Alkynyl quinazoline compound

Abstract

The invention relates to alkynyl quinazoline compounds. The present disclosure relates to compounds of Formula (I ') and pharmaceutically acceptable salts and stereoisomers thereof. The present disclosure also relates to methods of making these compounds, compositions comprising these compounds, and methods of using the same to prevent or treat abnormal cell growth in mammals, especially humans. # imgabs0 #

Description

[0001] This application is a divisional application of the invention patent application with application number 202080072199.2, application date August 14, 2020, and invention name “Alkynylquinazoline Compounds”.

[0002] Related applications

[0003] This application claims priority to and the benefit of U.S. Application No. 63 / 065,028, filed on August 13, 2020, and U.S. Application No. 62 / 887,392, filed on August 15, 2019, the entire contents of which are incorporated herein by reference. Technical Field

[0004] The present disclosure relates to novel compounds that are inhibitors of receptor tyrosine kinases (RTKs), in particular oncogenic mutants of ErbB receptors. The present disclosure also relates to methods of preparing these compounds, compositions comprising these compounds, and methods of using them to prevent or treat abnormal cell growth in mammals, particularly humans. Background Art

[0005] Mutations that affect the intracellular catalytic domain or the extracellular ligand binding domain of ErbB receptors may produce oncogenic activity (the ErbB protein family consists of four members, including ErbB-1, also known as epidermal growth factor receptor (EGFR) and Erb-2, also known as HER2 in humans). ErbB inhibitors are known treatments for a variety of cancers. However, not every patient responds satisfactorily to such treatments. Therefore, there has long been a need in the art for new therapies that can address the variable responsiveness of cancer patients to known therapies. The present disclosure provides compositions and methods for preventing or treating cancer in patients with these oncogenic mutations, where no variable responsiveness is observed when treating patients with these ErbB mutants using existing standards of care. Summary of the Invention

[0006] In some aspects, the present disclosure provides a compound of formula (I'):

[0007]

[0008] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0009] W is CH or N;

[0010] Z is optionally replaced by one or more R Z substituted 3- to 12-membered heterocycloalkyl;

[0011] Each R Zare independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3 to 10 membered heterocycloalkyl or 5 to 10 membered heteroaryl; wherein said -O-(C1-C6 alkyl), said -NH(C1-C6 alkyl), said -N(C1-C6 alkyl)2, said C1-C6 alkyl, said C2-C6 alkenyl, said C2-C6 alkynyl, said C3-C 10 Cycloalkyl, the C6-C 10 The aryl group, the 3 to 10 membered heterocycloalkyl group or the 5 to 10 membered heteroaryl group are optionally substituted by one or more R Za replace;

[0012] Each R Za are independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl;

[0013] T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein said -O-(C1-C6 alkyl), said -NH-(C1-C6 alkyl), said C1-C6 alkyl, said C2-C6 alkenyl or said C2-C6 alkynyl is optionally replaced by one or more R T replace;

[0014] Each R T are independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3 to 10 membered heterocycloalkyl or 5 to 10 membered heteroaryl; wherein said -O-(C1-C6 alkyl), said -NH(C1-C6 alkyl), said -N(C1-C6 alkyl)2, said C1-C6 alkyl, said C2-C6 alkenyl, said C2-C6 alkynyl, said C3-C 10 Cycloalkyl, the C6-C 10 The aryl group, the 3 to 10 membered heterocycloalkyl group or the 5 to 10 membered heteroaryl group are optionally substituted by one or more RTa replace;

[0015] Each R Ta are independently halogen, CN, -OH, -NH2, -C(=O)OH, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl;

[0016] Ar 1 is optionally replaced by one or more R A1 Substituted C6-C 10 aryl;

[0017] Each R A1 are independently halogen, CN, -OH, -NH2, -OR A1a , -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3 to 10 membered heterocycloalkyl or 5 to 10 membered heteroaryl; wherein said -O-(C1-C6 alkyl), said -NH(C1-C6 alkyl), said -N(C1-C6 alkyl)2, said C1-C6 alkyl, said C2-C6 alkenyl, said C2-C6 alkynyl, said C3-C 10 Cycloalkyl, the C6-C 10 The aryl group, the 3 to 10 membered heterocycloalkyl group or the 5 to 10 membered heteroaryl group are optionally substituted by one or more R A1a replace; and

[0018] Each R A1a are independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3 to 10 membered heterocycloalkyl or 5 to 10 membered heteroaryl; wherein said -O-(C1-C6 alkyl), said -NH(C1-C6 alkyl), said -N(C1-C6 alkyl)2, said C1-C6 alkyl, said C2-C6 alkenyl, said C2-C6 alkynyl, said C3-C 10 Cycloalkyl, the C6-C 10The aryl group, the 3 to 10 membered heterocycloalkyl group or the 5 to 10 membered heteroaryl group are optionally substituted by one or more R A1b replace; and

[0019] Each R A1b are independently halogen, CN, -OH or -NH2.

[0020] In some aspects, the present disclosure provides a compound having Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0021]

[0022] in

[0023] W is CH or N, preferably CH;

[0024] X 1 Is -O-, -S-, or -NR 3 -;

[0025] R a 、R b independently of each other are hydrogen, 1-4 Alkyl, or R a One of the is if X 1 It is NR 3 , then with X 1 Ring-forming -(CH2) p , or R a One of them is with R 2 Ring-forming -(CH2) p ;

[0026] R c 、R d are independently hydrogen or C 1-4 alkyl;

[0027] R 1 is H or F;

[0028] R 2 is hydrogen or C 1-4 Alkyl, or with R 3 or with R a One of the ring-forming -(CH2) q ;

[0029] R 3 is hydrogen or C 1-4 Alkyl, preferably hydrogen or methyl, or with R 2 Ring-forming -(CH2) p -;

[0030] m is 1, 2, or 3;

[0031] n is 0, 1, or 2;

[0032] p is 1 or 2;

[0033] q is 0, 1, or 2; and

[0034] Ar 1 is a 6-membered aryl group which is unsubstituted or substituted by one or more of the following groups: halogen, -CF3, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy-C6 aryl, C 1-6 Alkoxy-C 5-6 Heteroaryl, amino, amino C 1-4 Alkyl, C 1-6 Alkylamino, C 1-6 Aminoalkyl-C6 aryl, C 1-6 aminoalkyl-C 5-6 Heteroaryl, C 1-6 Alkoxycarbonyl, C 1-6 Alkoxyaminocarbonyl, aryl C 1-6 Alkoxy or C6 aryl.

[0035] In some embodiments, when X 1 Yes-NR 3 -, R 2 Not hydrogen.

[0036] In some embodiments, when X 1 Yes-NR 3 -, R 2 It is C 1-4 Alkyl, or with R 3 or with R a One of the ring-forming -(CH2) q -.

[0037] In some embodiments, X 1 Yes-NR 3 -, and R 2 Not hydrogen.

[0038] In some embodiments, X 1 Yes-NR 3 -, and R 2 It is C 1-4 Alkyl, or with R 3 or with R a One of the ring-forming -(CH2) q -.

[0039] In some embodiments, X 1 It is NR 3 or O and where R 3 It is methyl, ethyl, n-propyl or n-butyl.

[0040] In some embodiments, R 1 It's hydrogen.

[0041] In some embodiments, R 2 is methyl, ethyl, n-propyl or n-butyl, preferably methyl or R 2 is with R 3 -(CH2)- or -(CH2)2 forming a ring, or R 2 is with R a One of them forms a -(CH2)- or -(CH2)2 ring.

[0042] In which R a One of the R 3 In some embodiments where a ring is formed, the formed ring is a 4-, 5-, or 6-membered ring, or a 5- or 6-membered ring, or a 5-membered ring.

[0043] In which R a One of the 3 In some embodiments where a ring is formed, the formed ring is a 3-membered, 4-membered, 5-membered, or 6-membered ring.

[0044] In which R 2 One of the R 3 In some embodiments where a ring is formed, the formed ring is a 4-, 5-, or 6-membered ring, or a 5- or 6-membered ring, or a 6-membered ring.

[0045] In some embodiments, Ar 1 having formula I or a pharmaceutically acceptable salt or stereoisomer thereof,

[0046]

[0047] in

[0048] R 4 It is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy-C6 aryl, C 1-6 Alkoxy-C 5-6 Heteroaryl, amino C 1-4 Alkyl, C 1-6Alkylamino, C 1-6 Aminoalkyl-C6 aryl, C 1-6 aminoalkyl-C 5-6 Heteroaryl, C 1-6 Alkoxycarbonyl, C 1-6 Alkoxyamino-carbonyl, aryl C 1-6 Alkoxy or C6 aryl;

[0049] R 5 、R 5 '、R 6 、R 6 ' are independently hydrogen, -CF3 or halogen, preferably F, Cl.

[0050] In some embodiments, R 1 It's hydrogen.

[0051] In some embodiments, R c and R d is hydrogen. In some embodiments, R b 、R c and R d It's hydrogen.

[0052] In some embodiments, R 2 is methyl or R 2 is with R 3 -(CH2)- or -(CH2)2- forming a ring, or R 2 is with R a One of them forms a -(CH2)- or -(CH2)2- ring.

[0053] In some embodiments, Ar 1 having formula ii-1, ii-2, ii-3 or ii-4 or a pharmaceutically acceptable salt or stereoisomer thereof,

[0054]

[0055] in

[0056] X 2 is O, NH, or NMe;

[0057] X 3 is CH or N;

[0058] o is 0 or 1;

[0059] R 4 is hydrogen or halogen, preferably F or Cl;

[0060] R 5 、R 5 '、R 6 、R 6' are independently hydrogen, -CF3 or halogen, preferably F or Cl;

[0061] R 7 is hydrogen or halogen, preferably F.

[0062] In some embodiments, R 5 Is F and / or R 6 It is F or Cl.

[0063] In some embodiments, R 1 It's hydrogen.

[0064] In some embodiments, R 2 is methyl or R 2 is with R 3 -(CH2)- or -(CH2)2- forming a ring, or R 2 is with R a One of them forms a -(CH2)- or -(CH2)2- ring.

[0065] In some embodiments, R c and R d is hydrogen. In some embodiments, R b 、R c and R d It's hydrogen.

[0066] In some embodiments, Ar 1 having formula iii-1, iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7 or a pharmaceutically acceptable salt or stereoisomer thereof,

[0067]

[0068] in

[0069] X 3 is CH or N;

[0070] o is 0 or 1;

[0071] R 4 is hydrogen or halogen, preferably F or Cl;

[0072] R 5 、R 6 are independently hydrogen, -CF3 or halogen, preferably F or Cl;

[0073] R 7 is hydrogen or halogen, preferably F.

[0074] In some embodiments, R 5 Is F and / or R 6 It is F or Cl.

[0075] In some embodiments, R 1 It's hydrogen.

[0076] In some embodiments, R c and R d is hydrogen. In some embodiments, R b 、R c and R d It's hydrogen.

[0077] In some embodiments, R 2 is methyl or R 2 is with R 3 -(CH2)- or -(CH2)2- forming a ring, or R 2 is with R a One of them forms a -(CH2)- or -(CH2)2- ring.

[0078] In some embodiments, Ar 1 having formula iii-1, iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7 or a pharmaceutically acceptable salt or stereoisomer thereof,

[0079]

[0080] in

[0081] X 3 is C or N, preferably N;

[0082] o is 0 or 1;

[0083] R 4 is hydrogen or halogen, preferably F or Cl;

[0084] R 5 、R 6 are independently hydrogen, -CF3 or halogen, preferably F or Cl;

[0085] R 7 is hydrogen or halogen, preferably F.

[0086] In some embodiments, R 5 is F and / or R 6 It is F or Cl.

[0087] In some embodiments, R 1 It's hydrogen.

[0088] In some embodiments, R c and R d is hydrogen. In some embodiments, R b 、Rc and R d It's hydrogen.

[0089] In some embodiments, R 2 is methyl or R 2 is with R 3 -(CH2)- or -(CH2)2- forming a ring, or R 2 is with R a One of them forms a -(CH2)- or -(CH2)2- ring.

[0090] In some embodiments, Ar 1 having formula iv-1, iv-2, iv-3 or iv-4, iv-5, iv-6, iv-7, iv-8 or iv-9 or a pharmaceutically acceptable salt or stereoisomer thereof,

[0091]

[0092] in

[0093] o is 0 or 1;

[0094] R 4 is hydrogen or halogen, preferably F or Cl;

[0095] R 5 、R 6 are independently hydrogen, -CF3 or halogen, preferably F or Cl;

[0096] R 7 is hydrogen or halogen, preferably F.

[0097] In some embodiments, R 5 Is F and / or R 6 It is F or Cl.

[0098] In some embodiments, R 1 It's hydrogen.

[0099] In some embodiments, R c and R d is hydrogen. In some embodiments, R b 、R c and R d It's hydrogen.

[0100] In some embodiments, R 2 is methyl or R 2 is with R 3 -(CH2)- or -(CH2)2- forming a ring, or R 2 is with R aIn some embodiments, R 7 It's F.

[0101] In some embodiments, the present disclosure provides a compound or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound has Formula IIa or IIb,

[0102]

[0103] in

[0104] X 1 Is -O- or -NR 3 -;

[0105] R 1 is H or F;

[0106] R 2 is hydrogen or C 1-4 Alkyl, preferably methyl, or 3 Ring-forming -(CH2) q -;

[0107] R 3 is hydrogen or C 1-4 Alkyl, preferably hydrogen or methyl, or with R 2 Ring-forming -(CH2) p -;

[0108] m is 1, 2, or 3;

[0109] n is 0, 1, or 2;

[0110] p is 1 or 2;

[0111] q is 0, 1, or 2;

[0112] r is 0 or 1;

[0113] s is 1 or 2; and

[0114] Ar 1 is a 6-membered aryl group which is unsubstituted or substituted by one or more of the following groups: halogen, -CF3, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy-C6 aryl, C 1-6 Alkoxy-C 5-6 Heteroaryl, amino, amino C 1-4 Alkyl, C1-6 Alkylamino, C 1-6 Aminoalkyl-C6 aryl, C 1-6 aminoalkyl-C 5-6 Heteroaryl, C 1-6 Alkoxycarbonyl, C 1-6 Alkoxyaminocarbonyl, aryl C 1-6 Alkoxy or C6 aryl.

[0115] In some embodiments, R 1 It's hydrogen.

[0116] In some embodiments, R 2 is methyl or R 2 is with R 3 -(CH2)- or -(CH2)2- forming a ring.

[0117] In some embodiments, when X 1 Yes-NR 3 -, R 2 Not hydrogen.

[0118] In some embodiments, when X 1 Yes-NR 3 -, R 2 It is C 1-4 Alkyl, or with R 3 or with R a One of the ring-forming -(CH2) q -.

[0119] In some embodiments, X 1 Yes-NR 3 -, and R 2 Not hydrogen.

[0120] In some embodiments, X 1 Yes-NR 3 -, and R 2 It is C 1-4 Alkyl, or with R 3 or with R a One of the ring-forming -(CH2) q -.

[0121] In some embodiments, the present disclosure provides a compound or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound has Formula III,

[0122]

[0123] in

[0124] R 1 is H or F;

[0125] Ar 1 is a 6-membered aryl group which is unsubstituted or substituted by one or more of the following groups: halogen, -CF3, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy-C6 aryl, C 1-6 Alkoxy-C 5-6 Heteroaryl, amino, amino C 1-4 Alkyl, C 1-6 Alkylamino, C 1-6 Aminoalkyl-C6 aryl, C 1-6 aminoalkyl-C 5-6 Heteroaryl, C 1-6 Alkoxycarbonyl, C 1-6 alkoxyaminocarbonyl or C6 aryl; and

[0126] Z is selected from

[0127]

[0128] In some embodiments, R 1 It's hydrogen.

[0129] In some embodiments, the present disclosure provides a compound or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound has Formula IV,

[0130]

[0131] in

[0132] R 1 is H or F;

[0133] R 4 It is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy-C6 aryl, C 1-6 Alkoxy-C 5-6 Heteroaryl, amino C 1-4 Alkyl, C 1-6 Alkylamino, C 1-6 Aminoalkyl-C6 aryl, C 1-6 aminoalkyl-C 5-6 Heteroaryl, C 1-6Alkoxycarbonyl, C 1-6 Alkoxyamino-carbonyl or C6 aryl;

[0134] R 5 、R 5 '、R 6 、R 6 ' are independently hydrogen, -CF3 or halogen, preferably F or Cl; and

[0135] Z is selected from

[0136]

[0137] In some embodiments, R 5 Is F and / or R 6 It is F or Cl.

[0138] In some embodiments, R 1 It's hydrogen.

[0139] In some embodiments, the present disclosure provides a compound or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound has formula V-1, V-2, V-3 or V-4,

[0140]

[0141] in

[0142] X 2 is O, NH, or NMe;

[0143] X 3 is C or N;

[0144] R 1 is H or F;

[0145] R 4 is hydrogen or halogen, preferably F or Cl;

[0146] R 5 、R 5 '、R 6 、R 6 ' are independently hydrogen, -CF3 or halogen, preferably F or Cl;

[0147] o is 0 or 1;

[0148] R 7 is hydrogen or halogen, preferably F; and

[0149] Z is selected from

[0150]

[0151] In some embodiments, R 5Is F and / or R 6 It is F or Cl.

[0152] In some embodiments, R 1 It's hydrogen.

[0153] In some embodiments, the present disclosure provides a compound or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound has Formula VI-1, VI-2, VI-3 or VI-4,

[0154]

[0155] in

[0156] X 2 is O, NH, or NMe;

[0157] X 3 is C or N;

[0158] R 1 is H or F;

[0159] o is 0 or 1;

[0160] R 4 is hydrogen or halogen, preferably F or Cl;

[0161] R 5 、R 6 are independently hydrogen, -CF3 or halogen, preferably F or Cl;

[0162] R 7 is hydrogen or halogen, preferably F; and

[0163] Z is selected from

[0164]

[0165] In some embodiments, R 5 Is F and / or R 6 It is F or Cl.

[0166] In some embodiments, R 1 It's hydrogen.

[0167] In some embodiments, the present disclosure provides a compound or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound has formula VII-1, VII-2, VII-3 or VII-4, VII-5, VII-6, VII-7, VII-8 or VII-9,

[0168]

[0169] in

[0170] R 1 is H or F;

[0171] o is 0 or 1;

[0172] R 4 is hydrogen or halogen, preferably F or Cl;

[0173] R 5 、R 6 are independently hydrogen, -CF3 or halogen, preferably F or Cl;

[0174] R 7 is hydrogen or halogen, preferably F;

[0175] Z is selected from

[0176]

[0177] In some embodiments, R 5 Is F and / or R 6 It is F or Cl.

[0178] In some embodiments, R 1 is hydrogen. In certain embodiments, R 7 It's F.

[0179] In some aspects, the present disclosure relates to a composition comprising a compound according to any of the embodiments described herein, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0180] In some embodiments, the composition includes a pharmaceutically acceptable carrier.

[0181] In some embodiments, the composition includes a second therapeutically active agent.

[0182] In some aspects, the disclosure relates to a method of inhibiting an oncogenic variant of an ErbB receptor (eg, an oncogenic variant of EGFR), comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.

[0183] In some aspects, the present disclosure relates to a method of inhibiting an oncogenic variant of an ErbB receptor (eg, an oncogenic variant of EGFR), the method comprising administering to a subject in need thereof a composition described herein.

[0184] In some aspects, the disclosure relates to a method of preventing or treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.

[0185] In some aspects, the present disclosure relates to a method of preventing or treating cancer comprising administering a composition described herein to a subject in need thereof.

[0186] In some aspects, the disclosure relates to compounds described herein for use in inhibiting oncogenic variants of ErbB receptors (eg, oncogenic variants of EGFR).

[0187] In some aspects, the disclosure relates to compounds described herein for use in preventing or treating cancer.

[0188] In some aspects, the disclosure relates to the compositions described herein for inhibiting oncogenic variants of ErbB receptors (eg, oncogenic variants of EGFR).

[0189] In some aspects, the disclosure relates to the compositions described herein for use in preventing or treating cancer.

[0190] In some aspects, the disclosure relates to the use of the compounds described herein for the manufacture of a medicament for inhibiting oncogenic variants of ErbB receptors (eg, oncogenic variants of EGFR).

[0191] In some aspects, the disclosure relates to the use of the compounds described herein for the manufacture of a medicament for the prevention or treatment of cancer.

[0192] In some embodiments, the cancer is glioblastoma.

[0193] In some aspects, the present disclosure relates to a method of preventing or treating glioblastoma, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any of the embodiments described herein.

[0194] In some aspects, the disclosure relates to a compound according to any of the embodiments described herein for use in preventing or treating glioblastoma.

[0195] In some aspects, the present disclosure relates to a method of preventing or treating glioblastoma, comprising administering to a subject in need thereof a composition according to any of the embodiments described herein.

[0196] In some aspects, the present disclosure relates to a composition according to any of the embodiments described herein for use in preventing or treating glioblastoma. DETAILED DESCRIPTION

[0197] The present disclosure relates to compounds that are inhibitors of receptor tyrosine kinases (RTKs), specifically oncogenic mutants of ErbB receptors. In some embodiments of the present invention, oncogenic mutants of ErbB receptors are also allosteric mutants of ErbB receptors. In some embodiments, allosteric mutants may include or consist of ErbB receptor variants having mutations in sequences outside the ATP binding site. In some embodiments, allosteric mutants may include or consist of ErbB receptor variants having mutations in sequences within one or more of exon 19, exon 20, or the C1-C2 extracellular dimerization interface.

[0198] Mutations affecting the intracellular catalytic domain or the extracellular ligand-binding domain of ErbB receptors may produce oncogenic activity (the ErbB protein family consists of four members, including ErbB-1, also known as epidermal growth factor receptor (EGFR) and Erb-2, also known as HER2 in humans). Extracellular mutants of ErbB receptors in cancer, including EGFR-Viii (also EGFR-V3) and HER2-S310F, are constitutively activated in the absence of ligands, exhibiting persistent signaling that is resistant to downregulation and is both transforming and tumorigenic (Nishikawa, Ji et al., 1994, 2013, Francis, Zhang et al., 2014). Its expression is associated with metastasis and poor long-term overall survival.

[0199] In glioblastoma (also known as glioblastoma multiforme or GBM), EGFR-Viii is expressed by 20% of tumors (Sugawa, Ekstrand et al., 1990, Brennan, Verhaak et al., 2013). EGFR-Viii expression in GBM tends to be mutually exclusive with the expression of other RTK oncogenes, which are co-expressed with EGFR variants in only 7% of GBM tumors (Furnari, Cloughesy et al., 2015). These data show how EGFR-Viii in GBM has a dominant and mutually exclusive expression pattern compared to other oncogenic drivers. EGFR-Viii is also expressed by approximately 30% of SCCHN tumors (Sok, Coppelli et al., 2006, Keller, Shroyer et al., 2010, Wheeler, Suzuki et al., 2010, Tinhofer, Klinghammer et al., 2011, Wheeler, Egloff et al., 2015) and 10% of squamous NSCLC (Ji, Zhao et al., 2006, Sasaki, Kawano et al., 2007) and is associated with resistance to current therapeutic drugs, including the anti-EGFR antibody cetuximab (Sok, Coppelli et al., 2006, Tinhofer, Klinghammer et al., 2011). Normal tissues do not express this oncogenic receptor variant.

[0200] RNA sequencing data revealed that EGFR-Viii is just one of several aberrant splice variants of EGFR expressed in GBM tumors. Two other variants result in truncations of exons 12-13 (EGFR-Vvi) and 14-15 (EGFR-Vii). Like EGFR-Viii, EGFR-Vii is both transforming and tumorigenic. In addition to splice variants, GBM tumors also express a series of EGFR point mutations, including C620Y, A289V, and G598V, which are both transforming and tumorigenic.

[0201] HER2-S310F is the most common HER2 mutation expressed in human tumors, expressed by approximately 0.5% of all tumors. HER2-S310F expression is mutually exclusive with HER2 amplification. HER2-S310F is highly oncogenic, converting BaF3 cells (a murine interleukin-3 (IL-3)-dependent progenitor B cell line) to IL-3 independence and promoting tumor growth in vivo.

[0202] Short insertions within exon 20 of EGFR and HER2 are expressed by lung adenocarcinoma tumors and other tumor groups. ErbB exon 20 insertion mutants are expressed in 4-5% of lung adenocarcinoma tumors. Examples include HER2-YVMA, EGFR-SVD, and EGFR-NPH. These ErbB exon 20 insertion mutants are highly oncogenic, converting BaF3 cells to IL-3 independence and promoting tumor growth in vivo.

[0203] ErbB inhibitors are known treatments for a variety of cancers. However, not every patient responds satisfactorily to this treatment. Therefore, there has long been a need in the art for new therapies that can address the variable responsiveness of cancer patients to known therapies. Because standard of care existed before the development of the compositions and methods disclosed herein, the present invention is able to overcome some of these shortcomings of the standard of care.

[0204] Abnormal ErbB receptor activation

[0205] Although the mechanisms described herein are applicable to any form of cancer in which the EGFR variants of the present disclosure are expressed, the prevalence of these variants in glioblastoma (GBM) is provided by way of example. Other cancers expressing the EGFR variants of the present disclosure include, but are not limited to, solid cancers, epithelial cancers and / or cancers of epithelial origin, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, glioblastoma (GBM), head and neck cancer, lung cancer, and non-small cell lung cancer (NSCLC).

[0206] In GBM tumors, EGFR is often the target of genomic mutations and alternative splicing events that lead to changes in the extracellular dimer interface. Many tumors express more than one abnormal isoform. The present disclosure provides the activation mechanisms of the most common variants EGFR-Viii, EGFR-Vii, EGFR-Vvi, EGFR-G598V, and EGFR-A289V. Although each isoform / point mutant is the result of a different extracellular domain change, they are all activated by a common mechanism involving covalent ligand-independent dimerization.

[0207] AMG-595 (Amgen) is an EGFR-Viii isoform-selective antibody that is inactive against wild-type EGFR or other splice-activated variants. Rindopepimut (Celldex) is a vaccine that selectively generates an immune response against tumor cells that express EGFR-Viii but not wild-type EGFR or other splice-activated isoforms. Other EGFR isoforms expressed in GBM tumors (EGFR-Vii and EGFR-Vvi) are constitutively active covalent receptors, and their expression may limit the breadth and duration of therapeutic benefit of ErbB inhibitors that are selective for EGFR-Viii only. Therefore, it may be useful to exclude patients whose tumors express EGFR-Vii, EGFR-Vvi, or EGFR extracellular domain point mutants from EGFR-Viii-selective therapies.

[0208] The heterogeneous expression pattern of multiple extracellular domain variants of ErbB receptors in tumors suggests that small molecule inhibitors that inhibit all variants are preferred. Compared with the EGFR catalytic domain mutations observed in NSCLC, the covalently activated EGFR isoform family responds very differently to small molecule ErbB inhibitors. Importantly, type I inhibitors, including erlotinib, all induce the formation of covalent EGFR dimers and increase EGFR phosphorylation at subsaturating concentrations, an activity that is further enhanced when the ErbB inhibitor is washed away. This manifests as a paradoxical activation of proliferation at subsaturating concentrations.

[0209] The discovery of paradoxical proliferation activation under subsaturating concentrations of type I ErbB inhibitors further demonstrates a series of extracellular variants of HER2, which are prevalent in many cancers including breast cancer and bladder cancer. All variants exist in the form of covalently activated receptors, and after treatment with type I inhibitors including saputinib and afatinib, the level of covalent dimers increases. Like covalently activated EGFR variants, subsaturating doses of type I inhibitors paradoxically increase the phosphorylation of HER2 variants, thereby increasing the proliferation of cells expressing them.

[0210] Compared to type I inhibitors, the present disclosure demonstrates that non-type I (e.g., type II) inhibitors comprising neratinib do not paradoxically activate cells expressing ErbB extracellular domain variants. Compared to wild-type EGFR, neratinib was found to be an example of a preferred molecule that is both potent and selective for each member of the covalently activated EGFR family.

[0211] In general, the present disclosure provides structure / function relationships for predicting how structural changes affecting the receptor region distal to the active site can confer significantly different responses to small molecule active site inhibitors. The discovery of the abnormal activation of covalently activated ErbB receptor variants by type I inhibitors described herein has important clinical significance. The data disclosed herein provide a mechanistic explanation for the clinical studies of the failure of type I inhibitors in tumor types where the expression of covalently activated ErbB receptors is very common. This includes erlotinib and gefitinib in GBM tumors, erlotinib in SCCHN tumors, and sabutinib in breast tumors.

[0212] Glioblastoma

[0213] Glioblastoma (GBM), also known as grade IV astrocytoma, is the most common form of brain cancer. The outcome of this disease is dismal. Surgery followed by radiation therapy and temozolomide is the standard of care, however, this results in a median overall survival (OS) of only 14.6 months, and few patients survive for five years. Over the past decade, little progress has been made in extending the survival of GBM patients. Although bevacizumab has shown an improved progression-free survival benefit in the recurrent setting, adding bevacizumab to standard of care therapy in the first-line setting has not produced an OS benefit.

[0214] EGFR is the most frequently altered oncogene in GBM. In addition to EGFR gene amplification, many tumors express variants resulting from aberrant splicing or genomic mutations. The first recognized variant, EGFR-Viii, results from a truncation of exons 2–7 and is expressed by approximately 20% of GBM tumors. EGFR-Viii is oncogenic. EGFR-Viii is constitutively activated in the absence of EGF ligand and exhibits persistent signaling that is resistant to downregulation. Thus, EGFR-Viii is both transforming and tumorigenic. EGFR-Viii expression is associated with poor long-term overall survival in GBM.

[0215] RNA sequencing data revealed that EGFR-Viii is just one of several aberrant splice variants of EGFR expressed in GBM tumors. Two other variants result in truncation of exons 12-13 (EGFR-Vvi) and 14-15 (EGFR-Vii). Like EGFR-Viii, EGFR-Vii is both transforming and tumorigenic. In addition to splice variants, GBM tumors also express a series of EGFR point mutations, including C620Y, A289V, and G598V, which are both transforming and tumorigenic. The observation that many tumors express more than one receptor variant further exacerbates the complexity of EGFR alterations in GBM.

[0216] Because the expression of multiple EGFR variants in GBM can generate transforming and tumorigenic activity, and because EGFR is the most frequently altered oncogene present in GBM tumors, EGFR is a particularly attractive target for small-molecule ErbB inhibitors. Following the success of small-molecule EGFR therapies (erlotinib, gefitinib, and afatinib) against NSCLC tumors harboring activating mutations in EGFR, these agents were tested in GBM. Despite intensive clinical investigation of this group of ErbB inhibitors in GBM, involving >30 clinical trials and >1500 patients, none has yielded any benefit, even for those tumors expressing EGFR-Viii. Surprisingly, some evidence suggests that erlotinib promotes disease progression. A phase 2 study evaluating erlotinib in combination with radiation and temozolomide showed median PFS (mPFS) and median OS (mOS) of 2.8 and 8.6 months, respectively, compared with 6.9 and 14.6 months, respectively, for patients receiving radiation and temozolomide alone. Another randomized phase II trial of erlotinib showed that patients whose tumors expressed EGFR-Viii had worse progression when they received erlotinib compared with patients who received standard of care therapy. The clinical failure of ErbB inhibitors such as erlotinib in GBM tumors has cast doubt on the role of EGFR as a driver of GBM tumor growth and has raised questions about why ErbB inhibitors, which are so effective in treating EGFR mutations in lung cancer, are so ineffective in treating EGFR variants in GBM.

[0217] A notable feature of EGFR variants expressed in GBM is their location within the extracellular domain. This contrasts with the activating EGFR mutations found in lung cancer, which typically reside in the intracellular catalytic domain. EGFR is composed of four extracellular domains (two ligand-binding domains and two cysteine-rich regions), a transmembrane domain, and an intracellular catalytic domain. Ligand binding promotes dimerization of the extracellular cysteine-rich domains (CR1 and CR2), an event that confers dimerization of the intracellular domains and activation of the receptor’s catalytic activity. Almost all EGFR splicing events and mutations in GBM affect the extracellular region, specifically the two cysteine-rich regions (CR1 and CR2) that form the extracellular dimer interface. The CR region contains >40 cysteine ​​residues, all of which form intramolecular disulfide bonds. In EGFR-Viii, truncation of exons 2–7 results in a partial loss of the sequence encoding the CR1 region. The result is the loss of a cysteine ​​from the Cys295-Cys307 pair, leaving Cys307 as a free, unpaired cysteine. For EGFR-Viii, this cysteine ​​can form an intermolecular disulfide bond with another EGFR monomer to drive covalent dimerization and constitutively activated receptors. Mutation of cysteine ​​307 to serine (C307S) prevents the formation of covalently dimerized EGFR-Viii and is inactive.

[0218] Although several recent preclinical studies have shown that EGFR kinase inhibitors such as erlotinib are very ineffective at inhibiting EGFR-Viii, a mechanism for this effect has not yet been proposed. There is also a lack of understanding of the mechanisms responsible for activation of other extracellular domain variants in GBM, including EGFR-Vii and EGFR-A289V. The present disclosure provides mechanisms for receptor activation and effects on ErbB inhibitor activity for a panel of four of the most common extracellular domain variants in GBM, EGFR-Viii, EGFR-Vii, EGFR-Vvi, EGFR-G598V, and EGFR-A289V.

[0219] The present disclosure shows that, like EGFR-Viii, another group of EGFR variants commonly found in GBM (EGFR-Vii, EGFR-Vvi, EGFR-G598V and EGFR-A289V) all exist as constitutively active covalent dimers and together form a family of EGFR isoforms activated by this common mechanism. In addition, the present disclosure shows that the propensity of these variants to covalently dimerize is related to the conformation of the intracellular catalytic site, thereby conferring different activities to various types of small molecule inhibitors that bind to this distal site. Inhibitors that stabilize the active conformation of the kinase (type I inhibitors, including erlotinib) induce all covalently activated EGFR isoforms to form covalent dimers. This is related to the tendency of type I inhibitors to increase EGFR phosphorylation at subsaturating concentrations and paradoxically stimulate the proliferation of cells expressing covalently activated EGFR isoforms.

[0220] In the case of small molecule inhibitors that stabilize the inactive kinase conformation (type II inhibitors, including lapatinib and neratinib), neither enhanced dimerization nor paradoxical EGFR activation was observed. Examples of type II inhibitors have been identified that are potent inhibitors of covalently activated EGFR isoforms compared to WT-EGFR and are selective for this family.

[0221] Similar to the mutation identified for EGFR, the present disclosure identifies a group of splicing events and mutations that affect the CR domains of HER2 and HER4. The present disclosure proves that this group of splicing events and mutations that affect the CR domains of HER2 and HER4 exist as covalent dimers and are abnormally activated by agents with type I binding modes. These data provide a mechanistic explanation for the failure of multiple clinical trials involving type I inhibitors, including clinical trials of >30 type I ErbB inhibitors in GBM. In general, these data show that tumors expressing covalently activated EGFR isoforms should be excluded from treatment with type I ErbB inhibitors such as erlotinib because they have abnormal activation. These data further demonstrate the utility of optimizing type II ErbB inhibitors for the covalently activated ErbB family.

[0222] definition

[0223] Unless otherwise stated, the following general definitions apply to all compounds of the present disclosure according to the specification.

[0224] As used herein, the term "compounds of the present disclosure" refers to compounds represented by any of the formulae described herein (e.g., Formulae (I')-(IV') and (I) to (VII)) and any of the specific examples disclosed herein.

[0225] It will be understood that while the compounds disclosed herein may be presented in a particular configuration, such a particular configuration should not be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer, or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers, or stereoisomers. In some embodiments, a compound presented herein in a particular configuration is intended to encompass and refer to each of the available isomers, tautomers, regioisomers, and stereoisomers of the compound or any mixture thereof; and presentation is further intended to refer to a specific configuration of the compound.

[0226] Further, it should be understood that although the compounds disclosed herein may be presented without specifying a configuration (e.g., without specifying a stereochemistry), such presentation is intended to encompass all available isomers, tautomers, regioisomers, and stereoisomers of the compounds. In some embodiments, presentation of a compound herein without specifying a configuration is intended to refer to each of the available isomers, tautomers, regioisomers, and stereoisomers of the compound or any mixture thereof.

[0227] As used herein, the term "isomerism" refers to compounds that have the same molecular formula but differ in the sequence in which their atoms are bonded or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers." Stereoisomers that are not mirror images of one another are termed "diastereomers," and stereoisomers that are non-superimposable mirror images of one another are termed "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a "racemic mixture."

[0228] As used herein, the term "chiral center" refers to a carbon atom bonded to four different substituents.

[0229] As used herein, "chiral isomer" refers to a compound having at least one chiral center. Compounds having more than one chiral center can exist as individual diastereomers or as a mixture of diastereomers (referred to as a "diastereomeric mixture"). When one chiral center is present, the stereoisomer can be characterized by the absolute configuration (R or S) of the chiral center. The absolute configuration refers to the spatial arrangement of the substituents attached to the chiral center. The substituents contemplated for attachment to the chiral center are ordered according to the Sequence Rule of Cahn, Ingold, and Prelog (Cahn et al., Angew. Chem. Int. Edit. 1966, 5, 385; corrigendum 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia, 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0230] As used herein, the term "geometric isomers" refers to the existence of diastereomers due to hindered rotation around a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). The names of these configurations are distinguished by the prefixes cis and trans, or Z and E, which indicate whether the groups are on the same or opposite sides of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.

[0231] It will be understood that "independently of each other" means that when a group occurs more than one time in any compound, its definition on each occurrence is independent of every other occurrence.

[0232] It is further understood that the dashed line (or wavy line transverse to a bond) depicts the site of attachment of the residues (ie, partial formula).

[0233] As used herein, the term "halogen" or "hal" may be fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

[0234] As used herein, "alkyl," "C1, C2, C3, C4, C5, or C6 alkyl," or "C1-C6 alkyl" is intended to include C1, C2, C3, C4, C5, or C6 straight-chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5, or C6 branched-chain saturated aliphatic hydrocarbon groups. For example, C1-C6 alkyl is intended to include C1, C2, C3, C4, C5, and C6 alkyl groups. Examples of alkyl groups include moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, or n-hexyl. In some embodiments, a straight-chain or branched alkyl group has six or fewer carbon atoms (e.g., C1-C6 for straight chain and C3-C6 for branched chain), and in another embodiment, a straight-chain or branched alkyl group has four or fewer carbon atoms. In some embodiments, the term "alkyl," as used herein, refers to a fully saturated branched or unbranched hydrocarbon moiety. The term "C 1-4 "Alkyl" refers to a fully saturated, branched or unbranched hydrocarbon moiety having 1, 2, 3 or 4 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl.

[0235] As used herein, the term "optionally substituted alkyl" refers to an unsubstituted alkyl group or an alkyl group having a specified substituent replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino) groups. alkylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonic acid group (sulphonato), sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moiety.

[0236] As used herein, the term "alkenyl" comprises an unsaturated aliphatic group similar in length and possible substitution to the above-mentioned alkyl group but containing at least one double bond. For example, the term "alkenyl" comprises straight-chain alkenyl (for example, vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl) and branched alkenyl. In certain embodiments, straight or branched alkenyl has six or less carbon atoms (for example, C2-C6 for straight chain, C3-C6 for side chain) in its main chain. The term "C2-C6" comprises the alkenyl containing two to six carbon atoms. The term "C3-C6" comprises the alkenyl containing three to six carbon atoms.

[0237] As used herein, the term "optionally substituted alkenyl" refers to unsubstituted alkenyl or alkenyl having the specified substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and urea), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0238] As used herein, the term "alkynyl" includes unsaturated aliphatic groups similar in length and possible substitution to the above-mentioned alkyl groups but containing at least one triple bond. For example, "alkynyl" includes straight chain alkynyl (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl) and branched chain alkynyl. In certain embodiments, straight or branched chain alkynyl has six or less carbon atoms (e.g., C2-C6 for straight chain, C3-C6 for branched chain) in its backbone. The term "C2-C6" includes alkynyl groups containing two to six carbon atoms. The term "C3-C6" includes alkynyl groups containing three to six carbon atoms. As used herein, "C2-C6 alkenylene linker" or "C2-C6 alkynylene linker" is intended to include C2, C3, C4, C5 or C6 chain (straight or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, a C2-C6 alkenylene linker is intended to include C2, C3, C4, C5, and C6 alkenylene linker groups.

[0239] As used herein, the term "optionally substituted alkynyl" refers to unsubstituted alkynyl groups or alkynyl groups having the specified substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and urea), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0240] Other optionally substituted moieties such as optionally substituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl include both unsubstituted moieties and moieties having one or more of the specified substituents. For example, substituted heterocycloalkyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.

[0241] As used herein, the term "alkoxy" or "alkoxyl" includes substituted and unsubstituted alkyl groups covalently linked to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, butoxy, and pentoxy.

[0242] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spirocyclic) system having 3 to 30 carbon atoms (e.g., C3-C12, C3-C10, or C3-C8). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthyl, adamantyl, and hexahydroindenyl. It should be understood that for polycyclic (e.g., fused, bridged, or spirocyclic) systems, only one of the rings needs to be non-aromatic.

[0243] As used herein, the term "aryl" refers to a group having aromatic properties, including "conjugated" or polycyclic ring systems having one or more aromatic rings, and does not contain any heteroatoms in the ring structure. The term aryl includes both monovalent and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, and the like. In some embodiments, aryl is phenyl.

[0244] As used herein, the term "heterocycloalkyl" refers to a saturated or partially unsaturated 3-8 membered monocyclic ring, a 7-12 membered bicyclic ring (fused, bridged or spiro) or an 11-14 membered tricyclic ring system (fused, bridged or spiro having one or more heteroatoms (such as O, N, S, P or Se)), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, e.g., 1, 2, 3, 4, 5 or 6 heteroatoms, unless otherwise specified. Examples of heterocycloalkyl include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxirane, azetidinyl, oxetanyl, thienyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepinyl, 1,4-oxa-5-azabicyclo, [2.2.1] heptyl, 2,5-diazabicyclo[2.2.1] heptyl, 2-oxa-6-azaspiro[3.3] heptyl, 2,6-diazaspiro[3.3] heptyl, 1,4-dioxa-8-azaspiro[4.5]decyl, 1,4-dioxaspiro[4.5]decyl, 1-oxaspiro[4.5]decyl, 1-azaspiro[4.5]decyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl, 7'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl, Hexane-1,5'-furo[3,4-b]pyridinyl]-yl, 3'H-spiro[cyclohexane-1,1'-furo[3,4-c]pyridinyl]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4- c]pyridindenyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptyl, 2-methyl-2-azaspiro[3.3]heptyl, 2-aza[3.5]nonyl, 2-methyl-2-azaspiro[3.5]nonyl, 2-azaspiro[4.5]decyl, 2-methyl-2-azaspiro[4.5]decyl, 2-oxazaspiro[3.4]octanyl, 2-oxazaspiro[3.4]octanyl-6-yl, etc. In the case of polycyclic heterocycloalkyl, only one ring in the heterocycloalkyl needs to be non-aromatic.In some embodiments, the heterocycloalkyl group is oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, 3-oxabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexanyl, 2-azaspiro[3.3]heptanyl, 2-oxa-5-azaspiro[3.4]octanyl, wherein the oxetanyl, the tetrahydrofuranyl, the pyrrolidinyl, the piperidinyl, the morpholinyl, the 3-oxabicyclo[3.1.0]hexanyl, the 3-azabicyclo[3.1.0]hexanyl, the 2-azaspiro[3.3]heptanyl or the 2-oxa-5-azaspiro[3.4]octanyl group.

[0245] As used herein, the term "heteroaryl" is intended to include a stable 5-, 6-, or 7-membered monocyclic aromatic heterocycle or a 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic aromatic heterocycle consisting of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or other substituents as defined). The nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., N→O and S(O)). p , wherein p = 1 or 2). It should be noted that the total number of S and O atoms in the aromatic heterocycle is not greater than 1. In some embodiments, the term "heteroaryl" refers to a (completely) aromatic ring system having 3, 4, 5 or 6 ring atoms, preferably 6 ring atoms, selected from C, N, O or S, preferably C, N or O, more preferably C, N, wherein the number of N atoms is preferably 0, 1, 2 or 3, and the number of O and S atoms is 0, 1 or 2, respectively. Examples of "heteroaryl" include furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl (pyrazinyl), pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiazolyl, thienyl, etc. Preferred examples of "heteroaryl" include pyridinyl.

[0246] In some embodiments, the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups are substituted at one or more ring positions (e.g., ring carbon or heteroatom such as N) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl In some embodiments, the cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are substituted with halogen (e.g., F or Cl).

[0247] As used herein, the term "substituted" means that any one or more hydrogen atoms on the designated atom are replaced by a selection from the indicated group, provided that the normal atomic valence of the designated atom is not exceeded and that the substitution forms a stable compound. When the substituent is oxo or keto (i.e., =O), 2 hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0248] The terms "nucleic acid" and "polynucleotide" are used interchangeably herein to refer to single-stranded or double-stranded RNA, DNA, or mixed polymers. A polynucleotide may comprise genomic sequences, extragenomic sequences, and plasmid sequences that express or may be adapted to express a polypeptide, as well as smaller engineered gene segments.

[0249] "Isolated nucleic acid" is a nucleic acid that is substantially separated from other genomic DNA sequences and proteins or complexes that naturally accompany the native sequence, such as ribosomes and polymerases. The term encompasses nucleic acid sequences that have been removed from their naturally occurring environment and includes recombinant or cloned DNA isolates and chemically synthesized analogs or analogs biosynthesized by heterologous systems. Substantially pure nucleic acid includes nucleic acid in isolated form. This, of course, refers to the initially isolated nucleic acid and does not exclude genes or sequences that have been artificially added to the isolated nucleic acid later.

[0250] The term "polypeptide" is used in its conventional sense, i.e., as an amino acid sequence. Polypeptides are not limited to a specific length of the product. Peptides, oligopeptides, and proteins are included within the definition of polypeptide, and such terms are used interchangeably herein unless otherwise specified. This term also does not refer to or exclude post-expression modifications of the polypeptide, such as glycosylation, acetylation, phosphorylation, and the like, as well as other modifications known in the art, both naturally occurring and non-naturally occurring. A polypeptide can be an intact protein or a subsequence thereof.

[0251] An "isolated" polypeptide is one that has been identified, separated, and / or recovered from a component of its natural environment. In preferred embodiments, the isolated polypeptide will be purified (1) to achieve greater than 95% by weight of the polypeptide as determined by the Lowry method, and most preferably greater than 99% by weight, (2) to a concentration sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (3) to be homogenized by SDS-PAGE under reducing or non-reducing conditions using Coomassie blue or, preferably, silver stain. An isolated polypeptide includes the polypeptide in situ within recombinant cells since at least one component of the polypeptide's natural environment will not be present. Ordinarily, however, an isolated polypeptide will be prepared by at least one purification step.

[0252] A "native sequence" polynucleotide is a polynucleotide having the same nucleotide sequence as a polynucleotide derived from nature. A "native sequence" polypeptide is a polypeptide having the same amino acid sequence as a polypeptide (e.g., EGFR) derived from nature (e.g., from any species). Such native sequence polynucleotides and polypeptides can be isolated from nature or can be produced by recombinant or synthetic means.

[0253] As the term is used herein, a polynucleotide "variant" is a polynucleotide that typically differs from the polynucleotides specifically disclosed herein in one or more substitutions, deletions, additions, and / or insertions.

[0254] As used herein, a polypeptide "variant" is a polypeptide that generally differs from the polypeptides specifically disclosed herein in one or more substitutions, deletions, additions and / or insertions or inversions. Such variants may be naturally occurring, non-naturally occurring, or may be synthetically produced.

[0255] EGFR mutations (or variants) of the present disclosure may include one or more substitutions, deletions, additions and / or insertions or inversions of the function of the resulting protein resulting from the change in the amino acid sequence. Mutations may be detected, for example, by comparison or alignment of the nucleic acid or amino acid sequence with the wild-type sequence.

[0256] When comparing polynucleotide sequences or polypeptide sequences, the two sequences are said to be "identical" if the nucleotide sequence or amino acid sequence in the two sequences is the same when aligned for maximum correspondence, as described below. Comparisons between two sequences are typically performed by comparing the sequences over a comparison window to identify and compare local regions of sequence similarity. As used herein, a "comparison window" refers to a segment of at least about 20, typically about 30 to about 75, or about 40 to about 50 contiguous positions in which a sequence can be compared to a reference sequence having the same number of contiguous positions after the two sequences have been optimally aligned.

[0257] Sequences can be optimally aligned for comparison using the Megalign program in the Lasergene bioinformatics software suite (DNASTAR, Madison, Wisconsin) using default parameters. This program embodies several alignment schemes described in the following references: Dayhoff, MO (1978) "A model of evolutionary change in proteins - Matrices for detecting distant relationships." Dayhoff, MO (ed.) Atlas of Protein Sequence and Structure, National Biomedical Research Foundation, Washington, D.C., Vol. 5, Supplement 3, pp. 345-358; Hein J. (1990) Unified Approach to Alignment and Phylogenes, p. 626. -645 pages; Methods in Enzymology, vol. 183, Academic Press, Inc., San Diego, CA; Higgins, DG and Sharp, PM (1989) CABIOS 5:151-153; Myers, EW and Muller W. (1988) CABIOS 4:11-17; Robinson, ED (1971) Comb. Theor. 11:105; Santou, N. Nes, M. (1987) Mol. Biol. Evol. 4:406-425; Sneath, PHA and Sokal, RR (1973) Numerical Classification: Principles and Practice of Numerical Classification. Taxonomy—the Principles and Practice of Numerical Taxonomy, Freeman Press, St. Francis, CA; Wilbur, WJ and Lipman, DJ (1983) Proc. Natl. Acad., Sci. USA 80:726–730.

[0258] Alternatively, optimal alignment of sequences for comparison can be performed by the local identity algorithm of Smith and Waterman (1981) Add. APL. Math 2:482; the identity alignment algorithm of Needleman and Wunsch (1970) J. Mol. Biol 48:443; by the method of finding similarity of Pearson and Lipman (1988) Proc. Natl. Acad. Sci. USA 85:2444; by computerized implementations of these algorithms (GAP, BESTFIT, BLAST, FASTA, and TFASTA in the Wisconsin Genetics Software Package at the Genetics Computer Group (GCG), 575 Science Avenue, Madison, Wisconsin), or by inspection.

[0259] A preferred example of an algorithm suitable for determining percent sequence identity and sequence similarity is the BLAST and BLAST 2.0 algorithms described in, respectively, Altschul et al. (1977) Nucl. Acids Res. 25:3389-3402 and Altschul et al. (1990) J. Mol. Biol 215:403-410. BLAST and BLAST 2.0 can be used, for example, with the parameters described herein to determine the percent sequence identity of polynucleotides and polypeptides of the present invention. Software for performing BLAST analysis is publicly available through the National Center for Biotechnology Information.

[0260] In an illustrative example, for nucleotide sequences, the cumulative score can be calculated using the parameters M (reward score for a pair of matching residues; always >0) and N (penalty score for mismatching residues; always <0). Extension of the word hit in each direction is halted if: the cumulative alignment score decreases by the amount X from its maximum achieved value; the cumulative score becomes zero or lower due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment. The BLASTN program uses a word length (W) of 11 and an expectation (E) of 10 and the BLOSUM62 scoring matrix (see Henikoff and Henikoff, (1989) Proc. Natl. Acad. Sci. USA 89:109-15), alignments (B) of 50, an expectation (E) of 10, M=5, N=-4, and a comparison of both chains as defaults.

[0261] For amino acid sequences, a scoring matrix can be used to calculate the cumulative score. Extension of the word hit in each direction is halted if: the cumulative alignment score decreases by the quantity X from its maximum achieved value; the cumulative score becomes zero or lower due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment.

[0262] In one method, the "percentage of sequence identity" is determined by comparing two optimally aligned sequences over a comparison window of at least 20 positions, wherein the portion of the polynucleotide sequence or polypeptide sequence in the comparison window may include additions or deletions (i.e., gaps) of 20% or less, typically 5% to 15% or 10% to 12%, compared to the reference sequence (excluding additions or deletions) to allow the two sequences to be optimally aligned. The percentage is calculated by determining the number of positions where the identical nucleic acid base or amino acid residue appears in the two sequences to yield the number of matched positions; dividing the number of matched positions by the total number of positions in the reference sequence (i.e., the window size); and multiplying the result by 100 to yield the percentage of sequence identity.

[0263] The wild-type EGFR sequence of the present disclosure may comprise or consist of the following amino acid sequence:

[0264]

[0265]

[0266] (SEQ ID NO: 1, corresponding to epidermal growth factor receptor [Homo sapiens] and Genbank accession number CAA25240).

[0267] The wild-type HER2 receptor sequence of the present disclosure may comprise or consist of the following amino acid sequence:

[0268]

[0269] (SEQ ID NO:2, corresponding to receptor tyrosine-protein kinase erbB-2 isoform a precursor [Homo sapiens] and GenBank Accession No. NP_004439).

[0270] The wild-type HER2 receptor sequence of the present disclosure may comprise or consist of the following amino acid sequence:

[0271]

[0272] (SEQ ID NO:3, corresponding to receptor tyrosine-protein kinase erbB-2 isoform b [Homo sapiens] and GenBank Accession No. NP_001005862).

[0273] The wild-type HER2 receptor sequence of the present disclosure may comprise or consist of the following amino acid sequence:

[0274]

[0275]

[0276] (SEQ ID NO:4, corresponding to receptor tyrosine-protein kinase erbB-2 isoform c [Homo sapiens] and GenBank Accession No. NP_001276865).

[0277] The wild-type HER2 receptor sequence of the present disclosure may comprise or consist of the following amino acid sequence:

[0278]

[0279] (SEQ ID NO:5, corresponding to receptor tyrosine-protein kinase erbB-2 isoform d precursor [Homo sapiens] and GenBank Accession No. NP_001276866).

[0280] The wild-type HER2 receptor sequence of the present disclosure may comprise or consist of the following amino acid sequence:

[0281]

[0282] (SEQ ID NO:6, corresponding to receptor tyrosine-protein kinase erbB-2 isoform e [Homo sapiens] and GenBank Accession No. NP_001276867).

[0283] Based on the definitions given throughout the application, a person skilled in the art knows which combinations are comprehensively possible and realistic, for example, combinations of groups which result in heteroatoms directly linked to each other are generally not envisaged.

[0284] Compounds of the present disclosure

[0285] In some aspects, the present disclosure provides a compound of formula (I'):

[0286]

[0287] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0288] W is CH or N;

[0289] Z is optionally replaced by one or more R Z substituted 3- to 12-membered heterocycloalkyl;

[0290] Each R Z are independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3 to 10 membered heterocycloalkyl or 5 to 10 membered heteroaryl; wherein said -O-(C1-C6 alkyl), said -NH(C1-C6 alkyl), said -N(C1-C6 alkyl)2, said C1-C6 alkyl, said C2-C6 alkenyl, said C2-C6 alkynyl, said C3-C 10 Cycloalkyl, the C6-C 10 The aryl group, the 3 to 10 membered heterocycloalkyl group or the 5 to 10 membered heteroaryl group are optionally substituted by one or more R Za replace;

[0291] Each R Za are independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl;

[0292] T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein said -O-(C1-C6 alkyl), said -NH-(C1-C6 alkyl), said C1-C6 alkyl, said C2-C6 alkenyl or said C2-C6 alkynyl is optionally replaced by one or more R T replace;

[0293] Each R T are independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10aryl, 3 to 10 membered heterocycloalkyl or 5 to 10 membered heteroaryl; wherein said -O-(C1-C6 alkyl), said -NH(C1-C6 alkyl), said -N(C1-C6 alkyl)2, said C1-C6 alkyl, said C2-C6 alkenyl, said C2-C6 alkynyl, said C3-C 10 Cycloalkyl, the C6-C 10 The aryl group, the 3 to 10 membered heterocycloalkyl group or the 5 to 10 membered heteroaryl group are optionally substituted by one or more R Ta replace;

[0294] Each R Ta are independently halogen, CN, -OH, -NH2, -C(=O)OH, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl;

[0295] Ar 1 is optionally replaced by one or more R A1 Substituted C6-C 10 aryl;

[0296] Each R A1 are independently halogen, CN, -OH, -NH2, -OR A1a , -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3 to 10 membered heterocycloalkyl or 5 to 10 membered heteroaryl; wherein said -O-(C1-C6 alkyl), said -NH(C1-C6 alkyl), said -N(C1-C6 alkyl)2, said C1-C6 alkyl, said C2-C6 alkenyl, said C2-C6 alkynyl, said C3-C 10 Cycloalkyl, the C6-C 10 The aryl group, the 3 to 10 membered heterocycloalkyl group or the 5 to 10 membered heteroaryl group are optionally substituted by one or more R A1a replace; and

[0297] Each R A1a are independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C10 aryl, 3 to 10 membered heterocycloalkyl or 5 to 10 membered heteroaryl; wherein said -O-(C1-C6 alkyl), said -NH(C1-C6 alkyl), said -N(C1-C6 alkyl)2, said C1-C6 alkyl, said C2-C6 alkenyl, said C2-C6 alkynyl, said C3-C 10 Cycloalkyl, the C6-C 10 The aryl group, the 3 to 10 membered heterocycloalkyl group or the 5 to 10 membered heteroaryl group are optionally substituted by one or more R A1b replace; and

[0298] Each R A1b are independently halogen, CN, -OH or -NH2.

[0299] In some aspects, the compound has formula (I') or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0300] W is CH or N;

[0301] Z is optionally replaced by one or more R Z substituted 3- to 12-membered heterocycloalkyl;

[0302] Each R Z are independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl or 5 to 10 membered heteroaryl; wherein said -O-(C1-C6 alkyl), said -NH(C1-C6 alkyl), said -N(C1-C6 alkyl)2, said C1-C6 alkyl, said C2-C6 alkenyl, said C2-C6 alkynyl, said C3-C 10 Cycloalkyl, the C6-C 10 Aryl, said 3 or 5 to 10 membered heteroaryl are optionally substituted by one or more R Za replace;

[0303] Each R Za are independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl;

[0304] T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein said -O-(C1-C6 alkyl), said -NH-(C1-C6 alkyl), said C1-C6 alkyl, said C2-C6 alkenyl or said C2-C6 alkynyl is optionally replaced by one or more R T replace;

[0305] Each R T are independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3 to 7 membered heterocycloalkyl or 5 to 10 membered heteroaryl; wherein said -O-(C1-C6 alkyl), said C1-C6 alkyl, said C2-C6 alkenyl, said C2-C6 alkynyl, said C3-C 10 Cycloalkyl, the C6-C 10 The aryl group, the 3 to 7 membered heterocycloalkyl group or the 5 to 10 membered heteroaryl group are optionally substituted by one or more R Ta replace;

[0306] Each R Ta are independently halogen, CN, -OH, -NH2, -C(=O)OH, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl;

[0307] Ar 1 is optionally replaced by one or more R A1 Substituted C6-C 10 aryl;

[0308] Each R A1 are independently halogen, CN, -OH, -NH2, -OR A1a , -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein the -O-(C1-C6 alkyl), the -NH(C1-C6 alkyl), the -N(C1-C6 alkyl)2, the C1-C6 alkyl, the C2-C6 alkenyl or the C2-C6 alkynyl are optionally replaced by one or more R A1a replace; and

[0309] Each R A1aare independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein said -O-(C1-C6 alkyl), said -NH(C1-C6 alkyl), said -N(C1-C6 alkyl)2, said C1-C6 alkyl, said C2-C6 alkenyl or said C2-C6 alkynyl are optionally substituted by one or more R A1b replace; and

[0310] Each R A1b are independently halogen, CN, -OH or -NH2;

[0311] The condition is that when Z is When Ar 1 is a C6-C 10 Aryl.

[0312] In some aspects, the compound has formula (I') or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0313] W is CH or N;

[0314] Z is optionally replaced by one or more R Z substituted 3- to 12-membered heterocycloalkyl;

[0315] Each R Z are independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl or 5 to 10 membered heteroaryl; wherein said -O-(C1-C6 alkyl), said -NH(C1-C6 alkyl), said -N(C1-C6 alkyl)2, said C1-C6 alkyl, said C2-C6 alkenyl, said C2-C6 alkynyl, said C3-C 10 Cycloalkyl, the C6-C 10 Aryl, said 3 or 5 to 10 membered heteroaryl are optionally substituted by one or more R Za replace;

[0316] Each R Za are independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl;

[0317] T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein said -O-(C1-C6 alkyl), said -NH-(C1-C6 alkyl), said C1-C6 alkyl, said C2-C6 alkenyl or said C2-C6 alkynyl is optionally replaced by one or more R T replace;

[0318] Each R T are independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3 to 7 membered monocyclic heterocycloalkyl or 5 to 10 membered heteroaryl; wherein said -O-(C1-C6 alkyl), said C1-C6 alkyl, said C2-C6 alkenyl, said C2-C6 alkynyl, said C3-C 10 Cycloalkyl, the C6-C 10 The aryl group, the 3 to 7 membered heterocycloalkyl group or the 5 to 10 membered heteroaryl group are optionally substituted by one or more R Ta replace;

[0319] Each R Ta are independently halogen, CN, -OH, -NH2, -C(=O)OH, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl;

[0320] Ar 1 is optionally replaced by one or more R A1 Substituted C6-C 10 aryl;

[0321] Each R A1 are independently halogen, CN, -OH, -NH2, -OR A1a , -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein the -O-(C1-C6 alkyl), the -NH(C1-C6 alkyl), the -N(C1-C6 alkyl)2, the C1-C6 alkyl, the C2-C6 alkenyl or the C2-C6 alkynyl are optionally replaced by one or more R A1a replace; and

[0322] Each R A1a are independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein said -O-(C1-C6 alkyl), said -NH(C1-C6 alkyl), said -N(C1-C6 alkyl)2, said C1-C6 alkyl, said C2-C6 alkenyl or said C2-C6 alkynyl are optionally substituted by one or more R A1b replace; and

[0323] Each R A1b are independently halogen, CN, -OH or -NH2;

[0324] The condition is that when Z is When Ar 1 is a C6-C 10 Aryl.

[0325] In some embodiments, the compound has formula (I') or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0326] W is CH;

[0327] Z is optionally replaced by one or more R Z substituted 3- to 12-membered heterocycloalkyl;

[0328] Each R Z is independently halogen, -O-(C1-C6 alkyl), C1-C6 alkyl or 3- to 10-membered heterocycloalkyl; wherein said -O-(C1-C6 alkyl), said C1-C6 alkyl or said 3- to 10-membered heterocycloalkyl is optionally substituted with one or more halogen;

[0329] T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl or the C2-C6 alkynyl is optionally replaced by one or more R T replace;

[0330] Each R T is independently halogen, -OH, -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2 or 3-7 membered heterocycloalkyl; wherein said -O-(C1-C6 alkyl), said -N(C1-C6 alkyl)2 or said 3-7 membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH;

[0331] Ar 1is optionally replaced by one or more R A1 Substituted C6-C 10 aryl;

[0332] Each R A1 are independently optionally replaced by one or more R A1a Substituted halogen, -OR A1a or -O-(C1-C6 alkyl); and

[0333] Each R A1a Independently C6-C 10 aryl or 5 to 10 membered heteroaryl; wherein the C6-C 10 The aryl or the 5- to 10-membered heteroaryl is optionally substituted with one or more halogens.

[0334] In some embodiments, the compound has formula (I') or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0335] W is CH;

[0336] Z is optionally replaced by one or more R Z substituted 3- to 12-membered heterocycloalkyl;

[0337] Each R Z is independently halogen, -O-(C1-C6 alkyl), C1-C6 alkyl or 3- to 10-membered heterocycloalkyl; wherein said -O-(C1-C6 alkyl), said C1-C6 alkyl or said 3- to 10-membered heterocycloalkyl is optionally substituted with one or more halogen;

[0338] T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl or the C2-C6 alkynyl is optionally replaced by one or more R T replace;

[0339] Each R T is independently halogen, -OH, -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2 or 3 to 7 membered monocyclic heterocycloalkyl; wherein said -O-(C1-C6 alkyl), said -N(C1-C6 alkyl)2 or said 3 to 7 membered monocyclic heterocycloalkyl is optionally substituted with one or more -C(=O)OH;

[0340] Ar 1 is optionally replaced by one or more R A1 Substituted C6-C 10 aryl;

[0341] Each R A1are independently optionally replaced by one or more R A1a Substituted halogen, -OR A1a or -O-(C1-C6 alkyl); and

[0342] Each R A1a Independently C6-C 10 aryl or 5 to 10 membered heteroaryl; wherein the C6-C 10 The aryl or the 5- to 10-membered heteroaryl is optionally substituted with one or more halogens.

[0343] In some embodiments, the compound has formula (I') or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0344] W is CH;

[0345] Z is optionally replaced by one or more R Z substituted 3- to 12-membered heterocycloalkyl;

[0346] Each R Z are independently halogen, -O-(C1-C6 alkyl) or C1-C6 alkyl; wherein said -O-(C1-C6 alkyl) or said C1-C6 alkyl is optionally substituted with one or more halogen;

[0347] T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl or the C2-C6 alkynyl is optionally replaced by one or more R T replace;

[0348] Each R T is independently halogen, -OH, -O-(C1-C6 alkyl) or 3- to 7-membered heterocycloalkyl; wherein said -O-(C1-C6 alkyl) or said 3- to 7-membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH;

[0349] Ar 1 is optionally replaced by one or more R A1 Substituted C6-C 10 aryl;

[0350] Each R A1 are independently optionally replaced by one or more R A1a Substituted halogen, -OR A1a or -O-(C1-C6 alkyl); and

[0351] Each R A1a Independently C6-C 10 aryl or 5 to 10 membered heteroaryl; wherein the C6-C10 Aryl or the 5- to 10-membered heteroaryl is optionally substituted with one or more halogens;

[0352] The condition is that when Z is When Ar 1 is a C6-C 10 Aryl.

[0353] In some embodiments, the compound has formula (I') or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0354] W is CH;

[0355] Z is optionally replaced by one or more R Z substituted 3- to 12-membered heterocycloalkyl;

[0356] Each R Z are independently halogen, -O-(C1-C6 alkyl) or C1-C6 alkyl; wherein said -O-(C1-C6 alkyl) or said C1-C6 alkyl is optionally substituted with one or more halogen;

[0357] T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl or the C2-C6 alkynyl is optionally replaced by one or more R T replace;

[0358] Each R T is independently halogen, -OH, -O-(C1-C6 alkyl) or 3 to 7 membered monocyclic heterocycloalkyl; wherein said -O-(C1-C6 alkyl) or said 3 to 7 membered monocyclic heterocycloalkyl is optionally substituted with one or more -C(=O)OH;

[0359] Ar 1 is optionally replaced by one or more R A1 Substituted C6-C 10 aryl;

[0360] Each R A1 are independently optionally replaced by one or more R A1a Substituted halogen, -OR A1a or -O-(C1-C6 alkyl); and

[0361] Each R A1a Independently C6-C 10 aryl or 5 to 10 membered heteroaryl; wherein the C6-C 10 Aryl or the 5- to 10-membered heteroaryl is optionally substituted with one or more halogens;

[0362] The condition is that when Z is When Ar 1 is a C6-C 10 Aryl.

[0363] In some embodiments, the compound has formula (I') or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0364] W is CH;

[0365] Z is optionally replaced by one or more R Z substituted 3- to 12-membered heterocycloalkyl;

[0366] Each R Z are independently halogen, -O-(C1-C6 alkyl) or C1-C6 alkyl; wherein said -O-(C1-C6 alkyl) or said C1-C6 alkyl is optionally substituted with one or more halogen;

[0367] T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl or the C2-C6 alkynyl is optionally replaced by one or more R T replace;

[0368] Each R T is independently halogen, -OH, -O-(C1-C6 alkyl) or 3- to 7-membered heterocycloalkyl; wherein said -O-(C1-C6 alkyl) or said 3- to 7-membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH;

[0369] Ar 1 is a C6-C 10 Aryl.

[0370] In some embodiments, the compound has formula (I') or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0371] W is CH;

[0372] Z is optionally replaced by one or more R Z substituted 3- to 12-membered heterocycloalkyl;

[0373] Each R Z are independently halogen, -O-(C1-C6 alkyl) or C1-C6 alkyl; wherein said -O-(C1-C6 alkyl) or said C1-C6 alkyl is optionally substituted with one or more halogen;

[0374] T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl or the C2-C6 alkynyl is optionally replaced by one or more R T replace;

[0375] Each R T is independently halogen, -OH, -O-(C1-C6 alkyl) or 3 to 7 membered monocyclic heterocycloalkyl; wherein said -O-(C1-C6 alkyl) or said 3 to 7 membered monocyclic heterocycloalkyl is optionally substituted with one or more -C(=O)OH;

[0376] Ar 1 is a C6-C 10 Aryl.

[0377] In some embodiments, the compound has formula (I') or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0378] W is CH;

[0379] Z is a 3- to 12-membered heterocycloalkyl group optionally substituted with one or more C1-C6 alkyl groups;

[0380] T is C2-C6 alkenyl optionally substituted with one or more 6-membered heterocycloalkyl; and

[0381] Ar 1 is a C6 aryl group optionally substituted by one or more halogens.

[0382] In some embodiments, the compound has formula (I') or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0383] W is CH;

[0384] Z is a 3- to 12-membered heterocycloalkyl group optionally substituted with one or more C1-C6 alkyl groups;

[0385] T is C2-C6 alkenyl optionally substituted with one or more 6-membered monocyclic heterocycloalkyl; and

[0386] Ar 1 is a C6 aryl group optionally substituted by one or more halogens.

[0387] Variable W

[0388] In some embodiments, W is CH.

[0389] In some embodiments, W is N.

[0390] Variables Z, RZ and R Za

[0391] In some embodiments, Z is optionally replaced by one or more R Z substituted 3- to 12-membered heterocycloalkyl; and

[0392] Each R Z is independently halogen, -O-(C1-C6 alkyl), C1-C6 alkyl or 3- to 10-membered heterocycloalkyl; wherein said -O-(C1-C6 alkyl), said C1-C6 alkyl or said 3- to 10-membered heterocycloalkyl is optionally substituted with one or more halogen.

[0393] In some embodiments, Z is a 3- to 12-membered heterocycloalkyl.

[0394] In some embodiments, Z is replaced by one or more R Z Substituted 3- to 12-membered heterocycloalkyl.

[0395] In some embodiments, Z is oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, 3-oxabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexanyl, 2-azaspiro[3.3]heptanyl, 2-oxa-5-azaspiro[3.4]octanyl, wherein the oxetanyl, the tetrahydrofuranyl, the pyrrolidinyl, the piperidinyl, the morpholinyl, the 3-oxabicyclo[3.1.0]hexanyl, the 3-azabicyclo[3.1.0]hexanyl, the 2-azaspiro[3.3]heptanyl or the 2-oxa-5-azaspiro[3.4]octanyl is optionally replaced by one or more R Z replace.

[0396] In some embodiments, Z is oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, 3-oxabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexanyl, 2-azaspiro[3.3]heptanyl, 2-oxa-5-azaspiro[3.4]octanyl, wherein the oxetanyl, the tetrahydrofuranyl, the pyrrolidinyl, the piperidinyl, the morpholinyl, the 3-oxabicyclo[3.1.0]hexanyl, the 2-azaspiro[3.3]hexanyl or the 2-oxa-5-azaspiro[3.4]octanyl is optionally replaced by one or more R Z replace.

[0397] In some embodiments, Z is

[0398] In some embodiments, Z is

[0399] In some embodiments, z is In some embodiments, z is In some embodiments, z is

[0400] In some embodiments, Z is In some embodiments, z is

[0401] In some embodiments, z is

[0402] In some embodiments, z is

[0403] In some embodiments, Z is

[0404] In some embodiments, z is

[0405] In some embodiments, z is

[0406] In some embodiments, at least one R Z It's a halogen.

[0407] In some embodiments, at least one R Z It is F or Cl.

[0408] In some embodiments, at least one R Z It's F.

[0409] In some embodiments, at least one R Z It's Cl.

[0410] In some embodiments, at least one R Z is F, and at least one R Z It's Cl.

[0411] In some embodiments, at least one R Z It is CN, -OH or -NH2.

[0412] In some embodiments, at least one R Z -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10aryl, 3 to 10 membered heterocycloalkyl or 5 to 10 membered heteroaryl; wherein said -O-(C1-C6 alkyl), said -NH(C1-C6 alkyl), said -N(C1-C6 alkyl)2, said C1-C6 alkyl, said C2-C6 alkenyl, said C2-C6 alkynyl, said C3-C 10 Cycloalkyl, the C6-C 10 The aryl group, the 3 to 10 membered heterocycloalkyl group or the 5 to 10 membered heteroaryl group are optionally substituted by one or more R Za replace.

[0413] In some embodiments, at least one R Z is optionally replaced by one or more R Za Substituted-O-(C1-C6 alkyl).

[0414] In some embodiments, at least one R Z It is -O-(C1-C6 alkyl).

[0415] In some embodiments, at least one R Z It is -OCH3.

[0416] In some embodiments, at least one R Z is one or more R Za Substituted-O-(C1-C6 alkyl).

[0417] In some embodiments, at least one R Z is -O-(C1-C6 alkyl) optionally substituted with one or more halogens (eg, F or Cl).

[0418] In some embodiments, at least one R Z is -NH(C1-C6 alkyl) or -N(C1-C6 alkyl) 2, wherein said -NH(C1-C6 alkyl) or said -N(C1-C6 alkyl) 2 is optionally replaced by one or more R Za replace.

[0419] In some embodiments, at least one R Z is optionally replaced by one or more R Za Substituted C1-C6 alkyl.

[0420] In some embodiments, at least one R Z It is a C1-C6 alkyl group.

[0421] In some embodiments, at least one R Z is methyl, ethyl or propyl (eg, isopropyl).

[0422] In some embodiments, at least one R Z is one or more RZa Substituted C1-C6 alkyl.

[0423] In some embodiments, at least one R Z is C1-C6 alkyl optionally substituted with one or more halogens (eg, F or Cl).

[0424] In some embodiments, at least one R Z It is a C1-C6 alkyl group substituted by one or more F groups.

[0425] In some embodiments, at least one R Z It's CF3.

[0426] In some embodiments, at least one R Z is C2-C6 alkenyl or C2-C6 alkynyl, wherein the C2-C6 alkenyl or the C2-C6 alkynyl is optionally substituted by one or more R Za replace.

[0427] In some embodiments, at least one R Z It is C3-C 10 Cycloalkyl, C6-C 10 aryl, 3 to 10 membered heterocycloalkyl or 5 to 10 membered heteroaryl; wherein the C3-C 10 Cycloalkyl, the C6-C 10 The aryl group, the 3 to 10 membered heterocycloalkyl group or the 5 to 10 membered heteroaryl group are optionally substituted by one or more R Za replace.

[0428] In some embodiments, at least one R Z is optionally replaced by one or more R Za Substituted C3-C 10 Cycloalkyl.

[0429] In some embodiments, at least one R Z is optionally replaced by one or more R Za Substituted C6-C 10 Aryl.

[0430] In some embodiments, at least one R Z is optionally replaced by one or more R Za Substituted 3- to 10-membered heterocycloalkyl.

[0431] In some embodiments, at least one R Z is optionally replaced by one or more R Za Substituted 4-membered heterocycloalkyl.

[0432] In some embodiments, at least one R Z It is a 4-membered heterocycloalkyl group.

[0433] In some embodiments, at least one R Z It is an oxetane group.

[0434] In some embodiments, at least one R Z is optionally replaced by one or more R Za Substituted 5- to 10-membered heteroaryl.

[0435] In some embodiments, at least one R Za It's a halogen.

[0436] In some embodiments, at least one R Za It is F or Cl.

[0437] In some embodiments, at least one R Za It's F.

[0438] In some embodiments, at least one R Za It's Cl.

[0439] In some embodiments, at least one R Za CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl.

[0440] Variables T, R T and R Ta

[0441] In some embodiments, T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein said -O-(C1-C6 alkyl), said -NH-(C1-C6 alkyl), said C1-C6 alkyl, said C2-C6 alkenyl or said C2-C6 alkynyl is optionally replaced by one or more R T replace;

[0442] Each R T are independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10aryl, 3 to 7 membered heterocycloalkyl or 5 to 10 membered heteroaryl; wherein said -O-(C1-C6 alkyl), said C1-C6 alkyl, said C2-C6 alkenyl, said C2-C6 alkynyl, said C3-C 10 Cycloalkyl, the C6-C 10 The aryl group, the 3 to 7 membered heterocycloalkyl group or the 5 to 10 membered heteroaryl group are optionally substituted by one or more R Ta replace; and

[0443] Each R Ta are independently halogen, CN, -OH, -NH2, -C(=O)OH, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl.

[0444] In some embodiments, T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein said -O-(C1-C6 alkyl), said -NH-(C1-C6 alkyl), said C1-C6 alkyl, said C2-C6 alkenyl or said C2-C6 alkynyl is optionally replaced by one or more R T replace;

[0445] Each R T are independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3 to 7 membered monocyclic heterocycloalkyl or 5 to 10 membered heteroaryl; wherein said -O-(C1-C6 alkyl), said C1-C6 alkyl, said C2-C6 alkenyl, said C2-C6 alkynyl, said C3-C 10 Cycloalkyl, the C6-C 10 The aryl group, the 3 to 7 membered monocyclic heterocycloalkyl group or the 5 to 10 membered heteroaryl group are optionally substituted by one or more R Ta replace; and

[0446] Each R Ta are independently halogen, CN, -OH, -NH2, -C(=O)OH, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl.

[0447] In some embodiments, T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl, or the C2-C6 alkynyl is optionally replaced by one or more R T replace; and

[0448] Each R T independently halogen, -OH, -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2 or 3- to 7-membered heterocycloalkyl; wherein said -O-(C1-C6 alkyl), said -N(C1-C6 alkyl)2 or said 3- to 7-membered heterocycloalkyl are optionally substituted by one or more -C(=O)OH.

[0449] In some embodiments, T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl, or the C2-C6 alkynyl is optionally replaced by one or more R T replace; and

[0450] Each R T is independently halogen, -OH, -O-(C1-C6 alkyl) or 3- to 7-membered heterocycloalkyl; wherein said -O-(C1-C6 alkyl) or said 3- to 7-membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH.

[0451] In some embodiments, T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl, or the C2-C6 alkynyl is optionally replaced by one or more R T replace; and

[0452] Each R T independently halogen, -OH, -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2 or 3 to 7 membered monocyclic heterocycloalkyl; wherein said -O-(C1-C6 alkyl), said -N(C1-C6 alkyl)2 or said 3 to 7 membered monocyclic heterocycloalkyl are optionally substituted by one or more -C(=O)OH.

[0453] In some embodiments, T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl, or the C2-C6 alkynyl is optionally replaced by one or more R T replace; and

[0454] Each R T is independently halogen, -OH, -O-(C1-C6 alkyl) or 3- to 7-membered heterocycloalkyl; wherein said -O-(C1-C6 alkyl) or said 3- to 7-membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH.

[0455] In some embodiments, T is optionally replaced by one or more R T Substituted-O-(C1-C6 alkyl).

[0456] In some embodiments, T is -O-(C1-C6 alkyl).

[0457] In some embodiments, T is -OCH3.

[0458] In some embodiments, T is optionally replaced by one or more R T Substituted-NH-(C1-C6 alkyl).

[0459] In some embodiments, T is -NH-(C1-C6 alkyl).

[0460] In some embodiments, T is -NHCH3.

[0461] In some embodiments, T is optionally replaced by one or more R T Substituted-C1-C6 alkyl.

[0462] In some embodiments, T is C1-C6 alkyl.

[0463] In some embodiments, T is methyl or ethyl.

[0464] In some embodiments, T is methyl.

[0465] In some embodiments, T is ethyl.

[0466] In some embodiments, T is replaced by one or more R T Substituted C1-C6 alkyl.

[0467] In some embodiments, T is C1-C6 alkyl substituted with one or more halogens (eg, F or Cl).

[0468] In some embodiments, T is methyl substituted with one or more halogens (eg, F or Cl).

[0469] In some embodiments, T is -CHFCl.

[0470] In some embodiments, T is C1-C6 alkyl substituted with one or more CN.

[0471] In some embodiments, T is -CH2CN.

[0472] In some embodiments, T is optionally replaced by one or more R T 取代的C2 -C6 alkenyl.

[0473] In some embodiments, T is C2-C6 alkenyl.

[0474] In some embodiments, T is vinyl (ie, -CH=CH2).

[0475] In some embodiments, T is propenyl (eg, -C(CH3)=CH2 or -CH=CH-CH3).

[0476] In some embodiments, T is pentenyl (eg, -CH=CH-C(CH3)2).

[0477] In some embodiments, T is replaced by one or more R T 取代的C2 -C6 alkenyl.

[0478] In some embodiments, T is C2-C6 alkenyl substituted with one or more -OH, -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2, or 3- to 10-membered heterocycloalkyl; wherein the 3- to 10-membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH.

[0479] In some embodiments, T is C2-C6 alkenyl substituted with one or more -OH groups.

[0480] In some embodiments, T is C2-C6 alkenyl substituted with one or more -O-(C1-C6 alkyl).

[0481] In some embodiments, T is C2-C6 alkenyl substituted with one or more -OCH3.

[0482] In some embodiments, T is C2-C6 alkenyl substituted with one or more -N(C1-C6 alkyl)2.

[0483] In some embodiments, T is C2-C6 alkenyl substituted with one or more -N(CH3)2.

[0484] In some embodiments, T is C2-C6 alkenyl substituted with one or more 3- to 10-membered heterocycloalkyl groups.

[0485] In some embodiments, T is C2-C6 alkenyl substituted with one or more 3- to 10-membered heterocycloalkyl groups; wherein said 3- to 10-membered heterocycloalkyl groups are optionally substituted with one or more -C(=O)OH groups.

[0486] In some embodiments, T is C2-C6 alkenyl substituted with one or more 3- to 7-membered heterocycloalkyl groups.

[0487] In some embodiments, T is C2-C6 alkenyl substituted with one or more 3- to 7-membered heterocycloalkyl groups; wherein said 3- to 7-membered heterocycloalkyl groups are optionally substituted with one or more -C(=O)OH groups.

[0488] In some embodiments, T is C2-C6 alkenyl substituted with one or more 3- to 7-membered heterocycloalkyl groups.

[0489] In some embodiments, T is C2-C6 alkenyl substituted with one or more 3- to 7-membered monocyclic heterocycloalkyl groups.

[0490] In some embodiments, T is C2-C6 alkenyl substituted with one or more 3 to 7 membered monocyclic heterocycloalkyl; wherein said 3 to 7 membered monocyclic heterocycloalkyl is optionally substituted with one or more -C(=O)OH.

[0491] In some embodiments, T is C2-C6 alkenyl substituted with one or more 3- to 7-membered monocyclic heterocycloalkyl groups.

[0492] In some embodiments, T is C2-C6 alkenyl substituted with one or more 6-membered heterocycloalkyl; wherein the 6-membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH.

[0493] In some embodiments, T is C2-C6 alkenyl substituted with one or more 6-membered heterocycloalkyl groups.

[0494] In some embodiments, T is C2-C6 alkenyl substituted with one or more 6-membered monocyclic heterocycloalkyl; wherein the 6-membered monocyclic heterocycloalkyl is optionally substituted with one or more -C(=O)OH.

[0495] In some embodiments, T is C2-C6 alkenyl substituted with one or more 6-membered monocyclic heterocycloalkyl groups.

[0496] In some embodiments, T is optionally replaced by one or more R T Substituted C2-C6 alkynyl.

[0497] In some embodiments, T is C2-C6 alkynyl.

[0498] In some embodiments, T is propynyl (eg, -C≡C-CH3).

[0499] In some embodiments, T is replaced by one or more R T Substituted C2-C6 alkynyl.

[0500] In some embodiments, T is replaced by one or more R T Substituted propynyl.

[0501] In some embodiments, T is -C≡C-CH2-R T .

[0502] In some embodiments, T is C2-C6 alkynyl substituted with one or more 3- to 10-membered heterocycloalkyl groups.

[0503] In some embodiments, T is propynyl substituted with one or more 3- to 10-membered heterocycloalkyl groups.

[0504] In some embodiments, T is C2-C6 alkynyl substituted with one or more 3- to 7-membered heterocycloalkyl groups.

[0505] In some embodiments, T is propynyl substituted with one or more 3- to 7-membered heterocycloalkyl groups.

[0506] In some embodiments, T is

[0507] In some embodiments, T is

[0508] In some embodiments, T is

[0509] In some embodiments, T is

[0510] In some embodiments, T is

[0511] In some embodiments, T is

[0512] In some embodiments, T is

[0513] In some embodiments, T is

[0514] In some embodiments, at least one R T is a halogen (eg, F or Cl).

[0515] In some embodiments, at least one R T It's F.

[0516] In some embodiments, at least one R T It's Cl.

[0517] In some embodiments, at least one RT It is CN, -OH or -NH2.

[0518] In some embodiments, at least one R T It is CN.

[0519] In some embodiments, at least one R T It is -OH.

[0520] In some embodiments, at least one R T is -O-(C1-C6 alkyl), -NH(C1-C6 alkyl) or -N(C1-C6 alkyl) 2; wherein said O-(C1-C6 alkyl), said -NH(C1-C6 alkyl) or said -N(C1-C6 alkyl) 2 is optionally replaced by one or more R Ta replace.

[0521] In some embodiments, at least one R T is -O-(C1-C6 alkyl) or -N(C1-C6 alkyl) 2; wherein said O-(C1-C6 alkyl) or said -N(C1-C6 alkyl) 2 is optionally replaced by one or more R Ta replace.

[0522] In some embodiments, at least one R T It is -O-(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[0523] In some embodiments, at least one R T It is -O-(C1-C6 alkyl).

[0524] In some embodiments, at least one R T It is -N(C1-C6 alkyl)2.

[0525] In some embodiments, at least one R T is C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein said C1-C6 alkyl, said C2-C6 alkenyl or said C2-C6 alkynyl is optionally substituted by one or more R Ta replace.

[0526] In some embodiments, at least one R T It is C3-C 10 Cycloalkyl, C6-C 10 aryl, 3 to 10 membered heterocycloalkyl or 5 to 10 membered heteroaryl; wherein the C3-C 10 Cycloalkyl, the C6-C 10 The aryl group, the 3 to 10 membered heterocycloalkyl group or the 5 to 10 membered heteroaryl group are optionally substituted by one or more R Ta replace.

[0527] In some embodiments, at least one R T is optionally replaced by one or more R Ta Substituted 3- to 10-membered heterocycloalkyl.

[0528] In some embodiments, at least one R T is one or more R Ta Substituted 3- to 10-membered heterocycloalkyl.

[0529] In some embodiments, at least one R T is a 3- to 10-membered heterocycloalkyl group substituted by one or more C(=O)OH groups.

[0530] In some embodiments, at least one R T is optionally replaced by one or more R Ta Substituted 3- to 7-membered heterocycloalkyl.

[0531] In some embodiments, at least one R T It is a 3- to 7-membered heterocycloalkyl group.

[0532] In some embodiments, at least one R T is one or more R Ta Substituted 3- to 7-membered heterocycloalkyl.

[0533] In some embodiments, at least one R T is a 3- to 7-membered heterocycloalkyl group substituted by one or more C(=O)OH groups.

[0534] In some embodiments, at least one R T is optionally replaced by one or more R Ta Substituted 6-membered heterocycloalkyl.

[0535] In some embodiments, at least one R T It is a 6-membered heterocycloalkyl group.

[0536] In some embodiments, at least one R T is one or more R Ta Substituted 6-membered heterocycloalkyl.

[0537] In some embodiments, at least one R T is a 6-membered heterocycloalkyl substituted by one or more C(=O)OH.

[0538] In some embodiments, at least one R T is optionally replaced by one or more R Ta Substituted 3- to 7-membered monocyclic heterocycloalkyl.

[0539] In some embodiments, at least one R TIt is a 3- to 7-membered monocyclic heterocycloalkyl group.

[0540] In some embodiments, at least one R T is one or more R Ta Substituted 3- to 7-membered monocyclic heterocycloalkyl.

[0541] In some embodiments, at least one R T is a 3- to 7-membered monocyclic heterocycloalkyl substituted by one or more C(=O)OH.

[0542] In some embodiments, at least one R T is optionally replaced by one or more R Ta Substituted 6-membered monocyclic heterocycloalkyl.

[0543] In some embodiments, at least one R T It is a 6-membered monocyclic heterocycloalkyl group.

[0544] In some embodiments, at least one R T is one or more R Ta Substituted 6-membered monocyclic heterocycloalkyl.

[0545] In some embodiments, at least one R T is a 6-membered monocyclic heterocycloalkyl substituted by one or more C(=O)OH.

[0546] In some embodiments, at least one R Ta It is C(=O)OH.

[0547] In some embodiments, at least one R Ta Halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl.

[0548] Variable Ar 1 、R A1 、R A1a and R A1b

[0549] In some embodiments, Ar 1 is optionally replaced by one or more R A1 Substituted C6-C 10 aryl;

[0550] Each R A1 are independently halogen, CN, -OH, -NH2, -ORA1a , -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein the -O-(C1-C6 alkyl), the -NH(C1-C6 alkyl), the -N(C1-C6 alkyl)2, the C1-C6 alkyl, the C2-C6 alkenyl or the C2-C6 alkynyl are optionally replaced by one or more R A1a replace;

[0551] Each R A1a are independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein said -O-(C1-C6 alkyl), said -NH(C1-C6 alkyl), said -N(C1-C6 alkyl)2, said C1-C6 alkyl, said C2-C6 alkenyl or said C2-C6 alkynyl are optionally substituted by one or more R A1b replace; and

[0552] Each R A1b are independently halogen, CN, -OH or -NH2.

[0553] In some embodiments, Ar 1 It is C6-C 10 Aryl.

[0554] In some embodiments, Ar 1 is one or more R A1 Substituted C6-C 10 Aryl.

[0555] In some embodiments, Ar 1 is one or more R A1 Substituted phenyl.

[0556] In some embodiments, Ar 1 is one or more halogens, -OR A1a or -O-(C1-C6 alkyl) substituted phenyl; wherein said -O-(C1-C6 alkyl) is optionally substituted by one or more R A1a Replace; and each R A1a Independently C6-C 10 aryl or 5 to 10 membered heteroaryl; wherein the C6-C 10 The aryl or the 5- to 10-membered heteroaryl is optionally substituted with one or more halogens.

[0557] In some embodiments, Ar 1is phenyl substituted by one or more halogens.

[0558] In some embodiments, Ar 1 is phenyl substituted by one or more F or Cl.

[0559] In some embodiments, Ar 1 It is a phenyl group substituted with one F and one Cl.

[0560] In some embodiments, Ar 1 is phenyl optionally substituted by one or more halogens, wherein the phenyl is further substituted by -O-(C6-C 10 aryl) or -O-(5 to 10 membered heteroaryl); wherein said -O-(C6-C 10 aryl) or the -O-(5- to 10-membered heteroaryl) is optionally substituted with one or more halogens.

[0561] In some embodiments, Ar 1 is phenyl optionally substituted with one or more halogens, wherein said phenyl is further substituted with -O-phenyl or -O-pyridyl; wherein said -O-phenyl or said -O-pyridyl is optionally substituted with one or more halogens.

[0562] In some embodiments, Ar 1 is phenyl optionally substituted with one or more halogens, wherein said phenyl is further substituted with -O-phenyl; wherein said -O-phenyl is optionally substituted with one or more halogens.

[0563] In some embodiments, Ar 1 is phenyl optionally substituted with one or more halogens, wherein said phenyl is further substituted with -O-pyridyl; wherein said -O-pyridyl is optionally substituted with one or more halogens.

[0564] In some embodiments, Ar 1 yes

[0565] In some embodiments, Ar 1 yes

[0566] In some embodiments, Ar 1 yes

[0567] In some embodiments, Ar 1 yes

[0568] In some embodiments, Ar 1 yes

[0569] In some embodiments, Ar 1 yes In some embodiments, Ar 1 yes

[0570] In some embodiments, Ar 1 yes In some embodiments, Ar 1 yes In some embodiments, Ar 1 yes In some embodiments, Ar 1 yes In some embodiments, Ar 1 yes In some embodiments, Ar 1 yes In some embodiments, Ar 1 yes In some embodiments, at least one R A1 is a halogen (eg, F or Cl).

[0571] In some embodiments, at least one R A1 It's F.

[0572] In some embodiments, at least one R A1 It's Cl.

[0573] In some embodiments, at least one R A1 is F, and at least one R A1 It's Cl.

[0574] In some embodiments, at least one R A1 It is CN, -OH or -NH2.

[0575] In some embodiments, at least one R A1 Yes-OR A1a .

[0576] In some embodiments, at least one R A1 Yes-O-(C6-C 10 aryl) or -O-(5- to 10-membered heteroaryl); wherein said -O-(C6-C 10 aryl) or said -O-(5 to 10 membered heteroaryl) is optionally substituted by one or more R A1b replace.

[0577] In some embodiments, at least one R A1 Yes-O-(C6-C 10aryl) or -O-(5- to 10-membered heteroaryl); wherein said -O-(C6-C 10 aryl) or the -O-(5- to 10-membered heteroaryl) is optionally substituted with one or more halogens.

[0578] In some embodiments, at least one R A1 is -O-phenyl or -O-pyridinyl; wherein said -O-phenyl or said -O-pyridinyl is optionally substituted with one or more halogens.

[0579] In some embodiments, at least one R A1 is -O-phenyl optionally substituted by one or more halogens.

[0580] In some embodiments, at least one R A1 is -O-pyridinyl optionally substituted by one or more halogens.

[0581] In some embodiments, at least one R A1 is -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, wherein said -O-(C1-C6 alkyl), said -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted by one or more R A1a replace.

[0582] In some embodiments, at least one R A1 is optionally replaced by one or more R A1a Substituted-O-(C1-C6 alkyl).

[0583] In some embodiments, at least one R A1 is one or more R A1a Substituted-O-(C1-C6 alkyl).

[0584] In some embodiments, at least one R A1 is one or more C6-C 10 -O-(C1-C6 alkyl) substituted with aryl or 5 to 10 membered heteroaryl, wherein the C6-C 10 The aryl or the 5- to 10-membered heteroaryl is optionally substituted with one or more halogens.

[0585] In some embodiments, at least one R A1 Yes -O-CH2-R A1a .

[0586] In some embodiments, at least one R A1It is -O-CH2-(C6-C 10 aryl) or -O-CH2-(5 to 10 membered heteroaryl), wherein the -O-CH2-(C6-C 10 aryl) or -O-CH2-(5- to 10-membered heteroaryl) is optionally substituted with one or more halogens.

[0587] In some embodiments, at least one R A1 is -O-CH2-phenyl or -O-CH2-pyridyl, wherein said -O-CH2-phenyl or said -O-CH2-pyridyl is optionally substituted with one or more halogens.

[0588] In some embodiments, at least one R A1 is -O-CH2-phenyl optionally substituted by one or more halogens.

[0589] In some embodiments, at least one R A1 is -O-CH2-pyridyl optionally substituted by one or more halogens.

[0590] In some embodiments, at least one R A1 It is C3-C 10 Cycloalkyl, C6-C 10 aryl, 3 to 10 membered heterocycloalkyl or 5 to 10 membered heteroaryl; wherein the C3-C 10 Cycloalkyl, the C6-C 10 The aryl group, the 3 to 10 membered heterocycloalkyl group or the 5 to 10 membered heteroaryl group are optionally substituted by one or more R A1a replace.

[0591] In some embodiments, at least one R A1a is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, wherein said -O-(C1-C6 alkyl), said -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally replaced by one or more R A1b replace.

[0592] In some embodiments, at least one R A1a It is C3-C 10 Cycloalkyl, C6-C 10 aryl, 3 to 10 membered heterocycloalkyl or 5 to 10 membered heteroaryl; wherein the C3-C 10 Cycloalkyl, the C6-C 10The aryl group, the 3 to 10 membered heterocycloalkyl group or the 5 to 10 membered heteroaryl group are optionally substituted by one or more R A1b replace.

[0593] In some embodiments, at least one R A1a It is C3-C 10 Cycloalkyl, C6-C 10 aryl, 3 to 10 membered heterocycloalkyl or 5 to 10 membered heteroaryl; wherein the C3-C 10 Cycloalkyl, the C6-C 10 The aryl group, the 3- to 10-membered heterocycloalkyl group, or the 5- to 10-membered heteroaryl group is optionally substituted with one or more halogens.

[0594] In some embodiments, at least one R A1a It is C6-C 10 aryl or 5 to 10 membered heteroaryl; wherein the C6-C 10 The aryl or the 5- to 10-membered heteroaryl is optionally substituted with one or more halogens.

[0595] In some embodiments, at least one R A1a is phenyl or pyridinyl; wherein said phenyl or said pyridinyl is optionally substituted with one or more halogens.

[0596] In some embodiments, at least one R A1a is phenyl optionally substituted by one or more halogens.

[0597] In some embodiments, at least one R A1a is pyridinyl optionally substituted by one or more halogens.

[0598] In some embodiments, at least one R A1b It's a halogen.

[0599] In some embodiments, at least one R A1b It's F.

[0600] In some embodiments, at least one R A1b It's Cl.

[0601] In some embodiments, at least one R A1b is F, and at least one R A1b It's Cl.

[0602] In some embodiments, at least one R A1b It is CN, -OH or -NH2.

[0603] Exemplary embodiments of compounds

[0604] In some embodiments, when Z is but

[0605] T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein said -O-(C1-C6 alkyl), said -NH-(C1-C6 alkyl), said C1-C6 alkyl or said C2-C6 alkynyl is optionally replaced by one or more R T substituted; and wherein the C2-C6 alkenyl is replaced by one or more R T replace,

[0606] Each R T are independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3 to 10 membered heterocycloalkyl or 5 to 10 membered heteroaryl; wherein said -O-(C1-C6 alkyl), said C1-C6 alkyl, said C2-C6 alkenyl, said C2-C6 alkynyl, said C3-C 10 Cycloalkyl, the C6-C 10 The aryl group, the 3 to 10 membered heterocycloalkyl group or the 5 to 10 membered heteroaryl group are optionally substituted by one or more R Ta replace; and

[0607] Each R Ta are independently halogen, CN, -OH, -NH2, -C(=O)OH, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl.

[0608] In some embodiments, when Z is When T is not

[0609] In some embodiments, when Z is When Ar 1 is a C6-C 10 Aryl.

[0610] In some embodiments, Z is not

[0611] In some embodiments, Z is not

[0612] In some embodiments, T is not

[0613] In some embodiments, the compound has formula (II'):

[0614]

[0615] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0616] In some embodiments, the compound has formula (II'):

[0617]

[0618] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0619] In some embodiments, the compound has formula (III') or (III'-a):

[0620]

[0621] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0622] In some embodiments, the compound has formula (IV') or (IV'-a):

[0623]

[0624] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0625] In some aspects, the present disclosure provides a compound having Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0626]

[0627] in

[0628] W is CH or N, preferably CH;

[0629] X 1 It is -O-, -S-, -NR 3 -;

[0630] R a 、R b independently of each other are hydrogen, 1-4 Alkyl, or R a One of the is if X 1 It is NR 3 , then with X 1 Ring-forming -(CH2) p , or R a One of them is with R 2 Ring-forming -(CH2)p ;

[0631] R c 、R d are independently hydrogen or C 1-4 alkyl;

[0632] R 1 is H or F;

[0633] R 2 is hydrogen or C 1-4 Alkyl, or with R 3 or with R a One of the ring-forming -(CH2) q ;

[0634] R 3 is hydrogen or C 1-4 Alkyl, preferably hydrogen or methyl, or with R 2 Ring-forming -(CH2) p -;

[0635] m is 1, 2, or 3;

[0636] n is 0, 1, or 2;

[0637] p is 1 or 2;

[0638] q is 0, 1, or 2; and

[0639] Ar 1 is a 6-membered aryl group which is unsubstituted or substituted by one or more of the following groups: halogen, -CF3, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy-C6 aryl, C 1-6 Alkoxy-C 5-6 Heteroaryl, amino, amino C 1-4 Alkyl, C 1-6 Alkylamino, C 1-6 Aminoalkyl-C6 aryl, C 1-6 aminoalkyl-C 5-6 Heteroaryl, C 1-6 Alkoxycarbonyl, C 1-6 Alkoxyaminocarbonyl, aryl C 1-6 Alkoxy or C6 aryl.

[0640] In some embodiments of compounds of Formula I, W is CH.

[0641] In some embodiments, when n is 0, R 2 is with R 3 or with R a One of the ring-forming -(CH2) q -.

[0642] In some embodiments, when n is 0, R 2 is with R 3 Ring-forming -(CH2) q -.

[0643] In some embodiments, n is 0, and R 2 is with R 3 or with R a One of the ring-forming -(CH2) q -.

[0644] In some embodiments, n is 0, and R 2 is with R 3 Ring-forming -(CH2) q -.

[0645] In some embodiments of the compound of Formula I, X 1 Is -O- or -NR 3 -, more preferably -NR 3 -.

[0646] In some embodiments of the compound of Formula I, R b is always hydrogen, so that only R a may not be hydrogen. For example, R b can be hydrogen and R a It can be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, or with R 2 Preferably, R b may be hydrogen, and R a It can be methyl or with R 2 -(CH2)- or -(CH2)2- forming a ring. In addition, R a and R b Both can be hydrogen.

[0647] In some embodiments, X 1 The ring of which it is a part is a monocyclic or bicyclic ring.

[0648] In some embodiments of the compound of Formula I, R c is always hydrogen, so that only R d It may not be hydrogen. For example, R c can be hydrogen and R dIt can be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. c can be hydrogen and R d It can be methyl. In addition, R c and R d Both can be hydrogen.

[0649] In some embodiments of the compound of Formula I, R 1 It's hydrogen.

[0650] In some embodiments of the compound of Formula I, R c and R d In some embodiments of the compound of Formula I, R b 、R c and R d In some embodiments of the compound of Formula I, R 1 、R b 、R c and R d It's hydrogen.

[0651] In which R a One of the R 3 In some embodiments of compounds of Formula I that form a ring, the formed ring is a 4-membered, 5-membered, or 6-membered ring, or a 5-membered or 6-membered ring, or a 5-membered ring.

[0652] In which R a One of the R 3 In some embodiments of compounds of Formula I that form a ring, the formed ring is a 3-membered, 4-membered, 5-membered, or 6-membered ring.

[0653] In which R 2 One of the R 3 In some embodiments of compounds of Formula I that form a ring, the formed ring is a 4-, 5-, or 6-membered ring, or a 5- or 6-membered ring, or a 6-membered ring.

[0654] In some embodiments of the compound of Formula I, R 2 It is C 1-4 Alkyl, or with R 3 or with R a Ring-forming -(CH2) q -. For example, R 2 can be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, or R 2 is with R 3 -(CH2)- or -(CH2)2 forming a ring, or R 2 is with R a One of them forms a ring -(CH2)- or -(CH2)2-. Preferably, R 2can be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl, or R 2 is with R 3 -(CH2)- or -(CH2)2- forming a ring, or R 2 is with R a More preferably, R 2 It may be methyl.

[0655] In some embodiments of the compound of Formula I, R 3 is hydrogen or methyl or R 3 is with R 2 -(CH2)- or -(CH2)2- forming a ring.

[0656] In some embodiments of compounds of Formula I, n is 0 and m is 1, 2, or 3; or n is 0 and m is 1 or 2; or n is 1 and m is 1, 2, or 3; or n is 1 and m is 1 or 2; or n is 2 and m is 1, 2, or 3; or n is 2 and m is 1 or 2; or n is 0, 1 or 2 and m is 1 or 2; or n is 0, 1 or 2 and m is 1; or n is 1 or 2 and m is 1, 2, or 3; or n is 1 or 2 and m is 1 or 2; or n is 1 or 2 and m is 1 or 3; or n is 1 or 2 and m is 2 or 3.

[0657] In some embodiments of the compound of Formula I, X 1 Can be combined with R 2 The carbon atoms directly bonded form a heterocyclic ring. For example, X 1 Can form 4-membered, 5-membered, 6-membered or 7-membered heterocyclic ring. In some embodiments of the compound of formula I, X 1 Substituted or unsubstituted oxetanyl, thianyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiopyranyl, dihydropyranyl, tetrahydropyranyl, piperidinyl, oxetanyl, thienyl, azepanyl, azabicyclo[2.2.1]heptane or azabicyclo[2.2.2]octane can be formed, preferably azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, more preferably azetidinyl, pyrrolidinyl or piperidinyl.

[0658] In some embodiments of the compound of Formula I, Ar 1 having formula I or a pharmaceutically acceptable salt or stereoisomer thereof,

[0659]

[0660] in

[0661] R 4 Hydrogen, halogen, C1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy-C6 aryl, C 1-6 Alkoxy-C 5-6 Heteroaryl, amino C 1-4 Alkyl, C 1-6 Alkylamino, C 1-6 Aminoalkyl-C6 aryl, C 1-6 aminoalkyl-C 5-6 Heteroaryl, C 1-6 Alkoxycarbonyl, C 1-6 Alkoxyamino-carbonyl, aryl C 1-6 Alkoxy or C6 aryl;

[0662] R 5 、R 5 '、R 6 、R 6 ' are independently hydrogen, -CF3 or halogen, preferably F, Cl.

[0663] In some embodiments of the compound of Formula I, wherein Ar 1 With formula i, R 4 It is hydrogen, fluorine, chlorine, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 1-4 Alkoxy-C6 aryl, C 1-4 Alkoxy-C 5-6 Heteroaryl, amino C 1-4 Alkyl, C 1-4 Alkylamino, C 1-4 Aminoalkyl-C6 aryl, C 1-4 aminoalkyl-C6 heteroaryl, C 1-4 Alkoxycarbonyl, C 1-4 Alkoxyaminocarbonyl or C6 aryl.

[0664] In some embodiments of the compound of Formula I, wherein Ar 1 With formula i, R 4 It is hydrogen, fluorine, chlorine, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C1-4 Alkoxy-C6 aryl, C 1-4 Alkoxy-C 5-6 heteroaryl or C6 aryl.

[0665] In some embodiments of the compound of Formula I, wherein Ar 1 With formula i, R 4 Typically hydrogen, fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-propoxy, n-butoxy, isobutoxy, n-pentyloxy, isopentyl, n-hexyloxy, isohexyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, methoxymethyl, methoxyethyl, methoxypropyl, methyl Oxybutyl, methoxypentyl, methoxyhexyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, ethoxyhexyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, propoxyhexyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, butoxyhexyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, pentoxyhexyl, hexyl Oxymethyl, hexyloxyethyl, hexyloxypropyl, hexyloxybutyl, hexyloxypentyl, hexyloxyhexyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl, methylamino, ethylamino, propylamino, butylamino, pentylamino, hexylamino, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, methoxyaminocarbonyl, ethoxyaminocarbonyl, propoxyaminocarbonyl, butoxyaminocarbonyl , pentyloxyaminocarbonyl, hexyloxyaminocarbonyl, phenylmethoxy, phenylethoxy, phenylpropoxy, phenylbutoxy, phenylpentyloxy, phenylhexyloxy, m-fluorophenylmethoxy, m-fluorophenylphenylethoxy, m-fluorophenylphenylpropoxy, m-fluorophenylphenylbutoxy, m-fluorophenylphenylpentyloxy, m-fluorophenylphenylhexyloxy, pyridylmethoxy, pyridylethoxy, pyridylpropoxy, pyridylbutoxy, pyridylpentyloxy, pyridylhexyloxy, phenyl, pyridyl or naphthyl.

[0666] In some embodiments of the compound of Formula I, wherein Ar 1 With formula i, R 5 and R 6 are independently hydrogen, -CF3, F or Cl, and R 5 ' and R 6 ' is hydrogen. Preferably, R 4 Hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy-C6 aryl, C 1-6 Alkoxy-C 5-6 Heteroaryl, amino C 1-4 Alkyl, C 1-6 Alkylamino, C 1-6 Aminoalkyl-C6 aryl, C 1-6 aminoalkyl-C 5-6 Heteroaryl, C 1-6 Alkoxycarbonyl, C 1-6 Alkoxyamino-carbonyl, aryl C 1-6 Alkoxy or C6 aryl.

[0667] In some embodiments of the compound of Formula I, wherein Ar 1 With formula i, R 5 and R 6 are independently hydrogen, -CF3, F or Cl, and R 5 ' and R 6 ' is hydrogen. Preferably, R 4 It is hydrogen, fluorine, chlorine, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 1-4 Alkoxy-C6 aryl, C 1-4 Alkoxy-C 5-6 Heteroaryl, amino C 1-4 Alkyl, C 1-4 Alkylamino, C 1-4 Aminoalkyl-C6 aryl, C 1-4 aminoalkyl-C6 heteroaryl, C 1-4 Alkoxycarbonyl, C 1-4 Alkoxyaminocarbonyl or C6 aryl.

[0668] In some embodiments of the compound of Formula I, wherein Ar 1 Having formula i, Ar 1 includes only 1, 2 or 3 substituents other than hydrogen. Thus, R 4 、R 5 、R 5 '、R 6 or R 6 At least two of ' may be hydrogen.

[0669] In some embodiments of the compound of Formula I, wherein Ar 1 With formula i, R1 It can be hydrogen and / or R 2 It can be methyl or R 2 is with R 3 -(CH2)- or -(CH2)2- forming a ring, or R 2 is with R a One of them forms a -(CH2)- or -(CH2)2- ring.

[0670] In some embodiments of the compound of Formula I, wherein Ar 1 With formula i, R c and R d In some embodiments of the compound of Formula I, wherein Ar 1 With formula i, R b 、R c and R d It's hydrogen.

[0671] In some embodiments of the compound of Formula I, wherein Ar 1 Having formula i, wherein R a One of the R 3 The ring is formed, and the formed ring is a 4-membered, 5-membered, or 6-membered ring, or a 5-membered or 6-membered ring, or a 5-membered ring.

[0672] In some embodiments of the compound of Formula I, wherein Ar 1 Having formula i, wherein R a One of the R 3 The ring is formed, and the formed ring is a 3-membered, 4-membered, 5-membered or 6-membered ring.

[0673] In some embodiments of the compound of Formula I, wherein Ar 1 Having formula i, wherein R 2 One of the R 3 The ring is formed, and the formed ring is a 4-membered, 5-membered, or 6-membered ring, or a 5-membered, 6-membered ring, or a 6-membered ring.

[0674] In some embodiments of the compound of Formula I, Ar 1 having formula ii-1 or a pharmaceutically acceptable salt or stereoisomer thereof,

[0675]

[0676] in

[0677] R 4 is hydrogen, F or Cl;

[0678] R 5 、R 5 '、R 6 、R 6' are independently hydrogen, -CF3 or halogen, preferably F, Cl.

[0679] In some embodiments of the compound of Formula I, Ar 1 having formula ii-2, ii-3 or ii-4 or a pharmaceutically acceptable salt or stereoisomer thereof,

[0680]

[0681] in

[0682] X 2 is O, NH, or NMe;

[0683] X 3 is CH or N;

[0684] o is 0 or 1;

[0685] R 5 、R 5 '、R 6 、R 6 ' are independently hydrogen, -CF3 or halogen, preferably F or Cl;

[0686] R 7 is hydrogen or halogen, preferably F.

[0687] Those skilled in the art will understand that if X 3 represents CH, then R 7 Usually it can also be combined with this carbon, so that X 3 Can be CR 7 Preferably, the corresponding aryl or heteroaryl is only represented by a single R 7 In addition, it is understood that when X 3 When N is R 7 Usually it does not need to be combined with N.

[0688] In some embodiments of the compound of Formula I, wherein Ar 1 Having formula ii-1, ii-2, ii-3 or ii-4, R 5 and R 6 are independently hydrogen, -CF3, F or Cl, and R 5 ' and R 6 'It's hydrogen.

[0689] In some embodiments of the compound of Formula I, wherein Ar 1 Having formula ii-1, ii-2, ii-3 or ii-4, if X 3 is N, then R 7 is hydrogen and / or if X 3 is CH, then R 7 It's F.

[0690] In some embodiments of the compound of Formula I, wherein Ar 1 Having formula ii-1, ii-2, ii-3 or ii-4, o is 1.

[0691] In some embodiments of the compound of Formula I, wherein Ar 1 Having formula ii-1, ii-2, ii-3 or ii-4, R 5 Is F and / or R 6 It is F or Cl.

[0692] In some embodiments of the compound of Formula I, wherein Ar 1 Having formula ii-1, ii-2, ii-3 or ii-4, R c and R d In some embodiments of the compound of Formula I, wherein Ar 1 Having formula ii-1, ii-2, ii-3 or ii-4, R b 、R c and R d It's hydrogen.

[0693] In some embodiments of the compound of Formula I, wherein Ar 1 Having formula ii-1, ii-2, ii-3 or ii-4, wherein R a One of the R 3 The ring is formed, and the formed ring is a 4-membered, 5-membered, or 6-membered ring, or a 5-membered or 6-membered ring, or a 5-membered ring.

[0694] In some embodiments of the compound of Formula I, wherein Ar 1 Having formula ii-1, ii-2, ii-3 or ii-4, wherein R a One of the R 3 The ring is formed, and the formed ring is a 3-membered, 4-membered, 5-membered or 6-membered ring.

[0695] In some embodiments of the compound of Formula I, wherein Ar 1 Having formula ii-1, ii-2, ii-3 or ii-4, wherein R 2 One of the R 3 The ring is formed, and the formed ring is a 4-membered, 5-membered, or 6-membered ring, or a 5-membered, 6-membered ring, or a 6-membered ring.

[0696] In some embodiments of the compound of Formula I, wherein Ar 1 Having formula ii-1, ii-2, ii-3 or ii-4, R 2 is methyl or R 2 is with R 3 -(CH2)- or -(CH2)2- forming a ring, or R2 is with R a One of them forms a -(CH2)- or -(CH2)2- ring.

[0697] In some embodiments, X 2 is O, making Ar 1 having formula ii-1a or a pharmaceutically acceptable salt or stereoisomer thereof,

[0698]

[0699] in

[0700] R 4 is hydrogen, F or Cl;

[0701] R 5 、R 5 '、R 6 、R 6 ' are independently hydrogen, -CF3 or halogen, preferably F, Cl.

[0702] In some embodiments, X 2 is O, making Ar 1 having formula ii-2a, ii-3a or ii-4a or a pharmaceutically acceptable salt or stereoisomer thereof,

[0703]

[0704] in

[0705] X 3 is CH or N, preferably N;

[0706] o is 0 or 1;

[0707] R 5 、R 5 '、R 6 、R 6 ' are independently hydrogen, -CF3 or halogen, preferably F or Cl;

[0708] R 7 is hydrogen or halogen, preferably F.

[0709] In some embodiments of the compound of Formula I, wherein Ar 1 Having formula ii-1a, ii-2a, ii-3a or ii-4a, R 5 and R 6 are independently hydrogen, -CF3, F or Cl, and R 5 ' and R 6 'It's hydrogen.

[0710] In some embodiments of the compound of Formula I, wherein Ar 1 Having formula ii-1a, ii-2a, ii-3a or ii-4a, o is 1.

[0711] In some embodiments of the compound of Formula I, wherein Ar 1 Having formula ii-1a, ii-2a, ii-3a or ii-4a, R 5 Is F and / or R 6 It is F or Cl.

[0712] In some embodiments of the compound of Formula I, wherein Ar 1 Having formula ii-1a, ii-2a, ii-3a or ii-4a, if X 3 is N, then R 7 is hydrogen and / or if X 3 is CH, then R 7 It's F.

[0713] In some embodiments of the compound of Formula I, wherein Ar 1 Having formula ii-1a, ii-2a, ii-3a or ii-4a, R 2 is methyl or R 2 is with R 3 -(CH2)- or -(CH2)2- forming a ring, or R 2 is with R a One of them forms a -(CH2)- or -(CH2)2- ring.

[0714] In some embodiments of the compound of Formula I, wherein Ar 1 Having formula ii-1a, ii-2a, ii-3a or ii-4a, R c and R d In some embodiments of the compound of Formula I, wherein Ar 1 Having formula ii-1a, ii-2a, ii-3a or ii-4a, R b 、R c and R d It's hydrogen.

[0715] In some embodiments of the compound of Formula I, wherein Ar 1 having the formula ii-1a, ii-2a, ii-3a or ii-4a, wherein R a One of the R 3 The ring is formed, and the formed ring is a 4-membered, 5-membered, or 6-membered ring, or a 5-membered or 6-membered ring, or a 5-membered ring.

[0716] In some embodiments of the compound of Formula I, wherein Ar 1having the formula ii-1a, ii-2a, ii-3a or ii-4a, wherein R a One of the R 3 The ring is formed, and the formed ring is a 3-membered, 4-membered, 5-membered or 6-membered ring.

[0717] In some embodiments of the compound of Formula I, wherein Ar 1 having the formula ii-1a, ii-2a, ii-3a or ii-4a, wherein R 2 One of the R 3 The ring is formed, and the formed ring is a 4-membered, 5-membered, or 6-membered ring, or a 5-membered, 6-membered ring, or a 6-membered ring.

[0718] In some embodiments, X 3 is N, making Ar 1 having formula ii-1b or a pharmaceutically acceptable salt or stereoisomer thereof,

[0719]

[0720] in

[0721] R 4 is hydrogen, F or Cl;

[0722] R 5 、R 5 '、R 6 、R 6 ' are independently hydrogen, -CF3 or halogen, preferably F, Cl.

[0723] In some embodiments, X 3 is N, making Ar 1 having formula ii-2b, ii-3b, ii-4b, ii-5b or a pharmaceutically acceptable salt or stereoisomer thereof,

[0724]

[0725] in

[0726] X 2 is O, NH or NMe, preferably O;

[0727] o is 0 or 1;

[0728] R 5 、R 5 '、R 6 、R 6 ' are independently hydrogen, -CF3 or halogen, preferably F or Cl,

[0729] R 7 is hydrogen or halogen, preferably F.

[0730] In some embodiments of the compound of Formula I, wherein Ar 1 having the formula ii-1b, ii-2b, ii-3b, ii-4b or ii-5b, R 5 and R 6 are independently hydrogen, -CF3, F or Cl, and R 5 ' and R 6 It's hydrogen.

[0731] In some embodiments of the compound of Formula I, wherein Ar 1 Having formula ii-1b, ii-2b, ii-3b, ii-4b or ii-5b, o is 1.

[0732] In some of the compounds of Formula I, wherein Ar 1 With ii-1b, ii-2b, ii-3b, ii-4b or ii-5b, R 5 Is F and / or R 6 It is F or Cl.

[0733] In some of the compounds of Formula I, wherein Ar 1 is formula ii-1b, ii-2b, ii-3b, ii-4b or ii-5b, R 7 It's F.

[0734] In some of the compounds of Formula I, wherein Ar 1 having the formula ii-1b, ii-2b, ii-3b, ii-4b or ii-5b, R 2 is methyl or R 2 is with R 3 -(CH2)- or -(CH2)2- forming a ring, or R 2 is with R a One of them forms a -(CH2)- or -(CH2)2- ring.

[0735] In some embodiments of the compound of Formula I, wherein Ar 1 having the formula ii-1b, ii-2b, ii-3b or ii-4b, R c and R d In some embodiments of the compound of Formula I, wherein Ar 1 having the formula ii-1b, ii-2b, ii-3b or ii-4b, R b 、R c and R d It's hydrogen.

[0736] In some embodiments of the compound of Formula I, wherein Ar 1 having the formula ii-1b, ii-2b, ii-3b or ii-4b, wherein Ra One of the R 3 The ring is formed, and the formed ring is a 4-membered, 5-membered, or 6-membered ring, or a 5-membered or 6-membered ring, or a 5-membered ring.

[0737] In some embodiments of the compound of Formula I, wherein Ar 1 having the formula ii-1b, ii-2b, ii-3b or ii-4b, wherein R a One of the R 3 The ring is formed, and the formed ring is a 3-membered, 4-membered, 5-membered or 6-membered ring.

[0738] In some embodiments of the compound of Formula I, wherein Ar 1 With ii-1b, ii-2b, ii-3b or ii-4b, wherein R 2 One of the R 3 The ring is formed, and the formed ring is a 4-membered, 5-membered, or 6-membered ring, or a 5-membered, 6-membered ring, or a 6-membered ring.

[0739] In some embodiments, X 2 is O, and X 3 is N, making Ar 1 having formula ii-1c or a pharmaceutically acceptable salt or stereoisomer thereof,

[0740]

[0741] in

[0742] R 4 is hydrogen, F or Cl;

[0743] R 5 、R 5 '、R 6 、R 6 ' are independently hydrogen, -CF3 or halogen, preferably F, Cl.

[0744] In some embodiments, X 2 is O, and X 3 is N, making Ar 1 having formula ii-2c, ii-3c, ii-4c, ii-5c or a pharmaceutically acceptable salt or stereoisomer thereof,

[0745]

[0746] in

[0747] o is 0 or 1;

[0748] R 4 is hydrogen, F or Cl;

[0749] R5 、R 5 '、R 6 、R 6 ' are independently hydrogen, -CF3 or halogen, preferably F or Cl;

[0750] R 7 is hydrogen or halogen, preferably F.

[0751] In some embodiments of the compound of Formula I, wherein Ar 1 Having formula ii-1c, ii-2c, ii-3c, ii-4c or ii-5c, R 5 and R 6 are independently hydrogen, -CF3, F or Cl, and R 5 ' and R 6 'It's hydrogen.

[0752] In some embodiments of the compound of Formula I, wherein Ar 1 Having formula ii-1c, ii-2c, ii-3c, ii-4c or ii-5c, o is 1.

[0753] In some embodiments of the compound of Formula I, wherein Ar 1 Having formula ii-1c, ii-2c, ii-3c, ii-4c or ii-5c, R 5 Is F and / or R 6 It is F or Cl.

[0754] In some embodiments of the compound of Formula I, wherein Ar 1 Having formula ii-1c, ii-2c, ii-3c, ii-4c or ii-5c, R 7 It's F.

[0755] In some embodiments of the compound of Formula I, wherein Ar 1 With ii-1c, ii-2c, ii-3c, ii-4c or ii-5c, R 2 is methyl or R 2 is with R 3 -(CH2)- or -(CH2)2- forming a ring, or R 2 is with R a One of them forms a -(CH2)- or -(CH2)2- ring.

[0756] In some embodiments of the compound of Formula I, wherein Ar 1 Having formula ii-1c, ii-2c, ii-3c or ii-4c, R c and R d In some embodiments of the compound of Formula I, wherein Ar 1Having formula ii-1c, ii-2c, ii-3c or ii-4c, R b 、R c and R d It's hydrogen.

[0757] In some embodiments of the compound of Formula I, wherein Ar 1 Having formula ii-1c, ii-2c, ii-3c or ii-4c, wherein R a One of the R 3 The ring is formed, and the formed ring is a 4-membered, 5-membered, or 6-membered ring, or a 5-membered or 6-membered ring, or a 5-membered ring.

[0758] In some embodiments of the compound of Formula I, wherein Ar 1 Having formula ii-1c, ii-2c, ii-3c or ii-4c, wherein R a One of the R 3 The ring is formed, and the formed ring is a 3-membered, 4-membered, 5-membered or 6-membered ring.

[0759] In some embodiments of the compound of Formula I, wherein Ar 1 With ii-1c, ii-2c, ii-3c or ii-4c, wherein R 2 One of the R 3 The ring is formed, and the formed ring is a 4-membered, 5-membered, or 6-membered ring, or a 5-membered, 6-membered ring, or a 6-membered ring.

[0760] In some embodiments of the compound of Formula I, Ar 1 having formula iii-1 or a pharmaceutically acceptable salt or stereoisomer thereof,

[0761]

[0762] in

[0763] R 4 is hydrogen or halogen, preferably F or Cl;

[0764] R 5 、R 6 are independently hydrogen, -CF3 or halogen, preferably F, Cl.

[0765] In some embodiments of the compound of Formula I, Ar 1 having formula iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7 or a pharmaceutically acceptable salt or stereoisomer thereof,

[0766]

[0767] in

[0768] X 3 is CH or N, preferably N;

[0769] o is 0 or 1;

[0770] R 5 、R 6 are independently hydrogen, -CF3 or halogen, preferably F or Cl;

[0771] R 7 is hydrogen or halogen, preferably F.

[0772] In some embodiments of the compound of Formula I, wherein Ar 1 Having formula iii-1, iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7, R 5 and R 6 are independently hydrogen, -CF3, F or Cl, and R 5 ' and R 6 'It's hydrogen.

[0773] In some embodiments of the compound of formula I, wherein Ar 1 Having the formula iii-1, iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7, o is 1.

[0774] In some embodiments of the compound of formula I, wherein Ar 1 Having formula iii-1, iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7, R 5 Is F and / or R 6 It is F or Cl.

[0775] In some embodiments of the compound of Formula I, wherein Ar 1 Having formula iii-1, iii-2, iii-3 or iii-4, if X 3 is N, then R 7 is hydrogen and / or if X 3 is CH, then R 7 It's F.

[0776] In some embodiments of the compound of formula I, wherein Ar 1 Having formula iii-1, iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7, R 2 is methyl or R 2 is with R 3 -(CH2)- or -(CH2)2- forming a ring, or R 2 is with R aOne of them forms a -(CH2)- or -(CH2)2- ring.

[0777] In some embodiments of the compound of Formula I, wherein Ar 1 Having formula iii-1, iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7, R c and / or R d In some embodiments of the compound of Formula I, wherein Ar 1 Having formula iii-1, iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7, R b 、R c and R d It's hydrogen.

[0778] In some embodiments of the compound of formula I, wherein Ar 1 having the formula iii-1, iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7, wherein R a One of the R 3 The ring is formed, and the formed ring is a 4-membered, 5-membered, or 6-membered ring, or a 5-membered or 6-membered ring, or a 5-membered ring.

[0779] In some embodiments of the compound of formula I, wherein Ar 1 Having iii-1, iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7, wherein R a One of the R 3 The ring is formed, and the formed ring is a 3-membered, 4-membered, 5-membered or 6-membered ring.

[0780] In some embodiments of the compound of Formula I, wherein Ar 1 Having iii-1, iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7, wherein R 2 One of the R 3 The ring is formed, and the formed ring is a 4-membered, 5-membered, or 6-membered ring, or a 5-membered, 6-membered ring, or a 6-membered ring.

[0781] In some embodiments, X 3 is N, making Ar 1 having formula iv-2, iv-3 or iv-4, iv-5, iv-6 or iv-7, or X 3 It is C that makes Ar 1 Having formula iv-8 or iv-9,

[0782]

[0783] in

[0784] o is 0 or 1;

[0785] R 5 、R 6 are independently hydrogen, -CF3 or halogen, preferably F or Cl;

[0786] R 7 is hydrogen or halogen, preferably F.

[0787] In some embodiments of the compound of Formula I, wherein Ar 1 having formula iv-2, iv-3, iv-4, iv-5, iv-6, iv-7, iv-8 or iv-9, R 5 and R 6 are independently hydrogen, -CF3, F or Cl, and R 5 ' and R 6 'It's hydrogen.

[0788] In some embodiments of the compound of Formula I, wherein Ar 1 having iv-2, iv-3 or iv-4, iv-5, iv-6, iv-7, iv-8 or iv-9, and o is 1.

[0789] In some embodiments of the compound of Formula I, wherein Ar 1 having formula iv-2, iv-3, iv-4, iv-5, iv-6, iv-7, iv-8 or iv-9, R 5 Is F and / or R 6 It is F or Cl.

[0790] In some embodiments of the compound of Formula I, wherein Ar 1 With iiv-2, iv-3 or iv-4, iv-5, iv-6, iv-7, iv-8 or iv-9, R 7 It's F.

[0791] In some embodiments of the compound of Formula I, wherein Ar 1 With IV-2, IV-3 or IV-4, IV-5, IV-6, IV-7, IV-8 or IV-9, R 2 is methyl or R 2 is with R 3 -(CH2)- or -(CH2)2- forming a ring, or R 2 is with R a One of them forms a -(CH2)- or -(CH2)2- ring.

[0792] In some embodiments of the compound of Formula I, wherein Ar 1With IV-2, IV-3 or IV-4, IV-5, IV-6, IV-7, IV-8 or IV-9, R c and R d In some embodiments of the compound of Formula I, wherein Ar 1 having formula iv-1, iv-2, iv-3 or iv-4, iv-5, iv-6, iv-7, iv-8 or iv-9, R b 、R c and R d It's hydrogen.

[0793] In some embodiments of the compound of Formula I, wherein Ar 1 having formula iv-2, iv-3, iv-4, iv-5, iv-6, iv-7, iv-8, or iv-9, wherein R a One of the R 3 The ring is formed, and the formed ring is a 4-membered, 5-membered, or 6-membered ring, or a 5-membered or 6-membered ring, or a 5-membered ring.

[0794] In some embodiments of the compound of Formula I, wherein Ar 1 With iv-2, iv-3 or iv-4, iv-5, iv-6, iv-7, iv-8 or iv-9, wherein R a One of the R 3 The ring is formed, and the formed ring is a 3-membered, 4-membered, 5-membered or 6-membered ring.

[0795] In some embodiments of the compound of formula I, wherein Ar 1 With iv-2, iv-3 or iv-4, iv-5, iv-6, iv-7, iv-8 or iv-9, wherein R 2 One of the R 3 The ring is formed, and the formed ring is a 4-membered, 5-membered, or 6-membered ring, or a 5-membered, 6-membered ring, or a 6-membered ring.

[0796] In some embodiments, the present disclosure provides a compound or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound has Formula IIa or IIb,

[0797]

[0798] in

[0799] X 1 Yes -O-, -NR 3 -;

[0800] R 1 is H or F;

[0801] R 2 is hydrogen or C 1-4Alkyl, preferably methyl, or 3 Ring-forming -(CH2) q -;

[0802] R 3 is hydrogen or C 1-4 Alkyl, preferably hydrogen or methyl, or with R 2 Ring-forming -(CH2) p -;

[0803] m is 1, 2, or 3;

[0804] n is 0, 1, or 2;

[0805] p is 1 or 2;

[0806] q is 0, 1, or 2;

[0807] r is 0 or 1;

[0808] s is 1 or 2; and

[0809] Ar 1 is a 6-membered aryl group which is unsubstituted or substituted by one or more of the following groups: halogen, -CF3, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy-C6 aryl, C 1-6 Alkoxy-C 5-6 Heteroaryl, amino, amino C 1-4 Alkyl, C 1-6 Alkylamino, C 1-6 Aminoalkyl-C6 aryl, C 1-6 aminoalkyl-C 5-6 Heteroaryl, C 1-6 Alkoxycarbonyl, C 1-6 Alkoxyaminocarbonyl, aryl C 1-6 Alkoxy or C6 aryl.

[0810] In some embodiments of compounds of Formula IIa or IIb, X 1 Yes-NR 3 -.

[0811] In some embodiments of compounds of Formula IIa or IIb, R 1 It's hydrogen.

[0812] In some embodiments of compounds of Formula IIa or IIb, R 2 It is C 1-4 Alkyl, or with R3 Ring-forming -(CH2) q -. For example, R 2 can be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, R 2 is with R 3 Preferably, R 2 can be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl, R 2 is with R 3 More preferably, R 2 It can be methyl, R 2 is with R 3 -(CH2)- or -(CH2)2- forming a ring.

[0813] In some embodiments of compounds of Formula IIa or IIb, R 3 is hydrogen or methyl, is R 2 -(CH2)- or -(CH2)2- forming a ring.

[0814] In some embodiments of compounds of Formula IIa or IIb, X 1 It is NR 3 .

[0815] In some embodiments of compounds of Formula IIa, n is 0 and m is 1, 2, or 3; or n is 0 and m is 1 or 2; or n is 1 and m is 1, 2, or 3; or n is 1 and m is 1 or 2; or n is 2 and m is 1, 2, or 3; or n is 2 and m is 1 or 2; or n is 0, 1, or 2 and m is 1 or 2; or n is 0, 1, or 2 and m is 1; or n is 1 or 2 and m is 1, 2, or 3; or n is 1 or 2 and m is 1 or 2; or n is 1 or 2 and m is 1 or 3; or n is 1 or 2 and m is 2 or 3.

[0816] In some embodiments of compounds of Formula lib, r is 0 and s is 1 or 2, or r is 1 and s is 1 or 2, or r is 0 or 1 and s is 1, or r is 0 or 1 and s is 2.

[0817] In some embodiments of compounds of Formula IIa or IIb, X 1 Can be combined with R 2 The carbon atoms directly bonded form a heterocyclic ring. For example, X 1 Can form 4-membered, 5-membered, 6-membered or 7-membered heterocyclic ring or heterobicyclic ring. In some embodiments of the compound of formula I, X 1Substituted or unsubstituted oxetanyl, thianyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiopyranyl, dihydropyranyl, tetrahydropyranyl, piperidinyl, oxetanyl, thienyl, azepanyl, azabicyclo[2.2.1]heptane or azabicyclo[2.2.2]octane can be formed, preferably azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, more preferably azetidinyl, pyrrolidinyl or piperidinyl.

[0818] In some embodiments of compounds of Formula IIa or IIb, Ar 1 having formula I or a pharmaceutically acceptable salt or stereoisomer thereof,

[0819]

[0820] in

[0821] R 4 It is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy-C6 aryl, C 1-6 Alkoxy-C 5-6 Heteroaryl, amino C 1-4 Alkyl, C 1-6 Alkylamino, C 1-6 Aminoalkyl-C6 aryl, C 1-6 aminoalkyl-C 5-6 Heteroaryl, C 1-6 Alkoxycarbonyl, C 1-6 Alkoxyamino-carbonyl, aryl C 1-6 Alkoxy or C6 aryl;

[0822] R 5 、R 5 '、R 6 、R 6 ' are independently hydrogen, -CF3 or halogen, preferably F, Cl.

[0823] In some embodiments of compounds of Formula IIa or IIb, wherein Ar 1 With formula i, R 4 It is hydrogen, fluorine, chlorine, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 1-4Alkoxy-C6 aryl, C 1-4 Alkoxy-C 5-6 Heteroaryl, amino C 1-4 Alkyl, C 1-4 Alkylamino, C 1-4 Aminoalkyl-C6 aryl, C 1-4 aminoalkyl-C6 heteroaryl, C 1-4 Alkoxycarbonyl, C 1-4 Alkoxyaminocarbonyl or C6 aryl.

[0824] In some embodiments of compounds of Formula IIa or IIb, wherein Ar 1 With formula i, R 4 It is hydrogen, fluorine, chlorine, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 1-4 Alkoxy-C6 aryl, C 1-4 Alkoxy-C 5-6 heteroaryl or C6 aryl.

[0825] In some embodiments of compounds of Formula IIa or IIb, wherein Ar 1 With formula i, R 4Typically hydrogen, fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-propoxy, n-butoxy, isobutoxy, n-pentyloxy, isopentyl, n-hexyloxy, isohexyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, methoxymethyl, methoxyethyl, methoxypropyl, methyl Oxybutyl, methoxypentyl, methoxyhexyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, ethoxyhexyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, propoxyhexyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, butoxyhexyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, pentoxyhexyl, hexyl Oxymethyl, hexyloxyethyl, hexyloxypropyl, hexyloxybutyl, hexyloxypentyl, hexyloxyhexyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl, methylamino, ethylamino, propylamino, butylamino, pentylamino, hexylamino, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, methoxyaminocarbonyl, ethoxyaminocarbonyl, propoxyaminocarbonyl, butoxyaminocarbonyl , pentyloxyaminocarbonyl, hexyloxyaminocarbonyl, phenylmethoxy, phenylethoxy, phenylpropoxy, phenylbutoxy, phenylpentyloxy, phenylhexyloxy, m-fluorophenylmethoxy, m-fluorophenylphenylethoxy, m-fluorophenylphenylpropoxy, m-fluorophenylphenylbutoxy, m-fluorophenylphenylpentyloxy, m-fluorophenylphenylhexyloxy, pyridylmethoxy, pyridylethoxy, pyridylpropoxy, pyridylbutoxy, pyridylpentyloxy, pyridylhexyloxy, phenyl, pyridyl or naphthyl.

[0826] In some embodiments of compounds of Formula IIa or IIb, wherein Ar 1 With formula i, R 5 and R 6 are independently hydrogen, -CF3, F or Cl, and R 5 ' and R 6 ' is hydrogen. Preferably, R 4 It is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy-C6 aryl, C 1-6 Alkoxy-C 5-6 Heteroaryl, amino C1-4 Alkyl, C 1-6 Alkylamino, C 1-6 Aminoalkyl-C6 aryl, C 1-6 aminoalkyl-C 5-6 Heteroaryl, C 1-6 Alkoxycarbonyl, C 1-6 Alkoxyamino-carbonyl, aryl C 1-6 Alkoxy or C6 aryl.

[0827] In some embodiments of compounds of Formula IIa or IIb, wherein Ar 1 With formula i, R 5 and R 6 are independently hydrogen, -CF3, F or Cl, and R 5 ' and R 6 ' is hydrogen. Preferably, R 4 It is hydrogen, fluorine, chlorine, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 1-4 Alkoxy-C6 aryl, C 1-4 Alkoxy-C 5-6 Heteroaryl, amino C 1-4 Alkyl, C 1-4 Alkylamino, C 1-4 Aminoalkyl-C6 aryl, C 1-4 aminoalkyl-C6 heteroaryl, C 1-4 Alkoxycarbonyl, C 1-4 Alkoxyaminocarbonyl or C6 aryl.

[0828] In some embodiments of compounds of Formula IIa or IIb, wherein Ar 1 Having formula i, Ar 1 includes only 1, 2 or 3 substituents other than hydrogen. Thus, R 4 、R 5 、R 5 '、R 6 or R 6 At least two of ' may be hydrogen.

[0829] In some embodiments of compounds of Formula IIa or IIb, wherein Ar 1 With formula i, R 1 It can be hydrogen and / or R 2 It can be methyl or it can be R 3 -(CH2)- or -(CH2)2- forming a ring.

[0830] In some embodiments of compounds of Formula IIa or IIb, Ar 1 having formula ii-1 or a pharmaceutically acceptable salt or stereoisomer thereof,

[0831]

[0832] in

[0833] R 4 is hydrogen, F or Cl;

[0834] R 5 、R 5 '、R 6 、R 6 ' are independently hydrogen, -CF3 or halogen, preferably F, Cl.

[0835] In some embodiments of compounds of Formula IIa or IIb, Ar 1 having formula ii-2, ii-3 or ii-4 or a pharmaceutically acceptable salt or stereoisomer thereof,

[0836]

[0837] in

[0838] X 2 is O, NH, or NMe;

[0839] X 3 is C or N;

[0840] o is 0 or 1;

[0841] R 5 、R 5 '、R 6 、R 6 ' are independently hydrogen, -CF3 or halogen, preferably F or Cl;

[0842] R 7 is hydrogen or halogen, preferably F.

[0843] In some embodiments of compounds of Formula IIa or IIb, wherein Ar 1 Having formula ii-1, ii-2, ii-3 or ii-4, R 5 and R 6 are independently hydrogen, -CF3, F or Cl, and R 5 ' and R 6 'It's hydrogen.

[0844] In some embodiments of compounds of Formula IIa or IIb, wherein Ar 1 Having formula ii-1, ii-2, ii-3 or ii-4, o is 1.

[0845] In some embodiments of compounds of Formula IIa or IIb, wherein Ar 1 Having formula ii-1, ii-2, ii-3 or ii-4, R 5 Is F and / or R 6 It is F or Cl.

[0846] In some embodiments of compounds of Formula IIa or IIb, wherein Ar 1 Having formula ii-1, ii-2, ii-3 or ii-4, R 2 Is methyl or with R 3 -(CH2)- or -(CH2)2- forming a ring.

[0847] In some embodiments of compounds of Formula IIa or IIb, wherein Ar 1 Having formula ii-1, ii-2, ii-3 or ii-4, if X 3 is N, then R 7 is hydrogen and / or if X 3 is CH, then R 7 It's F.

[0848] In some embodiments of the compound of Formula IIa, wherein Ar 1 having formula ii-1, ii-2, ii-3 or ii-4, n is 0 and m is 1, 2 or 3; or n is 0 and m is 1 or 2; or n is 1 and m is 1, 2 or 3; or n is 1 and m is 1 or 2; or n is 2 and m is 1, 2 or 3; or n is 2 and m is 1 or 2; or n is 0, 1 or 2 and m is 1 or 2; or n is 0, 1 or 2 and m is 1; or n is 1 or 2 and m is 1, 2 or 3; or n is 1 or 2 and m is 1 or 2; or n is 1 or 2 and m is 1 or 3; or n is 1 or 2 and m is 2 or 3.

[0849] In some embodiments of the compound of Formula IIb, wherein Ar 1 Having formula ii-1, ii-2, ii-3 or ii-4, r is 0 and s is 1 or 2, or r is 1 and s is 1 or 2, or r is 0 or 1 and s is 1, or r is 0 or 1 and s is 2.

[0850] In some embodiments, X 2 is O, making Ar 1 having formula ii-1a or a pharmaceutically acceptable salt or stereoisomer thereof,

[0851]

[0852] in

[0853] R 4 is hydrogen, F or Cl;

[0854] R 5 、R 5 '、R 6 、R 6 ' are independently hydrogen, -CF3 or halogen, preferably F, Cl.

[0855] In some embodiments, X 2 is O, making Ar 1 having formula ii-2a, ii-3a or ii-4a or a pharmaceutically acceptable salt or stereoisomer thereof,

[0856]

[0857] in

[0858] X 3 is CH or N, preferably N;

[0859] o is 0 or 1;

[0860] R 5 、R 5 '、R 6 、R 6 ' are independently hydrogen, -CF3 or halogen, preferably F or Cl;

[0861] R 7 is hydrogen or halogen, preferably F.

[0862] In some embodiments of compounds of Formula IIa or IIb, wherein Ar 1 Having formula ii-1a, ii-2a, ii-3a or ii-4a, R 5 and R 6 are independently hydrogen, -CF3, F or Cl, and R 5 ' and R 6 'It's hydrogen.

[0863] In some embodiments of compounds of Formula IIa or IIb, wherein Ar 1 Having formula ii-1a, ii-2a, ii-3a or ii-4a, o is 1.

[0864] In some embodiments of compounds of Formula IIa or IIb, wherein Ar 1 Having formula ii-1a, ii-2a, ii-3a or ii-4a, R 5 Is F and / or R 6 It is F or Cl.

[0865] In some embodiments of compounds of Formula IIa or IIb, wherein Ar 1 Having formula ii-1a, ii-2a, ii-3a or ii-4a, if X 3 is N, then R 7 is hydrogen and / or if X 3 is CH, then R 7 It's F.

[0866] In some embodiments of compounds of Formula IIa or IIb, wherein Ar 1 Having formula ii-1a, ii-2a, ii-3a or ii-4a, R 2 Is methyl or with R 3 -(CH2)- or -(CH2)2- forming a ring.

[0867] In some embodiments of the compound of Formula IIa, wherein Ar 1 having formula ii-a-1, ii-2a, ii-3a or ii-4a, n is 0 and m is 1, 2 or 3; or n is 0 and m is 1 or 2; or n is 1 and m is 1, 2 or 3; or n is 1 and m is 1 or 2; or n is 2 and m is 1, 2 or 3; or n is 2 and m is 1 or 2; or n is 0, 1 or 2 and m is 1 or 2; or n is 0, 1 or 2 and m is 1; or n is 1 or 2 and m is 1, 2 or 3; or n is 1 or 2 and m is 1 or 2; or n is 1 or 2 and m is 1 or 3; or n is 1 or 2 and m is 2 or 3.

[0868] In some embodiments of the compound of Formula IIb, wherein Ar 1 Having formula ii-1a, ii-2a, ii-3a or ii-4a, r is 0 and s is 1 or 2, or r is 1 and s is 1 or 2, or r is 0 or 1 and s is 1, or r is 0 or 1 and s is 2.

[0869] In some embodiments of compounds of Formula IIa or IIb, X 3 is N, making Ar 1 having formula ii-1b or a pharmaceutically acceptable salt or stereoisomer thereof,

[0870]

[0871] in

[0872] R 4 is hydrogen, F or Cl;

[0873] R 5 、R 5 '、R 6 、R 6' are independently hydrogen, -CF3 or halogen, preferably F, Cl.

[0874] In some embodiments of compounds of Formula IIa or IIb, X 3 is N, making Ar 1 having formula ii-2b, ii-3b, ii-4b, ii-5b or a pharmaceutically acceptable salt or stereoisomer thereof,

[0875]

[0876] in

[0877] X 2 is O, NH or NMe, preferably O;

[0878] o is 0 or 1;

[0879] R 5 、R 5 '、R 6 、R 6 ' are independently hydrogen, -CF3 or halogen, preferably F or Cl;

[0880] R 7 is hydrogen or halogen, preferably F.

[0881] In some embodiments of compounds of Formula IIa or IIb, wherein Ar 1 having the formula ii-1b, ii-2b, ii-3b, ii-4b or ii-5b, R 5 and R 6 are independently hydrogen, -CF3, F or Cl, and R 5 ' and R 6 'It's hydrogen.

[0882] In some embodiments of compounds of Formula IIa or IIb, wherein Ar 1 Having formula ii-1b, ii-2b, ii-3b, ii-4b or ii-5b, o is 1.

[0883] In some embodiments of compounds of Formula IIa or IIb, wherein Ar 1 having the formula ii-1b, ii-2b, ii-3b, ii-4b or ii-5b, R 5 Is F and / or R 6 It is F or Cl.

[0884] In some embodiments of compounds of Formula IIa or IIb, wherein Ar 1 having the formula ii-1b, ii-2b, ii-3b, ii-4b or ii-5b, R 7 It's F.

[0885] In some embodiments of compounds of Formula IIa or IIb, wherein Ar 1 having the formula ii-1b, ii-2b, ii-3b, ii-4b or ii-5b, R 2 Is methyl or with R 3 -(CH2)- or -(CH2)2- forming a ring.

[0886] In some embodiments of the compound of Formula IIa, wherein Ar 1 Having formula ii-1b, ii-2b, ii-3b or ii-4b, n is 0 and m is 1, 2 or 3; or n is 0 and m is 1 or 2; or n is 1 and m is 1, 2 or 3; or n is 1 and m is 1 or 2; or n is 2 and m is 1, 2 or 3; or n is 2 and m is 1 or 2; or n is 0, 1 or 2 and m is 1 or 2; or n is 0, 1 or 2 and m is 1; or n is 1 or 2 and m is 1, 2 or 3; or n is 1 or 2 and m is 1 or 2; or n is 1 or 2 and m is 1 or 3; or n is 1 or 2 and m is 2 or 3.

[0887] In some embodiments of the compound of Formula IIb, wherein Ar 1 Having formula ii-1b, ii-2b, ii-3b or ii-4b, r is 0 and s is 1 or 2, or r is 1 and s is 1 or 2, or r is 0 or 1 and s is 1, or r is 0 or 1 and s is 2.

[0888] In some embodiments of compounds of Formula IIa or IIb, Ar 1 having formula ii-1c or a pharmaceutically acceptable salt or stereoisomer thereof,

[0889]

[0890] in

[0891] R 4 is hydrogen, F or Cl;

[0892] R 5 、R 5 '、R 6 、R 6 ' are independently hydrogen, -CF3 or halogen, preferably F, Cl.

[0893] In some embodiments of compounds of Formula IIa or IIb, X 2 is O, and X 3 is N, making Ar 1having formula ii-2c, ii-3c, ii-4c, ii-5c or a pharmaceutically acceptable salt or stereoisomer thereof,

[0894]

[0895] in

[0896] o is 0 or 1;

[0897] R 5 、R 5 '、R 6 、R 6 ' are independently hydrogen, -CF3 or halogen, preferably F or Cl;

[0898] R 7 is hydrogen or halogen, preferably F.

[0899] In some embodiments of compounds of Formula IIa or IIb, wherein Ar 1 Having formula ii-1c, ii-2c, ii-3c, ii-4c or ii-5c, R 5 and R 6 are independently hydrogen, -CF3, F or Cl, and R 5 ' and R 6 'It's hydrogen.

[0900] In some embodiments of compounds of Formula IIa or IIb, wherein Ar 1 Having formula ii-1c, ii-2c, ii-3c, ii-4c or ii-5c, o is 1.

[0901] In some embodiments of compounds of Formula IIa or IIb, wherein Ar 1 Having formula ii-1c, ii-2c, ii-3c, ii-4c or ii-5c, R 5 Is F and / or R 6 It is F or Cl.

[0902] In some embodiments of compounds of Formula IIa or IIb, wherein Ar 1 Having formula ii-1c, ii-2c, ii-3c, ii-4c or ii-5c, R 7 It's F.

[0903] In some embodiments of compounds of Formula IIa or IIb, wherein Ar 1 Having formula ii-1c, ii-2c, ii-3c, ii-4c or ii-5c, R 2 Is methyl or with R 3 -(CH2)- or -(CH2)2- forming a ring.

[0904] In some embodiments of the compound of Formula IIa, wherein Ar 1 Having formula ii-1c, ii-2c, ii-3c or ii-4c, n is 0 and m is 1, 2 or 3; or n is 0 and m is 1 or 2; or n is 1 and m is 1, 2 or 3; or n is 1 and m is 1 or 2; or n is 2 and m is 1, 2 or 3; or n is 2 and m is 1 or 2; or n is 0, 1 or 2 and m is 1 or 2; or n is 0, 1 or 2 and m is 1; or n is 1 or 2 and m is 1, 2 or 3; or n is 1 or 2 and m is 1 or 2; or n is 1 or 2 and m is 1 or 3; or n is 1 or 2 and m is 2 or 3.

[0905] In some embodiments of the compound of Formula IIb, wherein Ar 1 Having formula ii-1c, ii-2c, ii-3c or ii-4c, r is 0 and s is 1 or 2, or r is 1 and s is 1 or 2, or r is 0 or 1 and s is 1, or r is 0 or 1 and s is 2.

[0906] In some embodiments of compounds of Formula IIa or IIb, Ar 1 having formula iii-1 or a pharmaceutically acceptable salt or stereoisomer thereof,

[0907]

[0908] in

[0909] R 4 is hydrogen or halogen, preferably F or Cl;

[0910] R 5 、R 6 are independently hydrogen, -CF3 or halogen, preferably F, Cl.

[0911] In some embodiments of compounds of Formula IIa or IIb, Ar 1 having formula iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7 or a pharmaceutically acceptable salt or stereoisomer thereof,

[0912]

[0913] in

[0914] X 3 is CH or N, preferably N;

[0915] o is 0 or 1;

[0916] R 5 、R6 are independently hydrogen, -CF3 or halogen, preferably F or Cl;

[0917] R 7 is hydrogen or halogen, preferably F.

[0918] In some embodiments of compounds of Formula IIa or IIb, wherein Ar 1 Having formula iii-1, iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7, R 5 and R 6 are independently hydrogen, -CF3, F or Cl, and R 5 ' and R 6 'It's hydrogen.

[0919] In some embodiments of compounds of Formula IIa or IIb, wherein Ar 1 Having the formula iii-1, iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7, o is 1.

[0920] In some embodiments of compounds of Formula IIa or IIb, wherein Ar 1 Having formula iii-1, iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7, R 5 Is F and / or R 6 It is F or Cl.

[0921] In some embodiments of compounds of Formula IIa or IIb, wherein Ar 1 Having formula iii-1, iii-2, iii-3 or iii-4, if X 3 is N, then R 7 is hydrogen and / or if X 3 is CH, then R 7 It's F.

[0922] In some embodiments of the compound of Formula IIa or IIb, wherein Ar 1 Having formula iii-1, iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7, R 2 Is methyl or with R 3 -(CH2)- or -(CH2)2- forming a ring.

[0923] In some embodiments of the compound of Formula IIa, wherein Ar 1having formula iii-1, iii-2, ii-3 or iii-4, n is 0 and m is 1, 2 or 3; or n is 0 and m is 1 or 2; or n is 1 and m is 1, 2 or 3; or n is 1 and m is 1 or 2; or n is 2 and m is 1, 2 or 3; or n is 2 and m is 1 or 2; or n is 0, 1 or 2 and m is 1 or 2; or n is 0, 1 or 2 and m is 1; or n is 1 or 2 and m is 1, 2 or 3; or n is 1 or 2 and m is 1 or 2; or n is 1 or 2 and m is 1 or 3; or n is 1 or 2 and m is 2 or 3.

[0924] In some embodiments of the compound of Formula IIb, wherein Ar 1 Having formula iii-1, iii-2, iii-3 or iii-4, r is 0 and s is 1 or 2, or r is 1 and s is 1 or 2, or r is 0 or 1 and s is 1, or r is 0 or 1 and s is 2.

[0925] In some embodiments, X 3 is N, making Ar 1 having formula iv-2, iv-3 or iv-4, iv-5, iv-6 or iv-7, or X 3 It is C that makes Ar 1 Having formula iv-8 or iv-9,

[0926]

[0927] in

[0928] o is 0 or 1;

[0929] R 5 、R 6 are independently hydrogen, -CF3 or halogen, preferably F or Cl;

[0930] R 7 is hydrogen or halogen, preferably F.

[0931] In some embodiments of compounds of Formula IIa or IIb, wherein Ar 1 having formula iv-2, iv-3, iv-4, iv-5, iv-6, iv-7, iv-8 or iv-9, R 5 and R 6 are independently hydrogen, -CF3, F or Cl, and R 5 ' and R 6 'It's hydrogen.

[0932] In some embodiments of compounds of Formula IIa or IIb, wherein Ar 1having iv-2, iv-3 or iv-4, iv-5, iv-6, iv-7, iv-8 or iv-9, and o is 1.

[0933] In some embodiments of compounds of Formula IIa or IIb, wherein Ar 1 having formula iv-2, iv-3, iv-4, iv-5, iv-6, iv-7, iv-8 or iv-9, R 5 Is F and / or R 6 It is F or Cl.

[0934] In some embodiments of compounds of Formula IIa or IIb, wherein Ar 1 With IV-2, IV-3 or IV-4, IV-5, IV-6, IV-7, IV-8 or IV-9, R 7 It's F.

[0935] In some embodiments of compounds of Formula IIa or IIb, wherein Ar 1 having formula iv-2, iv-3, iv-4, iv-5, iv-6, iv-7, iv-8 or iv-9, R 2 Is methyl or with R 3 -(CH2)- or -(CH2)2- forming a ring.

[0936] In some embodiments of the compound of Formula IIa, wherein Ar 1 having formula iv-2, iv-3 or iv-4, iv-5, iv-6, iv-7, iv-8 or iv-9, n is 0 and m is 1, 2 or 3; or n is 0 and m is 1 or 2; or n is 1 and m is 1, 2 or 3; or n is 1 and m is 1 or 2; or n is 2 and m is 1, 2 or 3; or n is 2 and m is 1 or 2; or n is 0, 1 or 2 and m is 1 or 2; or n is 0, 1 or 2 and m is 1; or n is 1 or 2 and m is 1, 2 or 3; or n is 1 or 2 and m is 1 or 2; or n is 1 or 2 and m is 1 or 3; or n is 1 or 2 and m is 2 or 3.

[0937] In some embodiments of the compound of Formula IIb, wherein Ar 1 Having formula iv-2, iv-3 or iv-4, iv-5, iv-6, iv-7, iv-8 or iv-9, r is 0 and s is 1 or 2, or r is 1 and s is 1 or 2, or r is 0 or 1 and s is 1, or r is 0 or 1 and s is 2.

[0938] In some embodiments, the present disclosure provides a compound or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound has Formula III,

[0939]

[0940] in

[0941] R 1 is H or F;

[0942] Ar 1 is a 6-membered aryl group which is unsubstituted or substituted by one or more of the following groups: halogen, -CF3, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy-C6 aryl, C 1-6 Alkoxy-C 5-6 Heteroaryl, amino, amino C 1-4 Alkyl, C 1-6 Alkylamino, C 1-6 Aminoalkyl-C6 aryl, C 1-6 aminoalkyl-C 5-6 Heteroaryl, C 1-6 Alkoxycarbonyl, C 1-6 Alkoxyaminocarbonyl, aryl C 1-6 Alkoxy or C6 aryl;

[0943] Z is selected from

[0944]

[0945] In some embodiments of the compound of Formula III, R 1 It's hydrogen.

[0946] In some embodiments, the present disclosure provides a compound or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound has Formula IV,

[0947]

[0948] in

[0949] R 1 is H or F;

[0950] R 4 It is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6Alkoxy-C6 aryl, C 1-6 Alkoxy-C 5-6 Heteroaryl, amino C 1-4 Alkyl, C 1-6 Alkylamino, C 1-6 Aminoalkyl-C6 aryl, C 1-6 aminoalkyl-C 5-6 Heteroaryl, C 1-6 Alkoxycarbonyl, C 1-6 Alkoxyamino-carbonyl, aryl C 1-6 Alkoxy or C6 aryl;

[0951] R 5 、R 5 '、R 6 、R 6 ' are independently hydrogen, -CF3 or halogen, preferably F or Cl;

[0952] Z is selected from

[0953]

[0954] In some embodiments of the compound of Formula IV, R 4 It is hydrogen, fluorine, chlorine, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 1-4 Alkoxy-C6 aryl, C 1-4 Alkoxy-C 5-6 Heteroaryl, amino C 1-4 Alkyl, C 1-4 Alkylamino, C 1-4 Aminoalkyl-C6 aryl, C 1-4 aminoalkyl-C6 heteroaryl, C 1-4 Alkoxycarbonyl, C 1-4 Alkoxyaminocarbonyl or C6 aryl.

[0955] In some embodiments of the compound of Formula VI, R 4 It is hydrogen, fluorine, chlorine, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 1-4 Alkoxy-C6 aryl, C 1-4 Alkoxy-C 5-6 heteroaryl or C6 aryl.

[0956] In some embodiments of the compound of Formula IV, R 4 Typically hydrogen, fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-propoxy, n-butoxy, isobutoxy, n-pentyloxy, isopentyl, n-hexyloxy, isohexyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, methoxymethyl, methoxyethyl, methoxypropyl, methyl Oxybutyl, methoxypentyl, methoxyhexyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, ethoxyhexyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, propoxyhexyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, butoxyhexyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, pentoxyhexyl, hexyl Oxymethyl, hexyloxyethyl, hexyloxypropyl, hexyloxybutyl, hexyloxypentyl, hexyloxyhexyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl, methylamino, ethylamino, propylamino, butylamino, pentylamino, hexylamino, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, methoxyaminocarbonyl, ethoxyaminocarbonyl, propoxyaminocarbonyl, butoxyaminocarbonyl , pentyloxyaminocarbonyl, hexyloxyaminocarbonyl, phenylmethoxy, phenylethoxy, phenylpropoxy, phenylbutoxy, phenylpentyloxy, phenylhexyloxy, m-fluorophenylmethoxy, m-fluorophenylphenylethoxy, m-fluorophenylphenylpropoxy, m-fluorophenylphenylbutoxy, m-fluorophenylphenylpentyloxy, m-fluorophenylphenylhexyloxy, pyridylmethoxy, pyridylethoxy, pyridylpropoxy, pyridylbutoxy, pyridylpentyloxy, pyridylhexyloxy, phenyl, pyridyl or naphthyl.

[0957] In some embodiments of the compound of Formula IV, R 5和R 6 are independently hydrogen, -CF3, F or Cl, and R 5 ' and R 6 ' is hydrogen. Preferably, R 4 It is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy-C6 aryl, C 1-6 Alkoxy-C 5-6 Heteroaryl, amino C 1-4 Alkyl, C1-6 Alkylamino, C 1-6 Aminoalkyl-C6 aryl, C 1-6 aminoalkyl-C 5-6 Heteroaryl, C 1-6 Alkoxycarbonyl, C 1-6 Alkoxyamino-carbonyl, aryl C 1-6 Alkoxy or C6 aryl.

[0958] In some embodiments of the compound of formula IV, R 5 and R 6 are independently hydrogen, -CF3, F or Cl, and R 5 ' and R 6 ' is hydrogen. Preferably, R 4 It is hydrogen, fluorine, chlorine, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 1-4 Alkoxy-C6 aryl, C 1-4 Alkoxy-C 5-6 Heteroaryl, amino C 1-4 Alkyl, C 1-4 Alkylamino, C 1-4 Aminoalkyl-C6 aryl, C 1-4 aminoalkyl-C6 heteroaryl, C 1-4 Alkoxycarbonyl, C 1-4 Alkoxyaminocarbonyl or C6 aryl.

[0959] In some embodiments of the compound of Formula IV, Ar 1 includes only 1, 2 or 3 substituents other than hydrogen. Thus, R 4 、R 5 、R 5 '、R 6 or R 6 At least two of ' may be hydrogen.

[0960] In some embodiments of the compound of Formula IV, R 1 It may be hydrogen.

[0961] In some embodiments, the present disclosure provides a compound or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound has formula V-1,

[0962]

[0963] in

[0964] R 1is H or F;

[0965] R 4 is hydrogen or halogen, preferably F or Cl;

[0966] R 5 、R 5 '、R 6 、R 6 ' are independently hydrogen, -CF3 or halogen, preferably F or Cl;

[0967] Z is selected from

[0968]

[0969] In some embodiments, the present disclosure provides a compound or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound has formula V-2, V-3 or V-4,

[0970]

[0971] in

[0972] X 2 is O or NH or NMe;

[0973] X 3 is CH or N;

[0974] R 1 is H or F;

[0975] R 5 、R 5 '、R 6 、R 6 ' are independently hydrogen, -CF3 or halogen, preferably F or Cl;

[0976] o is 0 or 1;

[0977] R 7 is hydrogen or halogen, preferably F;

[0978] Z is selected from

[0979]

[0980] In some embodiments of compounds of Formula V-1, V-2, V-3, or V-4, R 4 It is hydrogen, chlorine or fluorine.

[0981] In some embodiments of compounds of Formula V-1, V-2, V-3, or V-4, R 5 and R 6 are independently hydrogen, -CF3, F or Cl, and R 5 ' and R 6' is hydrogen. Preferably, R 4 It is hydrogen, chlorine or fluorine.

[0982] In some embodiments of compounds of Formula V-1, V-2, V-3, or V-4, R 5 and R 6 are independently hydrogen, -CF3, F or Cl, and R 5 ' and R 6 ' is hydrogen. Preferably, R 4 It is hydrogen, chlorine or fluorine.

[0983] In some embodiments of compounds of Formula V-1, V-2, V-3, or V-4, Ar 1 includes only 1, 2 or 3 substituents other than hydrogen. Thus, R 4 、R 5 、R 5 '、R 6 or R 6 At least two of ' may be hydrogen.

[0984] In some embodiments of compounds of Formula V-1, V-2, V-3, or V-4, if X 3 is N, then R 7 is hydrogen and / or if X 3 is CH, then R 7 It's F.

[0985] In some embodiments of compounds of Formula V-1, V-2, V-3, or V-4, o is 1.

[0986] In some embodiments of compounds of Formula V-1, V-2, V-3, or V-4, R 1 It may be hydrogen.

[0987] In some embodiments of compounds of Formula V-2, V-3, or V-4, X 2 is O, producing a compound of formula V-2a, V-3a or V-4a or a pharmaceutically acceptable salt or stereoisomer thereof,

[0988]

[0989] in

[0990] X 3 is CH or N;

[0991] R 1 is H or F;

[0992] R 5 、R 5 '、R 6 、R 6' are independently hydrogen, -CF3 or halogen, preferably F or Cl;

[0993] o is 0 or 1;

[0994] R 7 is hydrogen or halogen, preferably F;

[0995] Z is selected from

[0996]

[0997] In some embodiments of compounds of Formula V-1, V-2a, V-3a, or V-4a, R 4 It is hydrogen, fluorine or chlorine.

[0998] In some embodiments of compounds of Formula V-1, V-2a, V-3a, or V-4a, R 5 and R 6 are independently hydrogen, -CF3, F or Cl, and R 5 ' and R 6 ' is hydrogen. Preferably, R 4 It is hydrogen, chlorine or fluorine.

[0999] In some embodiments of compounds of Formula V-1, V-2a, V-3a, or V-4a, R 5 and R 6 are independently hydrogen, -CF3, F or Cl, and R 5 ' and R 6 ' is hydrogen. Preferably, R 4 It is hydrogen, chlorine or fluorine.

[1000] In some embodiments of compounds of Formula V-1, V-2a, V-3a, or V-4a, Ar 1 includes only 1, 2 or 3 substituents other than hydrogen. Thus, R 4 、R 5 、R 5 '、R 6 or R 6 At least two of ' may be hydrogen.

[1001] In some embodiments of compounds of Formula V-1, V-2a, V-3a, or V-4a, if X 3 is N, then R 7 is hydrogen and / or if X 3 is CH, then R 7 It's F.

[1002] In some embodiments of compounds of Formula V-1, V-2a, V-3a, or V-4a, o is 1.

[1003] In some embodiments of compounds of Formula V-1, V-2a, V-3a, or V-4a, R 1 It may be hydrogen.

[1004] In some embodiments of compounds of Formula V-2, V-3, or V-4, X 3 is N, producing a compound of formula V-2b, V-3b, V-4b or a pharmaceutically acceptable salt or stereoisomer thereof, or X 3 is C, producing a compound of formula V-5b or a pharmaceutically acceptable salt or stereoisomer thereof,

[1005]

[1006] in

[1007] X 2 is O, NH, or NMe;

[1008] R 1 is H or F;

[1009] R 5 、R 5 '、R 6 、R 6 ' are independently hydrogen, -CF3 or halogen, preferably F or Cl;

[1010] o is 0 or 1;

[1011] R 7 is hydrogen or halogen, preferably F;

[1012] Z is selected from

[1013]

[1014] In some embodiments of compounds of Formula V-1, V-2b, V-3b, V-4b, or V-5b, R 4 They are hydrogen, fluorine and chlorine.

[1015] In some embodiments of compounds of Formula V-1, V-2b, V-3b, V-4b, or V-5b, R 5 and R 6 are independently hydrogen, -CF3, F or Cl, and R 5 ' and R 6 ' is hydrogen. Preferably, R 4 It is hydrogen, chlorine or fluorine.

[1016] In some embodiments of compounds of Formula V-1, V-2b, V-3b, V-4b, or V-5b, R 5 and R 6 are independently hydrogen, -CF3, F or Cl, and R5 ' and R 6 ' is hydrogen. Preferably, R 4 It is hydrogen, fluorine, chlorine, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, hydroxy C 1-5 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, amino C 1-4 Alkyl, C 1-4 Alkylamino, C 1-4 Alkoxycarbonyl, C 1-4 Alkoxyaminocarbonyl, aryl C 1-4 Alkoxy, heteroaryl C 1-4 Alkoxy or aryl.

[1017] In some embodiments of compounds of Formula V-1, V-2b, V-3b, V-4b, or V-5b, Ar 1 includes only 1, 2 or 3 substituents other than hydrogen. Thus, R 4 、R 5 、R 5 '、R 6 or R 6 At least two of ' may be hydrogen.

[1018] In some embodiments V-2b, V-3b, V-4b or V-5b, o is 1.

[1019] In some embodiments of compounds of Formula V-1, V-2b, V-3b, V-4b, or V-5b, R 7 It's F.

[1020] In some embodiments of compounds of Formula V-1, V-2b, V-3b, V-4b, or V-5b, R 1 It may be hydrogen.

[1021] In some embodiments, the present disclosure provides a compound or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound has formula VI-1,

[1022]

[1023] in

[1024] R 1 is H or F;

[1025] R 4 is hydrogen or halogen, preferably F or Cl;

[1026] R 5 、R 6are independently hydrogen, -CF3 or halogen, preferably F or Cl;

[1027] R 7 is hydrogen or halogen, preferably F;

[1028] Z is selected from

[1029]

[1030] In some embodiments, the present disclosure provides a compound or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound has formula VI-2, VI-3 or VI-4,

[1031]

[1032] in

[1033] X 2 is O, NH, or NMe;

[1034] X 3 is CH or N;

[1035] R 1 is H or F;

[1036] o is 0 or 1;

[1037] R 5 、R 6 are independently hydrogen, -CF3 or halogen, preferably F or Cl;

[1038] R 7 is hydrogen or halogen, preferably F;

[1039] Z is selected from

[1040]

[1041] In some embodiments of compounds of Formula VI-1, VI-2, VI-3, or VI-4, R 4 It is hydrogen, chlorine or fluorine.

[1042] In some embodiments of compounds of Formula VI-1, VI-2, VI-3, or VI-4, o is 1.

[1043] In some embodiments of compounds of Formula VI-1, VI-2, VI-3, or VI-4, R 5 Is F and / or R 6 It is F or Cl.

[1044] In some embodiments of compounds of Formula VI-1, VI-2, VI-3, or VI-4, if X 3 is N, then R 7is hydrogen and / or if X 3 is CH, then R 7 It's F.

[1045] In some embodiments of compounds of Formula VI-1, VI-2, VI-3, or VI-4, R 1 It may be hydrogen.

[1046] In some embodiments of compounds of Formula VI-2, VI-3, or VI-4, X 2 is O, producing a compound of Formula VI-2a, VI-3a or VI-4a or a pharmaceutically acceptable salt or stereoisomer thereof,

[1047]

[1048] in

[1049] X 3 is CH or N;

[1050] R 1 is H or F;

[1051] R 5 、R 6 are independently hydrogen, -CF3 or halogen, preferably F or Cl;

[1052] o is 0 or 1;

[1053] R 7 is hydrogen or halogen, preferably F;

[1054] Z is selected from

[1055]

[1056] In some embodiments of compounds of Formula VI-1, VI-2a, VI-3a, or VI-4a, R 4 It is hydrogen, fluorine or chlorine.

[1057] In some embodiments of compounds of Formula VI-1, VI-2a, VI-3a, or VI-4a, o is 1.

[1058] In some embodiments of compounds of Formula VI-1, VI-2a, VI-3a, or VI-4a, R 5 Is F and / or R 6 It is F or Cl.

[1059] In some embodiments of compounds of Formula VI-1, VI-2a, VI-3a, or VI-4a, if X 3 is N, then R 7 is hydrogen and / or if X 3 is CH, then R 7It's F.

[1060] In some embodiments of compounds of Formula VI-1, VI-2a, VI-3a, or VI-4a, R 1 It may be hydrogen.

[1061] In some embodiments of compounds of Formula VI-2, VI-3, or VI-4, X 3 is N, producing a compound of Formula VI-2b, VI-3b, VI-4b or a pharmaceutically acceptable salt or stereoisomer thereof, or X 3 is C, producing a compound of formula VI-5b or a pharmaceutically acceptable salt or stereoisomer thereof,

[1062]

[1063] in

[1064] X 2 is O, NH, or NMe;

[1065] R 1 is H or F;

[1066] R 5 、R 6 are independently hydrogen, -CF3 or halogen, preferably F or Cl;

[1067] o is 0 or 1;

[1068] R 7 is hydrogen or halogen, preferably F;

[1069] Z is selected from

[1070]

[1071] In some embodiments of compounds of Formula VI-1, VI-2b, VI-3b, VI-4b, or VI-5b, R 4 It is hydrogen, fluorine or chlorine.

[1072] In some embodiments of compounds of Formula VI-1, VI-2b, VI-3b, VI-4b, or VI-5b, o is 1.

[1073] In some embodiments of compounds of Formula VI-1b, VI-2b, VI-3b, VI-4b, or VI-5b, R 5 Is F and / or R 6 It is F or Cl.

[1074] In some embodiments of compounds of Formula VI-1, VI-2b, VI-3b, VI-4b, or VI-5b, R 7 It's F.

[1075] In some embodiments of compounds of Formula VI-1, VI-2b, VI-3b, VI-4b, or VI-5b, R 1 It may be hydrogen.

[1076] In some embodiments, the present disclosure provides a compound or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound has Formula VII-1,

[1077]

[1078] in

[1079] R 1 is H or F, preferably H;

[1080] R 4 is hydrogen or halogen, preferably F or Cl;

[1081] R 5 、R 6 are independently hydrogen, -CF3 or halogen, preferably F or Cl;

[1082] Z is selected from

[1083]

[1084] In some embodiments, the present disclosure provides a compound or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound has formula VII-2, VII-3 or VII-4, VII-5, VII-6, VII-7, VII-8 or VII-9,

[1085]

[1086] in

[1087] R 1 is H or F, preferably H;

[1088] o is 0 or 1;

[1089] R 5 、R 6 are independently hydrogen, -CF3 or halogen, preferably F or Cl;

[1090] R 7 is hydrogen or halogen, preferably F;

[1091] Z is selected from

[1092]

[1093] In some embodiments of compounds of Formula VII-1, VII-2, VII-3, VII-4, VII-5, VII-6, VII-7, VII-8, or VII-9, R 4 It is hydrogen, fluorine or chlorine.

[1094] In some embodiments of compounds of Formula VII-1, VII-2, VII-3, or VII-4, VII-5, VII-6, VII-7, VII-8, or VII-9, o is 1.

[1095] In some embodiments of compounds of Formula VII-1, VII-2, VII-3, VII-4, VII-5, VII-6, VII-7, VII-8, or VII-9, R 5 is F and / or R 6 It is F or Cl.

[1096] In some embodiments of compounds of Formula VII-1, VII-2, VII-3, VII-4, VII-5, VII-6, VII-7, VII-8, or VII-9, R 7 It's F.

[1097] In some embodiments of compounds of Formula VII-1, VII-2, VII-3, VII-4, VII-5, VII-6, VII-7, VII-8, or VII-9, R 1 It may be hydrogen.

[1098] In some embodiments, the compound is selected from the compounds described in Tables 1 and 2, pharmaceutically acceptable salts thereof, and stereoisomers thereof.

[1099] In some embodiments, the compound is selected from the compounds described in Tables 1 and 2 and pharmaceutically acceptable salts thereof.

[1100] In some embodiments, the compound is selected from the compounds described in Tables 1 and 2.

[1101] In some embodiments, the compound is selected from the compounds described in Table 1, pharmaceutically acceptable salts thereof, and stereoisomers thereof.

[1102] In some embodiments, the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[1103] In some embodiments, the compound is selected from the compounds described in Table 1.

[1104] In some embodiments, the compound is selected from the compounds described in Table 2, pharmaceutically acceptable salts thereof, and stereoisomers thereof.

[1105] In some embodiments, the compound is selected from the compounds described in Table 2 and pharmaceutically acceptable salts thereof.

[1106] In some embodiments, the compound is selected from the compounds described in Table 2.

[1107] Table 1

[1108]

[1109]

[1110]

[1111]

[1112] Table 2

[1113]

[1114]

[1115]

[1116]

[1117]

[1118]

[1119]

[1120]

[1121]

[1122]

[1123]

[1124]

[1125]

[1126]

[1127]

[1128]

[1129]

[1130]

[1131] In some aspects, the present disclosure provides a compound that is an isotopic derivative (eg, an isotopically labeled compound) of any one of the compounds of the formulae disclosed herein.

[1132] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Tables 1 and 2, a pharmaceutically acceptable salt thereof, and a stereoisomer thereof.

[1133] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Tables 1 and 2 and pharmaceutically acceptable salts thereof.

[1134] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Tables 1 and 2.

[1135] It should be understood that any of a variety of art-recognized techniques can be used to prepare isotopic derivatives. For example, isotopic derivatives can generally be prepared by replacing non-isotopically labeled reagents with isotopically labeled reagents and implementing the procedures disclosed in the schemes and / or examples described herein.

[1136] In some embodiments, the isotopic derivative is a deuterium-labeled compound.

[1137] In some embodiments, the isotopic derivative is a deuterium-labeled compound of any of the compounds of the formulae disclosed herein.

[1138] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in Tables 1 and 2, a pharmaceutically acceptable salt thereof, and a stereoisomer thereof.

[1139] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in Tables 1 and 2, and pharmaceutically acceptable salts thereof.

[1140] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in Tables 1 and 2.

[1141] In some embodiments, the compound is selected from the compounds described in Table 3, pharmaceutically acceptable salts thereof, and stereoisomers thereof.

[1142] In some embodiments, the compound is selected from the compounds described in Table 3 and pharmaceutically acceptable salts thereof.

[1143] In some embodiments, the compound is a compound described in Table 3.

[1144] Table 3

[1145]

[1146] It will be appreciated that a deuterium-labeled compound includes deuterium atoms having an abundance substantially greater than the natural abundance of deuterium, which is 0.015%.

[1147] In some embodiments, the deuterium-labeled compound has a deuterium enrichment factor of at least 3500 (52.5% deuterium incorporation at each deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) per deuterium atom. As used herein, the term "deuterium enrichment factor" means the ratio between the abundance of deuterium and the natural abundance of deuterium.

[1148] It should be understood that any of a variety of techniques recognized in the art can be used to prepare deuterium-labeled compounds. For example, deuterium-labeled compounds can generally be prepared by replacing non-deuterium-labeled reagents with deuterium-labeled reagents and implementing the procedures disclosed in the schemes and / or examples described herein.

[1149] The compounds of the present invention or pharmaceutically acceptable salts or solvates thereof containing the above-mentioned deuterium atoms are within the scope of the present invention. 2 H) substitutions may offer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

[1150] The compounds of the present disclosure may contain one or more asymmetric centers in the molecule. Compounds for which stereochemistry is not specified are understood to include all optical isomers (e.g., diastereomers, enantiomers, etc.) in pure or substantially pure form, as well as mixtures thereof (e.g., racemic mixtures, or mixtures enriched in enantiomers). How to prepare such optically active forms is well known in the art (e.g., by resolving racemic forms through recrystallization techniques, by synthesizing from optically active starting materials, by chiral synthesis, or by using chiral stationary phases for chromatographic separation and other methods).

[1151] The compound can be an isotopically labeled compound, for example, a compound containing various isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, iodine or chlorine. The disclosed compounds can exist in tautomeric forms and mixtures, and separate tautomers are contemplated. In addition, some compounds may exhibit polymorphism.

[1152] The compounds of the present disclosure include their free forms and pharmaceutically acceptable salts and stereoisomers. Pharmaceutically acceptable salts include all typical pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the compounds of the present invention can be synthesized from compounds of the present disclosure containing basic or acidic moieties by conventional chemical methods, see, for example, Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Sciences (J. Pharm. ScL), 1977: 66: 1-19.

[1153] For example, conventional pharmaceutically acceptable salts of basic compounds include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylamine, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, and the like. Conventional pharmaceutically acceptable salts of acidic compounds include those derived from inorganic bases, including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganese, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic 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-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, hydrazine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[1154] Compounds of the present disclosure may exist in solid, i.e. crystalline or non-crystalline form (optionally as solvates) or liquid form. In the solid state, it may exist in the form of its mixture or as its mixture. In crystalline solvates, solvent molecules are incorporated into the crystal lattice during crystallization. The formation of solvates may include non-aqueous solvents, such as but not limited to ethanol, isopropanol, DMSO, acetic acid, ethanolamine or ethyl acetate, or aqueous solvents, such as water (also referred to as "hydrates"). It is well known that crystalline forms (and their solvates) may exhibit polymorphism, i.e., exist in different crystal structures referred to as "polymorphs", which have the same chemical composition, but differ in stacking, geometric arrangement and other descriptive properties of the crystalline solid state. Therefore, polymorphs may have different physical properties that can be used for identification, such as shape, density, hardness, deformability, stability and solubility characteristics, and may show different melting points, IR spectra and X-ray powder diffraction patterns. For example, during the preparation of compounds of the present disclosure, such different polymorphs may be produced by changing or adjusting reaction conditions or reagents.

[1155] In some aspects, the present disclosure also provides methods for preparing the compounds of the present disclosure. Generally, they are prepared according to the synthetic methods shown in the experimental section.

[1156] It should be understood that the synthetic methods of the present disclosure can tolerate a wide variety of functional groups and therefore can use a variety of substituted starting materials. The methods essentially provide the desired final compound at or near the end of the entire process, but in some cases it may be necessary to further convert the compound into a pharmaceutically acceptable salt thereof.

[1157] It will be understood that the compounds of the present disclosure can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature or from readily prepared intermediates, by employing standard synthetic methods and procedures known to those skilled in the art or which will be apparent to the skilled artisan in view of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and for functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th ed., John Wiley & Sons: New York, 2001; and Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd ed., John Wiley & Sons: New York, 1999; and Larocque Comprehensive Organic Transformations (VCH Publishers Inc., (1989); L. Fieser and M. Fieser, Fisher and Fisher's Reagents for Organic Synthesis, 3rd ed., John Wiley & Sons: New York, 1999; and Larocque Comprehensive Organic Transformations (VCH Publishers Inc., (1989)); L. Fieser and M. Fieser, Fisher and Fisher's Reagents for Organic Synthesis, 5th ed., John Wiley & Sons: New York, 2001; and Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd ed., John Wiley & Sons: New York, 1999; and Larocque Comprehensive Organic Transformations (VCH Publishers Inc., (1989)); L. Fieser and M. Fieser, Fisher and Fisher's Reagents for Organic Synthesis, 3rd ed., John Wiley & Sons: New York, 1999; and Larocque Comprehensive Organic Transformations (VCH Publishers Inc., (1989)). and Fieser's Reagents for Organic Synthesis, John Wiley & Sons, (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley & Sons, (1995) are useful and recognized reference textbooks on organic synthesis known to those skilled in the art.

[1158] Those of ordinary skill in the art will note that during the reaction sequence and synthesis scheme described herein, the order of some steps can be changed, such as the introduction and removal of blocking groups. Those of ordinary skill in the art will recognize that some groups may need to be protected from the influence of reaction conditions by using blocking groups. Blocking groups can also be used to distinguish similar functional groups in molecules. The blocking group list and how to introduce and remove these groups can be found in Greene, TW, Wuts, PGM, " Blocking Groups in Organic Synthesis ", 3rd edition, John Wiley & Sons: New York, 1999.

[1159] Bioassay

[1160] Once generated, compounds designed, selected, and / or optimized by the methods described herein can be characterized using various assays known to those skilled in the art to determine whether the compounds possess biological activity. For example, molecules can be characterized by conventional assays, including but not limited to those described below, to determine whether they possess the predicted activity, binding activity, and / or binding specificity.

[1161] In addition, high throughput screening can be used to accelerate the analysis using such assays. Therefore, the activity of the molecules described herein can be quickly screened using techniques known in the art. For example, general methods for performing high throughput screening are described in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High throughput assays can use one or more different assay techniques, including but not limited to those described below.

[1162] Various in vitro or in vivo bioassays can be suitable for detecting the effects of the compounds of the present disclosure. These in vitro or in vivo bioassays can include, but are not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and assays described herein.

[1163] Pharmaceutical composition

[1164] In some aspects, the present disclosure further provides a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of the present disclosure or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers and / or excipients (also referred to as diluents). An excipient is "acceptable" in the sense that it is compatible with the other ingredients of the formulation and is not harmful to the recipient thereof (i.e., the patient). As used herein, the term "therapeutically effective amount" refers to an amount of a compound of the present disclosure (either by itself or in the form of a pharmaceutical composition) that is effective to produce some desired therapeutic effect.

[1165] The pharmaceutical composition may be in the form of a unit dosage containing a predetermined amount of a compound of the present disclosure per unit dose. Such units may contain a therapeutically effective dose of a compound of the present disclosure or a salt thereof, or a portion of a therapeutically effective dose, such that multiple unit dosage forms may be administered at a given time to achieve the desired therapeutically effective dose. Preferred unit dosage formulations are those containing a daily dose or subdose of a compound of the present disclosure or a salt thereof, or an appropriate fraction thereof.

[1166] The compounds of the present disclosure can be administered in solid or liquid form by any acceptable means, including (1) oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions); tablets, e.g., tablets intended for buccal, sublingual, and systemic absorption; boluses; powders; granules; pastes applied to the tongue; (2) parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection, e.g., as a sterile solution or suspension or sustained-release formulation; (3) topical application, e.g., as a cream, ointment, or controlled-release patch or spray applied to the skin; (4) intravaginally or intrauterinely, e.g., as a pessary, cream, or foam; (5) sublingually; (6) ophthalmically; (7) transdermally; or (8) nasally; (9) pulmonary; or (10) intrathecally.

[1167] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition or vehicle involved in carrying or transporting the subject compound from one organ or part of the body to another, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, magnesium talc, calcium or zinc stearate or stearic acid), or solvent encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) 11) polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) pH buffer solutions; (21) polyesters, polycarbonates and / or polyanhydrides; and (22) other non-toxic compatible substances used in pharmaceutical compositions.

[1168] Such compositions may contain additional components conventional in pharmaceutical formulations, for example, wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavorings and fragrances, preservatives and antioxidants, pH adjusters, bulking agents and additional active agents. Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and (3) metal chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[1169] Such compositions can be prepared by any method known in the art, for example, by associating the active ingredient with one or more carriers and / or excipients. Different compositions and examples of carriers and / or excipients are well known to those skilled in the art and are described in detail, for example, in Remington: The Science and Practice of Pharmacy. Pharmaceutical Press, 2013; Rowe, Sheskey, Quinn: Handbook of Pharmaceutical Excipients, Pharmaceutical Press, 2009. Excipients that can be used to prepare pharmaceutical compositions can include one or more of the following: buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, fragrances, flavorings, diluents, and other known additives to provide a composition suitable for administration.

[1170] As indicated above, the compounds of the present disclosure can be in solid or liquid form and administered by a variety of routes in any convenient administration form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, pastes, and the like.

[1171] In the solid dosage forms for oral administration of the present disclosure (capsules, tablets, pills, dragees, powders, granules, pellets, etc.), the compound is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, seaweed, or any of the following: Alginic acid, certain silicates, and sodium carbonate; (5) solution retardants, such as paraffin; (6) absorption promoters, such as quaternary ammonium compounds and surfactants, such as poloxamer and sodium lauryl sulfate; (7) wetting agents, such as cetyl alcohol, glyceryl monostearate, and nonionic surfactants; (8) absorbents, such as kaolin and bentonite; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) coloring agents; and (11) controlled release agents, such as crospovidone or ethylcellulose. In the case of capsules, tablets, and pills, the pharmaceutical composition may also include a buffer. Similar types of solid compositions may also use excipients such as lactose or milk sugar and high molecular weight polyethylene glycol as fillers in soft-shell gelatin capsules and hard-shell gelatin capsules. Tablets can be prepared by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared using a binder (e.g., gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), a surfactant or a dispersant. Molded tablets can be manufactured by molding a mixture of a powdered compound moistened with an inert liquid diluent in a suitable machine. The tablets and other solid dosage forms of the pharmaceutical composition of the present disclosure (e.g., dragees, capsules, pills, and granules) can optionally be coated or prepared with a coating and a shell, such as other coatings well-known in the field of enteric coatings and pharmaceutical formulations. The dosage form can also be formulated to use, for example, different proportions of hydroxypropyl methylcellulose to provide a sustained or controlled release of the active ingredient therein to provide a desired release profile, other polymer matrices, liposomes, and / or microspheres. The dosage form can be formulated for quick release, for example, freeze-dried. The dosage form can for example be filtered through a bacteria-retaining filter or sterilized by mixing a sterilizing agent that can be dissolved in the form of the sterile solid composition in sterile water or some other sterile injectable media, and then use immediately. These compositions can also optionally contain an emulsifier and their composition can make it only or preferably in a certain part of the gastrointestinal tract, optionally release one or more active components in a delayed manner. The example of operable embedding composition comprises polymeric substances and wax.The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[1172] Liquid dosage forms for oral administration of compounds of the present disclosure include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to active ingredients, liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifying agents, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oil (particularly, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuran alcohol, polyethylene glycol and fatty acid esters of sorbitan and mixtures thereof. Oral compositions can also include adjuvants, such as wetting agents, emulsifying agents and suspending agents, sweeteners, flavorings, coloring agents, aromatics and preservatives.

[1173] In the form of a suspension, the compound may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, mixtures thereof, and the like.

[1174] Dosage forms of the pharmaceutical compositions of the present disclosure for rectal or vaginal administration include suppositories, which can be prepared by mixing one or more compounds of the present disclosure with one or more suitable non-irritating excipients or carriers, including, for example, cocoa butter, polyethylene glycol, suppository wax or salicylates, and which are solid at room temperature but liquid at body temperature and thus will melt in the rectum or vaginal cavity and release the active compound. Other suitable forms include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing appropriate carriers known in the art.

[1175] Dosage forms for topical or transdermal administration of a compound of the present disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound can be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that may be needed. In addition to the compound of the present disclosure, the ointments, pastes, creams, and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[1176] Dosage forms for administering the compounds of the present disclosure, such as powders and sprays, can contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. Sprays can additionally contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[1177] For use of the disclosed compound such as transdermal patch formulations can include absorption enhancers or retarder to increase or reduce the flux of the compound through the skin. The rate of this type of flux can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel. Other formulations contemplated include ophthalmic formulations, eye ointments, powders, solutions, etc. It should be understood that all contemplated compositions must be stable under manufacturing and storage conditions and can be preserved against the contamination of microorganisms such as bacteria and fungi.

[1178] The dosage level of the compound of the present invention in the pharmaceutical composition of the present invention can be adjusted to obtain the amount of the compound of the present invention that effectively realizes the desired therapeutic response and is harmless to the patient for specific patients, compositions and modes of administration. The dosage selected will depend on various factors, including the excretion or metabolic rate, absorption rate and absorption degree of the specific compound of the present invention used, the property of the specific compound of the present invention used, the administration route, the administration time, the specific compound used, the duration of prevention or treatment, other drugs, compounds and / or materials used in combination with the specific compound, the age, sex, weight, condition of illness, general health and previous medical history of the patient being treated, and similar factors well-known in the medical field. A physician with ordinary skills in the field can easily determine and prescribe the effective amount of the required pharmaceutical composition.

[1179] Typically, the appropriate daily dose of a compound of the present invention will be the amount of the compound at the lowest dose that effectively produces a therapeutic effect. This effective dose generally depends on the above factors. Typically, when used for the indicated analgesic effect, the range of oral, intravenous, intracerebroventricular and subcutaneous doses of a compound of the present invention for a patient will be about 0.0001 to about 100 mg, more generally 0.1 to 100 mg / kg per kilogram of recipient (patient, mammal) body weight per day. An acceptable daily dose can be about 1 to about 1000 mg / day, and for example, about 1 to about 100 mg / day.

[1180] The effective dose of the disclosed compounds can be divided into two, three, four, five, six or more sub-doses administered at appropriate intervals (daily, weekly or monthly) over a specific time period, optionally administered in unit dosage form. The preferred dose also depends on the above factors, for example, in terms of administration, and can be easily derived by those skilled in the medical or pharmaceutical fields.

[1181] Uses of compounds and compositions

[1182] The compounds of the present disclosure inhibit or modulate the activity of receptor tyrosine kinases, specifically extracellular mutants of ErbB receptors, such as, but not limited to, EGFR-Viii, EGFR-Vii, EGFR-Vvi, EGFR-A289V, EGFR-G598V, and HER2-S310F. Therefore, the compounds and compositions of the present disclosure can be used as pharmaceuticals, i.e., as pharmaceuticals in therapy, more specifically for preventing or treating cancer, as described in detail below. Therefore, in another aspect, the present disclosure provides a method for preventing or treating a mammal, such as a human, suffering from cancer, as described in detail below.

[1183] The term "prevention" or "preventing" refers to reducing or eliminating the symptoms or onset of a disease (e.g., cancer). Such prevention includes administering to the mammal, e.g., a human, a therapeutically effective amount of a compound of Formula I or a salt thereof (or a pharmaceutical composition containing a compound of Formula I or a salt thereof).

[1184] The term "treatment" or "treating" is intended to encompass both therapy and cure. Such treatment includes the step of administering to the mammal, such as a human, a therapeutically effective amount of a compound of formula I or a salt thereof (or a pharmaceutical composition containing a compound of formula I or a salt thereof).

[1185] Therefore, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition thereof, for preventing or treating cancer in a mammal, such as a human, as described in detail below.

[1186] In some aspects, the disclosure relates to a method of inhibiting an oncogenic variant of an ErbB receptor (eg, an oncogenic variant of EGFR), comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.

[1187] In some aspects, the present disclosure relates to a method of inhibiting an oncogenic variant of an ErbB receptor (eg, an oncogenic variant of EGFR), the method comprising administering to a subject in need thereof a composition described herein.

[1188] In some aspects, the disclosure relates to a method of preventing or treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.

[1189] In some aspects, the present disclosure relates to a method of preventing or treating cancer comprising administering a composition described herein to a subject in need thereof.

[1190] In some aspects, the disclosure relates to compounds described herein for use in inhibiting oncogenic variants of ErbB receptors (eg, oncogenic variants of EGFR).

[1191] In some aspects, the disclosure relates to compounds described herein for use in preventing or treating cancer.

[1192] In some aspects, the disclosure relates to the compositions described herein for inhibiting oncogenic variants of ErbB receptors (eg, oncogenic variants of EGFR).

[1193] In some aspects, the disclosure relates to the compositions described herein for use in preventing or treating cancer.

[1194] In some aspects, the disclosure relates to the use of the compounds described herein for the manufacture of a medicament for inhibiting oncogenic variants of ErbB receptors (eg, oncogenic variants of EGFR).

[1195] In some aspects, the disclosure relates to the use of the compounds described herein for the manufacture of a medicament for the prevention or treatment of cancer.

[1196] In some embodiments, the compound is selected from the compounds described in Tables 1 and 2, pharmaceutically acceptable salts thereof, and stereoisomers thereof.

[1197] In some embodiments, the compound is selected from the compounds described in Tables 1 and 2 and pharmaceutically acceptable salts thereof.

[1198] In some embodiments, the compound is selected from the compounds described in Tables 1 and 2.

[1199] In some embodiments, the cancer is a solid tumor.

[1200] In some embodiments, the cancer is bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, glioblastoma (GBM), head and neck cancer, lung cancer, non-small cell lung cancer (NSCLC), or any subtype thereof.

[1201] In some embodiments, the cancer is glioblastoma (GBM) or any subtype thereof.

[1202] In some embodiments, the cancer is glioblastoma.

[1203] In some embodiments, the cancer or tumor or cell thereof expresses an oncogenic variant of an ErbB receptor.

[1204] In some embodiments, the oncogenic variant of the ErbB receptor comprises an allosteric mutation.

[1205] In some embodiments, the oncogenic variant of the ErbB receptor is an allosteric variant of the ErbB receptor.

[1206] In some embodiments, the ErbB receptor is epidermal growth factor receptor (EGFR) or human epidermal growth factor receptor 2 (HER2) receptor.

[1207] In some embodiments, the ErbB receptor is epidermal growth factor receptor (EGFR).

[1208] In some embodiments, the ErbB receptor is a HER2 receptor.

[1209] In some embodiments, the cancer or tumor or cells thereof express an oncogenic variant of epidermal growth factor receptor (EGFR).

[1210] In some embodiments, the oncogenic variant of EGFR is an allosteric variant of EGFR.

[1211] In some embodiments, oncogenic variants of EGFR comprise allosteric mutations.

[1212] In some embodiments, the cancer or tumor or cells thereof express an oncogenic variant of the HER2 receptor.

[1213] In some embodiments, the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor.

[1214] In some embodiments, the oncogenic variant of the HER2 receptor comprises an allosteric mutation.

[1215] In some embodiments, oncogenic variants of EGFR include EGFR variant III (EGFR-Viii) mutations.

[1216] In some embodiments, oncogenic variants of EGFR include EGFR variant II (EGFR-Vii) mutations.

[1217] In some embodiments, oncogenic variants of EGFR include EGFR variant VI (EGFR-Vvi) mutations.

[1218] In some embodiments, the oncogenic variant of EGFR comprises a valine (V) substituted for an alanine (A) at position 289 of SEQ ID NO:1.

[1219] In some embodiments, the oncogenic variant of EGFR comprises a valine (V) substituted for a glycine (G) at position 598 of SEQ ID NO:1.

[1220] In some embodiments, the cancer or its tumor or cell expresses an oncogenic variant of EGFR, and wherein the oncogenic variant of EGFR is an allosteric variant of EGFR, the oncogenic variant of EGFR includes a modification to the EGFR structure, wherein the oncogenic variant of EGFR is capable of forming a covalently linked dimer, wherein the covalently linked dimer is constitutively active, and wherein the covalently linked dimer enhances the activity of EGFR when in contact with a type I ErbB inhibitor. In some embodiments, the modification of the EGFR structure includes modification of one or more of the nucleic acid sequence, amino acid sequence, secondary structure, tertiary structure, and quaternary structure. In some embodiments, the oncogenic variant includes a mutation, a splicing event, a post-translational process, a conformational change, or any combination thereof. In some embodiments, the modification of the EGFR structure occurs in the first cysteine-rich (CR1) region and / or the second cysteine-rich (CR2) region of EGFR. In some embodiments, the first cysteine-rich (CR1) region and / or the second cysteine-rich (CR2) region of EGFR include amino acid residues T211-R334 and / or C526-S645 of SEQ ID NO: 1, respectively. In some embodiments, the oncogenic variants of EGFR create a physical barrier to disulfide bond formation within the CR1 region and / or the CR2 region. In some embodiments, the oncogenic variants of EGFR remove the physical barrier to disulfide bond formation within the CR1 region and / or the CR2 region. In some embodiments, the oncogenic variants of EGFR include one or more free or unpaired cysteine ​​(C) residues located at the dimer interface of EGFR. In some embodiments, the oncogenic variants of EGFR include one or more free or unpaired cysteine ​​(C) residues at a site selected from the group consisting of: NO:1's C190-C199, C194-C207, C215-C223, C219-C231, C232-C240, C236-C248, C251-C260, C264-C291, C295-C307, C311-C326, C329-C333, C506-C515, C510-C523, C526-C535, C539-C555, C558-C571, C562-C579, C582-C591, C595-C617, C620-C628 and C624-C636.In some embodiments, the modification occurs within 10 angstroms or less of an intramolecular disulfide bond at a site selected from the group consisting of: C190-C199, C194-C207, C215-C223, C219-C231, C232-C240, C236-C248, C251-C260, C264-C291, C295-C307, C311-C326, C329-C333, C506-C515, C510-C523, C526-C535, C539-C555, C558-C571, C562-C579, C582-C591, C595-C617, C620-C628, and C624-C636 according to SEQ ID NO: 1.

[1221] In some embodiments, the cancer or its tumor or cell expresses an oncogenic variant of EGFR, and the oncogenic variant of EGFR is a mutation of EGFR, and the nucleotide sequence encoding the oncogenic variant of EGFR comprises a deletion or substitution comprising one or more amino acids encoding an adenosine triphosphate (ATP) binding site. In some embodiments, the ATP binding site comprises amino acids E746 to A750 of SEQ ID NO: 1. In some embodiments, the ATP binding site or its deletion or substitution comprises K858 of SEQ ID NO: 1. In some embodiments, the deletion comprises K858 of SEQ ID NO: 1. In some embodiments, arginine (R) is substituted for lysine (K) at position 858 of SEQ ID NO: 1 (K858R).

[1222] In some embodiments, the cancer or its tumor or cell expresses an oncogenic variant of EGFR, and wherein the oncogenic variant of EGFR is an allosteric variant of EGFR, and the nucleotide sequence encoding the oncogenic variant of EGFR comprises an insertion within the sequence encoding exon 20 or a portion thereof. In some embodiments, the sequence encoding exon 20 or a portion thereof comprises a sequence encoding KEILDEAYVMASVDNPHVCAR (SEQ ID NO: 7). In some embodiments, the sequence encoding exon 20 or a portion thereof comprises a sequence encoding the C-helix, the end of the C-helix, or the loop following the C-helix. In some embodiments, the insertion comprises the amino acid sequence of ASV, SVD, NPH, or FQEA. In some embodiments, the sequence encoding exon 20 or a portion thereof comprises one or more of the following: (a) the amino acid sequence ASV inserted between positions V769 and D770 of SEQ ID NO: 1; (b) the amino acid sequence SVD inserted between positions D770 and N771 of SEQ ID NO: 1; (c) the amino acid sequence NPH inserted between positions H773 and V774 of SEQ ID NO: 1; (d) the amino acid sequence FQEA inserted between positions A763 and Y764 of SEQ ID NO: 1; (e) the amino acid sequence PH inserted between positions H773 and V774 of SEQ ID NO: 1; (f) the amino acid G inserted between positions D770 and N771 of SEQ ID NO: 1; (g) the amino acid H inserted between positions H773 and V774 of SEQ ID NO: 1; (h) the amino acid sequence HV inserted between positions V774 and C775 of SEQ ID NO: 1; (i) the amino acid sequence FQEA inserted between positions A763 and Y764 of SEQ ID NO: 1; the amino acid sequence AH between positions H773 and V774 of SEQ ID NO:1; (j) the amino acid sequence SVA inserted between positions A767 and S768 of SEQ ID NO:1; (k) the amino acid sequence GYN substituted for DN between positions 770 and 771 of SEQ ID NO:1; (l) the amino acid H inserted between positions N771 and P772 of SEQ ID NO:1; (m) the amino acid Y inserted between positions H773 and V774 of SEQ ID NO:1; (n) the amino acid sequence PHVC inserted between positions C775 and R776 of SEQ ID NO:1; (o) the amino acid sequence YNPY substituted for H at position 773 of SEQ ID NO:1; (p) the amino acid sequence DNP inserted between positions P772 and H773 of SEQ ID NO:1; (q) the amino acid sequence VDS inserted between positions S768 and V769 of SEQ ID NO:1;(r) the amino acid H inserted between positions D770 and N771 of SEQ ID NO: 1; (s) the amino acid N inserted between positions N771 and P772 of SEQ ID NO: 1; (t) the amino acid sequence PNP inserted between positions P772 and H773 of SEQ ID NO: 1; (u) the amino acid sequence GSVDN substituted for DN between positions 770 and 771 of SEQ ID NO: 1; (v) the amino acid sequence GYP substituted for NP between positions 771 and 772 of SEQ ID NO: 1; (w) the amino acid G inserted between positions N771 and P772 of SEQ ID NO: 1; (x) the amino acid sequence GNP inserted between positions P772 and H773 of SEQ ID NO: 1; (y) the amino acid sequence GSV inserted between positions V769 and D770 of SEQ ID NO: 1; (z) the amino acid sequence GNPHVC substituted for VC between positions 774 and 775 of SEQ ID NO: 1; (aa) the amino acid sequence LQEA between positions A763 and Y764 of SEQ ID NO: 1; (bb) the amino acid sequence GL inserted between positions D770 and N771 of SEQ ID NO: 1; (cc) the amino acid Y inserted between positions D770 and N771 of SEQ ID NO: 1; (dd) the amino acid sequence NPY inserted between positions H773 and V774 of SEQ ID NO: 1; (ee) the amino acid sequence TH inserted between positions H773 and V774 of SEQ ID NO: 1; (ff) the amino acid sequence KGP replacing NP between positions 771 and 772 of SEQ ID NO: 1; (gg) the amino acid sequence SVDNP replacing NP between positions 771 and 772 of SEQ ID NO: 1; (hh) the amino acid sequence NN inserted between positions N771 and P772 of SEQ ID NO: 1; (ii) the amino acid T inserted between positions N771 and P772 of SEQ ID NO: 1; and (jj) the amino acid sequence NN replacing NP between positions 771 and 772 of SEQ ID NO: 1. The amino acid sequence of SV between positions 768 and 769 of NO:1 is STLASV.

[1223] In some embodiments, the cancer or tumor or cell thereof expresses an oncogenic variant of EGFR, and wherein the oncogenic variant of EGFR is an allosteric variant of EGFR, and the oncogenic variants of EGFR include EGFR-Vii, EGFR-Vvi, EGFR-R222C, EGFR-R252C, EGFR-R252P, EGFR-R256Y, EGFR-T263P, EGFR-Y270C, EGFR-A289T, EGFR-A289V, EGFR-A289 D. EGFR-H304Y, EGFR-G331R, EGFR-P596S, EGFR-P596L, EGFR-P596R, EGFR-G598V, EGFR-G598A, EGFR-G614D, E GFR-C620Y, EGFR-C614W, EGFR-C628F, EGFR-C628Y, EGFR-C636Y, EGFR-G645C, EGFR-Δ660, EGFR-Δ768, or any combination thereof.

[1224] In some embodiments, the cancer or tumor or cell thereof expresses one or more of: (a) a wild-type human epidermal growth factor receptor 2 (HER2) receptor or an oncogenic variant of the HER-2 receptor.

[1225] In some embodiments, the cancer or tumor or cell thereof expresses a wild-type HER-2 receptor comprising the amino acid sequence of SEQ ID NO: 2, 3, 4, 5, or 6.

[1226] In some embodiments, the cancer or tumor or cell thereof expresses an oncogenic variant of the HER-2 receptor, which is an allosteric variant of the HER2 receptor.

[1227] In some embodiments, the cancer or tumor or cell thereof expresses an oncogenic variant of the HER-2 receptor, and wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of the HER2 receptor comprising a phenylalanine (F) substituted for the serine (S) at position 310 of SEQ ID NO: 2 or 5.

[1228] In some embodiments, the cancer or tumor or cell thereof expresses an oncogenic variant of the HER-2 receptor, and wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of the HER2 receptor comprising a tyrosine (Y) substituted for the serine (S) at position 310 of SEQ ID NO: 2 or 5.

[1229] In some embodiments, the cancer or tumor or cell thereof expresses an oncogenic variant of the HER-2 receptor, and wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of the HER2 receptor comprising a glutamine (Q) substituted for the arginine (R) at position 678 of SEQ ID NO: 2 or 5.

[1230] In some embodiments, the cancer or tumor or cell thereof expresses an oncogenic variant of the HER-2 receptor, and wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of the HER2 receptor comprising a leucine (L) substituted for a valine (V) at position 777 of SEQ ID NO: 2 or 5.

[1231] In some embodiments, the cancer or tumor or cell thereof expresses an oncogenic variant of the HER-2 receptor, and wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of the HER2 receptor comprising a methionine (M) substituted for a valine (V) at position 777 of SEQ ID NO: 2 or 5.

[1232] In some embodiments, the cancer or tumor or cell thereof expresses an oncogenic variant of the HER-2 receptor, and wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of the HER2 receptor comprising an isoleucine (I) substituted for a valine (V) at position 842 of SEQ ID NO: 2 or 5.

[1233] In some embodiments, the cancer or tumor or cell thereof expresses an oncogenic variant of the HER-2 receptor, and wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of the HER2 receptor comprising an alanine (A) substituted for the leucine (L) at position 755 of SEQ ID NO: 2 or 5.

[1234] In some embodiments, the cancer or tumor or cell thereof expresses an oncogenic variant of the HER-2 receptor, and wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of the HER2 receptor comprising a proline (P) substituted for a leucine (L) at position 755 of SEQ ID NO: 2 or 5.

[1235] In some embodiments, the cancer or tumor or cell thereof expresses an oncogenic variant of the HER-2 receptor, and wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of the HER2 receptor comprising a serine (S) substituted for a leucine (L) at position 755 of SEQ ID NO: 2 or 5.

[1236] In some embodiments, the cancer or its tumor or cell expresses an oncogenic variant of the HER-2 receptor, and wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the nucleotide sequence encoding the oncogenic variant of the HER2 receptor comprises an insertion within the sequence encoding exon 20 or a portion thereof. In some embodiments, the sequence encoding exon 20 or a portion thereof comprises a sequence encoding KEILDEAYVMAGVGSPYVSR (SEQ ID NO: 8). In some embodiments, the sequence encoding exon 20 or a portion thereof comprises a sequence encoding the C-helix, the end of the C-helix, or the loop following the C-helix. In some embodiments, the insertion comprises the amino acid sequence of GSP or YVMA. In some embodiments, the sequence encoding exon 20 or a portion thereof comprises one or more of the following: (a) the amino acid sequence YVMA inserted between positions A775 and G776 of SEQ ID NO:2; (b) the amino acid sequence GSP inserted between positions P780 and Y781 of SEQ ID NO:2; (c) the amino acid sequence YVMA inserted between positions A771 and Y772 of SEQ ID NO:2; (d) the amino acid sequence YVMA inserted between positions A775 and G776 of SEQ ID NO:2; (e) the amino acid V inserted between positions V777 and G778 of SEQ ID NO:2; (f) the amino acid V inserted between positions V777 and G778 of SEQ ID NO:2; (g) the amino acid sequence AVGCV substituted for GV between positions 776 and 777 of SEQ ID NO:2; (h) the amino acid sequence LC substituted for G between positions 776 of SEQ ID NO:2; (i) the amino acid sequence LC substituted for G between positions 776 of SEQ ID NO:2; : (i) an amino acid sequence of SEQ ID NO:2 between positions 776 and 778, which replaces the amino acid sequence LCV of G between positions 776 and 777 of SEQ ID NO:2; (j) an amino acid sequence of GSP inserted between positions V777 and G778 of SEQ ID NO:2; (k) an amino acid sequence of PS replacing the LRE between positions 755 and 757 of SEQ ID NO:2; (l) an amino acid sequence of CPGSP replacing the SP between positions 779 and 780 of SEQ ID NO:2; (m) an amino acid C inserted between positions V777 and G778 of SEQ ID NO:2; (n) an amino acid sequence of VVMA replacing the AG between positions 775 and 776 of SEQ ID NO:2; (o) an amino acid sequence of VV replacing the G at position 776 of SEQ ID NO:2; (p) an amino acid sequence of AVCV replacing the GV between positions 776 and 777 of SEQ ID NO:2; (q) an amino acid sequence of VCV replacing the GV between positions 776 and 777 of SEQ ID NO:2;(r) amino acid G inserted between positions G778 and S779 of SEQ ID NO:2; (s) amino acid sequence PK replacing LRE between positions 755 and 757 of SEQ ID NO:2; (t) amino acid V inserted between positions A775 and G776 of SEQ ID NO:2; (u) amino acid sequence YAMA inserted between positions A775 and G776 of SEQ ID NO:2; (v) amino acid sequence CV replacing G at position 776 of SEQ ID NO:2; (w) amino acid sequence AVCGG replacing GVG between positions 776 and 778 of SEQ ID NO:2; (x) amino acid sequence CVCG replacing GVG between positions 776 and 778 of SEQ ID NO:2; (y) amino acid sequence VVVG replacing GVG between positions 776 and 778 of SEQ ID NO:2; (z) amino acid sequence SVGG replacing GVGS between positions 776 and 779 of SEQ ID NO:2; (aa) NO:2 between positions 776 and 779 of GVGS; (bb) substituted for the amino acid sequence VVGES of GVGS between positions 776 and 779 of SEQ ID NO:2; (cc) substituted for the amino acid sequence CVC of GV between positions 776 and 777 of SEQ ID NO:2; (dd) substituted for the amino acid sequence HVC of GV between positions 776 and 777 of SEQ ID NO:2; (ee) substituted for the amino acid sequence VAAGV of GV between positions 776 and 777 of SEQ ID NO:2; (ff) substituted for the amino acid sequence VAGV of GV between positions 776 and 777 of SEQ ID NO:2; (gg) substituted for the amino acid sequence VVV of GV between positions 776 and 777 of SEQ ID NO:2; (hh) inserted between positions G778 and S779 of SEQ ID NO:2; (ii) inserted between positions S779 and P780 of SEQ ID NO:2; (jj) substituted for the amino acid sequence GS of SEQ ID NO:2 between positions The amino acid sequence VPS of VLRE between positions 754 and 757 of SEQ ID NO:2; (kk) the amino acid E inserted between positions V777 and G778 of SEQ ID NO:2; (ll) the amino acid sequence MAGV inserted between positions V777 and G778 of SEQ ID NO:2; (mm) the amino acid S inserted between positions V777 and G778 of SEQ ID NO:2; (nn) the amino acid sequence SCV inserted between positions V777 and G778 of SEQ ID NO:2; and (oo) the amino acid sequence LMAY inserted between positions Y772 and V773 of SEQ ID NO:2.

[1237] In some embodiments, the cancer or tumor or cell thereof expresses an oncogenic variant of the HER-2 receptor, and wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of the HER2 receptor includes HER2-Δ16, HER2-C311R, HER2-S310F, p95-HER2-M611 or any combination thereof.

[1238] In some embodiments, the cancer or its tumor or cell expresses an oncogenic variant of the HER-4 receptor. In some embodiments, the oncogenic variant of the HER-4 receptor is an allosteric variant of the HER4 receptor. In some embodiments, the oncogenic variant of the HER4 receptor comprises a deletion of exon 16 (HER4-Δ16).

[1239] In some embodiments, the cancer, tumor, or cell thereof expresses an oncogenic variant of EGFR, wherein the sequence encoding the oncogenic variant of EGFR comprises a deletion of exon 20 or a portion thereof, and wherein the cancer, tumor, or cell thereof does not comprise a second oncogenic variant in a sequence other than EGFR exon 20. In some embodiments, the second oncogenic variant comprises a sequence encoding one or more of the EGFR kinase domain (KD), BRAF, NTRK, and KRAS.

[1240] In some embodiments, the cancer, tumor, or cell thereof expresses an oncogenic variant of EGFR, wherein the sequence encoding the oncogenic variant of EGFR comprises a deletion of exon 20 or a portion thereof, and wherein the cancer, tumor, or cell thereof does not comprise markers indicative of responsiveness to immunotherapy.

[1241] In some embodiments, the oncogenic variant (e.g., allosteric variant) or the oncogenic mutation (e.g., allosteric mutation) is detected by a Food and Drug Administration (FDA)-approved diagnostic test.

[1242] In some embodiments, the subject is treated with a therapeutic agent other than a compound of the present disclosure prior to treatment with the compound of the present disclosure.

[1243] In some embodiments, the cancer or its tumor or cell is insensitive or resistant to treatment with a therapeutic agent other than a compound of the present disclosure. In some embodiments, the cancer or its tumor or cell is insensitive or resistant to treatment with a type I inhibitor. In some embodiments, the cancer or its tumor or cell is insensitive or resistant to treatment with one or more of the following: gefitinib, erlotinib, afatinib, osimertinib, necitumumab, crizotinib, alectinib, ceritinib, dabrafenib, trametinib, afatinib, saputinib, dacomitinib, canertinib, pelitinib, WZ4002, WZ8040, WZ3146, CO-1686, and AZD9291.

[1244] In some embodiments, the subject has an adverse reaction to treatment with a therapeutic agent that is different from a compound of the present disclosure. In some embodiments, the subject has an adverse reaction to treatment with a type I inhibitor. In some embodiments, the subject has an adverse reaction to treatment with one or more of the following: gefitinib, erlotinib, afatinib, osimertinib, nacimol, crizotinib, alectinib, ceritinib, dabrafenib, trametinib, afatinib, saputinib, dacomitinib, canertinib, pelitinib, WZ4002, WZ8040, WZ3146, CO-1686, and AZD9291. In some embodiments, the adverse reaction is activation of an oncogenic variant of EGFR, and wherein the oncogenic variant includes a mutation in the extracellular domain of the receptor. In some embodiments, the adverse reaction is activation of an oncogenic variant of the HER-2 receptor, and wherein the oncogenic variant includes a mutation in the extracellular domain of the receptor.

[1245] In some embodiments, the method further comprises administering to a subject in need thereof a therapeutically effective amount of a non-Type I inhibitor. In some embodiments, the non-Type I inhibitor comprises a small molecule Type II inhibitor.

[1246] In some embodiments, the method further comprises administering to a subject in need thereof a therapeutically effective amount of a non-Type I inhibitor. In some embodiments, the non-Type I inhibitor comprises a small molecule Type II inhibitor.

[1247] In some embodiments, the compound is used in combination with a therapeutically effective amount of a non-Type I inhibitor. In some embodiments, the non-Type I inhibitor comprises a small molecule Type II inhibitor.

[1248] In some embodiments, the composition further comprises a non-Type I inhibitor. In some embodiments, the non-Type I inhibitor comprises a small molecule Type II inhibitor.

[1249] In some embodiments, a therapeutically effective amount reduces the severity of signs or symptoms of cancer.

[1250] In some embodiments, the signs of cancer include tumor grade, and wherein the reduction in severity of the signs includes a reduction in tumor grade.

[1251] In some embodiments, the signs of cancer include tumor metastasis, and wherein the reduction in severity of the signs includes elimination of metastasis or a reduction in the rate or extent of metastasis.

[1252] In some embodiments, the signs of cancer include tumor volume, and wherein the reduction in severity of the signs includes elimination of the tumor or a reduction in volume.

[1253] In some embodiments, the symptoms of cancer include pain, and wherein the reduction in severity of the symptoms includes elimination or alleviation of the pain.

[1254] In some embodiments, the therapeutically effective amount induces remission.

[1255] In some embodiments, a therapeutically effective amount improves the prognosis of a subject.

[1256] Such use (or prevention or treatment method) of a subject comprises administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof to a subject in need of such prevention or treatment by targeting allosteric variants and / or oncogenic variants of EGFR and HER-2 receptors.

[1257] The present disclosure contemplates administration of the compounds of the present disclosure alone or in combination with one or more additional therapeutic agents, such as other tyrosine kinase inhibitors: erlotinib hydrochloride (e.g., Tarceva(R) from Genentech / Roche), linifanib (or ABT869, Genentech), sunitinib malate (e.g., Sutent(R) from Pfizer), bosutinib (or SKI-606, described in U.S. Pat. No. 6,780,996), dasatinib (e.g., Sprycel(R) from Bristol-Myers Squibb), armala (e.g., pazopanib, e.g., Votrient(R) from GlaxoSmithKline), imatinib (e.g., imatinib), selegiline (e.g., selegiline), tamoxifen (e.g., tamoxifen), selegiline ... matinib) and imatinib mesylate (e.g., Novartis' Gilvec(R) and Gleevec(R)); vascular endothelial growth factor (VEG) receptor inhibitors (bevacizumab or Genentech / Roche's Avastin(R)), axitinib (or AG013736, described in WO01 / 002369), Brivanib Alaninate (or BMS-582664), motesanib ( or AMG-706, described in PCT WO02 / 066470), pasireotide (e.g., SOM230, described in WO02 / 010192), sorafenib (e.g., Nexavar(R)); HER2 receptor inhibitors: trastuzumab (e.g., Herceptin(R) from Genentech / Roche), neratinib (or HKI-272, described in WO05 / 028443), lapatinib (e.g., HER2 receptor inhibitors: trastuzumab (e.g., Herceptin(R) from Genentech / Roche), neratinib (or HKI-272, described in WO05 / 028443), lapatinib (e.g., HER2 receptor inhibitors: trastuzumab (e.g., Herceptin(R) from Genentech / Roche), lapatinib (e.g., HER2 receptor inhibitors: ) or lapatinib ditosylate (e.g., Tykerb(R) from GlaxoSmithKline); CD20 antibodies: rituximab (e.g., Riuxan(R) and MabThera(R) from Genentech / Roche), tositumomab (e.g., Bexxar(R) from GlaxoSmithKline), ofatumumab (e.g., Arzerra(R) from GlaxoSmithKline); Bcr / Abl kinase inhibitors: nilotinib hydrochloride (e.g., Tasigna(R) from Novartis);DNA synthesis inhibitors: capecitabine (e.g., Xeloda(R) from Roche), gemcitabine hydrochloride (e.g., Gemzar(R) from Eli Lilly), nelarabine (or Arranon(R) and Atriance(R) from GlaxoSmithKline); antitumor agents: oxaliplatin (e.g., Eloxatin(R) from Sanofi-Aventis, described in U.S. Pat. No. 4,169,846); epidermal growth factor receptor (EGFR) inhibitors. GFR) inhibitors: gefitinib (or Iressa(R)), afatinib (or Tovok(R) from Boehringer Ingelheim), cetuximab (e.g., Erbitux(R) from Bristol-Myers Squibb), panitumumab (e.g., Vectibix(R) from Amgen); HER dimerization inhibitors: pertuzumab (e.g., Omnitarg(R) from Genentech); human granulocyte colony-stimulating factor (G-CSF) modulators: filgrastim (e.g., Neupogen(R)); Immunomodulators: Afutuzumab (Roche(R)), pegfilgrastim (e.g., Amgen's Neulasta(R)), lenalidomide (e.g., CC-5013, e.g., Revlimid(R)), thalidomide (e.g., Thalomid(R)); (m) CD40 inhibitors: Dacetuzumab (e.g., SGN-40 or huS2C6 from Seattle Genetics); Apoptosis promoters apoptosis receptor agonist (PARA): Dulanermin (e.g., AMG-951 of Amgen / Genentech); Hedgehog antagonist: Vismodegib (or GDC-0449, described in WO06 / 028958); PI3K inhibitor: Pictilisib (or GDC-0941, described in WO09 / 036082 and WO09 / 055730), Dactolisib (or BEZ235 or NVP-BEZ235, described in WO 06 / 122806); Phospholipase A2 inhibitor: Anagrelide (e.g., Agrylin(R));BCL-2 inhibitor: Navitoclax (or ABT-263, described in WO09 / 155386); mitogen-activated protein kinase kinase (MEK) inhibitor: XL-518 (Cas No.: 1029872-29-4, ACC); aromatase inhibitor: exemestane (e.g., Aromasin(R) from Pfizer), letrozole (e.g., Femara(R) from Novartis), anastrozole (e.g., Arimidex(R)); topoisomerase I inhibitor: irinotecan (e.g., Camptosar(R) from Pfizer), topotecan hydrochloride (e.g., Hycamtin(R) from GlaxoSmithKline); topoisomerase II inhibitor: etoposide etoposide (e.g., VP-16 and etoposide phosphate, e.g., Toposar(R)), VePesid(R)) and Etopophos(R)), teniposide (e.g., VM-26, e.g., Vumon(R)); mTOR inhibitors: temsirolimus (e.g., Pfizer's Torisel(R)), ridaforolimus (formerly known as deferolimus, (or AP23573 and MK8669, described in WO03 / 064383), everolimus (e.g., Novartis' Afinitor(R)); osteoclast bone resorption inhibitor: zoledronic acid (or Novartis' Zometa(R)); CD33 antibody drug conjugate: Gemtuzumab ozogamicin) (e.g., Mylotarg(R) from Pfizer / Wyeth); CD22 antibody-drug conjugate: Inotuzumabozogamicin (also known as CMC-544 and WAY-207294, Hangzhou Saiqi Chemical Co., Ltd.); CD20 antibody-drug conjugate: Ibritumomab tiuxetan (e.g., Zevalin(R)); somatostatin analogs: octreotide (e.g., octreotide acetate, e.g., Sandostatin(R) and Sandostatin LAR(R)); synthetic interleukin 11 (IL-11): oprelvekin (e.g., Neumega(R) from Pfizer / Wyeth);Synthetic erythropoietin: Darbepoetin alfa (e.g., Aranesp(R) from Amgen); Receptor activator of nuclear factor kappa B (RANK) inhibitor: denosumab (e.g., Prolia(R) from Amgen); Thrombopoietin mimetic peptide: Romiplostim (e.g., Nplate(R) from Amgen); Cell growth stimulator: Palifermin (e.g., Kepivance(R) from Amgen); Anti-insulin-like growth factor-1 receptor (IGF-1R) antibodies: Figitumumab (e.g., CP-751,871, ACC), robatumumab (CAS No.: 934235-44-6); Anti-CS1 Antibody: Elotuzumab (HuLuc63, CAS No.: 915296-00-3); CD52 Antibody: Alemtuzumab (e.g., Campath(R)); CTLA-4 Inhibitors: Tremelimumab (IgG2 monoclonal antibody produced by Pfizer, formerly known as ticilimumab, CP-675,206), ipilimumab (CTLA-4 antibody, e.g., MDX-010, CAS No.: 477202-00-9); Histone Deacetylase Inhibitor (HDI): Voninostat (e.g., Zolinza(R) from Merck);Alkylating agents: Temozolomide (e.g., Temodar(R) and Temodal(R) from Schering-Plough / Merck), dactinomycins (e.g., actinomycin-D and e.g., Cosmegen(R)), melphalans (e.g., L-PAM, L-sabolic steroids, and melphalan, e.g., Alkeran(R)), hexamethylmelamine (e.g., hexamethylmelamine (HMM), e.g., Hexalen(R)), carmustine (e.g., BiCNU(R)), )), bendamustine (e.g., Treanda (R)), busulfan (e.g., Busulfex (R) and Myleran (R)), carboplatin (e.g., Paraplatin (R)), lomustine (e.g., CCNU, e.g., CeeNU (R)), cisplatin (e.g., CDDP, e.g., Platinol (R) and Platinol (R)-AQ), chlorambucil (e.g., Leukeran (R)), cyclophosphamide (cyclophosphamide) (e.g., Cytoxan(R) and Neosar(R)), dacarbazine (e.g., DTIC, DIC and imidazole carboxamide, e.g., DTIC-Dome(R)), altretamine (e.g., hexamethonium pyrimidine (HMM), e.g., Hexalen(R)), ifosfamide (e.g., Ifex(R)), procarbazine (e.g., Matulane(R)), dichloromethyldiethylamine (e.g., For example, nitrogen mustard, sinapines and methylchloroethylamine hydrochloride, for example, Mustarden (R)), streptozotocin (for example, Zanosar (R)), thiotepa (for example, thiophosphoramide, TESPA and TSPA, for example, Thioplex (R)); biological response modifiers: bacilluscalette-guerin (for example, theraCys (R) and TICE (R) BCG), denileukindiftitox (for example, Ontak (R));Antitumor antibiotics: doxorubicin (e.g., Adriamycin (R) and Rubex (R)), bleomycin (e.g., lenoxane (R)), daunorubicin (e.g., daunorubicin hydrochloride, daunorubicin and daunorubicin hydrochloride, for example, Cerubidine (R)), daunorubicin liposomes (daunorubicin citrate liposomes, for example, DaunoXome (R)), mitoxantrone (e.g., DHAD, for example, Novantrone (R)), epirubicin (e.g., Ellence; TM ), Idarubicin (e.g., Idamycin (R), Idamycin PFS (R)), Mitomycin C (e.g., Mutamycin (R)); Antimicrotubule agent: Estramustine (e.g., Emcyl (R)); Cathepsin K inhibitor: Odanacatib (or MK-0822, ACC Lanzhou Chon Chemical Company and ChemieTek, described in WO03 / 075836); Epothilone B analog: Ixabepilone (e.g., Lxempra (R) of Bristol-Myers Squibb); Heat shock protein (HSP) inhibitor: Tanespimycin (17-allylamino-17-demethoxygeldanamycin, e.g., KOS-953 and 17-AAG, described in US Pat. No. 4,261,989); TpoR agonist: Eltrombopag (e.g., Promacta(R) and Revolade(R) from GlaxoSmithKline); antimitotic: Docetaxel (e.g., Taxotere(R) from Sanofi-Aventis); adrenal steroid inhibitor: aminoglutethimide (e.g., Cytadren(R)); antiandrogen: Nilutamide (e.g., Nilandron(R) and Anandron(R)), bicalutamide (sold under the trade name Casodex(R)), flutamide (e.g., Fulexin(R)). TM); androgen: Fluoxymesterone (e.g., halotestin(R)); proteasome inhibitor: Bortezomib (e.g., Velcade(R)); CDK1 inhibitor: Alvocidib (e.g., flopirdol or HMR-1275, described in U.S. Pat. No. 5,621,002); gonadotropin-releasing hormone (GnRH) receptor agonist: Leuprorelin or Leuprorelin acetate (e.g., Viadure(R) of Bayer AG, Eligard(R) of Sanofi-Aventis, and Lupron(R) of Abbott Laboratories); taxane antineoplastic agent: Cabazitaxel, larotaxel; 5HT1a receptor agonist: Xaliproden (e.g., 5HT1a receptor agonist). oden) (or SR57746, described in US Pat. No. 5,266,573); HPC vaccines: Cervarix(R) sold by GlaxoSmithKline, Gardasil(R) sold by Merck; Iron chelators: Deferasinox (e.g., Exjade(R) from Novartis); Antimetabolites: Claribine (2-chlorodeoxyadenosine, e.g., leustatin(R)), 5-fluorouracil (e.g., Adrucil(R)), 6-thioguanine (e.g., Purinethol(R)), pemetrexed (e.g., Alimta(R)), cytarabine (e.g., cytosine arabinoside (Ara-C), e.g., Cytosar-U(R)), liposomal cytarabine (e.g., liposomal Ara-C, e.g., DepoCyt TM ), decitabine (eg, Dacogen(R)), hydroxyurea (eg, Hydrea(R), Droxia TM and Mylocel TM ), fludarabine (e.g., Fludara(R)), floxuridine (e.g., FUDR(R)), cladribine (e.g., 2-chlorodeoxyadenosine (2-CdA), e.g., Leustatin TM ), methotrexate (e.g., aminopterin, methotrexate sodium (MTX), e.g., Rheumatrex(R) and Trexall TM), pentostatin (e.g., Nipent(R)); bisphosphonates: pamidronate (e.g., Aredia(R)), zoledronic acid (e.g., Zometa(R)); demethylating agents: 5-azacitidine (e.g., Vidaza(R)), decitabine (e.g., Dacogen(R)); plant alkaloids: paclitaxel protein-bound (e.g., Abraxane(R)), vinblastine (e.g., vinblastine sulfate, vinblastine, and VLB, e.g., Alkaban-AQ(R) and Velban(R)), vincristine (e.g., vincristine sulfate, LCR, and VCR, e.g., Oncovin(R) and Vincasar Pfs(R)), vinorelbine (e.g., Navebine(R)), paclitaxel (e.g., taxol and Onxal TM); Retinoids: alitretinoin (e.g., Panretin(R)), tretinoin (all-trans retinoic acid, e.g., ATRA, e.g., Vesanoid(R)), isotretinoin (13-cis-retinoic acid, e.g., Accutane(R), Amnesteem(R), Claravis(R), Clarus(R), Decutan(R), Isotane(R), Izotech(R), Oratane(R), Isotret(R), and Sotret(R)), bexarotene (e.g., Targretin(R)); Glucocorticoids: Hydrocortisone (e.g., cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, and for example, Ala-Cort(R), hydrocortisone phosphate, Solu-Cortef(R), Hydrocort Acetate(R), and Lanacort(R)), dexamethasone, prednisolone (e.g., Delta-Cortel(R), Orapred(R), Pediapred(R), and Prelone(R)), prednisone (e.g., Deltasone(R), Liq uidRed(R), Meticorten(R) and Orasone(R)), methylprednisolone (e.g., 6-methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, for example, Duralone(R), Medralone(R), Medrol(R), M-Prednisol(R) and Solu-Medrol(R)); cytokines: interleukin-2 (e.g., aldesleukin and IL-2, for example, Proleukin(R)), interleukin-11 (e.g., oprevelkin, for example, Neumega(R)), alpha interferon-alpha (e.g., IFN-α, for example, Intron(R) A and Roferon-A(R)); Luteinizing hormone-releasing hormone (LHRH) agonists: Goserelin (e.g., Zoladex(R)); Progestins: Megestrol acetate (e.g., Megestrol acetate, e.g., Megace(R)); Miscellaneous cytotoxic agents: Arsenic trioxide (e.g., Trisenox(R)), Asparaginase (e.g., L-asparaginase, Erwinia L-asparaginase, e.g., Elspar(R) and Kidrolase(R)); Antinausea drugs: NK-1 receptor antagonists: Casopitant (e.g., Promacta(R) and Revolade(R) from GlaxoSmithKline);and cytoprotectants: amifostine (eg, Ethyol(R)), folinic acid (eg, calcium leucovorin, folinic acid factor, and folinic acid);

[1258] Exemplary embodiments

[1259] Example 1: A compound of formula (I'):

[1260]

[1261] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[1262] W is CH or N;

[1263] Z is optionally replaced by one or more R Z substituted 3- to 12-membered heterocycloalkyl;

[1264] Each R Z are independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3 to 10 membered heterocycloalkyl or 5 to 10 membered heteroaryl; wherein said -O-(C1-C6 alkyl), said -NH(C1-C6 alkyl), said -N(C1-C6 alkyl)2, said C1-C6 alkyl, said C2-C6 alkenyl, said C2-C6 alkynyl, said C3-C 10 Cycloalkyl, the C6-C 10 The aryl group, the 3 to 10 membered heterocycloalkyl group or the 5 to 10 membered heteroaryl group are optionally substituted by one or more R Za replace;

[1265] Each R Za are independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl;

[1266] T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein said -O-(C1-C6 alkyl), said -NH-(C1-C6 alkyl), said C1-C6 alkyl, said C2-C6 alkenyl or said C2-C6 alkynyl is optionally replaced by one or more R T replace;

[1267] Each R T are independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3 to 10 membered heterocycloalkyl or 5 to 10 membered heteroaryl; wherein said -O-(C1-C6 alkyl), said -NH(C1-C6 alkyl), said -N(C1-C6 alkyl)2, said C1-C6 alkyl, said C2-C6 alkenyl, said C2-C6 alkynyl, said C3-C 10 Cycloalkyl, the C6-C 10 The aryl group, the 3 to 10 membered heterocycloalkyl group or the 5 to 10 membered heteroaryl group are optionally substituted by one or more R Ta replace;

[1268] Each R Ta are independently halogen, CN, -OH, -NH2, -C(=O)OH, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl;

[1269] Ar 1 is optionally replaced by one or more R A1 Substituted C6-C 10 aryl;

[1270] Each R A1 are independently halogen, CN, -OH, -NH2, -OR A1a , -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10aryl, 3 to 10 membered heterocycloalkyl or 5 to 10 membered heteroaryl; wherein said -O-(C1-C6 alkyl), said -NH(C1-C6 alkyl), said -N(C1-C6 alkyl)2, said C1-C6 alkyl, said C2-C6 alkenyl, said C2-C6 alkynyl, said C3-C 10 Cycloalkyl, the C6-C 10 The aryl group, the 3 to 10 membered heterocycloalkyl group or the 5 to 10 membered heteroaryl group are optionally substituted by one or more R A1a replace; and

[1271] Each R A1a are independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3 to 10 membered heterocycloalkyl or 5 to 10 membered heteroaryl; wherein said -O-(C1-C6 alkyl), said -NH(C1-C6 alkyl), said -N(C1-C6 alkyl)2, said C1-C6 alkyl, said C2-C6 alkenyl, said C2-C6 alkynyl, said C3-C 10 Cycloalkyl, the C6-C 10 The aryl group, the 3 to 10 membered heterocycloalkyl group or the 5 to 10 membered heteroaryl group are optionally substituted by one or more R A1b replace; and

[1272] Each R A1b are independently halogen, CN, -OH or -NH2.

[1273] Embodiment 2: A compound according to any one of the preceding embodiments, wherein the compound has Formula (I') or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[1274] W is CH or N;

[1275] Z is optionally replaced by one or more R Z substituted 3- to 12-membered heterocycloalkyl;

[1276] Each R Z are independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10Aryl or 5 to 10 membered heteroaryl; wherein said -O-(C1-C6 alkyl), said -NH(C1-C6 alkyl), said -N(C1-C6 alkyl)2, said C1-C6 alkyl, said C2-C6 alkenyl, said C2-C6 alkynyl, said C3-C 10 Cycloalkyl, the C6-C 10 Aryl, said 3 or 5 to 10 membered heteroaryl are optionally substituted by one or more R Za replace;

[1277] Each R Za are independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl;

[1278] T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein said -O-(C1-C6 alkyl), said -NH-(C1-C6 alkyl), said C1-C6 alkyl, said C2-C6 alkenyl or said C2-C6 alkynyl is optionally replaced by one or more R T replace;

[1279] Each R T are independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3 to 7 membered heterocycloalkyl or 5 to 10 membered heteroaryl; wherein said -O-(C1-C6 alkyl), said C1-C6 alkyl, said C2-C6 alkenyl, said C2-C6 alkynyl, said C3-C 10 Cycloalkyl, the C6-C 10 The aryl group, the 3 to 7 membered heterocycloalkyl group or the 5 to 10 membered heteroaryl group are optionally substituted by one or more R Ta replace;

[1280] Each R Ta are independently halogen, CN, -OH, -NH2, -C(=O)OH, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl;

[1281] Ar 1 is optionally replaced by one or more R A1 Substituted C6-C 10 aryl;

[1282] Each R A1 are independently halogen, CN, -OH, -NH2, -OR A1a , -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein the -O-(C1-C6 alkyl), the -NH(C1-C6 alkyl), the -N(C1-C6 alkyl)2, the C1-C6 alkyl, the C2-C6 alkenyl or the C2-C6 alkynyl are optionally replaced by one or more R A1a replace; and

[1283] Each R A1a are independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein said -O-(C1-C6 alkyl), said -NH(C1-C6 alkyl), said -N(C1-C6 alkyl)2, said C1-C6 alkyl, said C2-C6 alkenyl or said C2-C6 alkynyl are optionally substituted by one or more R A1b replace; and

[1284] Each R A1b are independently halogen, CN, -OH or -NH2;

[1285] The condition is that when Z is When Ar 1 is a C6-C 10 Aryl.

[1286] Embodiment 3: A compound according to any one of the preceding embodiments, wherein the compound has Formula (I') or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[1287] W is CH or N;

[1288] Z is optionally replaced by one or more R Z substituted 3- to 12-membered heterocycloalkyl;

[1289] Each R Zare independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl or 5 to 10 membered heteroaryl; wherein said -O-(C1-C6 alkyl), said -NH(C1-C6 alkyl), said -N(C1-C6 alkyl)2, said C1-C6 alkyl, said C2-C6 alkenyl, said C2-C6 alkynyl, said C3-C 10 Cycloalkyl, the C6-C 10 Aryl, said 3 or 5 to 10 membered heteroaryl are optionally substituted by one or more R Za replace;

[1290] Each R Za are independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl;

[1291] T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein said -O-(C1-C6 alkyl), said -NH-(C1-C6 alkyl), said C1-C6 alkyl, said C2-C6 alkenyl or said C2-C6 alkynyl is optionally replaced by one or more R T replace;

[1292] Each R T are independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3 to 7 membered monocyclic heterocycloalkyl or 5 to 10 membered heteroaryl; wherein said -O-(C1-C6 alkyl), said C1-C6 alkyl, said C2-C6 alkenyl, said C2-C6 alkynyl, said C3-C 10 Cycloalkyl, the C6-C 10 The aryl group, the 3 to 7 membered monocyclic heterocycloalkyl group or the 5 to 10 membered heteroaryl group are optionally substituted by one or more R Ta replace;

[1293] Each R Taare independently halogen, CN, -OH, -NH2, -C(=O)OH, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl;

[1294] Ar 1 is optionally replaced by one or more R A1 Substituted C6-C 10 aryl;

[1295] Each R A1 are independently halogen, CN, -OH, -NH2, -OR A1a , -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein the -O-(C1-C6 alkyl), the -NH(C1-C6 alkyl), the -N(C1-C6 alkyl)2, the C1-C6 alkyl, the C2-C6 alkenyl or the C2-C6 alkynyl are optionally replaced by one or more R A1a replace; and

[1296] Each R A1a are independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein said -O-(C1-C6 alkyl), said -NH(C1-C6 alkyl), said -N(C1-C6 alkyl)2, said C1-C6 alkyl, said C2-C6 alkenyl or said C2-C6 alkynyl are optionally substituted by one or more R A1b replace; and

[1297] Each R A1b are independently halogen, CN, -OH or -NH2;

[1298] The condition is that when Z is When Ar 1 is a C6-C 10 Aryl.

[1299] Embodiment 4: A compound according to any one of the preceding embodiments, wherein the compound has Formula (I') or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[1300] W is CH;

[1301] Z is optionally replaced by one or more RZ substituted 3- to 12-membered heterocycloalkyl;

[1302] Each R Z is independently halogen, -O-(C1-C6 alkyl), C1-C6 alkyl or 3- to 10-membered heterocycloalkyl; wherein said -O-(C1-C6 alkyl), said C1-C6 alkyl or said 3- to 10-membered heterocycloalkyl is optionally substituted with one or more halogen;

[1303] T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl or the C2-C6 alkynyl is optionally replaced by one or more R T replace;

[1304] Each R T is independently halogen, -OH, -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2 or 3-7 membered heterocycloalkyl; wherein said -O-(C1-C6 alkyl), said -N(C1-C6 alkyl)2 or said 3-7 membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH;

[1305] Ar 1 is optionally replaced by one or more R A1 Substituted C6-C 10 aryl;

[1306] Each R A1 are independently optionally replaced by one or more R A1a Substituted halogen, -OR A1a or -O-(C1-C6 alkyl); and

[1307] Each R A1a Independently C6-C 10 aryl or 5 to 10 membered heteroaryl; wherein the C6-C 10 The aryl or the 5- to 10-membered heteroaryl is optionally substituted with one or more halogens.

[1308] Embodiment 5: A compound according to any one of the preceding embodiments, wherein the compound has Formula (I') or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[1309] W is CH;

[1310] Z is optionally replaced by one or more R Z substituted 3- to 12-membered heterocycloalkyl;

[1311] Each R Zis independently halogen, -O-(C1-C6 alkyl), C1-C6 alkyl or 3- to 10-membered heterocycloalkyl; wherein said -O-(C1-C6 alkyl), said C1-C6 alkyl or said 3- to 10-membered heterocycloalkyl is optionally substituted with one or more halogen;

[1312] T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl or the C2-C6 alkynyl is optionally replaced by one or more R T replace;

[1313] Each R T is independently halogen, -OH, -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2 or 3 to 7 membered monocyclic heterocycloalkyl; wherein said -O-(C1-C6 alkyl), said -N(C1-C6 alkyl)2 or said 3 to 7 membered monocyclic heterocycloalkyl is optionally substituted with one or more -C(=O)OH;

[1314] Ar 1 is optionally replaced by one or more R A1 Substituted C6-C 10 aryl;

[1315] Each R A1 are independently optionally replaced by one or more R A1a Substituted halogen, -OR A1a or -O-(C1-C6 alkyl); and

[1316] Each R A1a Independently C6-C 10 aryl or 5 to 10 membered heteroaryl; wherein the C6-C 10 The aryl or the 5- to 10-membered heteroaryl is optionally substituted with one or more halogens.

[1317] Embodiment 6: A compound according to any one of the preceding embodiments, wherein the compound has Formula (I') or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[1318] W is CH;

[1319] Z is optionally replaced by one or more R Z substituted 3- to 12-membered heterocycloalkyl;

[1320] Each R Z are independently halogen, -O-(C1-C6 alkyl) or C1-C6 alkyl; wherein said -O-(C1-C6 alkyl) or said C1-C6 alkyl is optionally substituted with one or more halogen;

[1321] T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl or the C2-C6 alkynyl is optionally replaced by one or more R T replace;

[1322] Each R T is independently halogen, -OH, -O-(C1-C6 alkyl) or 3- to 7-membered heterocycloalkyl; wherein said -O-(C1-C6 alkyl) or said 3- to 7-membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH;

[1323] Ar 1 is optionally replaced by one or more R A1 Substituted C6-C 10 aryl;

[1324] Each R A1 are independently optionally replaced by one or more R A1a Substituted halogen, -OR A1a or -O-(C1-C6 alkyl); and

[1325] Each R A1a Independently C6-C 10 aryl or 5 to 10 membered heteroaryl; wherein the C6-C 10 Aryl or the 5- to 10-membered heteroaryl is optionally substituted with one or more halogens;

[1326] The condition is that when Z is When Ar 1 is a C6-C 10 Aryl.

[1327] Embodiment 7: A compound according to any one of the preceding embodiments, wherein the compound has Formula (I') or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[1328] W is CH;

[1329] Z is optionally replaced by one or more R Z substituted 3- to 12-membered heterocycloalkyl;

[1330] Each R Z are independently halogen, -O-(C1-C6 alkyl) or C1-C6 alkyl; wherein said -O-(C1-C6 alkyl) or said C1-C6 alkyl is optionally substituted with one or more halogen;

[1331] T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl or the C2-C6 alkynyl is optionally replaced by one or more R T replace;

[1332] Each R T is independently halogen, -OH, -O-(C1-C6 alkyl) or 3 to 7 membered monocyclic heterocycloalkyl; wherein said -O-(C1-C6 alkyl) or said 3 to 7 membered monocyclic heterocycloalkyl is optionally substituted with one or more -C(=O)OH;

[1333] Ar 1 is optionally replaced by one or more R A1 Substituted C6-C 10 aryl;

[1334] Each R A1 are independently optionally replaced by one or more R A1a Substituted halogen, -OR A1a or -O-(C1-C6 alkyl); and

[1335] Each R A1a Independently C6-C 10 aryl or 5 to 10 membered heteroaryl; wherein the C6-C 10 Aryl or the 5- to 10-membered heteroaryl is optionally substituted with one or more halogens;

[1336] The condition is that when Z is When Ar 1 is a C6-C 10 Aryl.

[1337] Embodiment 8: A compound according to any one of the preceding embodiments, wherein the compound has Formula (I') or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[1338] W is CH;

[1339] Z is optionally replaced by one or more R Z substituted 3- to 12-membered heterocycloalkyl;

[1340] Each R Z are independently halogen, -O-(C1-C6 alkyl) or C1-C6 alkyl; wherein said -O-(C1-C6 alkyl) or said C1-C6 alkyl is optionally substituted with one or more halogen;

[1341] T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl or the C2-C6 alkynyl is optionally replaced by one or more R T replace;

[1342] Each R T is independently halogen, -OH, -O-(C1-C6 alkyl) or 3- to 7-membered heterocycloalkyl; wherein said -O-(C1-C6 alkyl) or said 3- to 7-membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH;

[1343] Ar 1 is a C6-C 10 Aryl.

[1344] Embodiment 9: A compound according to any one of the preceding embodiments, wherein the compound has Formula (I') or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[1345] W is CH;

[1346] Z is optionally replaced by one or more R Z substituted 3- to 12-membered heterocycloalkyl;

[1347] Each R Z are independently halogen, -O-(C1-C6 alkyl) or C1-C6 alkyl; wherein said -O-(C1-C6 alkyl) or said C1-C6 alkyl is optionally substituted with one or more halogen;

[1348] T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl or the C2-C6 alkynyl is optionally replaced by one or more R T replace;

[1349] Each R T is independently halogen, -OH, -O-(C1-C6 alkyl) or 3 to 7 membered monocyclic heterocycloalkyl; wherein said -O-(C1-C6 alkyl) or said 3 to 7 membered monocyclic heterocycloalkyl is optionally substituted with one or more -C(=O)OH;

[1350] Ar 1 is a C6-C 10 Aryl.

[1351] Embodiment 10: A compound according to any one of the preceding embodiments, wherein the compound has Formula (I') or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[1352] W is CH;

[1353] Z is a 3- to 12-membered heterocycloalkyl group optionally substituted with one or more C1-C6 alkyl groups;

[1354] T is C2-C6 alkenyl optionally substituted with one or more 6-membered heterocycloalkyl; and

[1355] Ar 1 is a C6 aryl group optionally substituted by one or more halogens.

[1356] Embodiment 11: A compound according to any one of the preceding embodiments, wherein the compound has Formula (I') or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[1357] W is CH;

[1358] Z is a 3- to 12-membered heterocycloalkyl group optionally substituted with one or more C1-C6 alkyl groups;

[1359] T is C2-C6 alkenyl optionally substituted with one or more 6-membered monocyclic heterocycloalkyl; and

[1360] Ar 1 is a C6 aryl group optionally substituted by one or more halogens.

[1361] Embodiment 12: A compound according to any one of the preceding embodiments, wherein W is CH.

[1362] Embodiment 13: A compound according to any one of the preceding embodiments, wherein W is N.

[1363] Embodiment 14: A compound according to any one of the preceding embodiments, wherein Z is optionally replaced by one or more R Z substituted 3- to 12-membered heterocycloalkyl; and

[1364] Each R Z is independently halogen, -O-(C1-C6 alkyl), C1-C6 alkyl or 3- to 10-membered heterocycloalkyl; wherein said -O-(C1-C6 alkyl), said C1-C6 alkyl or said 3- to 10-membered heterocycloalkyl is optionally substituted with one or more halogen.

[1365] Embodiment 15: A compound according to any one of the preceding embodiments, wherein Z is oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, 3-oxabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexanyl, 2-azaspiro[3.3]heptanyl, 2-oxa-5-azaspiro[3.4]octanyl, wherein the oxetanyl, the tetrahydrofuranyl, the pyrrolidinyl, the piperidinyl, the morpholinyl, the 3-oxabicyclo[3.1.0]hexanyl, the 3-azabicyclo[3.1.0]hexanyl, the 2-azaspiro[3.3]heptanyl or the 2-oxa-5-azaspiro[3.4]octanyl is optionally replaced by one or more R Z replace.

[1366] Embodiment 16: A compound according to any one of the preceding embodiments, wherein Z is oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, 3-oxabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexanyl, 2-azaspiro[3.3]heptanyl, 2-oxa-5-azaspiro[3.4]octanyl, wherein the oxetanyl, the tetrahydrofuranyl, the pyrrolidinyl, the piperidinyl, the morpholinyl, the 3-oxabicyclo[3.1.0]hexanyl, the 2-azaspiro[3.3]hexanyl or the 2-oxa-5-azaspiro[3.4]octanyl is optionally replaced by one or more R Z replace.

[1367] Embodiment 17: A compound according to any one of the preceding embodiments, wherein Z is

[1368]

[1369] Embodiment 18: A compound according to any one of the preceding embodiments, wherein Z is

[1370]

[1371] Embodiment 19: A compound according to any one of the preceding embodiments, wherein at least one R Z It's a halogen.

[1372] Embodiment 20: A compound according to any one of the preceding embodiments, wherein at least one R Z It is F or Cl.

[1373] Embodiment 21: A compound according to any one of the preceding embodiments, wherein at least one R Z It is CN, -OH or -NH2.

[1374] Embodiment 22: A compound according to any one of the preceding embodiments, wherein at least one R Z -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3 to 10 membered heterocycloalkyl or 5 to 10 membered heteroaryl; wherein said -O-(C1-C6 alkyl), said -NH(C1-C6 alkyl), said -N(C1-C6 alkyl)2, said C1-C6 alkyl, said C2-C6 alkenyl, said C2-C6 alkynyl, said C3-C 10 Cycloalkyl, the C6-C 10 The aryl group, the 3 to 10 membered heterocycloalkyl group or the 5 to 10 membered heteroaryl group are optionally substituted by one or more R Za replace.

[1375] Embodiment 23: A compound according to any one of the preceding embodiments, wherein at least one R Z is optionally replaced by one or more R Za Substituted-O-(C1-C6 alkyl).

[1376] Embodiment 24: A compound according to any one of the preceding embodiments, wherein at least one R Z It is -OCH3.

[1377] Embodiment 25: A compound according to any one of the preceding embodiments, wherein at least one R Z It is -O-(C1-C6 alkyl) substituted by one or more halogens.

[1378] Embodiment 26: A compound according to any one of the preceding embodiments, wherein at least one R Z It is a C1-C6 alkyl group.

[1379] Embodiment 27: A compound according to any one of the preceding embodiments, wherein at least one R Z is methyl, ethyl or propyl.

[1380] Embodiment 28: A compound according to any one of the preceding embodiments, wherein at least one R Z It is a C1-C6 alkyl group substituted by one or more halogens.

[1381] Embodiment 29: A compound according to any one of the preceding embodiments, wherein at least one R Z It's CF3.

[1382] Embodiment 30: A compound according to any one of the preceding embodiments, wherein at least one RZ It is C3-C 10 Cycloalkyl, C6-C 10 aryl, 3 to 10 membered heterocycloalkyl or 5 to 10 membered heteroaryl; wherein the C3-C 10 Cycloalkyl, the C6-C 10 The aryl group, the 3 to 10 membered heterocycloalkyl group or the 5 to 10 membered heteroaryl group are optionally substituted by one or more R Za replace.

[1383] Embodiment 31: A compound according to any one of the preceding embodiments, wherein at least one R Z is optionally replaced by one or more R Za Substituted 3- to 10-membered heterocycloalkyl.

[1384] Embodiment 32: A compound according to any one of the preceding embodiments, wherein at least one R Z is optionally replaced by one or more R Za Substituted 4-membered heterocycloalkyl.

[1385] Embodiment 33: A compound according to any one of the preceding embodiments, wherein at least one R Z It is an oxetane group.

[1386] Embodiment 34: A compound according to any one of the preceding embodiments, wherein at least one R Za It's a halogen.

[1387] Embodiment 35: A compound according to any one of the preceding embodiments, wherein at least one R Za It is F or Cl.

[1388] Embodiment 36: A compound according to any one of the preceding embodiments, wherein at least one R Za CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl.

[1389] Embodiment 37: A compound according to any one of the preceding embodiments, wherein T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein the -O-(C1-C6 alkyl), the -NH-(C1-C6 alkyl), the C1-C6 alkyl, the C2-C6 alkenyl or the C2-C6 alkynyl is optionally replaced by one or more R Treplace;

[1390] Each R T are independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3 to 7 membered heterocycloalkyl or 5 to 10 membered heteroaryl; wherein said -O-(C1-C6 alkyl), said C1-C6 alkyl, said C2-C6 alkenyl, said C2-C6 alkynyl, said C3-C 10 Cycloalkyl, the C6-C 10 The aryl group, the 3 to 7 membered heterocycloalkyl group or the 5 to 10 membered heteroaryl group are optionally substituted by one or more R Ta replace; and

[1391] Each R Ta are independently halogen, CN, -OH, -NH2, -C(=O)OH, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl.

[1392] Embodiment 38: A compound according to any one of the preceding embodiments, wherein T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein the -O-(C1-C6 alkyl), the -NH-(C1-C6 alkyl), the C1-C6 alkyl, the C2-C6 alkenyl or the C2-C6 alkynyl is optionally replaced by one or more R T replace;

[1393] Each R T are independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3 to 7 membered monocyclic heterocycloalkyl or 5 to 10 membered heteroaryl; wherein said -O-(C1-C6 alkyl), said C1-C6 alkyl, said C2-C6 alkenyl, said C2-C6 alkynyl, said C3-C 10 Cycloalkyl, the C6-C 10 The aryl group, the 3 to 7 membered monocyclic heterocycloalkyl group or the 5 to 10 membered heteroaryl group are optionally substituted by one or more R Ta replace; and

[1394] Each RTa are independently halogen, CN, -OH, -NH2, -C(=O)OH, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl.

[1395] Embodiment 39: A compound according to any one of the preceding embodiments, wherein T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl or the C2-C6 alkynyl is optionally replaced by one or more R T replace; and

[1396] Each R T independently halogen, -OH, -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2 or 3- to 7-membered heterocycloalkyl; wherein said -O-(C1-C6 alkyl), said -N(C1-C6 alkyl)2 or said 3- to 7-membered heterocycloalkyl are optionally substituted by one or more -C(=O)OH.

[1397] Embodiment 40: A compound according to any one of the preceding embodiments, wherein T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl or the C2-C6 alkynyl is optionally replaced by one or more R T replace; and

[1398] Each R T independently halogen, -OH, -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2 or 3 to 7 membered monocyclic heterocycloalkyl; wherein said -O-(C1-C6 alkyl), said -N(C1-C6 alkyl)2 or said 3 to 7 membered monocyclic heterocycloalkyl are optionally substituted by one or more -C(=O)OH.

[1399] Embodiment 41: A compound according to any one of the preceding embodiments, wherein T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl or the C2-C6 alkynyl is optionally replaced by one or more R T replace; and

[1400] Each R Tis independently halogen, -OH, -O-(C1-C6 alkyl) or 3- to 7-membered heterocycloalkyl; wherein said -O-(C1-C6 alkyl) or said 3- to 7-membered heterocycloalkyl is optionally substituted with one or more -C(=O)OH.

[1401] Embodiment 42: A compound according to any one of the preceding embodiments, wherein T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein the C1-C6 alkyl, the C2-C6 alkenyl or the C2-C6 alkynyl is optionally replaced by one or more R T replace; and

[1402] Each R T is independently halogen, -OH, -O-(C1-C6 alkyl) or a 3- to 7-membered monocyclic heterocycloalkyl; wherein said -O-(C1-C6 alkyl) or said 3- to 7-membered monocyclic heterocycloalkyl is optionally substituted with one or more -C(=O)OH.

[1403] Embodiment 43: A compound according to any one of the preceding embodiments, wherein T is optionally replaced by one or more R T Substituted-O-(C1-C6 alkyl).

[1404] Embodiment 44. A compound according to any one of the preceding embodiments, wherein T is -OCH3.

[1405] Embodiment 45: A compound according to any one of the preceding embodiments, wherein T is optionally replaced by one or more R T Substituted-NH-(C1-C6 alkyl).

[1406] Embodiment 46. A compound according to any one of the preceding embodiments, wherein T is -NHCH3.

[1407] Embodiment 47: A compound according to any one of the preceding embodiments, wherein T is optionally replaced by one or more R T Substituted C1-C6 alkyl.

[1408] Embodiment 48. A compound according to any one of the preceding embodiments, wherein T is C1-C6 alkyl.

[1409] Embodiment 49: A compound according to any one of the preceding embodiments, wherein T is methyl or ethyl.

[1410] Embodiment 50: A compound according to any one of the preceding embodiments, wherein T is C1-C6 alkyl substituted with one or more halogens.

[1411] Embodiment 51. A compound according to any one of the preceding embodiments wherein T is -CHFCl.

[1412] Embodiment 52: A compound according to any one of the preceding embodiments, wherein T is optionally replaced by one or more R T 取代的C2 -C6 alkenyl.

[1413] Embodiment 53. A compound according to any one of the preceding embodiments wherein T is C2-C6 alkenyl.

[1414] Embodiment 54. A compound according to any one of the preceding embodiments wherein T is vinyl.

[1415] Embodiment 55. A compound according to any one of the preceding embodiments, wherein T is propenyl.

[1416] Embodiment 56. A compound according to any one of the preceding embodiments, wherein T is pentenyl.

[1417] Embodiment 57: A compound according to any one of the preceding embodiments, wherein T is replaced by one or more R T 取代的C2 -C6 alkenyl.

[1418] Embodiment 58: A compound according to any of the preceding embodiments, wherein T is C2-C6 alkenyl substituted by one or more -OH, -O-(C1-C6 alkyl), -N(C1-C6 alkyl)2, or 3 to 10 membered heterocycloalkyl; wherein the 3 to 10 membered heterocycloalkyl is optionally substituted by one or more -C(=O)OH.

[1419] Embodiment 59. A compound according to any one of the preceding embodiments wherein T is C2-C6 alkynyl.

[1420] Embodiment 60. A compound according to any one of the preceding embodiments, wherein T is propynyl.

[1421] Embodiment 61: A compound according to any one of the preceding embodiments, wherein T is replaced by one or more R T Substituted C2-C6 alkynyl.

[1422] Embodiment 62: A compound according to any one of the preceding embodiments, wherein T is replaced by one or more R T Substituted propynyl.

[1423] Embodiment 63. A compound according to any one of the preceding Embodiments wherein T is propynyl substituted with one or more 3- to 10-membered heterocycloalkyl groups.

[1424] Embodiment 64: A compound according to any one of the preceding embodiments, wherein T is

[1425]

[1426] Embodiment 65: A compound according to any one of the preceding embodiments, wherein T is

[1427]

[1428] Embodiment 66: A compound according to any one of the preceding embodiments, wherein at least one R T It's a halogen.

[1429] Embodiment 67: A compound according to any one of the preceding embodiments, wherein at least one R T It is CN, -OH or -NH2.

[1430] Embodiment 68: A compound according to any one of the preceding embodiments, wherein at least one R T is -O-(C1-C6 alkyl), -NH(C1-C6 alkyl) or -N(C1-C6 alkyl) 2; wherein said O-(C1-C6 alkyl), said -NH(C1-C6 alkyl) or said -N(C1-C6 alkyl) 2 is optionally replaced by one or more R Ta replace.

[1431] Embodiment 69: A compound according to any one of the preceding embodiments, wherein at least one R T It is -O-(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[1432] Embodiment 70: A compound according to any one of the preceding embodiments, wherein at least one R T is C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein said C1-C6 alkyl, said C2-C6 alkenyl or said C2-C6 alkynyl is optionally substituted by one or more R Ta replace.

[1433] Embodiment 71: A compound according to any one of the preceding embodiments, wherein at least one R T It is C3-C 10 Cycloalkyl, C6-C 10 aryl, 3 to 10 membered heterocycloalkyl or 5 to 10 membered heteroaryl; wherein the C3-C 10 Cycloalkyl, the C6-C 10 The aryl group, the 3 to 10 membered heterocycloalkyl group or the 5 to 10 membered heteroaryl group are optionally substituted by one or more R Ta replace.

[1434] Embodiment 72: A compound according to any one of the preceding embodiments, wherein at least one R T is a 3- to 10-membered heterocycloalkyl group substituted by one or more C(=O)OH groups.

[1435] Embodiment 73: A compound according to any one of the preceding embodiments, wherein at least one R Ta It is C(=O)OH.

[1436] Embodiment 74: A compound according to any one of the preceding embodiments, wherein at least one R Ta Halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl.

[1437] Embodiment 75: A compound according to any one of the preceding embodiments, wherein Ar 1 is optionally replaced by one or more R A1 Substituted C6-C 10 aryl;

[1438] Each R A1 are independently halogen, CN, -OH, -NH2, -OR A1a , -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein the -O-(C1-C6 alkyl), the -NH(C1-C6 alkyl), the -N(C1-C6 alkyl)2, the C1-C6 alkyl, the C2-C6 alkenyl or the C2-C6 alkynyl are optionally replaced by one or more R A1a replace;

[1439] Each R A1a are independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein said -O-(C1-C6 alkyl), said -NH(C1-C6 alkyl), said -N(C1-C6 alkyl)2, said C1-C6 alkyl, said C2-C6 alkenyl or said C2-C6 alkynyl are optionally substituted by one or more R A1b replace; and

[1440] Each R A1bare independently halogen, CN, -OH or -NH2.

[1441] Embodiment 76: A compound according to any one of the preceding embodiments, wherein Ar 1 It is C6-C 10 Aryl.

[1442] Embodiment 77: A compound according to any one of the preceding embodiments, wherein Ar 1 is one or more R A1 Substituted C6-C 10 Aryl.

[1443] Embodiment 78: A compound according to any one of the preceding embodiments, wherein Ar 1 is one or more halogens, -OR A1a or -O-(C1-C6 alkyl) substituted phenyl; wherein said -O-(C1-C6 alkyl) is optionally substituted by one or more R A1a Replace; and each R A1a Independently C6-C 10 aryl or 5 to 10 membered heteroaryl; wherein the C6-C 10 The aryl or the 5- to 10-membered heteroaryl is optionally substituted with one or more halogens.

[1444] Embodiment 79: A compound according to any one of the preceding embodiments, wherein Ar 1 is phenyl substituted by one or more halogens.

[1445] Embodiment 80: A compound according to any one of the preceding embodiments, wherein Ar 1 It is a phenyl group substituted by one F or one Cl.

[1446] Embodiment 81: A compound according to any one of the preceding embodiments, wherein Ar 1 is phenyl optionally substituted by one or more halogens, wherein the phenyl is further substituted by -O-(C6-C 10 aryl) or -O-(5 to 10 membered heteroaryl); wherein said -O-(C6-C 10 aryl) or the -O-(5- to 10-membered heteroaryl) is optionally substituted with one or more halogens.

[1447] Embodiment 82: A compound according to any one of the preceding embodiments, wherein Ar 1 is phenyl optionally substituted with one or more halogens, wherein said phenyl is further substituted with -O-phenyl or -O-pyridyl; wherein said -O-phenyl or said -O-pyridyl is optionally substituted with one or more halogens.

[1448] Embodiment 83: A compound according to any one of the preceding embodiments, wherein Ar 1 yes

[1449] Embodiment 84: A compound according to any one of the preceding embodiments, wherein Ar 1 yes

[1450] Embodiment 85: A compound according to any one of the preceding embodiments, wherein Ar 1 yes

[1451] Embodiment 86: A compound according to any one of the preceding embodiments, wherein Ar 1 yes

[1452] Embodiment 87: A compound according to any one of the preceding embodiments, wherein at least one R A1 It's a halogen.

[1453] Embodiment 88: A compound according to any one of the preceding embodiments, wherein at least one R A1 is F and at least one R A1 It's Cl.

[1454] Embodiment 89: A compound according to any one of the preceding embodiments, wherein at least one R A1 It is CN, -OH or -NH2.

[1455] Embodiment 90: A compound according to any one of the preceding embodiments, wherein at least one R A1 Yes-OR A1a .

[1456] Embodiment 91: A compound according to any one of the preceding embodiments, wherein at least one R A1 Yes-O-(C6-C 10 aryl) or -O-(5- to 10-membered heteroaryl); wherein said -O-(C6-C 10 aryl) or said -O-(5 to 10 membered heteroaryl) is optionally substituted by one or more R A1b replace.

[1457] Embodiment 92: A compound according to any one of the preceding embodiments, wherein at least one R A1 Yes-O-(C6-C 10 aryl) or -O-(5- to 10-membered heteroaryl); wherein said -O-(C6-C10 aryl) or the -O-(5- to 10-membered heteroaryl) is optionally substituted with one or more halogens.

[1458] Embodiment 93: A compound according to any one of the preceding embodiments, wherein at least one R A1 is -O-phenyl or -O-pyridinyl; wherein said -O-phenyl or said -O-pyridinyl is optionally substituted with one or more halogens.

[1459] Embodiment 94: A compound according to any one of the preceding embodiments, wherein at least one R A1 is -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, wherein said -O-(C1-C6 alkyl), said -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted by one or more R A1a replace.

[1460] Embodiment 95: A compound according to any one of the preceding embodiments, wherein at least one R A1 is one or more C6-C 10 -O-(C1-C6 alkyl) substituted with aryl or 5 to 10 membered heteroaryl, wherein the C6-C 10 The aryl or the 5- to 10-membered heteroaryl is optionally substituted with one or more halogens.

[1461] Embodiment 96: A compound according to any one of the preceding embodiments, wherein at least one R A1 It is -O-CH2-(C6-C 10 aryl) or -O-CH2-(5 to 10 membered heteroaryl), wherein the -O-CH2-(C6-C 10 aryl) or -O-CH2-(5- to 10-membered heteroaryl) is optionally substituted with one or more halogens.

[1462] Embodiment 97: A compound according to any one of the preceding embodiments, wherein at least one R A1 is -O-CH2-phenyl or -O-CH2-pyridyl, wherein said -O-CH2-phenyl or said -O-CH2-pyridyl is optionally substituted with one or more halogens.

[1463] Embodiment 98: A compound according to any one of the preceding embodiments, wherein at least one R A1 It is C3-C 10 Cycloalkyl, C6-C 10aryl, 3 to 10 membered heterocycloalkyl or 5 to 10 membered heteroaryl; wherein the C3-C 10 Cycloalkyl, the C6-C 10 The aryl group, the 3 to 10 membered heterocycloalkyl group or the 5 to 10 membered heteroaryl group are optionally substituted by one or more R A1a replace.

[1464] Embodiment 99: A compound according to any one of the preceding embodiments, wherein at least one R A1a is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, wherein said -O-(C1-C6 alkyl), said -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally replaced by one or more R A1b replace.

[1465] Embodiment 100: A compound according to any one of the preceding embodiments, wherein at least one R A1a It is C3-C 10 Cycloalkyl, C6-C 10 aryl, 3 to 10 membered heterocycloalkyl or 5 to 10 membered heteroaryl; wherein the C3-C 10 Cycloalkyl, the C6-C 10 The aryl group, the 3 to 10 membered heterocycloalkyl group or the 5 to 10 membered heteroaryl group are optionally substituted by one or more R A1b replace.

[1466] Embodiment 101: A compound according to any one of the preceding embodiments, wherein at least one R A1a It is C6-C 10 aryl or 5 to 10 membered heteroaryl; wherein the C6-C 10 The aryl or the 5- to 10-membered heteroaryl is optionally substituted with one or more halogens.

[1467] Embodiment 102: A compound according to any one of the preceding embodiments, wherein at least one R A1a is phenyl or pyridinyl; wherein said phenyl or said pyridinyl is optionally substituted with one or more halogens.

[1468] Embodiment 103: A compound according to any one of the preceding embodiments, wherein at least one R A1b It's a halogen.

[1469] Embodiment 104: A compound according to any one of the preceding embodiments, wherein at least one R A1b is F and at least one RA1b It's Cl.

[1470] Embodiment 105: A compound according to any one of the preceding embodiments, wherein at least one R A1b It is CN, -OH or -NH2.

[1471] Embodiment 106: A compound according to any one of the preceding embodiments, wherein when Z is but

[1472] T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein said -O-(C1-C6 alkyl), said -NH-(C1-C6 alkyl), said C1-C6 alkyl or said C2-C6 alkynyl is optionally replaced by one or more R T substituted; and wherein the C2-C6 alkenyl is replaced by one or more R T replace,

[1473] Each R T are independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3 to 7 membered heterocycloalkyl or 5 to 10 membered heteroaryl; wherein said -O-(C1-C6 alkyl), said C1-C6 alkyl, said C2-C6 alkenyl, said C2-C6 alkynyl, said C3-C 10 Cycloalkyl, the C6-C 10 The aryl group, the 3 to 7 membered heterocycloalkyl group or the 5 to 10 membered heteroaryl group are optionally substituted by one or more R Ta replace; and

[1474] Each R Ta are independently halogen, CN, -OH, -NH2, -C(=O)OH, -O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl.

[1475] Embodiment 107: A compound according to any one of the preceding embodiments, wherein when Z is Then T is not

[1476] Embodiment 108: A compound according to any one of the preceding embodiments, wherein when T is Then Ar 1is a C6-C 10 Aryl.

[1477] Embodiment 109: A compound according to any one of the preceding embodiments, wherein Z is not

[1478] Embodiment 110: A compound according to any one of the preceding embodiments, wherein Z is not

[1479] Embodiment 111: A compound according to any one of the preceding embodiments, wherein T is not

[1480] Embodiment 112: A compound according to any one of the preceding embodiments, wherein the compound has Formula (II'):

[1481]

[1482] or a pharmaceutically acceptable salt or stereoisomer thereof.

[1483] Embodiment 113. A compound according to any one of the preceding embodiments, wherein the compound has Formula (II'):

[1484]

[1485] or a pharmaceutically acceptable salt or stereoisomer thereof.

[1486] Embodiment 114: A compound according to any one of the preceding embodiments, wherein the compound has formula (III') or (III'-a):

[1487]

[1488] or a pharmaceutically acceptable salt or stereoisomer thereof.

[1489] Embodiment 115. A compound according to any one of the preceding embodiments, wherein the compound has formula (IV') or (IV'-a):

[1490]

[1491] or a pharmaceutically acceptable salt or stereoisomer thereof.

[1492] Embodiment 116: A compound according to any one of the preceding embodiments, wherein the compound has Formula I

[1493]

[1494] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

[1495] W is CH or N;

[1496] X 1 It is -O-, -S-, -NR 3 -;

[1497] R a 、R b are independently hydrogen, C 1-4 Alkyl, or R a One of the is if X 1 It is NR 3 , then with X 1 Ring-forming -(CH2) p , or R a One of them is with R 2 Ring-forming -(CH2) p ;

[1498] R c 、R d are independently hydrogen or C 1-4 alkyl;

[1499] R 1 is H or F;

[1500] R 2 is hydrogen or C 1-4 Alkyl, or with R 3 or with R a One of the ring-forming -(CH2) q ;

[1501] R 3 is hydrogen or C 1-4 Alkyl, preferably hydrogen or methyl, or with R 2 Ring-forming -(CH2) p -;

[1502] m is 1, 2, or 3;

[1503] n is 0, 1, or 2;

[1504] p is 1 or 2;

[1505] q is 0, 1, or 2, and

[1506] Ar 1 is a 6-membered aryl group which is unsubstituted or substituted by one or more of the following groups: halogen, -CF3, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxy C 1-5 Alkyl, C1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy-C6 aryl, C 1-6 Alkoxy-C 5-6 Heteroaryl, amino, amino C 1-4 Alkyl, C 1-6 Alkylamino, C 1-6 Aminoalkyl-C6 aryl, C 1-6 aminoalkyl-C 5-6 Heteroaryl, C 1-6 Alkoxycarbonyl, C 1-6 Alkoxyaminocarbonyl, aryl C 1-6 Alkoxy or C6 aryl.

[1507] Embodiment 117: A compound according to any one of the preceding embodiments, wherein when X 1 Yes-NR 3 -, R 2 Not hydrogen.

[1508] Embodiment 118: A compound according to any one of the preceding embodiments, wherein when X 1 Yes-NR 3 -, R 2 It is C 1-4 Alkyl, or with R 3 or R a One of the ring-forming -(CH2) q -.

[1509] Embodiment 119: A compound according to any one of the preceding embodiments, wherein X 1 Yes-NR 3 -, and R 2 Not hydrogen.

[1510] Embodiment 120: A compound according to any one of the preceding embodiments, wherein X 1 Yes-NR 3 -, and R 2 It is C 1-4 Alkyl, or with R 3 or with R a One of the ring-forming -(CH2) q -.

[1511] Embodiment 121: A compound according to any one of the preceding embodiments, wherein when n is 0, R 2 is with R 3 or with R a One of the ring-forming -(CH2) q -.

[1512] Embodiment 122: A compound according to any one of the preceding embodiments, wherein when n is 0, R 2 is with R 3 Ring-forming -(CH2) q -.

[1513] Embodiment 123: A compound according to any one of the preceding embodiments, wherein n is 0, and R 2 is with R 3 or with R a One of the ring-forming -(CH2) q -.

[1514] Embodiment 124: A compound according to any one of the preceding embodiments, wherein n is 0, and R 2 is with R 3 Ring-forming -(CH2) q -.

[1515] Embodiment 125: A compound according to any one of the preceding embodiments, wherein X 1 It is NR 3 or O, and where R 3 It is methyl, ethyl, n-propyl or n-butyl.

[1516] Embodiment 126: A compound according to any one of the preceding embodiments, wherein R 1 It's hydrogen.

[1517] Embodiment 127: A compound according to any one of the preceding embodiments, wherein R 2 is methyl, ethyl, n-propyl or...

Claims

1. A compound, which is: or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

2. The compound according to claim 1, which is 3. The compound according to claim 1, which is a pharmaceutically acceptable salt of the following compound, 4. The compound according to claim 1, which is or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

5. The compound according to claim 4, which is 6. The compound according to claim 4, which is a pharmaceutically acceptable salt of the following compound, 7. The compound according to claim 1, which is or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

8. The compound according to claim 7, which is 9. The compound according to claim 7, which is a pharmaceutically acceptable salt of the following compound, 10. A composition comprising the compound according to any one of claims 1 to 9 and a pharmaceutically acceptable carrier.

11. Use of a compound according to any one of claims 1 to 9 in the preparation of a medicament for inhibiting oncogenic variants of ErbB receptors.

12. Use of the compound according to any one of claims 1 to 9 in the preparation of a medicament for preventing or treating cancer.

13. Use according to claim 12, wherein the cancer is a solid tumor.

14. The use according to claim 12, wherein the cancer is bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, glioblastoma (GBM), head and neck cancer, or lung cancer.

15. The use according to claim 12, wherein the lung cancer is non-small cell lung cancer (NSCLC).

16. The use according to claim 12, wherein the cancer is glioblastoma.

17. Use according to claim 12, wherein the cancer or tumor or cells thereof express oncogenic variants of ErbB receptors.

18. Use according to claim 17, wherein said oncogenic variant of said ErbB receptor comprises an allosteric mutation.

19. Use according to claim 17, wherein said oncogenic variant of ErbB receptor is an allosteric variant of said ErbB receptor.

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