mixture was stirred at rt for 3 h, and was then treated with water, extracted with EA. The organic layer was washed with brined, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica-gel column chromatography (PE: EA=3: 1～1: 1) to give 1.2 g of the title compound as a yellow solid. MS (ES+) : 196 [M+1] ⁺.

Step 3 1, 2-dimethyl-7-nitroquinazolin-4 (1H) -one

To a stirred solution of 2- (methylamino) -4-nitrobenzamide (1 g) in AcOH (12 mL) was added 1, 1, 1-triethoxyethane (12.5 g) . The mixture was stirred at 135℃ for 1.5 h under the pressure tank. After adjusting the pH to 9 with sat. Na ₂CO ₃ (aq. ) , the mixture was extracted with DCM. The organic layer was washed with brined, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica-gel column chromatography (DCM/MeOH=20: 1) to give 640 mg of the title compound as a yellow solid. MS (ES+) : 220 [M+1] ⁺.

Step 4 7-amino-1, 2-dimethylquinazolin-4 (1H) -one

To a stirred solution of 1, 2-dimethyl-7-nitroquinazolin-4 (1H) -one (400 mg) in EtOH/H ₂O (4: 1, 50 mL) were added NH ₄Cl (586 mg) and Fe (511 mg) at rt. The mixture was stirred at 80℃ for 5 h, and was then filtered through the diatomite. The filtrate was concentrated and the residue was slurred with EtOH to give 600 mg of title compound as a yellow solid. MS (ES+) : 190[M+1] ⁺.

Step 5 (S) -7- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -1, 2-dimethylquinazolin-4 (1H) -one

The title compound was synthesized using the same procedures as described in Example 38. MS (ES+) : 471.1 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.17 (s, 1H) , 9.36 (s, 1H) , 8.93 (d, J = 7.8 Hz, 1H) , 8.71 (s, 1H) , 7.96 –7.88 (m, 2H) , 7.80 (dd, J = 8.8, 1.8 Hz, 1H) , 7.44 (d, J = 7.3 Hz, 2H) , 7.37 (t, J = 7.5 Hz, 2H) , 7.27 (t, J = 7.3 Hz, 1H) , 5.47 (m, 1H) , 5.24 (t, J =4.9 Hz, 1H) , 3.92 (m, 1H) , 3.83 (m, 1H) , 3.64 (s, 3H) , 2.54 (s, 3H) .

EXAMPLE 64

(S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -3, 3-dimethyl-3, 4-dihydronaphthalen-1 (2H) -one

Step1 tert-butyl 4- (3-bromophenyl) -3, 3-dimethyl-4-oxobutanoate

To a stirred solution of 1- (3-bromophenyl) -2-methylpropan-1-one (730 mg) in THF (14 mL) was added LiHMDS (1.0 M in THF, 3.8 mL) at 0-10℃ under Ar. The mixture was stirred at 0-10℃ for 0.5 h, and then tert-butyl2-bromoacetate (756 mg) was added at 0-10℃. The mixture was stirred at rt for 3 h, and was then treated with water, extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica-gel column chromatography (EA/PE=3%) to give 430 mg of title compund as colorless oil.

Step 2 4- (3-bromophenyl) -3, 3-dimethyl-4-oxobutanoic acid

The mixture of tert-butyl 4- (3-bromophenyl) -3, 3-dimethyl-4-oxobutanoate (290 mg) in TFA/DCM (1: 1, 30 mL) was stirred at rt for 3 h, and was then concentrated. The residue was diluted with water, extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by Prep-TLC (EA: PE=1: 4) to give 180 mg of the title compound as a white solid.

Step 3 4- (3-bromophenyl) -3, 3-dimethylbutanoic acid

To a stirred solution of 4- (3-bromophenyl) -3, 3-dimethyl-4-oxobutanoic acid (170 mg) in diethylene glycol (9 mL) were added KOH (134 mg) and NH ₂NH ₂. H ₂O (1 mL) at rt under Ar. The mixture was stirred at 120 ℃ for 2 h. Then the mixture was concentrated to recycle the water inside the bottle and hydrazine. The residue was stirred at 180℃ under Ar for 1 h, and was then treated with water, extracted with EA. After adjusting the pH to 4-5 with 2N HCl (aq. ) , the aqueous layer was extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by Prep-TLC (EA: PE=1: 4) to give 79 mg of the title compound as a white solid.

¹H NMR (400 MHz, DMSO-d ₆) δ 7.47 –7.35 (m, 2H) , 7.26 (t, J = 7.7 Hz, 1H) , 7.19 (d, J = 7.8 Hz, 1H) , 2.62 (s, 2H) , 2.06 (s, 2H) , 0.94 (s, 5H) .

Step 4 6-bromo-3, 3-dimethyl-3, 4-dihydronaphthalen-1 (2H) -one

The mixture of 4- (3-bromophenyl) -3, 3-dimethylbutanoic acid (69 mg) in H ₂SO ₄ (3.5 mL) was stirred at 80℃ under Ar for 2 h, and was then treated with ice-water, extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by Prep-TLC (EA/PE=5%) to give 36 mg of the title compound as a white solid. MS (ES+) : 252.9 [M+1] ⁺.

¹H NMR (400 MHz, Chloroform-d) δ 7.87 (d, J = 8.3 Hz, 1H) , 7.47 –7.42 (m, 1H) , 7.40 (s, 1H) , 2.82 (s, 2H) , 2.49 (s, 2H) , 1.07 (s, 6H) .

Step 5 (S) -6- (4- (2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -3, 3-dimethyl-3, 4-dihydronaphthalen-1 (2H) -one

¹H NMR (400 MHz, DMSO-d ₆) δ 10.09 (s, 1H) , 9.35 (s, 1H) , 8.94 (d, J = 7.5 Hz, 1H) , 8.67 (s, 1H) , 7.73 (d, J = 8.5 Hz, 1H) , 7.56 (d, J = 10.5 Hz, 2H) , 7.42 (d, J = 7.6 Hz, 2H) , 7.35 (t, J = 7.5 Hz, 2H) , 7.25 (t, J = 7.2 Hz, 1H) , 5.40 (m, 1H) , 5.25 (t, J =4.9 Hz, 1H) , 3.92 (m, 1H) , 3.85 –3.79 (m, 1H) , 2.85 –2.65 (m, 2H) , 2.41 (s, 2H) , 1.02 (s, 3H) , 0.99 (s, 3H) .

EXAMPLE 65

(S) -2- ( (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-yl) amino) -4- ( (2-hydroxy-1-phenylethyl) amino) pyrimidine-5-carbonitrile

Step1 (S) -2-chloro-4- ( (2-hydroxy-1-phenylethyl) amino) pyrimidine-5-carbonitrile

To a stirred solution of 2, 4-dichloropyrimidine-5-carbonitrile (1 g) and DIEA (1.5 g) in ACN (10 ml) was added (S) -2-amino-2-phenylethanol (0.8 g) in portions at 5℃ under Ar. Then the mixture was stirred for 1 h at 5 ℃, and was then treated with water, extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel column chromatography (PE/EA=10/1～2/1) to got 360 mg of the title compound as a yellow solid. MS (ES+) : 275.1 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 8.88 (d, J = 7.9 Hz, 1H) , 8.58 (s, 1H) , 7.46 –7.39 (m, 2H) , 7.34 (t, J = 7.5 Hz, 2H) , 7.29 –7.21 (m, 1H) , 5.26 (td, J = 8.3, 4.9 Hz, 1H) , 5.05 (t, J = 5.7 Hz, 1H) , 3.85 (m, 1H) , 3.69 (m, 1H) .

Step 2 (S) -2- ( (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-yl) amino) -4- ( (2-hydroxy-1-phenylethyl) amino) pyrimidine-5-carbonitrile

A mixture of (S) -2-chloro-4- ( (2-hydroxy-1-phenylethyl) amino) pyrimidine-5-carbonitrile (350 mg, 1.274 mmol) , 6-amino-2, 2-dimethylbenzofuran-3 (2H) -one (226 mg) and p-toluenesulfonic acid monohydrate (243 mg) in 1, 4-dioxane (17.5 mL) was stirred at 100℃ for 2 h under Ar. After adjusting the pH to 8-9 with sat. NaHCO ₃ (aq. ) , the mixture was extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by Prep-TLC (PE: EA=1: 1) to give 359 mg of title compound as a yellow solid. MS (ES+) : 416 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.36 (s, 1H) , 8.47 (s, 1H) , 8.24 (d, J = 7.4 Hz, 1H) , 7.80 (s, 1H) , 7.55 –7.43 (m, 3H) , 7.31 (t, J = 7.5 Hz, 2H) , 7.21 (m, 2H) , 5.23 (m, 1H) , 5.11 (t, J = 5.7 Hz, 1H) , 3.90 –3.80 (m, 1H) , 3.69 (m, 1H) , 1.42 (s, 6H) .

EXAMPLE 66

(S) -6- ( (4- ( (2-hydroxy-1-phenylethyl) amino) -5- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyrimidin-2-yl) amino) -2, 2-dimethylbenzofuran-3 (2H) -one

Step 1 (S) -2- ( (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-yl) amino) -N-hydroxy-4- ( (2-hydroxy -1-phenylethyl) amino) pyrimidine-5-carboximidamide

To a stirred solution of Example 65 (335 mg) in n-BuOH (8.9 mL) were added hydroxylamine hydrochloride (169 mg) and DIEA (625 mg) at rt. The mixture was stirred at 80℃ for 2 h under Ar, and was then treated with water, extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by slurry with PE to give 286 mg of title compound as a yellow solid. MS (ES+) : 449 [M+1] ⁺.

Step 2 (S) -2- ( (2- ( (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-yl) amino) -5- (5-methyl -1, 2, 4-oxadiazol-3-yl) pyrimidin-4-yl) amino) -2-phenylethyl acetate

To a stirred solution of (S) -2- ( (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-yl) amino) -N-hydroxy-4- ( (2-hydroxy-1-phenylethyl) amino) pyrimidine-5-carboximidamide (110 mg) in AcOH (5.5 mL) was added acetic anhydride (1.1 mL) at rt. The mixture was stirred at 120℃ for 1 h under Ar. After adjusting the pH to 8-9 with sat. NaHCO ₃ (aq. ) , the mixture was extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated to give 93 mg of title compound as a yellow solid. MS (ES+) : 515 [M+1] ⁺.

Step 5 (S) -6- ( (4- ( (2-hydroxy-1-phenylethyl) amino) -5- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyrimidin-2-yl) amino) -2, 2-dimethylbenzofuran-3 (2H) -one

To a stirred solution of (S) -2- ( (2- ( (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-yl) amino) -5- (5-methyl-1, 2, 4-oxadiazol-3-yl) pyrimidin-4-yl) amino) -2-phenylethyl acetate (93 mg) in MeOH/H ₂O (9 mL, 4: 1) was added Lithium hydroxide monohydrate (22.5 mg) at rt. The mixture was stirred at rt for 1 h, and was then treated with water, extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by Prep-TLC (EA: PE=2: 1) to give 26 mg of title compound as a yellow solid. MS (ES+) : 473.1 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.25 (s, 1H) , 8.77 (s, 1H) , 8.33 (d, J = 7.1 Hz, 1H) , 7.80 (d, J = 1.7 Hz, 1H) , 7.43 (dd, J =9.4, 7.9 Hz, 3H) , 7.31 (t, J = 7.5 Hz, 2H) , 7.27 –7.15 (m, 2H) , 5.33 (m, 1H) , 5.28 (t, J = 5.0 Hz, 1H) , 3.90 (m, 1H) , 3.73 (m, 1H) , 2.71 (s, 3H) , 1.42 (s, 6H) .

EXAMPLE 67

2, 2-dimethyl-6- (5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -4- (pyridin-3-ylmethylamino) pyrimidin-2-ylamino) benzofuran-3 (2H) -one

Step 1 ethyl 2-chloro-4- (methylthio) pyrimidine-5-carboxylate

To a stirred solution of ethyl2, 4-dichloropyrimidine-5-carboxylate (30 g) and benzyltriethylammonium chloride (310 mg) in THF (450 mL) was added NaSMe (10.3 g) at -10 ℃ under Ar. The mixture was stirred at -10 ℃ for 3 h, and was then treated with water, extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by slurry with MTBE/PE (60 mL/120 mL) to give 10.6 g of the title compound as a yellow solid. MS (ES+) : 233.0 [M+1] ⁺.

Step 2 ethyl 2- (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-ylamino) -4- (methylthio) pyrimidine-5-carboxylate

The mixture of ethyl 2-chloro-4- (methylthio) pyrimidine-5-carboxylate (3 g) , TsOH. H ₂O (2.2 g) and 6-amino-2, 2-dimethylbenzofuran-3 (2H) -one (1.68 g) in 1.4-dioxane (30 mL) was stirred at 100 ℃ for 3 h, and was then treated with water. The resulting precipitate was filtered, dried to give 4.5 g of title compound as a yellow solid. MS (ES+) : 374.0 [M+1] ⁺.

Step 3 2- (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-ylamino) -4- (methylthio) pyrimidine-5-carboxylic acid

A mixture of ethyl2- (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-ylamino) -4- (methylthio) pyrimidine-5-carboxylate (3.5 g) and LiOH. H ₂O (1.2 g) in MeOH/H ₂O (35 mL/8.8 mL) was stirred at 60 ℃ for 3 h. After adjusting the pH to 1 with 1N HCl (aq. ) , the mixture was filtered. The filter cake was dissolved in THF, dried over anhydrous Na ₂SO ₄, filtered and concentrated to give 6 g of title compound as a yellow solid. MS (ES+) : 346.0 [M+1] ⁺.

Step 4 N- (2- (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-ylamino) -4- (methylthio) pyrimidine-5-carbonyloxy) acetimidamide

To a stirred solution of 2- (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-ylamino) -4- (methylthio) pyrimidine-5-carboxylic acid (6 g) in DMF (300 mL) were added HOBT (7.4 g) and EDCI (10 g) at 5℃ under Ar. The mixture was stirred at 5℃ for 0.5 h, and then N-hydroxyacetimidamide (2.3 g) was added at 5℃. The mixture was stirred at 5℃ for 1 h, and was then treated with water. The resulting precipitate was filtered, and was then dried to give 2.3 g of the title compound as a yellow solid. MS (ES+) : 402.1 [M+1] ⁺.

Step 5 2, 2-dimethyl-6- (5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -4- (methylthio) pyrimidin-2-ylamino) benzofuran-3 (2H) -one

A mixture of N- (2- (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-ylamino) -4- (methylthio) pyrimidine-5-carbonyloxy) acetimidamide (1 g) in toluene (100 mL) was stirred at 120 ℃ for 36 h, and was then concentrated to give 1 g of title compound as a yellow solid. MS (ES+) : 384.0 [M+1] ⁺.

Step 6 2, 2-dimethyl-6- (5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -4- (methylsulfinyl) pyrimidin-2-ylamino) benzofuran-3 (2H) -one

To a stirred solution of 2, 2-dimethyl-6- (5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -4- (methylthio) pyrimidin-2-ylamino) benzofuran-3 (2H) -one (1 g) in NMP (100 mL) was added m-CPBA (1.4 g) at 5℃ under Ar. The mixture was stirred at rt for 1 h, and was then treated with water, extracted with EA. The organic layer was washed with 5%NaHSO ₃ (aq. ) , water and brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated to give 1.3 g of title compound as a yellow solid. MS (ES+) : 400.0 [M+1] ⁺.

Step 7 2, 2-dimethyl-6- (5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -4- (pyridin-3-ylmethylamino) pyrimidin-2-ylamino) benzofuran-3 (2H) -one

To a stirred solution of 2, 2-dimethyl-6- (5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -4- (methylsulfinyl) pyrimidin-2-ylamino) benzofuran-3 (2H) -one (120 mg) and pyridin-3-ylmethanamine (49 mg) in NMP (6 mL) was added DIEA (77 mg) at rt under Ar. The mixture was stirred at 80℃ for 0.5 h, and was then treated with water, extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by Prep-TLC (MeOH/DCM=4%) to give 8.8 mg of the title compound as a white solid. MS (ES+) : 444.1 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.44 (s, 1H) , 8.82 (m, 2H) , 8.63 (s, 1H) , 8.45 (s, 1H) , 7.86 –7.70 (m, 2H) , 7.46 (d, J = 8.5 Hz, 1H) , 7.33 (m, 2H) , 4.90 (s, 2H) , 2.43 (s, 3H) , 1.37 (s, 6H) .

EXAMPLE 68

2, 2-dimethyl-6- (5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -4- (thiazol-2-ylmethylamino) pyrimidin-2-ylamino) benzofuran-3 (2H) -one

The title compound was synthesized using the same procedures as described in Example 67. MS (ES+) : 450.0 [M+1] ⁺. ¹H NMR (400 MHz, DMSO-d ₆) δ 10.49 (s, 1H) , 8.98 (t, J = 6.0 Hz, 1H) , 8.86 (s, 1H) , 7.77 (d, J = 3.2 Hz, 1H) , 7.68 (s, 1H) , 7.61 (d, J = 3.2 Hz, 1H) , 7.46 (d, J = 8.6 Hz, 1H) , 7.37 (d, J = 8.6 Hz, 1H) , 5.16 (d, J = 5.9 Hz, 2H) , 2.44 (s, 3H) , 1.37 (s, 6H) .

EXAMPLE 69

(S) -2- (2- (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-ylamino) -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-ylamino) -2-phenylacetic acid

Step 1 (S) -tert-butyl 2- (2- (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-ylamino) -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-ylamino) -2-phenylacetate

The title compound was synthesized using the same procedures as described in Example 67. MS (ES+) : 543.1 [M+1] ⁺.

Step 2 (S) -2- (2- (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-ylamino) -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-ylamino) -2-phenylacetic acid

A mixture of (S) -tert-butyl2- (2- (2, 2-dimethyl-3-oxo-2, 3-dihydrobenzofuran-6-ylamino) -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4-ylamino) -2-phenylacetate (174 mg) in DCM (8.5 mL) and TFA (11 mL) was stirred at rt for 4 h. The mixture was concentrated, and was then treated with water, extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by Prep-HPLC (Column: Green ODS-A, 21.2 x 250mm, 10um; Mobile A: water with 0.05%HCOOH, Mobile B: CH ₃CN; Gradient: 40%B over 2 min, 55%B over 15 min; Flow: 35 mL/min) to give 24 mg of the title compound as a white solid. MS (ES+) : 487.0 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.48 (s, 1H) , 9.40 (d, J = 6.4 Hz, 1H) , 8.84 (s, 1H) , 7.80 (d, J = 1.7 Hz, 1H) , 7.60 –7.47 (m, 3H) , 7.42 –7.21 (m, 4H) , 5.80 (d, J = 6.3 Hz, 1H) , 2.46 (s, 3H) , 1.43 (d, J = 2.7 Hz, 6H) .

EXAMPLE 70

1-acetyl-6- (4- ( (S) -2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -2-methylindolin-3-one

Step 1 4-bromo-2- (1-carboxyethylamino) benzoic acid

To a stirred solution of 2-amino-4-bromobenzoic acid (10 g) in MeOH (100 mL) and water (100 mL) were added methyl2-bromopropanoate (30 g) and K ₂CO ₃ (24.9 g) . The mixture was stirred at 100 ℃ for 53 h. Then NaOH (1.85 g) was added at rt, and was then stirred at 100℃ for 2 h. After adjusting the pH to 5 with 1N HCl (aq. ) , the mixture was filtered. The precipitate was dissolved in EA, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel column chromatography (EA: PE=20%～100%) to give 6.5 g of the title compound as a yellow solid. MS (ES+) : 288 [M+1] ⁺.

Step 2 1-acetyl-6-bromo-2-methyl-1H-indol-3-yl acetate

To a stirred solution of 4-bromo-2- (1-carboxyethylamino) benzoic acid (4 g) in acetic anhydride (56 g) was added NaOAc (3.6 g) . The mixture was stirred at 150 ℃ for 1 h under the pressure tank. After adjusting the pH to >7 with sat. NaHCO ₃ (aq. ) , the mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica-gel column chromatography (PE: EA=15: 1～9: 1) to give 1.7 g of the title compound as a yellow solid. MS (ES+) : 310 [M+1] ⁺.

Step 3 1-acetyl-6-bromo-2-methylindolin-3-one

To a stirred solution of 1-acetyl-6-bromo-2-methyl-1H-indol-3-yl acetate (1.5 g) in EtOH (150 mL) and water (150 mL) was added Na ₂SO ₃ (732 mg) . The mixture was stirred at 60 ℃ for 2 h under Ar. The solvent was removed in vacuum; the mixture was extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica-gel column chromatography (EA: PE=10%～20%) to give 630 mg of the title compound as a yellow solid. MS (ES+) : 268 [M+1] ⁺.

Step 4 tert-butyl 1-acetyl-2-methyl-3-oxoindolin-6-ylcarbamate

To a stirred solution of 1-acetyl-6-bromo-2-methylindolin-3-one (580 mg) in 1, 4-dioxane (17 mL) were added tert-butyl carbamate (760 mg) , Cs ₂CO ₃ (1.41 g) , Xant-phos (250 mg) and Pd ₂ (dba) ₃ (198 mg) at rt. The mixture was stirred at 100 ℃ for 2 h under Ar, and was then treated with water, extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica-gel column chromatography (EA: PE=10%～25%) to give 450 mg of the title compound as a yellow solid. MS (ES+) : 305.0 [M+1] ⁺.

Step 5 1-acetyl-6-amino-2-methylindolin-3-one

A mixture of tert-butyl 1-acetyl-2-methyl-3-oxoindolin-6-ylcarbamate (450 mg) in TFA/DCM (1: 1, 18 mL) was stirred at rt for 1 h, and was then concentrated in vacuum. After adjusting the pH to >7 with sat. NaHCO ₃ (aq. ) , extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated to give 210 mg of title compound as a yellow solid. MS (ES+) : 205.0 [M+1] ⁺.

Step 6 1-acetyl-6- (4- ( (S) -2-hydroxy-1-phenylethylamino) -5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-2-ylamino) -2-methylindolin-3-one

To a solution of (S) -2- (2-chloro-5- (1, 3, 4-oxadiazol-2-yl) pyrimidin-4-ylamino) -2-phenylethanol (98 mg) in 1, 4-dioxane (15 mL) were added 1-acetyl-6-amino-2-methylindolin-3-one (190 mg) , Cs ₂CO ₃ (201 mg) , X-phos (29 mg) and Pd ₂ (dba) ₃ (28 mg) at rt. The mixture was stirred at 100 ℃ for 2 h under Ar, and was then diluted with EA, filtered and concentrated. The residue was purified by Prep-TLC (EA) to give 19.4 mg of the title compound as a yellow solid. MS (ES+) : 486.1 [M+1] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 10.33 (s, 1H) , 9.37 (s, 1H) , 8.98 (m, 2H) , 8.69 (d, J = 1.0 Hz, 1H) , 7.66 –7.50 (m, 2H) , 7.47 –7.17 (m, 5H) , 5.64 (m, 1H) , 5.26 –5.09 (m, 1H) , 4.57 (d, J = 7.4 Hz, 1H) , 3.99 –3.88 (m, 1H) , 3.80 (m, 1H) , 2.36 (d, J = 4.1 Hz, 3H) , 1.46 (dd, J = 9.6, 7.0 Hz, 3H) .

Claims

A compound of Formula I or a pharmaceutically acceptable salt thereof:

Wherein

is

X is N or CH;

Y and Z are independently N, CR ⁴;

Z ¹ is N or CR ³;

R ¹ is selected from the group consisting of CO ₂H, CO ₂ (C _1-6alkyl) , cyano, C _1-6alkyl, C _3-6cycloalkyl, C _1-6alkoxy, -SC _1-6alkylC _3- ₆cycloalkyloxy, -C≡C-R ⁹, -CH=CHR ⁹, -C (O) NR ^aR ^b, S (O) ₂R ^a, -S (O) (NCN) R ^a, -P (O) R ^aR ^b, -P (O) (OR ^a) (OR ^b) , -NR ^cC (O) NR ^a ₂, -NR ^cS (O) ₂NR ^a ₂, -NR ^cS (O) ₂R ^a, -NR ^aR ^b, -NR ^aC (O) OR ^a, -S (O) ₂NR ^aR ^b, -NR ^cS (O) ₂NR ^aR ^b, -C (O) R ^a, C (O) NHNH ₂, -C (O) NHNHC (O) R ^a, -C (O) NHNHC (=NCH ₂CH ₃ (NH (CH ₂) _2-4N (CH ₃) ₂) , 1, 8-dioxa-3-azaspiro [4.5] dec-2-enyl, -C _1-6heteroalkyl, 5-10-membered heteroaryl, 3-10-membered heterocyclyl, or heterocyclylalkyl; each R ¹ is substituted with zero to 3 R ¹⁰;

R ² is -C _1-6alkyl, -C _2-6alkenyl, -C _2-6alkynyl, -C _0-10alkylene-C ₃- ₁₀cycloalkyl, -C _4-10cycloalkenyl, -C _0-10alkylene-3-10-membered heterocyclyl, -C _0-10alkylene-C _6-10aryl, -C _0-10alkylene-5-10-membered heteroaryl, -CHR ^d (CH ₂) _nR ^e, -CHR ^dC (OH) (R ^c) ₂, -CHR ^dC (NR ^aR ^b) (R ^c) ₂, -CHR ^d (CH ₂) _nC (OH) (R ^c) ₂, -CHR ^d (CH ₂) _nC (NR ^aR ^b) (R ^c) ₂, - (CH ₂) _mNR ^c (CH ₂) _mNR ^aR ^b, - (CH ₂) _nC (O) R ^c, - (CH ₂) _nNR ^aR ^b , - (CH ₂) _nC (O) NR ^aR ^b; R ² is substituted with zero to 3 R ¹⁰;

n is 0, 1, 2 or 3;

m is independently 0, 1, 2 or 3;

R ^a, R ^b and R ^c are independently hydrogen, -C _1-6alkyl, -C _1-6haloalkyl, -C _2-6alkenyl, -C _2-6alkynyl, -C ₃- ₁₀cycloalkyl, -C _4- ₁₀cycloalkenyl, -3-10-membered heterocyclyl, -C _6-10aryl, -5-10-membered heteroaryl, R ^a and R ^b or R ^b and R ^c are taken together with the atom (s) to which they are attached to form an optionally substituted 4-10 membered carbocyclyl, or heterocyclyl which contains 0-3 heteroatoms and is optionally substitute with 0-5 occurrences of R ¹⁰; R ^a, R ^b and R ^c are independently substituted with 0-5 occurrences of R ¹⁰;

R ^d is -C _3-6cycloalkyl, oxadiazolyl, oxazolyl, oxetanyl, phenyl, pyrazolyl, pyrazolo [l, 5-a] pyridinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, tetrahydropyrido [3, 4-d] pyrimidinyl, or thiazolyl; R ^d is substituted with zero to three R ¹⁰;

R ^e is independently selected from H, -OH, -CN, -C _1-6alkyl, -C _1-6haloalkyl, -C _1-3hydroxyalkyl, -CH ₂OCH ₃, -CH ₂OCF ₃, -CH ₂NR ^aR ^b, -CH ₂S (C _1-3alkyl) , or -CH ₂C (O) NR ^aR ^b;

R ³ and R ⁴ are independently selected from H, CH _3, CF ₃, CN or halo;

R ⁹ is H, -C _1-6alkyl, -C _2-6haloalkyl, -CO ₂R ^a, -C (O) NR ^aR ^b, -C _0-10alkylene-C _6-10aryl, -C _0-10alkylene-5-10-membered heteroaryl; R ⁹ is substituted with zero to three R ¹⁰;

R ¹⁰ is independently selected from C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxyl, C _1-6alkoxy, halo, hydroxy, oxo, amino, C _0- ₆alkylene-R ^c, C _0-6alkylene-NR ^bR ^c, C _0-6alkylene-NR ^bR ^c, C _0-6alkylene-C (O) NR ^aR ^b, C _0-6alkylene-NR ^cC (O) R ^b, C _0-6alkylene-S (O) ₂R ^b, C _0-6alkylene-S (O) ₂NR ^aR ^b, C _0-6alkylene-NR ^cS (O) ₂R ^b, C _0-6alkylene-NR ^cS (O) ₂NR ^aR ^b, C _0-6alkylene-P (O) R ^aR ^b, C _0- ₆alkylene-P (O) (OR ^a) (OR ^b) , C _0-6alkylene-cyano, C _0-6alkylene-C _3-8 cycloalkyl, C _0-6alkylene-5-10 membered heterocyclyl, C _0- ₆alkylene-C _6-10aryl, C _0-6alkylene-5-10 membered heteroaryl, C _2-6hydroxyalkyl, C _2-4hydroxy-fluoroalkyl, -S (C _1-2 alkyl) , azabicyclo [2.2.2] octanyl, fluoroazabicyclo [2.2.2] octanyl, aminobicyclo [1.1.1] pentanyl, dimethylaminobicyclo [1.1.1] pentanyl, acetamidobicyclo [1.1.1] pentanyl and (methoxycarbonyl) aminobicyclo [1.1.1] pentanyl; R ¹⁰ is substituted with zero to two substituents independently selected halogen, -CN, CF ₃, C (C _0-6alkyl) ₂OH; two adjacent R ¹⁰ are taken together with the atom (s) to which they are attached to form an optionally substituted 5-10 membered carbocyclyl or 5-10 membered heterocyclyl;

is selected from the following moieties:

R ⁵ and R ⁶ are independently selected from H, -C _1-6alkyl or -OC _1-6alkyl; R ⁵ and R ⁶ together with the carbon atom to which they are attached may form an optionally substituted 3-10 membered carbocyclyl, or 4-10 membered heterocyclyl which contains 1-3 heteroatoms and is optionally substitute with 0-5 occurrences of R ¹⁰;

L is O, S, NR ^c or absent

is a 4-8 membered heterocyclyl which contains a heteroatom V ^a;

V and V ^a are independently selected from O, S or NR ⁷;

W is OCR ^5aR ^6a, CR ^5aR ^6aO, NR ⁷CR ^5aR ^5b, CR ^5aR ^6aNR ⁷, (CR ^5aR ^6a) _t, SCR ^5aR ^6a or CR ^5aR ^6aS;

W ¹ is O, S or NR ⁷;

W ³-W ² may also be NR ⁷CR ⁸=CR ⁹, NR ⁷CR ⁸=N-

R ^5a and R ^6a are independently selected from H, -C _1-6alkyl or -OC _1-6alkyl; R ^5a and R ^6a together with the carbon atom to which they are attached may form an optionally substituted 3-10 membered carbocyclyl, or 4-10 membered heterocyclyl which contains 1-3 heteroatoms and is optionally substituted with 0-5 occurrences of R ¹⁰;

R ⁷, R ⁸ and R ⁹ are independently selected from H, -C _1-6alkyl, -C _1-6haloalkyl, -C _0-10alkylene-C _6-10aryl, -C _0-10alkylene-C _6- ₁₀cycloalkyl, -C _0-10alkylene-5-10-membered heteroaryl, with the proviso that R ⁷ and R ⁸ are not H or CH ₃ when L is absent;

R ⁷ and R ⁸ can be taken together with the atom (s) to which they are attached to form an optionally substituted 5-10 membered carbocyclyl or 5-10 membered heterocyclyl;

t is 2 or 3.
A compound of Formula II or a pharmaceutically acceptable salt thereof:

R ¹, R ², R ⁵, R ⁶, X, Y, Z and Z ¹ are defined as for Formula I;

W is OCR ^5aR ^6a, CR ^5aR ^6aO, NR ⁷CR ^5aR ^6a, CR ^5aR ^6aNR ⁷, (CR ^5aR ^6a) _t, SCR ^5aR ^6a or CR ^5aR ^6aS;

R ^5a and R ^6a are independently selected from H, -C _1-6alkyl or -OC _1-6alkyl; R ^5a and R ^6a together with the carbon atom to which they are attached may form an optionally substituted 3-10 membered carbocyclyl, or 4-10 membered heterocyclyl which contains 1-3 heteroatoms and is optionally substituted with 0-5 occurrences of R ¹⁰;

R ¹⁰ is defined as in Formula I;

t is 1, 2 or 3.
A compound of Formula III or a pharmaceutically acceptable salt thereof:

R ¹, R ², R ³, R ⁵, R ⁶, X, Y and Z are defined as for Formula I.
A compound of Formula IV or a pharmaceutically acceptable salt thereof:

R ¹, R ², R ³, R ⁵, R ⁶, R ⁷, X, Y and Z are defined as for Formula I.
A compound of Formula V or a pharmaceutically acceptable salt thereof:

R ¹, R ², R ³, R ⁵, R ^5a, R ^5b, R ⁶, R ⁷, X, Y and Z are defined as for Formula I.
A compound of Formula VI or a pharmaceutically acceptable salt thereof:

R ¹, R ², R ³, R ⁷, R ⁸, X, Y and Z are defined as for Formula I; L is O, NR ^c; R ⁷ and R8 may form an optionally substituted 4-6 membered heterocyclyl.
A compound of Formula VII and VII, or a pharmaceutically acceptable salt thereof:

R ¹, R ², R ³, R ⁷, X, Y and Z are defined as for Formula I.
A compound of Formula IX or a pharmaceutically acceptable salt thereof:

R ¹, R ², R ³, R ⁷, R ⁸, X, Y and Z are defined as for Formula I.
A compound of Formula VI or a pharmaceutically acceptable salt thereof:

R ¹, R ², R ³, R ⁷, R ⁸, X, Y and Z are defined as for Formula I.
A compound of Formula XI or a pharmaceutically acceptable salt thereof:

R ¹, R ², R ³, X, Y and Z are defined as for Formula I; j and k are independently 1 or 2.
A compound of Formula XII or a pharmaceutically acceptable salt thereof:

R ¹, R ², R ³, R ⁵, R ⁶, R ⁷, X, Y and Z are defined as for Formula I;

R ⁵, R ⁶, R ^5a and R ^6a are independently selected from H, -C _1-6alkyl or -OC _1-6alkyl; R ^5a and R ^6a, or R ⁵ and R ⁶ together with the carbon atom to which they are attached may form an optionally substituted 3-10 membered carbocyclyl, or 4-10 membered heterocyclyl which contains 1-3 heteroatoms and is optionally substituted with 0-5 occurrences of R ¹⁰;

R ¹⁰ is defined as in Formula I;

W ^2a is O, CR ^5aR ^6a, S or NR ⁷.
A compound of Formula XIII or a pharmaceutically acceptable salt thereof:

R ¹, R ², R ³, R ⁵, R ⁶, R ⁷, X, Y, Z ¹ and Z are defined as for Formula I;

R ⁵, R ⁶, R ^5a and R ^6a are independently selected from H, -C _1-6alkyl or -OC _1-6alkyl; R ^5a and R ^6a, or R ⁵ and R ⁶ together with the carbon atom to which they are attached may form an optionally substituted 3-10 membered carbocyclyl, or 4-10 membered heterocyclyl which contains 1-3 heteroatoms and is optionally substituted with 0-5 occurrences of R ¹⁰;

R ¹⁰ is defined as in Formula I;

W ¹ is O, CR ^5aR ^6a, S or NR ⁷.
A compound of Formula XIV or a pharmaceutically acceptable salt thereof:

R ¹, R ², R ³, R ⁵, R ⁶, R ⁷, X, Y, Z ¹ and Z are defined as for Formula I;

R ⁵, R ⁶, R ^5a and R ^6a are independently selected from H, -C _1-6alkyl or -OC _1-6alkyl; R ^5a and R ^6a, or R ⁵ and R ⁶ together with the carbon atom to which they are attached may form an optionally substituted 3-10 membered carbocyclyl, or 4-10 membered heterocyclyl which contains 1-3 heteroatoms and is optionally substituted with 0-5 occurrences of R ¹⁰;

R ¹⁰ is defined as in Formula I;

W ¹ is O, CR ^5aR ^6a, S or NR ⁷.
A compound of Formula XV or a pharmaceutically acceptable salt thereof:

R ¹, R ², R ³, R ⁷, R ⁸, R ⁹, X, Y, Z ¹ and Z are defined as for Formula I. R ⁷ and R ⁸ can be taken together with the atoms to which they are attached to form an optionally substituted 5-10 membered carbocyclyl or 5-10 membered heterocyclyl; R ⁸ and R ⁹ can be taken together with the atoms to which they are attached to form an optionally substituted 5-10 membered carbocyclyl or 5-10 membered heterocyclyl.
A compound of Formula XVI or a pharmaceutically acceptable salt thereof:

R ¹, R ², R ³, R ⁷, R ⁸, R ⁹, X, Y, Z ¹ and Z are defined as for Formula I. R ⁷ and R ⁸ can be taken together with the atom (s) to which they are attached to form an optionally substituted 5-10 membered carbocyclyl or 5-10 membered heterocyclyl.
According to Claim 1 to 15, a compound is selected from those described in Description of the Invention.
A ester or amide prodrug of a compound of Claims 1-17.
A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound or pharmaceutically acceptable salt thereof according to any of Claims 1-17.
A method for treating a condition mediated by HPK1 or overexpressed HPK1, comprising administering a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof according to any of Claims 1-17 or a pharmaceutical composition of Claim 8 to a subject in need.
A method of treating cancer, wherein the method comprising administering to a subject a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof according to any of Claims 1-17 or the pharmaceutical composition of Claim 8.
The method of Claim 10, wherein the cancer includes, but not limited to, lung cancer, breast cancer, ovarian cancer, prostate cancer, liver cancer, gastric cancer, esophageal cancer, pancreatic cancer, colon cancer, kidney cancer, head and neck cancer, bladder cancer, and/or a sarcoma.
A method of conditioning adoptive cell transfer therapy, wherein the method comprising treating engineered (such as CAR-T cells) or non-engineered T cells or other immune cells with the compound or pharmaceutically acceptable salt thereof according to any of claims 1-17 in adoptive cell transfer therapy before the T cells or immune cells are given back to patients.
The pharmaceutical composition of Claim 1-17 wherein the pharmaceutical composition further comprises one or more antineoplastic agents, wherein the antineoplastic agents include IDO inhibitors, EP2 and/or EP4 antagonists, angiogenesis inhibitors, ACAT1 inhibitors, cell proliferation and survival signal inhibitors, apoptosis inducers and agents, chemotherapies, target therapies, other kinase inhibitors, RNAi therapy, antisense therapy, vaccines, and immunotherapies including adoptive cell transfer therapy such as CAR-T therapy and antibodies such as CTLA4, PD-1/PD-L1, LAG-3, TIGIT, TIM-3 antibody, and the combination thereof.