CN112771042A

CN112771042A - Nalidinone and pyridylpyrimidinone compounds as protein kinase inhibitors

Info

Publication number: CN112771042A
Application number: CN201980063496.8A
Authority: CN
Inventors: 张卫鹏; 王宪龙; 刘洪彬; 周祖文; 王云岭; 杨理君; 李同双; 赵兴东; 邹宗尧; 高玉伟; 林舒; 王为波
Original assignee: Shanghai Fochon Pharmaceutical Co Ltd; Fochon Pharmaceuticals Ltd
Current assignee: Chongqing Fushang Yuanchuang Pharmaceutical Technology Co ltd
Priority date: 2018-09-28
Filing date: 2019-09-27
Publication date: 2021-05-07
Also published as: TW202028199A; WO2020063860A1

Abstract

The invention provides a class of PDGFR inhibitors, pharmaceutical compositions thereof and methods of use thereof.

Description

Nalidinone and pyridylpyrimidinone compounds as protein kinase inhibitors

This application claims priority to U.S. provisional application 62/738,497, which is incorporated herein by reference in its entirety.

Technical Field

The present invention relates to a novel class of compounds which inhibit protein kinases, or pharmaceutically acceptable salts thereof, which are useful as medicaments for the treatment of hyperproliferative diseases such as cancer and inflammation, or immune and autoimmune diseases.

Background

Hyperproliferative diseases such as cancer and inflammation have attracted the academic community to provide effective treatments for them. And efforts have been made in this regard to identify and target specific mechanisms that play a role in proliferative diseases.

Many members of the protein kinase family play an important role in coordinating the activities of various cellular processes and functions. Aberrant activation of kinases has been reported to cause or promote a variety of proliferative diseases such as cancer, rheumatoid arthritis, atherosclerosis and retinopathy. Thus, kinases are key therapeutic targets. Important examples of kinases involved in or contributing to the pathogenesis of proliferative diseases include, but are not limited to: PDGFR, C-KIT, C-MET, RET, AXL, MERKT, TYRO3, TRKA/B/C, EGFR, FGFR and FLT-3. Activation of these kinases occurs primarily through the downstream Ras/Raf/MEK/ERK signaling pathway. In the present invention, novel compounds having inhibitory activity against one or more protein kinases would be a successful treatment regimen for patients with abnormally activated kinases.

Therefore, compounds having protein kinase inhibitory activity are of great interest for the prevention and treatment of cancer. Although PDGFR inhibitors have been reported in the literature, e.g. WO1999028304 and WO2001083450, many have short half-lives or are toxic. Thus, there remains a need for novel PDGFR inhibitors that have at least one advantage in terms of therapeutic efficacy, stability, selectivity, safety and pharmacodynamic profile in the treatment of abnormal proliferative diseases. Based on the above, the invention provides a novel PDGFR inhibitor.

Brief description of the invention

The invention relates to a novel compound, pharmaceutically acceptable salts and pharmaceutical compositions thereof, and application as a medicament.

In one aspect, the present invention provides a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

z is selected from CR^XAnd N;

l is selected from-NR^AC(O)、-C(O)NR^A、-NR^AC(O)NR^Band-NR^ASO₂；

R¹is-NR^A1R^B1；

R²Selected from hydrogen, halogen, CN, C_1-10Alkyl radical, C_3-10Cycloalkyl and C_3-10cycloalkyl-C_1-4Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, wherein each alkyl, cycloalkyl, alkenyl and alkynyl is unsubstituted or substituted by at least one, such as 1,2, 3 or 4, independently selected from R^XSubstituted with the substituent(s);

each R³Independently selected from halogen, CN and C_1-10Alkyl, wherein alkyl is unsubstituted or substituted with at least one, such as 1,2, 3 or 4, independently selected from R^XSubstituted with the substituent(s);

R⁴selected from aryl and heteroaryl, wherein aryl and heteroaryl are each unsubstituted or substituted by at least one, such as 1,2, 3 or 4, independently selected from R^XSubstituted with the substituent(s);

R⁵selected from hydrogen, halogen, CN, C_1-10Alkyl radical, C_3-10Cycloalkyl and C_3-10cycloalkyl-C_1-4Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, wherein each alkyl, cycloalkyl, alkenyl and alkynyl is unsubstituted or substituted with at least one, such as 1,2, 3 or 4, independently selected from R^XSubstituted with the substituent(s);

R^Aand R^BAre each independently selected from hydrogen and C_1-10Alkyl, wherein alkyl is unsubstituted or substituted with at least one, such as 1,2, 3 or 4, independently selected from R^XSubstituted with the substituent(s);

R^A1and R^B1Are respectively and independently selected from hydrogen and C_1-10Alkyl radical, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl, -C (O) R^A2、-C(O)OR^A2、-C(O)NR^A2R^B2、-S(O)_rR^A2and-S (O)_rNR^A2R^B2Wherein each alkyl and cycloalkyl is unsubstituted or substituted by at least one, such as 1,2, 3 or 4, independently selected from R^XSubstituted with the substituent(s);

or R^A1And R^B1Together with the atom or atoms to which they are attached form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring may be unsubstituted or substituted with 1,2 or 3 heteroatoms selected from R^XSubstituted with the substituent(s);

each R^A2And R^B2Independently selected from hydrogen, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl, heterocyclyl-C_1-4Alkyl, aryl-C_1-4Alkyl, heteroaryl and heteroaryl-C_1-4Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one, such as 1,2, 3 or 4, independently selected from R^XSubstituted with the substituent(s);

or each R^A2And R^B2Together with the atom or atoms to which they are attached form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring may be unsubstituted or substituted with 1,2 or 3 heteroatoms selected from R^XSubstituted with the substituent(s);

each R^XIndependently selected from hydrogen, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl, heterocyclyl-C_1-4Alkyl, aryl-C_1-4Alkyl, heteroaryl-C_1-4Alkyl, halogen, CN, NO₂、-(CR^c1R^d1)_tNR^a1R^b1、-(CR^c1R^d1)_tOR^b1、-(CR^c1R^d1)_tC(O)R^a1、-(CR^c1R^d1)_tC(＝NR^e1)R^a1、-(CR^c1R^d1)_tC(＝N-OR^b1)R^a1、-(CR^c1R^d1)_tC(O)OR^b1、-(CR^c1R^d1)_tOC(O)R^b1、-(CR^c1R^d1)_tC(O)NR^a1R^b1、-(CR^c1R^d1)_tNR^a1C(O)R^b1、-(CR^c1R^d1)_tC(＝NR^e1)NR^a1R^b1、-(CR^c1R^d1)_tNR^a1C(＝NR^e1)R^b1、-(CR^c1R^d1)_tOC(O)NR^a1R^b1、-(CR^c1R^d1)_tNR^a1C(O)OR^b1、-(CR^c1R^d1)_tNR^a1C(O)NR^a1R^b1、-(CR^c1R^d1)_tNR^a1C(S)NR^a1R^b1、-(CR^c1R^d1)_tNR^a1C(＝NR^e1)NR^a1R^b1、-(CR^c1R^d1)_tS(O)_rR^b1、-(CR^c1R^d1)_tS(O)(＝NR^e1)R^b1、-(CR^c1R^d1)_tN＝S(O)R^a1R^b1、-(CR^c1R^d1)_tS(O)₂OR^b1、-(CR^c1R^d1)_tOS(O)₂R^b1、-(CR^c1R^d1)_tNR^a1S(O)_rR^b1、-(CR^c1R^d1)_tNR^a1S(O)(＝NR^e1)R^b1、-(CR^c1R^d1)_tS(O)_rNR^a1R^b1、-(CR^c1R^d1)_tS(O)(＝NR^e1)NR^a1R^b1、-(CR^c1R^d1)_tNR^a1S(O)₂NR^a1R^b1、-(CR^c1R^d1)_tNR^a1S(O)(＝NR^e1)NR^a1R^b1、-(CR^c1R^d1)_tP(O)R^a1R^b1And- (CR)^c1R^d1)_tP(O)(OR^a1)(OR^b1) Wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one, such as 1,2, 3 or 4, independently selected from R^YSubstituted with the substituent(s);

each R^a1And R^b1Independently selected from hydrogen, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl, heterocyclyl-C_1-4Alkyl, aryl-C_1-4Alkyl, heteroaryl and heteroaryl-C_1-4Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one, such as 1,2, 3 or 4, independently selected from R^YSubstituted with the substituent(s);

or each R^a1And R^b1Together with the atom or atoms to which they are attached form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring may be unsubstituted or substituted with 1,2 or 3 heteroatoms selected from R^YSubstituted with the substituent(s);

each R^c1And R^d1Independently selected from hydrogen, halogen, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl, heterocyclyl-C_1-4Alkyl, aryl-C_1-4Alkyl, heteroaryl and heteroaryl-C_1-4Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one, such as 1,2, 3 or 4, independently selected from R^YSubstituted with the substituent(s);

or each R^c1And R^d1Together with the carbon atom or atoms to which they are attached form aA 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, which ring may be unsubstituted or substituted with 1,2 or 3 heteroatoms selected from R^YSubstituted with the substituent(s);

each R^e1Independently selected from hydrogen, C_1-10Alkyl radical, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl, CN, NO₂、-OR^a2、-SR^a2、-S(O)_rR^a2、-C(O)R^a2、-C(O)OR^a2、-S(O)_rNR^a2R^b2and-C (O) NR^a2R^b2；

Each R^YIndependently selected from C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl, heterocyclyl-C_1-4Alkyl, aryl-C_1-4Alkyl, heteroaryl-C_1-4Alkyl, halogen, CN, NO₂、-(CR^c2R^d2)_tNR^a2R^b2、-(CR^c2R^d2)_tOR^b2、-(CR^c2R^d2)_tC(O)R^a2、-(CR^c2R^d2)_tC(＝NR^e2)R^a2、-(CR^c2R^d2)_tC(＝N-OR^b2)R^a2、-(CR^c2R^d2)_tC(O)OR^b2、-(CR^c2R^d2)_tOC(O)R^b2、-(CR^c2R^d2)_tC(O)NR^a2R^b2、-(CR^c2R^d2)_tNR^a2C(O)R^b2、-(CR^c2R^d2)_tC(＝NR^e2)NR^a2R^b2、-(CR^c2R^d2)_tNR^a2C(＝NR^e2)R^b2、-(CR^c2R^d2)_tOC(O)NR^a2R^b2、-(CR^c2R^d2)_tNR^a2C(O)OR^b2、-(CR^c2R^d2)_tNR^a2C(O)NR^a2R^b2、-(CR^c2R^d2)_tNR^a2C(S)NR^a2R^b2、-(CR^c2R^d2)_tNR^a2C(＝NR^e2)NR^a2R^b2、-(CR^c2R^d2)_tS(O)_rR^b2、-(CR^c2R^d2)_tS(O)(＝NR^e2)R^b2、-(CR^c2R^d2)_tN＝S(O)R^a2R^b2、-(CR^c2R^d2)_tS(O)₂OR^b2、-(CR^c2R^d2)_tOS(O)₂R^b2、-(CR^c2R^d2)_tNR^a2S(O)_rR^b2、-(CR^c2R^d2)_tNR^a2S(O)(＝NR^e2)R^b2、-(CR^c2R^d2)_tS(O)_rNR^a2R^b2、-(CR^c2R^d2)_tS(O)(＝NR^e2)NR^a2R^b2、-(CR^c2R^d2)_tNR^a2S(O)₂NR^a2R^b2、-(CR^c2R^d2)_tNR^a2S(O)(＝NR^e2)NR^a2R^b2、-(CR^c2R^d2)_tP(O)R^a2R^b2And- (CR)^c2R^d2)_tP(O)(OR^a2)(OR^b2) Wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one, such as 1,2, 3 or 4, independently selected from hydroxy, CN, amino, halogen, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkoxy, C_1-10Alkylthio radical, C_3-10Cycloalkylthio radical, C_1-10Alkylamino radical, C_3-10Cycloalkylamino, di (C)_1-10Alkyl) amino;

each R^a2And each R^b2Independently selected from hydrogen, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkoxy, C_1-10Alkylthio radical, C_3-10Cycloalkylthio radical, C_1-10Alkylamino radical, C_3-10Cycloalkylamino, di (C)_1-10Alkyl) amino, heterocyclyl-C_1-4Alkyl, aryl-C_1-4Alkyl, heteroaryl and heteroaryl-C_1-4Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted by at least one, such as 1,2, 3 or 4, independently selected from halogen, CN, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, hydroxy, C_1-10Alkoxy radical, C_3-10Cycloalkoxy, C_1-10Alkylthio radical, C_3-10Cycloalkylthio, amino, C_1-10Alkylamino radical, C_3-10Cycloalkylamino, di (C)_1-10Alkyl) amino;

or each R^a2And R^b2Together with the atom or atoms to which they are attached form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring may be unsubstituted or substituted with 1 or 2 heteroatoms selected from halogen, CN, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, hydroxy, C_1-10Alkoxy radical, C_3-10Cycloalkoxy, C_1-10Alkylthio radical, C_3-10Cycloalkylthio, amino, C_1-10Alkylamino radical, C_3-10Cycloalkylamino, di (C)_1-10Alkyl) amino;

each R^c2And R^d2Independently selected from hydrogen, halogen, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkoxy, C_1-10Alkyl sulfideBase, C_3-10Cycloalkylthio radical, C_1-10Alkylamino radical, C_3-10Cycloalkylamino, di (C)_1-10Alkyl) amino, heterocyclyl-C_1-4Alkyl, aryl-C_1-4Alkyl, heteroaryl and heteroaryl-C_1-4Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted by at least one, such as 1,2, 3 or 4, independently selected from halogen, CN, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, hydroxy, C_1-10Alkoxy radical, C_3-10Cycloalkoxy, C_1-10Alkylthio radical, C_3-10Cycloalkylthio, amino, C_1-10Alkylamino radical, C_3-10Cycloalkylamino, di (C)_1-10Alkyl) amino;

or each R^c2And R^d2Together with the carbon atom or atoms to which they are attached form a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, which ring may be unsubstituted or substituted by 1 or 2 heteroatoms selected from halogen, CN, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, hydroxy, C_1-10Alkoxy radical, C_3-10Cycloalkoxy, C_1-10Alkylthio radical, C_3-10Cycloalkylthio, amino, C_1-10Alkylamino radical, C_3-10Cycloalkylamino, di (C)_1-10Alkyl) amino;

each R^e2Independently selected from hydrogen, CN, NO₂，C_1-10Alkyl radical, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkoxy, -C (O) C_1-4Alkyl, -C (O) C_3-10Cycloalkyl, -C (O) OC_1-4Alkyl, -C (O) OC_3-10Cycloalkyl, -C (O) N (C)_1-4Alkyl radical)₂，-C(O)N(C_3-10Cycloalkyl radicals₂，-S(O)₂C_1-4Alkyl, -S (O)₂C_3-10Cycloalkyl, -S (O)₂N(C_1-4Alkyl radical)₂and-S (O)₂N(C_3-10Cycloalkyl radicals₂；

m is selected from 0, 1,2, 3 and 4;

each r is independently selected from 0, 1 and 2;

each t is independently selected from 0, 1,2, 3, and 4.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In another aspect, the present invention provides a method for modulating a protein kinase, comprising administering to a system or subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition, thereby modulating the protein kinase.

The invention also provides a method of treating, ameliorating or preventing a condition responsive to inhibition of a protein kinase, comprising administering to a system or subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof, optionally in combination with another therapeutic agent, to treat the condition.

Alternatively, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a protein kinase mediated disorder. In particular embodiments, the compounds can be used alone or in combination with another therapeutic agent to treat a protein kinase mediated disorder.

Alternatively, the present invention provides compounds of formula (I) for use in the treatment of protein kinase mediated disorders.

In particular, wherein the condition includes, but is not limited to, an autoimmune disease, a transplant disease, an infectious disease, or a cell proliferative disorder.

In addition, the present invention provides a method of treating a cell proliferative disorder, comprising administering to a system or subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof, optionally in combination with another therapeutic agent, to treat the disorder.

Alternatively, the present invention provides the use of a compound of formula (I) and/or a pharmaceutically acceptable salt for the manufacture of a medicament for the treatment of a cell proliferative disorder. In particular embodiments, the compounds can be used alone or in combination with another chemotherapeutic agent to treat a cell proliferative disorder.

In particular, wherein the cell proliferative disorder includes, but is not limited to, lymphoma, osteosarcoma, melanoma, or a tumor of the breast, kidney, prostate, colorectal, thyroid, ovarian, pancreatic, neuronal, lung, uterine or gastrointestinal tract.

In the above methods of using the compounds of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered to a system consisting of cells or tissues, or to a subject including a mammalian subject, such as a human or an animal.

Term(s) for

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this patent belongs. All patents, patent applications, published publications, etc. referred to herein are incorporated by reference in their entirety unless otherwise indicated. As used in this patent, the same terms are defined differently than the definitions in this section.

It is to be understood that both the foregoing general description and the following detailed description are explanatory only and are not restrictive of any claims. In this application, the use of the singular includes the plural unless specifically stated otherwise. It is noted that, in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It is also noted that "or" represents "and/or" unless stated otherwise. Furthermore, "comprising," "including," and like terms are not intended to be limiting.

Unless otherwise indicated, the conventional techniques of mass spectrometry, nuclear magnetic resonance, high performance liquid chromatography, infrared and ultraviolet/visible spectroscopy, and pharmacology used in this patent are prior art. Unless specifically defined, the nomenclature, protocols, and techniques involved in analytical chemistry, synthetic organic chemistry, pharmaceutical and pharmaceutical chemistry are those known in the art. Standard techniques are available for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and administration, and treatment of patients. The reaction and purification techniques may be carried out with reference to the manufacturer's instructions, or with reference to known, commonly used techniques, or with reference to the methods described in this patent. The techniques and procedures described above can be performed using methods that are conventional and well known in the literature cited in this specification. In the specification, groups and substituents may be selected by one skilled in the art to form stable structures and compounds.

When a substituent is referred to by a formula, the substituents in the formula are written from left to right as they are from right to left. E.g. CH₂O and OCH₂The same is true.

"substituted" means that the hydrogen atom is replaced with a substituent. It is noted that substituents on a particular atom are constrained by their valency.

The term "C" as used herein_i-j"or" i-j member "means that the moiety has i-j carbon atoms or i-j atoms. For example, "C_1-6By alkyl is meant that the alkyl group has 1 to 6 carbon atoms. Likewise, C_3-10Cycloalkyl means that the cycloalkyl group has 3 to 10 carbon atoms.

When any variable (e.g., R) occurs more than one time on the structure of a compound, it is independently defined in each instance. Thus, for example, if a group is substituted with 0-2R, that group may optionally be substituted with up to two R, and R has an independent choice in each case. In addition, combinations of substituents and/or variants thereof are permitted only if such combinations would result in stable compounds.

"one or more" or "at least one" means one, two, three, four, five, six, seven, eight, nine or more.

Unless otherwise indicated, the term "hetero" refers to a heteroatom or a heteroatom group (i.e., a group containing a heteroatom), i.e., an atom other than carbon and hydrogen atoms or a group containing such atoms. Preferably, the heteroatoms are independently selected from O, N, S, P, and the like. In embodiments involving two or more heteroatoms, the two or more heteroatoms may be the same, or the two or more heteroatoms may be partially or fully different.

"alkyl", whether used alone or in combination with other terms, refers to a branched or straight chain saturated aliphatic hydrocarbon group having the specified number of carbon atoms. Unless otherwise indicated, "alkyl" means C_1-10An alkyl group. For example, "C_1-6C in alkyl_1-6"refers to a straight or branched chain arrangement of 1,2, 3,4, 5 or 6 carbon atoms. For example, "C_1-8Alkyl "includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, heptyl, and octyl.

"cycloalkyl", alone or in combination with other terms, refers to a monocyclic or bridged saturated hydrocarbon ring system. Monocyclic cycloalkyl is a monocyclic hydrocarbon system containing 3 to 10 carbon atoms, no heteroatoms, no double bonds. Examples of monocyclic ring systems include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Bridged cycloalkyl is a polycyclic ring system containing 3 to 10 carbon atoms, which contains one or two alkylene bridges, each consisting of 1,2 or 3 carbon atoms, which connect two non-adjacent carbon atoms of the ring system. The cycloalkyl group may be fused with an aryl or heteroaryl group. In some embodiments, the cycloalkyl group is benzo-fused. Representative examples of bridged cycloalkane systems include, but are not limited to, bicyclo [3.1.1] heptane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] nonane, bicyclo [3.3.1] nonane, bicyclo [4.2.1] nonane, tricyclo [3.3.1.03,7] nonane, and tricyclo [3.3.1.13,7] decane (adamantane). The monocyclic and bridged hydrocarbon rings can be attached to the parent molecular moiety through any substitutable atom in the ring system.

"alkenyl", alone or in combination with other terms, refers to a nonaromatic, straight chain, branched or cyclic hydrocarbon radical containing from 2 to 10 carbon atoms and having at least one carbon-carbon double bond. In some embodiments, 1 carbon-carbon double bond is present, and up to 4 non-aromatic carbon-carbon double bonds may be present. Thus, "C_2－6Alkenyl "means alkenyl containing 2 to 6 carbon atoms. Alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 2-methylbutenyl, and cyclohexenyl. Straight, branched or cyclic in alkenyl groupsMoieties may contain double bonds, and if a substituted alkenyl group is indicated it may be substituted.

"alkynyl", whether used alone or in combination with other terms, refers to a straight, branched or cyclic hydrocarbon radical containing from 2 to 10 carbon atoms and at least one carbon-carbon triple bond. In some embodiments, up to 3 carbon-carbon triple bonds may be present. Thus, "C_2-6Alkynyl "refers to alkynyl groups containing 2-6 carbon atoms. Alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, 3-methylbutynyl, and the like. The straight, branched or cyclic portion of the alkynyl group may contain a triple bond, and a substituted alkynyl group, if indicated, may be substituted.

"halogen" means fluorine, chlorine, bromine, iodine.

"alkoxy", used alone or in combination with other terms, means an alkyl group, as defined above, attached to an oxygen atom by a single bond. The alkoxy group is attached to the molecule through an oxygen atom. Alkoxy groups may be represented as-O-alkyl. "C_1-10Alkoxy "refers to an alkoxy group containing 1 to 10 carbon atoms, and may be a straight chain or a branched structure. Alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, and the like.

"Cycloalkoxy", used alone or in combination with other terms, means a cycloalkyl group, as defined above, attached to an oxygen atom by a single bond. The cycloalkoxy group is attached to the molecule through an oxygen atom. Cycloalkoxy can be represented as-O-cycloalkyl. "C_3-10Cycloalkoxy "means a cycloalkoxy group containing 3 to 10 carbon atoms. The cycloalkoxy group may be fused to an aryl or heteroaryl group. In some embodiments, the cycloalkoxy group is benzo-fused. Cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, and the like.

"alkylthio", used alone or in combination with other terms, refers to an alkyl group, as defined above, attached to a sulfur atom by a single bond. Alkylthio groups are attached to the molecule through a sulfur atom. Alkylthio groups may be represented by-S-alkyl. "C_1-10Alkylthio "refers to an alkylthio group containing 1 to 10 carbon atoms and can be a straight chain or branched structure. Alkylthio groups include, but are not limited to, methylthio, and,Ethylthio, propylthio, isopropylthio, butylthio, hexylthio, and the like.

"Cycloalkylsulfanyl", used alone or in combination with other terms, means a cycloalkyl group as defined above attached by a single bond to a sulfur atom. The cycloalkylthio group is bonded to the molecule through a sulfur atom. The cycloalkylthio group may be represented as-S-cycloalkyl. "C_3-10Cycloalkylthio "means a cycloalkylthio group containing 3 to 10 carbon atoms. The cycloalkylthio group may be fused with an aryl group or a heteroaryl group. In some embodiments, the cycloalkylthio group is benzo-fused. Cycloalkylthio groups include, but are not limited to, cyclopropylthio, cyclobutylthio, and cyclohexylthio, and the like.

"alkylamino", used alone or in combination with other terms, refers to an alkyl group, as defined above, attached to a nitrogen atom by a single bond. The alkylamino group is attached to another molecule through a nitrogen atom. Alkylamino can be represented as-NH (alkyl). "C_1-10Alkylamino "refers to alkylamino groups containing 1 to 10 carbon atoms, which may be straight chain or branched. Alkylamino includes, but is not limited to, methylamino, ethylamino, propylamino, isopropylamino, butylamino, hexylamino and the like.

"Cycloalkylamino", used alone or in combination with other terms, refers to a cycloalkyl group, as defined above, attached to the nitrogen atom by a single bond. The cycloalkylamino group is linked to another molecule through a nitrogen atom. The cycloalkylamino group may be represented as-NH (cycloalkyl). "C_3-10Cycloalkylamino "refers to cycloalkylamino groups containing 3 to 10 carbon atoms. The cycloalkylamino group may be fused with an aryl or heteroaryl group. In some embodiments, cycloalkylamino is benzofused. Cycloalkylamino groups include, but are not limited to, cyclopropylamino, cyclobutylamino, cyclohexylamino and the like.

"Di (alkyl) amino", used alone or in combination with other terms, means two alkyl groups as defined above attached to the nitrogen atom by a single bond. The di (alkyl) amino group is attached to the molecule through a nitrogen atom. The di (alkyl) amino group may be represented by-N (alkyl)₂. ' two (C)_1-10Alkyl) amino "means a di (C) group in which the two alkyl moieties each contain 1 to 10 carbon atoms_1-10Alkyl) amino, which may be linear or branched.

"aryl", alone or in combination with other terms, means having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms ("C)_6-14Aryl "group), in particular a ring having 6 carbon atoms (" C)₆Aryl "groups), such as phenyl; or a ring having 10 carbon atoms ("C)₁₀Aryl "groups), such as naphthyl; or a ring having 14 carbon atoms ("C)₁₄Aryl "groups), such as anthracenyl. The aryl group may be fused with a cycloalkyl group or a heterocyclic group.

Divalent radicals, which are formed from substituted benzene derivatives and have free valence electrons present at the ring atoms, are designated as substituted phenylene radicals. Divalent radicals derived from monovalent polycyclic hydrocarbon radicals whose name ends with "-yl", which are obtained by removing one more hydrogen atom from a carbon atom containing a free valence electron, are named after the name of the monovalent radical plus "-idene (-idene)", for example, naphthyl, which has two attachment sites, is called naphthylidene.

"heteroaryl", used alone or in combination with other terms, means a monovalent, monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms (a "5-to 14-membered heteroaryl" group), in particular 5 or 6 or 9 or 10 atoms, and containing at least one heteroatom which may be the same or different, selected from N, O and S. The heteroaryl group may be fused with a cycloalkyl group or a heterocyclic group. In some embodiments, "heteroaryl" refers to

A 5-to 8-membered aromatic monocyclic ring containing 1 to 4, and in certain embodiments 1 to 3, heteroatoms selected from N, O and S, the remainder being carbon atoms; and

an 8-to-12-membered bicyclic ring containing 1 to 6, in certain embodiments 1 to 4, or in certain embodiments 1 to 3 heteroatoms selected from N, O and S, the remainder being carbon atoms, and wherein at least one heteroatom is present in the aromatic ring; and

an 11-to 14-membered tricyclic ring containing 1 to 8, in certain embodiments 1 to 6, or in certain embodiments 1 to 4, or in certain embodiments 1 to 3 heteroatoms selected from N, O and S, the remainder being carbon atoms.

When the total number of S and O in the heteroaryl group is greater than 1, these heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O in the heteroaryl is no greater than 2. In some embodiments, the total number of S and O in the heteroaryl is no greater than 1.

Examples of heteroaryl groups include, but are not limited to, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 3-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, pyridazinyl, triazinyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, thienyl, furyl.

Further, heteroaryl groups include, but are not limited to, indolyl, benzothienyl, benzofuranyl, benzimidazolyl, benzotriazolyl, quinoxalinyl, quinolinyl, and isoquinolinyl. "heteroaryl" includes any N-oxidized derivative of a nitrogen-containing heteroaryl.

The nomenclature of a monovalent heteroaryl group ends with the "-yl", the name of a derived divalent group being obtained by removing a further hydrogen atom from the carbon atom containing the free valence electron, this divalent group being the name of a monovalent group plus the "-idene" — "group", for example: the pyridyl group having two attachment sites is called a pyridylidene.

"heterocycle" (and derivatives thereof such as "heterocyclic" or "heterocyclyl") broadly refers to a saturated or unsaturated, monocyclic or polycyclic (e.g., bicyclic) cyclic aliphatic hydrocarbon system, typically having from 3 to 12 ring atoms, containing at least 1 (e.g., 2, 3 or 4) heteroatom (preferably oxygen, sulfur, nitrogen) independently selected from oxygen, sulfur, nitrogen and phosphorus. In polycyclic ring systems two or more rings may be linked by a fused, bridged or spiro ring, and the heterocyclic ring may be fused to an aryl or heteroaryl group. In some embodiments, the heterocyclic ring is benzo-fused. Heterocyclic also includes ring systems substituted with one or more oxo or imino moieties. In some embodiments, the C, N, S, and P atoms in the heterocycle are optionally substituted with oxo. In some embodiments, the C, S, and P atoms in the heterocycle are optionally substituted with an imino group, and the imino group may be unsubstituted or substituted. Either the carbon atom or the heteroatom of the heterocycle may be the attachment site, provided that a stable structure is formed. When a substituent is present on the heterocycle, the substituent may be attached to any heteroatom or carbon atom on the heterocycle, provided that a stable chemical structure is formed.

Suitable heterocycles include, for example, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 3-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, 1-pyrazolidinyl, 2-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, 5-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-piperazinyl, 2-piperazinyl, 3-piperazinyl, 1-hexahydropyridazinyl, 3-hexahydropyridazinyl and 4-hexahydropyridazinyl. Examples of heterocycles having one or more oxo moieties include, but are not limited to, piperidinyl-N-oxide, morpholinyl-N-oxide, 1-oxo-thiomorpholinyl, and 1, 1-dioxo-thiomorpholinyl. Bicyclic heterocycles include, but are not limited to:

as used herein, "aryl-alkyl" refers to an alkyl group as defined above substituted with an aryl group as defined above. Exemplary aralkyl groups include, but are not limited to, benzyl, phenethyl, naphthylmethyl, and the like. In some embodiments, aralkyl groups contain 7 to 20 or 7 to 11 carbon atoms. When using "aryl radicals C_1-4Alkyl "in which" C_1-4"refers to the number of carbon atoms in the alkyl portion rather than the aryl portion.

"Heterocyclylalkyl" as used herein means a heterocyclyl group, as defined above, substituted with an alkyl group, as defined above. When using "heterocyclyl C_1-4When alkyl isWherein "C_1-4"refers to the number of carbon atoms in the alkyl moiety rather than in the heterocyclyl moiety.

"cycloalkyl-alkyl" as used herein refers to an alkyl group as defined above substituted with a cycloalkyl group as defined above. When using "C_3-10cycloalkyl-C_1-4Alkyl "in which" C_3-10"refers to the number of carbon atoms in the cycloalkyl moiety rather than the alkyl moiety. Wherein "C_1-4"refers to the number of carbon atoms in the alkyl moiety rather than the cycloalkyl moiety.

As used herein, "heteroaryl-alkyl" refers to an alkyl group as defined above substituted with a heteroaryl group as defined above. When using "heteroaryl-C_1-4Alkyl "in which" C_1-4"refers to the number of carbon atoms in the alkyl moiety rather than in the heteroaryl moiety.

To avoid ambiguity, for example: when alkyl, cycloalkyl, heterocyclylalkyl, aryl, and/or heteroaryl substituents thereof are mentioned, it is meant that each of these groups is substituted individually or that these groups are mixed. That is: if R is aryl-C_1-4Alkyl, and may be unsubstituted or substituted with at least one substituent, such as 1,2, 3 or 4, independently selected from R^XIs understood that the aryl moiety may be unsubstituted or substituted with at least one, such as 1,2, 3 or 4, independently selected from R^XMay also be unsubstituted or substituted by at least one, such as 1,2, 3 or 4, independently selected from R^XIs substituted with the substituent(s).

"pharmaceutically acceptable salt" refers to a salt with a pharmaceutically acceptable non-toxic base or acid, including inorganic or organic bases and inorganic or organic acids. The salt of an inorganic base may be selected, for example, from: aluminum, ammonium, calcium, copper, iron, ferrous iron, lithium, magnesium, manganese, manganous, potassium, sodium and zinc salts. Further, the pharmaceutically acceptable salt of inorganic base may be selected from ammonium, calcium, magnesium, potassium, sodium salt. One or more crystal forms, or polymorphs, may be present in the solid salt, as well as solvates, such as hydrates. The pharmaceutically acceptable salts of organic non-toxic bases may be selected, for example, from: primary, secondary and tertiary amine salts, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, such as arginine, betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine.

When the compound referred to in this patent is a base, it is necessary to prepare a salt thereof with at least one pharmaceutically acceptable non-toxic acid selected from inorganic acids and organic acids. For example, selected from acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid. In some embodiments, these acids may be selected, for example: citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, fumaric acid, tartaric acid.

By "administering" or "administration" of a compound or a pharmaceutically acceptable salt thereof is meant providing a compound of the invention or a pharmaceutically acceptable salt thereof to a subject in need of treatment.

An "effective amount" is an amount of a compound or a pharmaceutically acceptable salt thereof that is capable of eliciting a biological or medical response in a tissue, system, animal or human that is observable by a researcher, veterinarian, clinician or other clinician.

"composition" comprising: the invention may take the form of a kit, article of manufacture, or any combination thereof. A pharmaceutical composition comprising: products comprising the active ingredient and an inert ingredient as a carrier, as well as products produced by any two or more of the ingredients, directly or indirectly, by combination, complexation or aggregation, or by dissociation of one or more of the ingredients, or by other types of reactions or interactions of one or more of the ingredients.

By "pharmaceutically acceptable" is meant compatible with the other ingredients of the formulation and not unacceptably toxic to the user.

"subject" refers to a subject having a disease, disorder, or the like, and includes mammals and non-mammals. Mammals include, but are not limited to, any member of the mammalian family: humans, non-human primates such as chimpanzees, and other apes and monkeys; farm animals such as cattle, horses, sheep's yang, goats, pigs; domestic animals such as rabbits, dogs, and cats; the experimental animals include rodents such as rats, mice, guinea pigs, and the like. Non-mammalian animals include, but are not limited to, birds, fish, and the like. In one embodiment of the invention, the mammal is a human.

"treating" includes alleviating, alleviating or ameliorating a disease or condition, preventing other conditions, ameliorating or preventing a metabolic factor underlying a condition, inhibiting a disease or condition, e.g., arresting the development of a disease or condition, alleviating a disease or condition, promoting remission of a disease or condition, or arresting the signs of a disease or condition, and extends to include prevention. "treating" also includes achieving a therapeutic benefit and/or a prophylactic benefit. Therapeutic benefit refers to eradication or amelioration of the condition being treated. In addition, therapeutic benefit is achieved by eradicating or ameliorating one or more physiological signs associated with the underlying disease, and amelioration of the disease in the patient is observed, although the patient may still be suffering from the underlying disease. Prophylactic benefit refers to the use of a composition by a patient to prevent the risk of a disease, or the use of a patient presenting with one or more physiological conditions of a disease, although the disease has not yet been diagnosed.

"protecting group" (Pg) refers to a class of substituents used to block or protect a particular functional group by reacting with other functional groups on a compound. For example, "amino protecting group" refers to a substituent attached to an amino group that blocks or protects the amino functionality on a compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, t-Butyloxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and the 9-fluorenylmethoxycarbonyl protecting group (Fmoc). Similarly, "hydroxy protecting group" means that a class of hydroxy substituents may haveEffectively block or protect hydroxyl functions. Suitable protecting groups include, but are not limited to, acetyl and silyl groups. "carboxy protecting group" refers to a class of carboxy substituents that function effectively to block or protect a carboxy group. Common carboxyl protecting groups include-CH₂CH₂SO₂Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfinyl) ethyl, 2- (diphenylphosphino) -ethyl, nitroethyl and the like. For general description and instructions for use of protecting groups, see references: greene, Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991。

"NH protecting group" includes, but is not limited to, trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzoyl, o-bromobenzyloxycarbonyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, t-pentyloxycarbonyl, t-butyloxycarbonyl, p-methoxybenzyloxycarbonyl, 3, 4-dimethoxybenzyloxycarbonyl, 4- (phenylazo) benzyloxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1-dimethylpropoxycarbonyl, isopropyloxycarbonyl, phthaloyl, succinyl, alanyl, leucyl, 1-adamantyloxycarbonyl, 8-quinolinyloxycarbonyl, benzyl, benzhydryl, trityl, 2-nitrobenzenesulfonyl, methylsulfonyl, p-toluenesulfonyl, N, N-dimethylaminomethylene, benzylidene, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-l-naphthylmethylene, 3-hydroxy-4-pyridylmethylidene, cyclohexylidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, 3-dimethyl-5-oxocyclohexylidene, diphenylphosphoryl, dibenzylphosphoryl, 5-methyl-2-oxo-2H-l, 3-dioxol-4-yl-methyl, trimethylsilyl, triethylsilyl and triphenylsilyl.

"C (O) OH" protecting groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 1-dimethylpropyl, n-butyl, t-butyl, phenyl, naphthyl, benzyl, benzhydryl, trityl, p-nitrobenzyl, p-methoxybenzyl, bis (p-methoxyphenyl) methyl, acetylmethyl, phenacyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl, p-methanesulfonylbenzoylmethyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, 2,2, 2-trichloroethyl, 2- (trimethylsilyl) ethyl, acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, phthalimidomethyl, succinimidylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, methoxyethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, Benzyloxymethyl, methylthiomethyl, 2-methylthioethyl, phenylthiomethyl, 1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl and tert-butylmethoxyphenylsilyl.

"OH or SH" protecting groups include, but are not limited to, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3, 4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, 1-dimethylpropoxycarbonyl, isopropyloxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2,2, 2-trichloroethoxycarbonyl, 2,2, 2-tribromoethoxycarbonyl, 2- (trimethylsilane) ethoxycarbonyl, 2- (phenylsulfonyl) ethoxycarbonyl, 2- (triphenylphosphonio) ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 4-ethoxy-1-naphthyloxycarbonyl, N-phenyloxycarbonyl, 8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl, benzoyl, methyl, tert-butyl, 2,2, 2-trichloroethyl, 2-trimethylsilylethyl, 1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl (phenylmethyl), p-methoxybenzyl, 3, 4-dimethoxybenzyl, diphenylmethyl, triphenylmethyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2,2, 2-trichloroethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, dichloroacetyl, benzoyl, chloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl, benzoyl, benzyl (phenylmethyl), p-methoxybenzyl, 3, 4-dimethoxybenzyl, diphenylmethyl, triphenyl, 1-ethoxyethyl group, methanesulfonyl group, p-toluenesulfonyl group, trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, diethylisopropylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, diphenylmethylsilyl group and tert-butylmethoxyphenylsilyl group.

Geometric isomers may exist in the compounds of the present invention. Compounds of the present invention may have carbon-carbon double bonds or carbon-nitrogen double bonds in either the E or Z configuration, where "E" represents the preferred substituent on the opposite side of the carbon-carbon double bond or carbon-nitrogen double bond and "Z" represents the preferred substituent on the same side of the carbon-carbon double bond or carbon-nitrogen double bond, as defined by Cahn-Ingold-Prelog preference. The compounds of the invention may also exist as mixtures of "E" and "Z" isomers. The substituents around the cycloalkyl or heterocyclyl group may be in either the cis or trans configuration. In addition, the present invention includes different isomers and mixtures thereof formed by different arrangements of substituents around the adamantane ring system. Two substituents around a single ring in an adamantane ring system are designated in either the Z or E relative configuration. See, for example, C.D.Jones, M.Kaselj, R.N.Salvatore, W.J.le Noble J.org.chem.1998,63, 2758-.

Compounds of the invention may contain asymmetrically substituted carbon atoms of R or S configuration, "R" and "S" are defined in IUPAC 1974Recommendations for Section E, functional Stereochemistry, Pure appl. chem. (1976)45, 13-10. Compounds containing asymmetrically substituted carbon atoms are racemates if the amounts of R and S configuration are the same. If one of the configurations is present in greater amounts than the other, the configuration of the chiral carbon atom is represented by the more abundant configuration, preferably with an enantiomeric excess of about 85-90%, more preferably about 95-99%, and even more preferably about 99% or more. Thus, the present invention encompasses racemic mixtures, relative and absolute stereoisomers, and mixtures of relative and absolute stereoisomers.

Isotopically enriched or labelled compounds

The compounds of the invention may exist in isotopically-labelled or enriched form, containing one or more atoms most prevalent in natureAtoms of different mass and mass number. The isotope may be a radioactive or non-radioactive isotope. Isotopes of atoms such as hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine include, but are not limited to,²H、³H、¹³C、¹⁴C、¹⁵N、¹⁸O、³²P、³⁵S、¹⁸F、³⁶cl and¹²⁵I. other isotopes and/or other atoms containing these atoms are also within the scope of the present invention.

In another embodiment, the isotopically labeled compound comprises deuterium (A), (B), (C), (²H) Tritium (a)³H) Or¹⁴Isotope of C. Isotopically-labeled compounds of the present invention can be obtained by employing procedures well known to those skilled in the art. These isotopically labeled compounds can be obtained by substituting a non-labeling reagent with an isotopically labeled reagent by referring to the examples and reaction schemes of the present invention. In certain examples, compounds can be treated with isotopic labeling agents to replace atoms with isotopic atoms, e.g., replacement of hydrogen with deuterium can be accomplished by deuterated acids such as D₂SO₄/D₂And exchanging the action of O.

The isotopically labeled compounds of the present invention are useful as standards for potency binding assays for PI3K inhibitors. Isotopically-containing compounds are useful in pharmaceutical research, evaluating the mechanism of action and metabolic pathways of non-isotopically-labeled parent compounds, and investigating the in vivo metabolic turnover of compounds (Blake et al.J.pharm.Sci.64,3,367-391 (1975)). Such metabolic studies are important for the design of safe and effective therapeutic agents, and can be judged to be toxic or carcinogenic to the active compound in vivo for use by the patient, or to the metabolite of the parent compound (Foster et al, Advances in Drug Research Vol.14, pp.2-36, Academic press, London, 1985; Kato et al, J.Labelled Comp.Radiopharmaceut.,36(10): 927. 932 (1995); Kushner et al, Can.J.Physiol.Pharmacol,77,79-88 (1999)).

In addition, drugs containing non-reflex active isotopes, such as deuterated drugs, known as "heavy drugs," are useful for treating diseases and disorders associated with PI3K activity. The proportion of a certain isotope in a compound that exceeds its natural abundance is called enrichment. Amounts of enrichment include, but are not limited to, for example, from about 0.5, 1,2, 3,4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96 to about 100 mol%.

Drug-stable isotopic labeling can alter its physicochemical properties, such as pKa and liquid solubility. If isotopic substitution affects the region associated with ligand-receptor interaction, then these effects and changes may affect the pharmacodynamic response of the drug molecule. Certain physical properties of stable isotope-labeled molecules differ from those of unlabeled molecules, while chemical and biological properties are the same, but with one important difference: any chemical bond containing a heavy isotope and another atom is stronger than a light isotope due to the increased mass of the heavy isotope. Accordingly, the presence of isotopes at the metabolic or enzymatic conversion sites slows the reaction and may alter its pharmacokinetic or pharmacodynamic properties compared to non-isotopically labeled compounds.

In embodiment (1), the present invention provides a compound represented by formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

z is selected from CR^XAnd N;

l is selected from-NR^AC(O)、-C(O)NR^A、-NR^AC(O)NR^Band-NR^ASO₂；

R¹is-NR^A1R^B1；

each R^A2And R^B2Independently selected from hydrogen, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl, heterocyclicradical-C_1-4Alkyl, aryl-C_1-4Alkyl, heteroaryl and heteroaryl-C_1-4Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one, such as 1,2, 3 or 4, independently selected from R^XSubstituted with the substituent(s);

each R^a1And R^b1Independently selected from hydrogen, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl, heterocyclyl-C_1-4Alkyl, aryl-C_1-4Alkyl, heteroaryl and heteroaryl-C_1-4Alkyl, each of which is alkyl, alkenylAlkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are unsubstituted or substituted with at least one, such as 1,2, 3 or 4, independently selected from R^YSubstituted with the substituent(s);

or each R^c1And R^d1Together with the carbon atom or atoms to which they are attached form a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, which ring may be unsubstituted or substituted by 1,2 or 3 heteroatoms selected from R^YSubstituted with the substituent(s);

Each R^YIndependently selected from C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl, heterocyclyl-C_1-4Alkyl, arylradical-C_1-4Alkyl, heteroaryl-C_1-4Alkyl, halogen, CN, NO₂、-(CR^c2R^d2)_tNR^a2R^b2、-(CR^c2R^d2)_tOR^b2、-(CR^c2R^d2)_tC(O)R^a2、-(CR^c2R^d2)_tC(＝NR^e2)R^a2、-(CR^c2R^d2)_tC(＝N-OR^b2)R^a2、-(CR^c2R^d2)_tC(O)OR^b2、-(CR^c2R^d2)_tOC(O)R^b2、-(CR^c2R^d2)_tC(O)NR^a2R^b2、-(CR^c2R^d2)_tNR^a2C(O)R^b2、-(CR^c2R^d2)_tC(＝NR^e2)NR^a2R^b2、-(CR^c2R^d2)_tNR^a2C(＝NR^e2)R^b2、-(CR^c2R^d2)_tOC(O)NR^a2R^b2、-(CR^c2R^d2)_tNR^a2C(O)OR^b2、-(CR^c2R^d2)_tNR^a2C(O)NR^a2R^b2、-(CR^c2R^d2)_tNR^a2C(S)NR^a2R^b2、-(CR^c2R^d2)_tNR^a2C(＝NR^e2)NR^a2R^b2、-(CR^c2R^d2)_tS(O)_rR^b2、-(CR^c2R^d2)_tS(O)(＝NR^e2)R^b2、-(CR^c2R^d2)_tN＝S(O)R^a2R^b2、-(CR^c2R^d2)_tS(O)₂OR^b2、-(CR^c2R^d2)_tOS(O)₂R^b2、-(CR^c2R^d2)_tNR^a2S(O)_rR^b2、-(CR^c2R^d2)_tNR^a2S(O)(＝NR^e2)R^b2、-(CR^c2R^d2)_tS(O)_rNR^a2R^b2、-(CR^c2R^d2)_tS(O)(＝NR^e2)NR^a2R^b2、-(CR^c2R^d2)_tNR^a2S(O)₂NR^a2R^b2、-(CR^c2R^d2)_tNR^a2S(O)(＝NR^e2)NR^a2R^b2、-(CR^c2R^d2)_tP(O)R^a2R^b2And- (CR)^c2R^d2)_tP(O)(OR^a2)(OR^b2) Wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one, such as 1,2, 3 or 4, independently selected from hydroxy, CN, amino, halogen, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkoxy, C_1-10Alkylthio radical, C_3-10Cycloalkylthio radical, C_1-10Alkylamino radical, C_3-10Cycloalkylamino, di (C)_1-10Alkyl) amino;

each R^a2And each R^b2Independently selected from hydrogen, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkoxy, C_1-10Alkylthio radical, C_3-10Cycloalkylthio radical, C_1-10Alkylamino radical, C_3-10Cycloalkylamino, di (C)_1-10Alkyl) amino, heterocyclyl-C_1-4Alkyl, aryl-C_1-4Alkyl, heteroaryl and heteroaryl-C_1-4Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted by at least one, such as 1,2, 3 or 4, independently selected from halogen, CN, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, hydroxy, C_1-10Alkoxy radical，C_3-10Cycloalkoxy, C_1-10Alkylthio radical, C_3-10Cycloalkylthio, amino, C_1-10Alkylamino radical, C_3-10Cycloalkylamino, di (C)_1-10Alkyl) amino;

each R^c2And R^d2Independently selected from hydrogen, halogen, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkoxy, C_1-10Alkylthio radical, C_3-10Cycloalkylthio radical, C_1-10Alkylamino radical, C_3-10Cycloalkylamino, di (C)_1-10Alkyl) amino, heterocyclyl-C_1-4Alkyl, aryl-C_1-4Alkyl, heteroaryl and heteroaryl-C_1-4Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted by at least one, such as 1,2, 3 or 4, independently selected from halogen, CN, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, hydroxy, C_1-10Alkoxy radical, C_3-10Cycloalkoxy, C_1-10Alkylthio radical, C_3-10Cycloalkylthio, amino, C_1-10Alkylamino radical, C_3-10Cycloalkylamino, di (C)_1-10Of alkyl) amino groupsSubstituent group substitution;

m is selected from 0, 1,2, 3 and 4;

each r is independently selected from 0, 1 and 2;

each t is independently selected from 0, 1,2, 3, and 4.

In another embodiment (2), the present invention provides a compound of embodiment (1), or a pharmaceutically acceptable salt thereof, wherein Z is CH.

In another embodiment (3), the present invention provides a compound of embodiment (1), or a pharmaceutically acceptable salt thereof, wherein Z is N.

In another embodiment (4), the present invention provides a compound of any one of embodiments (1) - (3), or a pharmaceutically acceptable salt thereof, wherein L is selected from-NR^AC(O)-、-C(O)NR^A-and-NR^AC(O)NR^B-。

In another embodiment (5), the present invention provides a compound of embodiment (4) or a pharmaceutically acceptable salt thereof, wherein L is-NR^AC(O)NR^B-。

In another embodiment (6), the present invention provides a compound of embodiment (5), or a pharmaceutically acceptable salt thereof, wherein L is-nhc (o) NH-.

In another embodiment (7), the present invention provides a compound of any one of embodiments (1) to (6), or a pharmaceutically acceptable salt thereof, wherein R is⁴Is aryl, wherein aryl is unsubstituted or substituted with at least one group independently selected from R^XIs substituted with the substituent(s).

In another embodiment (8), the present invention provides a compound of embodiment (7) or a pharmaceutically acceptable salt thereof, wherein R⁴Is phenyl, wherein phenyl is unsubstituted or substituted with at least one group independently selected from halogen, CN and C_1-10Alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from halogen.

In another embodiment (9), the present invention provides a compound of any one of embodiments (1) - (6), or a pharmaceutically acceptable salt thereof, wherein R⁴Is heteroaryl, wherein heteroaryl is unsubstituted or substituted with at least one group independently selected from R^XIs substituted with the substituent(s).

In another embodiment (10), the present invention provides a compound of embodiment (9), or a pharmaceutically acceptable salt thereof, wherein R⁴Is pyridyl, wherein pyridyl is unsubstituted or substituted with at least one group independently selected from halogen, CN and C_1-10Alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from halogen.

In another embodiment (11), the present invention provides a compound of any one of embodiments (1) - (10), or a pharmaceutically acceptable salt thereof, wherein R¹is-NR^A1R^B1Wherein R is^A1And R^B1Are respectively independently selected fromHydrogen and C_1-10Alkyl, wherein alkyl is unsubstituted or substituted with at least one R independently selected from^XIs substituted with the substituent(s).

In another embodiment (12), the present invention provides a compound of embodiment (11), or a pharmaceutically acceptable salt thereof, wherein R¹Is selected from-NHCH₃、-NH₂、

In another embodiment (13), the present invention provides a compound of any one of embodiments (1) - (12), or a pharmaceutically acceptable salt thereof, wherein R²Is hydrogen.

In another embodiment (14), the present invention provides a compound of any one of embodiments (1) - (13), or a pharmaceutically acceptable salt thereof, wherein each R is hydrogen or an alkyl, aryl, or cycloalkyl group³Independently selected from halogen and C_1-10An alkyl group.

In another embodiment (15), the present invention provides a compound of any one of embodiments (1) - (14), or a pharmaceutically acceptable salt thereof, wherein m is 2.

In another embodiment (16), the present invention provides a compound of embodiment (15), or a pharmaceutically acceptable salt thereof, wherein the substructure of formula (I)

Is selected from

In another embodiment (17), the present invention provides a compound of any one of embodiments (1) - (16), or a pharmaceutically acceptable salt thereof, wherein R⁵Selected from hydrogen, C_1-10Alkyl and C_3-10Cycloalkyl, wherein each alkyl and cycloalkyl is unsubstituted or substituted with at least one substituent independently selected from halogen.

In another embodiment (18), the present invention provides a compound of embodiment (17), or a pharmaceutically acceptable salt thereof, wherein R⁵Selected from hydrogen,Methyl, ethyl, isopropyl and cycloalkyl, wherein methyl, ethyl, isopropyl and cycloalkyl are unsubstituted or substituted with at least one substituent independently selected from halogen.

In another embodiment (19), the compounds provided herein are selected from

And pharmaceutically acceptable salts thereof.

In another embodiment (20), the present invention provides a compound of any one of embodiments (1) - (19), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

In another embodiment (21), the invention provides a method of treating, ameliorating or preventing a condition responsive to inhibition of PDGFR comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments (1) - (19), or a pharmaceutically acceptable salt thereof, or at least one pharmaceutical composition thereof, optionally in combination with a second therapeutic agent.

In another embodiment (22), the present invention provides the use of a compound of any one of embodiments (1) to (19), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of hyperproliferative diseases, such as cancer and inflammation, or immune and autoimmune diseases.

In another aspect, the invention provides a kit comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof; and instructions including one or more of the following: information on what disease state the ingredient applies to, information stored on the ingredient, dosage information, and instructions on how to use the ingredient. In one particular variant, the kit comprises the compound in a multiple dose form.

In another aspect, the present invention provides an article of manufacture comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof; and a packaging material. In one variation, the packaging material includes a container for containing the compound. In one particular variation, the container includes a label that identifies one or more of the following: instructions for what disease state the compound is to be administered, stored information, dosage information, and/or how to administer the compound. In another variation, the article of manufacture comprises the compound in a multiple dose form.

In another aspect, the invention provides a method of treatment comprising administering to a subject a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method of inhibiting a protein kinase by the action of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, with the protein kinase.

In another aspect, the present invention provides a method of inhibiting a protein kinase, comprising causing a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to be present in a subject to inhibit protein kinase activity in vivo.

In another aspect, the invention provides a method of inhibiting a protein kinase, comprising administering to a subject a first compound that converts in vivo to a second compound, wherein the second compound inhibits protein kinase activity in vivo, and the second compound is a compound or variant of any of the above embodiments.

In another aspect, the invention provides a method of treating a disease state for which protein kinase activity contributes to the pathology and/or symptomology of the disease, the method comprising causing a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof to be present in a subject.

In another aspect, the invention provides a method of treating a disease state for which protein kinase activity contributes to the pathology and/or symptomology of the disease state, the method comprising administering to a subject a first compound which converts in vivo to a second compound, wherein the second compound inhibits protein kinase activity in vivo. It is noted that the compounds of the present invention may be either pre-or post-conversion compounds.

In variations of each of the above methods, the disease state is selected from: cancerous proliferative diseases (e.g., brain, lung, squamous cell, bladder, stomach, pancreas, breast, head, neck, renal area (renal), kidney, ovary, prostate, colorectal, epidermal, esophageal, testicular, gynecological or thyroid cancer); non-cancerous proliferative diseases (e.g., benign skin hyperplasia (e.g., psoriasis), restenosis, and Benign Prostatic Hypertrophy (BPH)); pancreatitis; kidney disease; pain; preventing implantation of blastocysts; treating diseases associated with angiogenesis or vasculogenesis (e.g., tumor angiogenesis, acute and chronic inflammatory diseases such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, kaposi's sarcoma and ovarian cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, and epidermoid cancer); asthma; neutrophil chemotaxis (e.g., reperfusion injury from myocardial infarction and stroke and inflammatory arthritis); septic shock; t cell mediated diseases where immunosuppression is valuable (e.g., prevention of organ transplant rejection, graft versus host disease, lupus erythematosus, multiple sclerosis, and rheumatoid arthritis); atherosclerosis; inhibiting keratinocytes responsive to the growth factor mixture; chronic Obstructive Pulmonary Disease (COPD) and other diseases.

In another aspect, the invention provides a method of treating a disease state in which a mutation in a protein kinase gene contributes to the pathology and/or symptomology of the disease, such as melanoma, lung cancer, colon cancer and other types of tumors.

In another aspect, the present invention relates to the use of compounds and variants of any one of the above embodiments as medicaments. In another aspect, the present invention relates to the use of compounds and variants of any one of the above embodiments for the preparation of a medicament for inhibiting protein kinases.

In another aspect, the present invention relates to the use of compounds and variants of any one of the above embodiments for the manufacture of a medicament for the treatment of pathological and/or symptomatic disease states caused by protein kinase activity.

Administration and pharmaceutical compositions

Generally, the compounds of the present invention will be administered in a therapeutically effective amount, either alone or in combination with one or more therapeutic agents, by any of the usual and acceptable means known in the art. The therapeutically effective amount may vary widely depending on the severity of the disease, age and relative health of the subject, the potency of the compound used and other factors known in the art. For example, for the treatment of neoplastic diseases and immune system diseases, the required dosage will vary depending upon the mode of administration, the particular condition being treated and the desired effect.

In general, satisfactory results are achieved at daily dosages of from 0.001 to 100mg/kg body weight, in particular from about 0.03 to 2.5mg/kg body weight. Daily doses for larger mammals, such as humans, may be administered in a convenient form, for example in divided doses up to four times a day or in sustained release form, from about 0.5mg to about 2000mg, or more specifically, from 0.5mg to 1000 mg. Suitable unit dosage forms for oral administration contain from about 1 to 50mg of the active ingredient.

The compounds of the present invention may be administered in the form of pharmaceutical compositions, by any conventional route; e.g., enterally, e.g., orally, e.g., in the form of tablets or capsules, parenterally, e.g., in the form of injectable solutions or suspensions; or topically, e.g., in the form of a lotion, gel, ointment, or cream, or in the form of a nasal or suppository.

Pharmaceutical compositions containing a compound of the invention in free base or pharmaceutically acceptable salt form in association with at least one pharmaceutically acceptable carrier or diluent may be manufactured in conventional manner by means of mixing, granulating, coating, dissolving or lyophilizing processes. For example, pharmaceutical compositions comprising a compound of the invention in combination with at least one pharmaceutically acceptable carrier or diluent may be formulated in conventional manner by admixture with a pharmaceutically acceptable carrier or diluent. Unit dosage forms for oral administration contain, for example, from about 0.1mg to about 500mg of active substance.

In one embodiment, the pharmaceutical composition is a solution, including a suspension or dispersion, such as an isotonic aqueous solution, of the active ingredient. In the case of lyophilized compositions comprising the active ingredient alone or in admixture with a carrier such as mannitol, dispersions or suspensions may be prepared prior to use. The pharmaceutical compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. Suitable preservatives include, but are not limited to, antioxidants such as ascorbic acid, microbicides such as sorbic acid or benzoic acid. The solution or suspension may also contain a thickening agent including, but not limited to, sodium carboxymethylcellulose, dextran, polyvinylpyrrolidone, gelatin, or a solubilizing agent such as tween 80 (polyoxyethylene (20) sorbitan monooleate).

Suspensions in oils may contain, as oily component, vegetable oils, synthetic or semi-synthetic oils, commonly used for injection purposes. Examples include liquid fatty acid esters containing as the acid component a long chain fatty acid having from 8 to 22 carbon atoms, or in some embodiments, from 12 to 22 carbon atoms. Suitable liquid fatty acid esters include, but are not limited to, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid or corresponding unsaturated acids, such as oleic acid, elaidic acid, erucic acid, brassidic acid and linoleic acid, if desired, with antioxidants, such as vitamin E, 3-carotene or 3, 5-di-tert-butyl-hydroxytoluene. The alcohol component of these fatty acid esters may have six carbon atoms and may be monovalent or polyvalent, such as mono-, di-or trivalent alcohols. Suitable alcohol components include, but are not limited to, methanol, ethanol, propanol, butanol or pentanol or isomers thereof, ethylene glycol and glycerol.

Other suitable fatty acid esters include, but are not limited to, ethyl oleate, isopropyl myristate, isopropyl palmitate,

m2375, (polyoxyethylene glycerol),

m1944 CS (unsaturated polyglycolyzed glyceride prepared by alcoholysis of almond oil, containing glyceride and polyglycol ester), LABRASOL^TM(saturated PEGylated glycerides prepared by alcoholysis of TCM, containing glycerides and polyethylene glycol esters; all available from GaKefosse, France), and/or

812 (triglycerides of saturated fatty acids with chain lengths of C8 to C12, from huls AG, germany), and vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil or peanut oil.

Pharmaceutical compositions for oral administration may be obtained, for example, by mixing the active ingredient with one or more solid carriers, if desired granulating a resulting mixture, and processing the mixture or granules by adding further excipients, in the form of tablets or tablet cores.

Suitable carriers include, but are not limited to, fillers, for example sugars, such as lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and binders, for example starches, such as corn, wheat, rice or potato starch, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and/or, if desired, disintegrants, such as the above-mentioned starches, carboxymethyl starch, crosslinked polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium alginate. Additional excipients include flow-regulating agents and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol, or derivatives thereof.

The tablet cores may be provided with a suitable, optionally enteric, coating by using, inter alia, a concentrated sugar solution, which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or a coating solution in a suitable organic solvent or solvent mixture, or, for enteric coatings, a solution of a suitable cellulose preparation, such as an acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate solution. Dyes or pigments may be added to the tablets or tablet coatings, for example for identification purposes or to indicate different doses of the active ingredient.

Pharmaceutical compositions for oral administration may also include hard capsules, including gelatin or soft, sealed capsules containing gelatin and a plasticizer, such as glycerol or sorbitol. Hard capsules may contain the active ingredients in the form of granules, for example in admixture with fillers such as corn starch, binders and/or glidants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredient may be dissolved or suspended in suitable liquid excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene glycol or propylene glycol, to which stabilizers and detergents, for example of the fatty acid ester type of polyoxyethylene sorbitol, may also be added.

Pharmaceutical compositions suitable for rectal administration, for example suppositories, comprise a combination of the active ingredient and a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.

Pharmaceutical compositions suitable for parenteral administration may contain the active ingredient in water-soluble form, for example as a water-soluble salt or as an aqueous injection suspension containing a viscosity-increasing substance, for example sodium carboxymethylcellulose, an aqueous solution of sorbitol and/or dextran, and, if desired, a stabilizer. The active ingredient, optionally together with excipients, may also be in a lyophilized form and may be prepared as a solution by addition of a suitable solvent prior to parenteral administration. The solutions used, for example for parenteral administration, can also be used as infusion solutions. Injectable preparations are generally prepared under sterile conditions, and filled, for example, in ampoules or vials, and in sealed containers.

The invention also provides a pharmaceutical combination, e.g. a kit, comprising a) a compound disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one auxiliary agent. The kit may contain instructions for its use.

Combination therapy

The compounds or pharmaceutically acceptable salts described herein may be used alone or in combination with other therapeutic agents.

For example, the use of an adjuvant (adjuvant) may enhance the therapeutic effect of a compound of the invention (e.g., the therapeutic benefit of an adjuvant drug alone may be minimal, but in combination with another drug, may enhance the therapeutic benefit of a subject), or, for example, the therapeutic benefit of a subject may be enhanced by the combination of a compound of the invention with another therapeutic agent that is also therapeutically effective. For example, in the treatment of gout, the compound of the invention may be used in combination with another drug for gout therapy to enhance clinical benefit. Alternatively, for example, if the adverse effect of using the compounds of the present invention is nausea, then an anti-nausea agent may be used in combination. Alternatively, combination therapies may include, but are not limited to, physical therapy, psychotherapy, radiation therapy, compression therapy of diseased areas, rest, dietary improvement, and the like. Regardless of the disease, disorder, or condition, both therapies should have additive or synergistic effects to benefit the treatment of an individual.

Where the compounds of this patent are used in combination with other therapeutic agents, the pharmaceutical compositions of the compounds of this patent may be administered by the same route as the other drugs, or by different routes due to differences in physical and chemical properties. For example, oral administration of a compound of this patent may produce and maintain good blood levels, while intravenous administration of another therapeutic agent may be required. Thus, the compound of this patent and the other therapeutic agent may be administered simultaneously, sequentially or separately.

Examples

There are various methods for synthesizing the compound of formula (I) or a pharmaceutically acceptable salt thereof, and representative methods are listed in this example. However, it is to be noted that the compounds of formula (I) or pharmaceutically acceptable salts thereof may also be obtained by synthesis in other synthetic schemes.

In certain compounds of formula (I), the attachment of atoms to other atoms may result in the presence of particular stereoisomers (e.g. chiral centres). The synthesis of a compound of formula (I) or a pharmaceutically acceptable salt thereof may result in a mixture of different isomers (enantiomers, diastereomers). Unless a particular configuration is specified, all recited compounds include different stereoisomers that may exist.

The compounds of formula (I) may also be prepared as pharmaceutically acceptable acid addition salts, for example, by reacting the free base form of the compounds of the invention with a pharmaceutically acceptable inorganic or organic acid. Or a compound of formula (I) in free acid form with a pharmaceutically acceptable inorganic or organic base, to form a pharmaceutically acceptable base addition salt. Inorganic and organic acids and bases suitable for the preparation of pharmaceutically acceptable salts of the compounds of formula (I) are described in the definitions section of this application. In addition, salt forms of the compounds of formula (I) can also be prepared by using salts of the starting materials or intermediates.

The free acid or base of the compound of formula (I) may be prepared from the corresponding base addition salt or acid addition salt thereof. The acid addition salt forms of the compounds of formula (I) may be converted to the corresponding free base, for example by treatment with a suitable base such as ammonium hydroxide solution, sodium hydroxide and the like. The base addition salt forms of the compounds of formula (I) may be converted to the corresponding free acids, for example by treatment with a suitable acid such as hydrochloric acid and the like.

An N-oxide of a compound of formula (I) or a pharmaceutically acceptable salt thereof may be prepared by methods known in the art. For example, the N-oxide can be obtained by reacting a non-oxidized form of the compound of formula (I) with an oxidizing agent (e.g., trifluoroperacetic acid, peroxymaleic acid (permaleic acid), perbenzoic acid, peracetic acid, m-chloroperoxybenzoic acid, etc.) in an inert organic solvent (e.g., halogenated hydrocarbon such as dichloromethane) at 0 to 80 ℃. Alternatively, the N-oxides of the compounds of formula (I) may also be prepared from the N-oxides of the starting materials.

The non-oxidized compound of formula (I) can be prepared by reacting N-oxide thereof with a reducing agent (such as sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, phosphorus tribromide and the like) in a corresponding inert organic solvent (such as acetonitrile, ethanol, dioxane aqueous solution and the like) at 0-80 ℃.

Protected derivatives of compounds of formula (I) may be prepared by methods well known to those skilled in the art. For a detailed technical description of the addition and removal of protecting groups see: greene, Protecting Groups in Organic Synthesis,3rd edition, John Wiley & Sons, Inc.1999.

The methods, routes and labels and general knowledge used in the examples are in accordance with the current scientific literature, e.g., the journal of the American chemical Association or the journal of biochemistry. Unless otherwise indicated, standard single or three letter abbreviations generally refer to L-amino acid residues. All starting materials used were purchased from commercial suppliers and used without further purification unless otherwise indicated. For example, the following abbreviations are used in the examples and throughout the specification: g (g), mg (mg), L (L), mL (mL), μ L (μ L), psi (pounds per square inch), M (mol), mM (mmol), i.v. (i.v.), Hz (Hz), MHz (megahertz), mol (mol), mmol (mmol), RT (ambient temperature), min (min), h (h), mp (melting point), TLC (thin layer chromatography), RT (retention time), RP (reversed phase), MeOH (methanol), i-PrOH (isopropanol), TEA (triethylamine), TFA (trifluoroacetic acid), TFAA (trifluoroacetic anhydride), THF (tetrahydrofuran), DMSO (dimethyl sulfoxide), EtOAc (ethyl acetate), DME (1, 2-dimethylethane), DCM (dichloromethane), DCE (dichloroethane), DMF (N, N-dimethylformamide), DMPU (N, N' -dimethylpropyleneurea), CDI (1, 1-carbonyldiimidazole), IBCF (isobutyl chloroformate), HOAc (acetic acid), HOSu (N-hydroxysuccinimide), HOBT (1-hydroxybenzotriazole), Et₂O (diethyl ether), EDCI (1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride), BOC (t-butyloxycarbonyl), FMOC (9-fluorenylmethoxycarbonyl), DCC (dicyclohexylcarbodiimide), CBZ (benzyloxycarbonyl), Ac (acetyl), atm (atmospheric pressure), TMSE (2- (trimethylsilyl) ethyl), TMS (trimethylsilyl), TIPS (triisopropylsilyl), TBS (t-butyldimethylsilyl), DMAP (4-dimethylaminopyridine), Me (methyl), OMe (methoxy), Et (ethyl), tBu (t-butyl), HPLC (high performance liquid chromatography), BOP (2-oxo-3-oxazolidinyl) hypophosphoryl chloride), TBAF (tetra-n-butylammonium fluoride), mCPBA (m-chloroperoxybenzoic acid).

Ether or Et₂O is diethyl ether; brine is then a saturated aqueous NaCl solution. Unless otherwise indicated, all temperatures refer to degrees Celsius (degrees Celsius) and all reactions are carried out in an inert atmosphere at room temperature.

¹H NMR spectra were recorded using a Varian Mercury Plus 400 NMR spectrometer. Chemical shifts are expressed in ppm. The coupling constants are all in hertz (Hz). Apparent diversity is described in the split mode and is assigned as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and br (broad).

Low resolution Mass Spectrometry (MS) and compound purity data were from a Shimadzu LC/MS single quadrupole system equipped with an electrospray ion detector (ESI), ultraviolet detectors (220 and 254nm) and an Evaporative Light Scattering Detector (ELSD). Thin layer chromatography was performed using 0.25mm Asahi-poise silica gel plate (60F-254), 5% ethanol phosphomolybdate solution, ninhydrin or p-methoxybenzaldehyde solution and observing under an ultraviolet lamp. Silica gel (200-300 mesh, Qingdao ocean chemical Co., Ltd.) was used for flash column chromatography.

Synthetic route

The synthetic schemes for all compounds of the present invention are illustrated by the following schemes and examples. The starting materials used are commercially available or may be prepared according to established procedures or by methods exemplified herein.

It may be necessary to protect reactive groups in the reactions described below in order to prevent these reactive groups from participating in other undesired reactions: such as hydroxyl, amino, imino, mercapto or carboxyl groups, which are contained in the final product. Commonly used protecting Groups are referred to T.W.Greene and P.G.M.Wuts in "Protective Groups in Organic Chemistry" John Wiley and Sons, 1991.

The intermediates listed in the following schemes are known in the literature or are prepared by one skilled in the art according to similar methods.

The synthesis of the compounds of formula I disclosed in the present invention is illustrated by the synthesis of Ia and Ib shown in scheme 1. Reaction of II with ethyl cyanoacetate affords Ia-A, which may be further decarboxylated to give ester Ia-B. The conversion of the ester Ia-B to the aldehyde Ia-C can be achieved by reduction and oxidation reactions in that order. The aldehydes Ia-C and amines Ia-D are reacted in an organic acid such as HOAc to yield Ia. Alternatively, reaction of aldehyde Ib-A derived from ester II with amide Ib-B by reduction and oxidation gives compounds of formula Ib.

Synthesis scheme 1

Scheme 2 discloses a synthetic method for the compounds of formula Iaa disclosed in the present invention, with the synthesis of the compound of formula Ia as an illustration. Pyridones IIa-F are obtained by a series of conversion reactions, such as condensation with acetals IIa-B, substitution of dimethylamino groups with anilines IIa-D, and intramolecular cyclization in the presence of organic bases such as DBU, starting with commercially available or literature-reported tricarbonyl groups IIa-A. The hydroxy group of IIa-F is converted to a leaving group such as OTf, and IIa is then reacted with ethyl cyanoacetate IIa-G to produce Iaa-A, which is further decarboxylated to give the ester Iaa-B. The ester group in Iaa-B is converted into aldehyde, and then intramolecular cyclization is carried out by condensation of aldehyde and methylamine Iaa-F to obtain Iaa-G. Halide Iaa-G and imine Iaa-H are subjected to buchwald coupling reaction, and then diphenyl methylene group is deprotected to generate amine Iaa-J. Reaction of Iaa-J with isocyanate Iaa-K to prepare the compound of formula Iaa.

Synthesis scheme 2

In some cases, the above synthetic schemes may be ordered as appropriate in order to facilitate the reaction or to avoid the production of unnecessary reaction products. In order that the invention may be more fully understood, the following examples are set forth. These examples are only examples and should not be construed as limiting the invention.

Intermediate A

2-bromo-4-fluoro-5-iodoaniline (A)

1-bromo-5-fluoro-4-iodo-2-nitrobenzene (A-1)

To a suspension of 1-bromo-3-fluoro-4-iodobenzene (20.00g,66.50mmol) in concentrated sulfuric acid (100mL) at 0 deg.C was added dropwise fuming nitric acid (15 mL). After stirring at 0 ℃ for 20min, the mixture was returned to room temperature and stirred for a further 3 h. The reaction mixture was poured into ice water (300mL) and extracted with DCM (3X 100 mL). The extract was extracted with water and saturated Na₂S₂O₃The solution and saturated brine were washed successively with Na₂SO₄Drying and concentrating. The crude product was purified by silica gel column chromatography eluting with 1-5% EtOAc in n-hexane to give 1-bromo-5-fluoro-4-iodo-2-nitrobenzene (A-1).

2-bromo-4-fluoro-5-iodoaniline (A)

To a stirred mixture of 1-bromo-5-fluoro-4-iodo-2-nitrobenzene (A-1) (7.47g,21.6mmol) and NH₄Cl (9.26g,173mmol) in EtOH-H₂To a mixture of O (3:1,120mL) was added iron powder (9.67g,173 mmol). The mixture was heated to reflux for 2 h. After cooling, the reaction mixture was filtered through celite and washed with EtOAc (3 × 20 mL). The filtrate was concentrated and redissolved in EtOAc (200 mL). The solution was washed with water and saturated brine, and washed with Na₂SO₄Drying, concentrating to obtain 2-bromo-4-fluoro-5-iodoaniline (A), MS-ESI (M/z):316/318(1:1) [ M + 1]]⁺. Used directly in the next reaction without further purification.

Intermediate B

2-chloro-4-fluoro-5-iodoaniline (B)

The synthesis of 2-chloro-4-fluoro-5-iodoaniline (intermediate B) is a reference intermediate A synthesis method, and is prepared by using 1-chloro-3-fluoro-4-iodobenzene as a starting material. MS-ESI (M/z) 272[ M + 1]]⁺。

Intermediate C

2- (1- (2-bromo-4-fluoro-5-iodophenyl) -3-ethyl-5-formyl-2-oxo-1, 2-dihydropyridin-4-yl) ethane Nitrile (C)

Ethyl 1- (2-bromo-4-fluoro-5-iodophenyl) -5-ethyl-4-hydroxy-6-oxo-1, 6-dihydropyridine-3-carboxylic acid ester (C-1)

Starting material ethyl 1- (2-bromo-4-fluoro-5-iodophenyl) -5-ethyl-4-hydroxy-6-oxo-1, 6-dihydropyridine-3-carboxylate (C-1) synthesis reference J.Baskovc, et al, ACS Combinatorial Science,2012,14, 513-. Starting from commercially available diethyl 1, 3-acetonedicarboxylate and intermediate A.

Ethyl 1- (2-bromo-4-fluoro-5-iodophenyl) -5-ethyl-6-oxo-4- (((trifluoromethyl) -sulfonyl) oxy) -1, 6-dihydropyridine-3-carboxylic acid ester (C-2)

To a solution of 1- (2-bromo-4-fluoro-5-iodophenyl) -5-ethyl-4-hydroxy-6-oxo-1, 6-dihydropyridine-3-carboxylate (C-1) (4.91g,9.63mmol) in DCM (90mL) at 0 deg.C was added Et₃N (1.46g,14.4mmol) was then added Tf dropwise₂O (3.26g,11.6 mmol). The mixture was stirred back to room temperature for 2 h. The reaction mixture was diluted with water, the layers were separated and the aqueous layer was extracted with DCM. The organic solution was washed with saturated brine and Na₂SO₄Dried and concentrated to give the crude product. Purification by column chromatography on silica eluting with 5% EtOAc in n-hexane afforded ethyl 1- (2-bromo-4-fluoro-5-iodophenyl) -5-ethyl-6-oxo-4- (((trifluoromethyl) sulfonyl) oxy) -1, 6-dihydropyridine e-3-carboxylate (C-2). MS-ESI (M/z) 642/644(1:1) [ M + 1]]⁺。

Ethyl 1- (2-bromo-4-fluoro-5-iodophenyl) -4- (1-cyano-2-ethoxy-2-oxoethyl) -5-ethyl-6-oxo O-1, 6-dihydropyridine-3-carboxylic acid ester (C-3)

In N₂LiHMDS (1.0M in THF, 15.05mL,15.05mmol) was added to a solution of ethyl cyanoacetate (1.700g,15.05mmol) in THF (20mL) at 0 deg.C with protection. The mixture was stirred at this temperature for 30 min. A solution of ethyl 1- (2-bromo-4-fluoro-5-iodophenyl) -5-ethyl-6-oxo-4- (((trifluoromethyl) sulfonyl) oxy) -1, 6-dihydropyridine-3-carboxylate (C-2) (3.22g,5.02mmol) in THF (30mL) was added dropwise and the mixture was heated to 45 ℃ for 2 h. After cooling, the reaction mixture was washed with saturated NH₄Dilute aqueous Cl, extract with EtOAc (2 ×), wash the extracts with brine, Na₂SO₄Dried and concentrated to give the crude product. Purification by column chromatography on silica gel eluting with 10-20% EtOAc in n-hexane afforded ethyl 1- (2-bromo-4-fluoro-5-iodophenyl) -4- (1-cyano-2-ethoxy-2-oxoethyl) -5-ethyl-6-oxo-1, 6-dihydropyridine-3-carboxylate (C-3). MS-ESI (M/z) 605/607(1:1) [ M + 1]]⁺。

Ethyl 1- (2-bromo-4-fluoro-5-iodophenyl) -4- (cyanomethyl) -5-ethyl-6-oxo-1, 6-dihydropyridine-3- Carboxylic acid ester (C-4)

To a solution of ethyl 1- (2-bromo-4-fluoro-5-iodophenyl) -4- (1-cyano-2-ethoxy-2-oxoethyl) -5-ethyl-6-oxo-1, 6-dihydropyridine-3-carboxylate (C-3) (2.20g,3.64mmol) in DMSO (40mL) was added LiCl (308mg,7.27mmol) and water (131mg,7.27 mmol). The mixture was heated to 125 ℃ for 2 h. After cooling, the reaction mixture was diluted with water and extracted with EtOAc (3 ×). The extract was washed with saturated brine and then with Na₂SO₄Dried and concentrated to give the crude product. Purifying by silica gel column chromatography, eluting with 20-30% EtOAc in n-hexane to obtain ethyl 1- (2-bromo-4-fluoro-5-iodophenyl) -4- (cyanomethyl) -5-ethyl-6-oxo-1, 6-dihydropyridine-3-carboxylic acid ester (C-4). MS-ESI (M/z) 533/535(1:1) [ M + 1]]⁺。

1- (2-bromo-4-fluoro-5-iodophenyl) -4- (cyanomethyl) -5-ethyl-6-oxo-1, 6-dihydropyridine-3-carboxylic acid (C-5)

To ethyl 1- (2-bromo-4-fluoro-5-iodophenyl) -4- (cyanomethyl) -5-ethyl-6-oxo-1, 6-dihydropyridine-3-carboxylate (C-4) (1.82g,3.41mmol) in THF/H₂LiOH. H was added to the O (3:1,60mL) solution₂O (574mg,13.7 mmol). The mixture was stirred at room temperature for 14 h. Most of the THF was evaporated, the residue was acidified with 1N HCl to pH 2-3, and extracted with EtOAc (3 ×). The extract was washed with saturated brine and then with Na₂SO₄Dried and concentrated to give the crude product. Purification by column chromatography on silica eluting with 2-4% MeOH in DCM gave 1- (2-bromo-4-fluoro-5-iodophenyl) -4- (cyanomethyl) -5-ethyl-6-oxo-1, 6-dihydropyridine-3-carboxylic acid (C-5). MS-ESI (M/z) 505/507(1:1) [ M + 1]]⁺。

2- (1- (2-bromo-4-fluoro-5-iodophenyl) -3-ethyl-5- (hydroxymethyl) -2-oxo-1, 2-dihydropyridine-4- Yl) acetonitrile (C-6)

To a solution of 1- (2-bromo-4-fluoro-5-iodophenyl) -4- (cyanomethyl) -5-ethyl-6-oxo-1, 6-dihydropyridine-3-carboxylic acid (C-5) (1.52g,3.01mmol) in THF (45mL) at 0 deg.C was added dropwise human BH₃-SMe₂(458mg,6.02 mmol). The mixture was stirred at room temperature for 21 h. Dilute with water and extract with EtOAc (2 ×). The extract was washed with saturated brine and then with Na₂SO₄Drying and concentration gave a crude product which was purified by column chromatography on silica eluting with 30-50% EtOAc in n-hexane to give 2- (1- (2-bromo-4-fluoro-5-iodophenyl) -3-ethyl-5- (hydroxymethyl) -2-oxo-1, 2-dihydropyridin-4-yl) acetonitrile (C-6). MS-ESI (M/z) 491/493(1:1) [ M + 1]]⁺。

To 2- (1- (2-bromo-4-fluoro-5-iodophenyl) benzene at 0 deg.CA solution of 3-ethyl-5- (hydroxymethyl) -2-oxo-1, 2-dihydropyridin-4-yl) acetonitrile (C-6) (701mg,1.43mmol) in DCM (18mL) was added dess-martin oxidant (1.21g,2.86 mmol). The mixture was stirred at room temperature for 2 h. The mixture was directly purified by silica gel column chromatography eluting with 30-40% EtOAc in n-hexane to give 2- (1- (2-bromo-4-fluoro-5-iodophenyl) -3-ethyl-5-formyl-2-oxo-1, 2-dihydropyridin-4-yl) acetonitrile (C). MS-ESI (M/z) 489/491(1:1) [ M + 1]]⁺。

Intermediate D

2- (1- (2-chloro-4-fluoro-5-iodophenyl) -3-ethyl-5-formyl-2-oxo-1, 2-dihydropyridin-4-yl) ethyl Nitrile (D)

The synthesis of 2- (1- (2-chloro-4-fluoro-5-iodophenyl) -3-ethyl-5-formyl-2-oxo-1, 2-dihydropyridin-4-yl) acetonitrile (intermediate D) is the synthesis of reference intermediate C, starting from commercially available diethyl 1, 3-acetonedicarboxylate and intermediate B. MS-ESI (M/z):445[ M + 1]]⁺。

Intermediate E

2, 4-difluoro-5-iodoaniline (E)

1, 5-difluoro-2-iodo-4-nitrobenzene (E-1)

To a solution of 2, 4-difluoro-1-nitrobenzene (10.0g,62.9mmol) in TfOH (28mL) at 0 deg.C was added NIS (14.2g,62.9 mmol). The reaction solution was stirred at room temperature for 3 hours, quenched by pouring into ice water, and DCM was extracted with dichloromethane (2 ×). Extracting with 10% NaHSO₃The solution was washed with saturated brine and Na₂SO₄Dried and concentrated to give the title compound 1, 5-difluoro-2-iodo-4-nitrobenzene (E-1).

2, 4-difluoro-5-iodoaniline (E)

To 1, 5-difluoro-2-iodo-4-nitrobenzene (E-1) (13.4g,44.3mmol) and NH at room temperature₄Cl (18.8g,355mmol) in EtOH/H₂A solution of O (210mL/70mL) was added slowly to Fe powder (19.9g,355mmol), heated to 80 deg.C and stirred for 0.5 h. The reaction was cooled to room temperature filtered through celite and the EtOH evaporated under vacuum. The residue was extracted with EtOAc (2X), washed with saturated brine, Na₂SO₄Drying and concentration gave the title compound, 2, 4-difluoro-5-iodoaniline (E), as a crude product. MS-ESI (M/z) 256[ M + 1]]⁺。

Intermediate F

2- (3-cyclopropyl-1- (2, 4-difluoro-5-iodophenyl) -5-formyl-2-oxo-1, 2-dihydropyridin-4-yl) Acetonitrile (F)

Ethyl 2-cyclopropyl acetate (F-1)

To a solution of 2-cyclopropylacetic acid (12.1g,121mmol) in anhydrous EtOH (60mL) at 0 deg.C was slowly added dropwise SOCl₂(28.6g,242mmol) and then heated to 70 ℃ for reaction overnight. The mixture was cooled to room temperature and H was added₂O, extraction with hexane/EtOAc (3:1), washing with brine, Na₂SO₄Drying and evaporation of the solvent under reduced pressure below 30 ℃ gave the title compound ethyl 2-cyclopropylacetate (F-1).

1- (tert-butyl) 3-ethyl 2-cyclopropylmalonate (F-2)

To a solution of diisopropylamine (29.8g,295mmol) in THF (150mL) at-20 deg.C was added n-BuLi (2.5M in hexane, 118mL,295mmol) dropwise and stirred for 20 min. The solution was cooled to-60 ℃ and ethyl 2-cyclopropylacetate (F-1) (15.1g,118mmol) was added, after which the temperature was returned to-10 ℃ for 1.5 hours. Cooled again to-60 ℃. After addition of di-tert-butyl dicarbonate (27g,124mmol), the reaction was stirred at room temperature for 2 hours. The mixture is treated with saturated NH₄Quenched with aqueous Cl and 1M H₃PO₄Acidifying to pH 6-7, EtOAc extraction, washing with water and saturated brine, and Na₂SO₄Dried and concentrated. The residue was purified by column chromatography on silica gel eluting with PE/EtOAc (10:1) to give the title compound 1- (tert-butyl) 3-ethyl 2-cyclopropylmalonate (F-2). MS-ESI (M/z):229[ M +1 [)]⁺。

2-cyclopropyl-3-ethoxy-3-oxopropanoic acid (F-3)

A solution of 1- (tert-butyl) 3-ethyl 2-cyclopropylmalonate (F-2) (12.2g,53.5mmol) and hydrochloric acid (12M,45mL,535mmol) in dioxane (22mL) was stirred at room temperature for 2 hours. The mixture was diluted with water, extracted with EtOAc, washed with saturated brine, Na₂SO₄Drying and concentration gave the title compound 2-cyclopropyl-3-ethoxy-3-oxopropanoic acid (F-3). MS-ESI (M/z):173[ M + 1]]⁺。

Ethyl 2-cyclopropyl-3- (2, 2-dimethyl-4, 6-dioxo-1, 3-dioxan-5-yl) -3-oxopropanoate (F-4)

2-cyclopropyl-3-ethoxy-3-oxopropanoic acid (F-3) (8.27g,48.1mmol), cyclodiosyl malonate (isopropylidene) (6.58g,45.7mmol), DCC (14.9g,72.3mmol) and DMAP (8.80g,72.1mmol) were stirred in DCM (110mL) at room temperature overnight. Filtering, sequentially adding 1N HCl and H to the filtrate₂O, washing with saturated brine, Na₂SO₄Drying and concentration gave the title compound ethyl 2-cyclopropyl-3- (2, 2-dimethyl-4, 6-dioxo-1, 3-dioxan-5-yl) -3-oxopropanoate (F-4) as crude product. MS-ESI (M/z):299[ M + 1]]⁺。

2-cyclopropyl-4- ((dimethylamino) methylene) -3-oxoglutarate diethyl ester (F-5)

A solution of crude ethyl 2-cyclopropyl-3- (2, 2-dimethyl-4, 6-dioxo-1, 3-dioxan-5-yl) -3-oxopropanoate (F-4) (18g) in EtOH (240mL) was stirred at 80 ℃ overnight. DMF-DMA (16g) was then added dropwise and stirred at 80 ℃ for 2 hours. The solvent was evaporated under reduced pressure and purified by silica gel column chromatography eluting with PE/EtOAc (10:1-6:1-4:1-3:1) to give the title compound diethyl 2-cyclopropyl-4- ((dimethylamino) methylene) -3-oxoglutarate (F-5), MS-ESI (M/z):298[ M + 1] ESI]⁺.

The synthesis of the title compound 2- (3-cyclopropyl-1- (2, 4-difluoro-5-iodophenyl) -5-formyl-2-oxo-1, 2-dihydropyridin-4-yl) acetonitrile (F) was prepared as described for intermediate C starting from 2-cyclopropyl-4- ((dimethylamino) methylene) -3-oxoglutarate diethyl ester (F-5) and intermediate E. MS-ESI (M/z):441[ M +1 [)]⁺.

Example 1

1- (4-bromo-5- (4-ethyl-6- (methylamino) -3-oxo-2, 7-naphthyridin-2 (3H) -yl) -2-fluorophenyl) -3-benzene Urea (1)

2- (2-bromo-4-fluoro-5-iodophenyl) -4-ethyl-6- (methylamino) -2, 7-naphthyridin-3 (2H) -one (1a)

To a solution of 2- (1- (2-bromo-4-fluoro-5-iodophenyl) -3-ethyl-5-formyl-2-oxo-1, 2-dihydropyridin-4-yl) acetonitrile (intermediate C,300mg,0.613mmol) in DCE (10mL) was added Bu₄NBr (49mg,0.15mmol), HOAc (441mg,7.36mmol) and 5N MeNH₂(aq.,1.23mL,6.13 mmol). The mixture was placed in a sealed tube and heated at 70 ℃ for 20 h. After cooling, the mixture was taken up in saturated NaHCO₃Dilute aqueous solution and extract with DCM (5 ×) containing 10% MeOH. Extracting with Na₂SO₄Dried and concentrated to give the crude product. Purification by column chromatography on silica eluting with 5-10% MeOH in DCM gave 2- (2-bromo-4-fluoro-5-iodophenyl) -4-ethyl-6- (methylamino) -2, 7-naphthyridin-3 (2H) -one (1 a): MS-ESI (M/z):502/504(1:1) [ M + 1]]⁺.

2- (2-bromo-5- ((diphenylmethylene) amino) -4-fluorophenyl) -4-ethyl-6- (methylamino) -2, 7-naphthyridine-3 (2H) -ketones (1b)

To 2- (2-bromo-4-fluoro-5-iodophenyl) -4-ethyl-6- (methyl)Amino) -2, 7-naphthyridin-3 (2H) -one (1a,249mg,0.496mmol) in dioxane (7.5mL) was added benzophenone imine (108mg,0.595mmol), Pd₂(dba)₃(22.7mg,0.0248mmol), xanthphos (28.7mg,0.0496mmol), and Cs₂CO₃(323mg,0.992 mmol). The mixture was heated at 90 ℃ for 8h under a nitrogen atmosphere. After cooling, the mixture was diluted with water and extracted with EtOAc (3 ×). Extracting with Na₂SO₄Dried and concentrated to give the crude product. Purification by column chromatography on silica gel eluting with 40-60% EtOAc in n-hexane afforded 2- (2-bromo-5- ((diphenylmethylene) amino) -4-fluorophenyl) -4-ethyl-6- (methylamino) -2, 7-naphthyridin-3 (2H) -one (1b). MS-ESI (M/z):555/557(1:1) [ M + 1]]⁺.

2- (5-amino-2-bromo-4-fluorophenyl) -4-ethyl-6- (methylamino) -2, 7-naphthyridin-3 (2H) -one (1c)

To a solution of 2- (2-bromo-5- ((diphenylmethylene) amino) -4-fluorophenyl) -4-ethyl-6- (methylamino) -2, 7-naphthyridin-3 (2H) -one (1b,115mg,0.206mmol) in THF (3mL) was added 2N HCl (0.15 mL). The mixture was stirred at room temperature for 20min with saturated NaHCO₃Dilute aqueous solution and extract with EtOAc (2 ×). Extracting with Na₂SO₄Dried and concentrated to give the crude product. Purification by column chromatography on silica gel eluting with 50-80% EtOAc in n-hexane afforded 2- (5-amino-2-bromo-4-fluorophenyl) -4-ethyl-6- (methylamino) -2, 7-naphthyridin-3 (2H) -one (1c). MS-ESI (M/z):391/393(1:1) [ M + 1]]⁺.

To a solution of 2- (5-amino-2-bromo-4-fluorophenyl) -4-ethyl-6- (methylamino) -2, 7-naphthyridin-3 (2H) -one (1c,14.4mg,0.0368mmol) in THF (0.5mL) was added triethylamine (3.7mg,0.037mmol) and phenyl isocyanate (38.8mg,0.326mmol), the mixture was stirred at room temperature for 16H, the mixture was diluted with water and extracted with EtOAc (2X). Extracting with Na₂SO₄Dried and concentrated to give the crude product. Purification by column chromatography on silica gel eluting with 10-15% MeOH in DCM gave 1- (4-bromo-5- (4-ethyl-6- (methylamino) -3-oxo-2, 7-naphthyridin-2 (3H) -yl) -2-fluorophenyl) -3-benzeneBased urea (1), MS-ESI (M/z):510/512(1:1) [ M + 1]]⁺.

Example 2

1- (4-chloro-5- (4-ethyl-6- (methylamino) -3-oxo-2, 7-naphthyridin-2 (3H) -yl) -2-fluorophenyl) -3-benzene Radical urea (2)

The synthesis of 1- (4-chloro-5- (4-ethyl-6- (methylamino) -3-oxo-2, 7-naphthyridin-2 (3H) -yl) -2-fluorophenyl) -3-phenylurea (2) was prepared starting from intermediate D, following the synthetic procedure described in reference example 1. MS-ESI (M/z) 466[ M + 1]]⁺.

Example 3

1- (5- (6-amino-4-ethyl-3-oxo-2, 7-naphthyridin-2 (3H) -yl) -4-bromo-2-fluorophenyl) -3-phenylurea (3)

2- (2-bromo-4-fluoro-5-iodophenyl) -6- ((2, 4-dimethoxybenzyl) amino) -4-ethyl-2, 7-naphthyridine-3 (2H) -ketones (3a)

To a solution of 2- (1- (2-bromo-4-fluoro-5-iodophenyl) -3-ethyl-5-formyl-2-oxo-1, 2-dihydropyridin-4-yl) acetonitrile (intermediate C,100mg,0.204mmol) in DCE (2mL) was added 2, 4-Dimethoxybenzylamine (DMBNH)₂68mg,0.41mmol) and HOAc (25mg,0.41 mmol). The mixture was stirred at room temperature for 3h and then saturated NaHCO was used₃And (5) diluting the aqueous solution. Extract 10% MeOH in DCM (5 ×). Extracting with Na₂SO₄Dried and concentrated to give the crude product. Purification by column chromatography on silica eluting with 5-10% MeOH in DCM gave 2- (2-bromo-4-fluoro-5-iodophenyl) -6- ((2, 4-dimethoxybenzyl) amino) -4-ethyl-2, 7-naphthyridin-3 (2H) -one (3 a): MS-ESI (M/z):638/640(1:1) [ M + 1]]⁺.

2- (2-bromo-5- ((diphenylmethylene) amino)) -4-fluorophenyl) -6- ((2, 4-dimethoxybenzyl) amino) -4- Ethyl-2, 7-naphthyridin-3 (2H) -one (3b)

To a solution of 2- (2-bromo-4-fluoro-5-iodophenyl) -6- ((2, 4-dimethoxybenzyl) -amino) -4-ethyl-2, 7-naphthyridin-3 (2H) -one (3a) (107mg,0.168mmol) in dioxane (5mL) was added benzophenone imine (40mg,0.336mmol), Pd₂(dba)₃(15.3mg,0.017mmol), xantphos (19.4mg,0.034mmol), and Cs₂CO₃(109mg,0.336 mmol). The mixture was reacted at 90 ℃ for 8h under a nitrogen atmosphere. After cooling, the mixture was diluted with water and extracted with EtOAc (3 ×). Extracting with Na₂SO₄Dried and concentrated to give the crude product. Purification by column chromatography on silica gel eluting with 40-60% EtOAc in n-hexane afforded 2- (2-bromo-5- ((diphenylmethylene) amino) -4-fluorophenyl) -6- ((2, 4-dimethoxybenzyl) amino) -4-ethyl-2, 7-naphthyridin-3 (2H) -one (3b). MS-ESI (M/z):691/693(1:1) [ M + 1]]⁺.

2- (5-amino-2-bromo-4-fluorophenyl) -6- ((2, 4-dimethoxybenzyl) amino) -4-ethyl-2, 7-naphthyridine-3 (2H) -ketones (3c)

To a solution of 2- (2-bromo-5- ((diphenylmethylene) amino) -4-fluorophenyl) -6- ((2, 4-dimethoxybenzyl) amino) -4-ethyl-2, 7-naphthyridin-3 (2H) -one (3b) (58mg,0.084mmol) in THF (2mL) was added 2N HCl (0.1 mL). The mixture was stirred at room temperature for 20min and then saturated NaHCO was used₃Dilute aqueous solution and extract with EtOAc (2 ×). Extracting with Na₂SO₄Dried and concentrated to give the crude product. Purification by column chromatography on silica gel eluting with 50-80% EtOAc in n-hexane afforded 2- (5-amino-2-bromo-4-fluorophenyl) -6- ((2, 4-dimethoxybenzyl) amino) -4-ethyl-2, 7-naphthyridin-3 (2H) -one (3c). MS-ESI (M/z):527/529(1:1) [ M + 1]]⁺.

1- (4-bromo-5- (6- ((2, 4-dimethoxybenzyl) amino) -4-ethyl-3-oxo-2, 7-naphthyridine-2 (3H) - 2-fluorophenyl) -3-phenylurea (3d)

To 2- (5-amino-2-bromo-4-fluorophenyl) -6- ((2, 4-dimethoxybenzyl) -amino) -4-ethyl-2, 7-naphthyridin-3 (2H) -one (3c) (18.7mg,0.0356mmol) in THF (0.5mL)Triethylamine (3.7mg,0.037mmol) and phenyl isocyanate (42.3mg,0.356mmol) were added to the solution. The mixture was stirred at room temperature for 16h, diluted with water and extracted with EtOAc (2 ×). Extracting with Na₂SO₄Dried and concentrated to give the crude product. Purification by column chromatography on silica gel eluting with 10-15% MeOH in DCM gave 1- (4-bromo-5- (6- ((2, 4-dimethoxybenzyl) amino) -4-ethyl-3-oxo-2, 7-naphthyridin-2 (3H) -yl) -2-fluorophenyl) -3-phenylurea (3d). MS-ESI (M/z):646/648(1:1) [ M + 1]]⁺.

To a solution of 1- (4-bromo-5- (6- ((2, 4-dimethoxybenzyl) amino) -4-ethyl-3-oxo-2, 7-naphthyridin-2 (3H) -yl) -2-fluorophenyl) -3-phenylurea (3d) (13.1mg,0.020mmol) in DCM (0.8mL) was added TFA (0.8 mL). The mixture was stirred at room temperature for 30min and then saturated NaHCO was used₃Dilute aqueous solution and extract with EtOAc (2 ×). Extracting with Na₂SO₄Dried and concentrated to give the crude product. Purification by column chromatography on silica gel eluting with 4% MeOH in DCM gave 1- (5- (6-amino-4-ethyl-3-oxo-2, 7-naphthyridin-2 (3H) -yl) -4-bromo-2-fluorophenyl) -3-phenylurea (3). MS-ESI (M/z):496/498(1:1) [ M + 1]]⁺.

Example 4

1- (5- (4-cyclopropyl-6- (methylamino) -3-oxo-2, 7-naphthyridin-2 (3H) -yl) -2, 4-difluorophenyl) -3- Phenyl urea (4)

The synthesis of 1- (5- (4-cyclopropyl-6- (methylamino) -3-oxo-2, 7-naphthyridin-2 (3H) -yl) -2, 4-difluorophenyl) -3-phenylurea (4) was prepared as described for reference example 1, starting from intermediate F. MS-ESI (M/z):462(1:1) [ M + 1]]⁺。

Examples 5-101 listed in Table 1 are essentially the same as examples 1-4, using either commercially available starting materials or prepared according to literature procedures. Table 1 gives the names and structures of examples 5-101.

TABLE 1

Biological activity assay

MTS assay kit was purchased from Promega. DMEM medium, RPMI-1640 medium fetal bovine serum and penicillin-streptomycin were purchased from BI. Glutamine and dimethyl sulfoxide (DMSO) were purchased from Sigma. The culture medium of Kasumi-1 is RPMI-1640+ 25% FBS.

The inhibitory effect of the compounds on KIT mutations was examined by assaying the inhibitory effect of the compounds on the proliferation of Kasumi-1(KIT exon 17N822K) cells. Digesting the cells, inoculating the Kasumi-1 cells into a 96-well plate at a cell concentration of 30000/well and 5% CO at 37 ℃₂Incubate for 4 h. Parallel 3 wells of different concentrations (final concentrations 10000, 3333.3, 1111.1, 370, 123, 41, 14, 4.6 and 1.5nM) of compounds were added to 96 well cell culture plates at 37 deg.C, 5% CO₂And (5) incubating for 120 h. MTS was added to each well at a concentration of 20. mu.L MTS per 100. mu.L of the medium. After 2h incubation, the reaction was stopped by adding 25. mu.L of 10% SDS to each well. The absorbance at 490nm and 650nm was measured with a microplate reader. IC calculation Using GraphPad Prism 5.0₅₀。

Selected compounds prepared as described above were tested according to the biological methods described herein. The results are shown in the following table:

TABLE 2

Claims

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

z is selected from CR^XAnd N;

l is selected from-NR^AC(O)、-C(O)NR^A、-NR^AC(O)NR^Band-NR^ASO₂；

R¹is-NR^A1R^B1；

or R^A1And R^B1Together with the single or multiple atoms to which they are attachedForm a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring may be unsubstituted or substituted with 1,2 or 3 heteroatoms selected from R^XSubstituted with the substituent(s);

each R^XIndependently selected from hydrogen, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl, heterocyclyl-C_1-4Alkyl, aryl-C_1-4Alkyl, heteroaryl-C_1-4Alkyl, halogen, CN, NO₂、-(CR^c1R^d1)_tNR^a1R^b1、-(CR^c1R^d1)_tOR^b1、-(CR^c1R^d1)_tC(O)R^a1、-(CR^c1R^d1)_tC(＝NR^e1)R^a1、-(CR^c1R^d1)_tC(＝N-OR^b1)R^a1、-(CR^c1R^d1)_tC(O)OR^b1、-(CR^c1R^d1)_tOC(O)R^b1、-(CR^c1R^d1)_tC(O)NR^a1R^b1、-(CR^c1R^d1)_tNR^a1C(O)R^b1、-(CR^c1R^d1)_tC(＝NR^e1)NR^a1R^b1、-(CR^c1R^d1)_tNR^a1C(＝NR^e1)R^b1、-(CR^c1R^d1)_tOC(O)NR^a1R^b1、-(CR^c1R^d1)_tNR^a1C(O)OR^b1、-(CR^c1R^d1)_tNR^a1C(O)NR^a1R^b1、-(CR^c1R^d1)_tNR^a1C(S)NR^a1R^b1、-(CR^c1R^d1)_tNR^a1C(＝NR^e1)NR^a1R^b1、-(CR^c1R^d1)_tS(O)_rR^b1、-(CR^c1R^d1)_tS(O)(＝NR^e1)R^b1、-(CR^c1R^d1)_tN＝S(O)R^a1R^b1、-(CR^c1R^d1)_tS(O)₂OR^b1、-(CR^c1R^d1)_tOS(O)₂R^b1、-(CR^c1R^d1)_tNR^a1S(O)_rR^b1、-(CR^c1R^d1)_tNR^a1S(O)(＝NR^e1)R^b1、-(CR^c1R^d1)_tS(O)_rNR^a1R^b1、-(CR^c1R^d1)_tS(O)(＝NR^e1)NR^a1R^b1、-(CR^c1R^d1)_tNR^a1S(O)₂NR^a1R^b1、-(CR^c1R^d1)_tNR^a1S(O)(＝NR^e1)NR^a1R^b1、-(CR^c1R^d1)_tP(O)R^a1R^b1And- (CR)^c1R^d1)_tP(O)(OR^a1)(OR^b1) Wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted by at least one, such as 1,2, 3 or 4, independentlySelected from R^YSubstituted with the substituent(s);

each R^a2And each R^b2Independently selected from hydrogen, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkoxy, C_1-10Alkylthio radical, C_3-10Cycloalkylthio radical, C_1-10Alkylamino radical, C_3-10Cycloalkylamino, di (C)_1-10Alkyl) amino, heterocyclyl-C_1-4Alkyl, aryl-C_1-4Alkyl radicalHeteroaryl and heteroaryl-C_1-4Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted by at least one, such as 1,2, 3 or 4, independently selected from halogen, CN, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, hydroxy, C_1-10Alkoxy radical, C_3-10Cycloalkoxy, C_1-10Alkylthio radical, C_3-10Cycloalkylthio, amino, C_1-10Alkylamino radical, C_3-10Cycloalkylamino, di (C)_1-10Alkyl) amino;

each R^c2And R^d2Independently selected from hydrogen, halogen, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkoxy, C_1-10Alkylthio radical, C_3-10Cycloalkylthio radical, C_1-10Alkylamino radical, C_3-10Cycloalkylamino, di (C)_1-10Alkyl) amino, heterocyclyl-C_1-4Alkyl, aryl-C_1-4Alkyl, heteroaryl and heteroaryl-C_1-4Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl andheteroaryl is unsubstituted or substituted by at least one, such as 1,2, 3 or 4, independently selected from halogen, CN, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, hydroxy, C_1-10Alkoxy radical, C_3-10Cycloalkoxy, C_1-10Alkylthio radical, C_3-10Cycloalkylthio, amino, C_1-10Alkylamino radical, C_3-10Cycloalkylamino, di (C)_1-10Alkyl) amino;

m is selected from 0, 1,2, 3 and 4;

each r is independently selected from 0, 1 and 2;

each t is independently selected from 0, 1,2, 3, and 4.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Z is CH.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Z is N.

4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein L is selected from-NR^AC(O)-、-C(O)NR^A-and-NR^AC(O)NR^B-。

5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein L is-NR^AC(O)NR^B-。

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein L is-NHC (O) NH-.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R⁴Is aryl, wherein aryl is unsubstituted or substituted with at least one group independently selected from R^XIs substituted with the substituent(s).

8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein R⁴Is phenyl, wherein phenyl is unsubstituted or substituted with at least one group independently selected from halogen, CN and C_1-10Alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from halogen.

9. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R⁴Is heteroaryl, wherein heteroaryl is unsubstituted or substituted with at least one group independently selected from R^XIs substituted with the substituent(s).

10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein R⁴Is a pyridyl group, wherein the pyridyl group is unsubstituted or is independently selected from at least oneHalogen, CN and C_1-10Alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from halogen.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein R¹is-NR^A1R^B1Wherein R is^A1And R^B1Are each independently selected from hydrogen and C_1-10Alkyl, wherein alkyl is unsubstituted or substituted with at least one R independently selected from^XIs substituted with the substituent(s).

12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein R¹Is selected from-NHCH₃、-NH₂、

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein R²Is hydrogen.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein each R³Independently selected from halogen and C_1-10An alkyl group.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein m is 2.

16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein the substructure of formula (I)

Is selected from

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R⁵Selected from hydrogen, C_1-10Alkyl and C_3-10Cycloalkyl, wherein each alkyl and cycloalkyl is unsubstituted or substituted with at least one substituent independently selected from halogen.

18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein R⁵Selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, and cycloalkyl, wherein methyl, ethyl, isopropyl, and cycloalkyl are unsubstituted or substituted with at least one substituent independently selected from the group consisting of halogen.

19. A compound selected from:

and pharmaceutically acceptable salts thereof.

20. A pharmaceutical composition comprising a compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

21. A method of treating, ameliorating, or preventing a condition that is responsive to inhibition of PDGFR comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, or at least one pharmaceutical composition thereof, and optionally in combination with a second therapeutic agent.

22. Use of a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of hyperproliferative diseases, such as cancer and inflammation, or immune and autoimmune diseases.