Compounds and compositions for inducing chondrogenesis
阅读说明：本技术 诱导软骨发生的化合物和组合物 (Compounds and compositions for inducing chondrogenesis ) 是由 崔夏洵 姜纪清 J·P·拉伊内斯 B·恩古耶 H·M·J·彼得拉西 王志成 于 2018-06-07 设计创作，主要内容包括：本发明提供了一种具有式(I)的化合物或其药学上可接受的盐；或其药学上可接受的盐、互变异构体或立体异构体,其中变量如本文中所定义。本发明进一步提供了包含此类化合物的药物组合物；以及使用此类化合物治疗哺乳动物的关节损害或损伤、诱导透明软骨产生或诱导软骨发生性祖细胞分化为成熟软骨细胞的方法。<Image he="339" wi="560" file="DDA0002303788290000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The present invention provides a compound having formula (I) or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the variables are as defined herein. The invention further provides pharmaceutical compositions comprising such compounds; and methods of using such compounds to treat joint damage or injury, to induce hyaline cartilage production, or to induce the differentiation of chondrogenic progenitor cells into mature chondrocytes in a mammal.)
1. A compound having formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof;
wherein R is0Is hydrogen or C1-6An alkyl group;
R2is phenyl; a 5-or 6-membered heteroaryl or a 5-or 6-membered heterocyclyl, each having 1 to 3 heteroatoms selected from N, O and S; wherein R is2Is unsubstituted or substituted by 1 to 3 substituents independently selected from halo, C1-6Alkyl, halo substituted C1-6Alkyl radical, C1-6Alkoxy, halo substituted C1-6Alkoxy, cyano, C1-6Alkylsulfonyl, unsubstituted phenyl or by halogen or C1-6Alkyl substituted phenyl;
R3is a 5-or 6-membered heteroaryl having 1 to 2 heteroatoms selected from N, O and S; wherein R is3Is unsubstituted or substituted by 1 to 3 substituents independently selected from halo, C1-6Alkyl, halo substituted C1-6Alkyl radical, C1-6Alkoxy or-NR5R6Substituted with the substituent(s);
R1a、R1b、R4aand R4bEach independently is hydrogen, halo, hydroxy, C1-6Alkoxy radical, C1-6Alkyl, -NR7R8or-NR7-(CR9R10)2-4-OR11(ii) a Or wherein R is1aAnd R1bOne and R4aAnd R4bOne of which taken together forms a cyclopropyl group, said R1a、R1b、R4aAnd R4bTwo carbon atoms are attached respectively;
R5、R6、R7、R9、R10and R11Each independently is hydrogen or C1-6An alkyl group;
R8is hydrogen, C3-7Cycloalkyl or a 5-or 6-membered heterocyclyl having 1-3 heteroatoms selected from N, O and S; wherein said R8C of (A)3-7Cycloalkyl or 5-or 6-membered heterocyclyl being unsubstituted or substituted by hydroxy or C1-6Alkyl substitution;
alternatively, R5And R6Or R7And R8To which it is attached at-NR5R6or-NR7R8In (a) together with the nitrogen atomForming a 5-or 6-membered heterocyclic group having 1-3 heteroatoms selected from N, O and S;
provided that R is1a、R1b、R4aAnd R4bNot all hydrogen; and is
With the further proviso that when R1a、R1b、R4aOr R4bIs C1-6In the case of alkyl, the other substituents on the same carbon ring atom are not hydrogen.
2. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound has formula (1A), (1B), (1C), (1D), (1E), (1F), (1G), (1H), (1I), (1J), (1K), (1L), (2A), (2B), (2C), (2D), (2E), (2F), (2G), (2H), (2I), (2J), (2K), or (2L);
3. the compound of claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is of formula (1A), formula (1C), formula (1G), formula (1L), formula (2A), formula (2C), formula (2G), or formula (2L).
4. The compound of any one of claims 1-3, wherein R1aAnd R1bOne is hydrogen and the other is hydroxy, fluoro, methoxy, methylamino, (2-hydroxyethyl) amino, di-methylamino, morpholin-4-yl, methyl, ((tetrahydro-2H-pyran-4-yl) amino) or (3-hydroxycyclobutyl) amino.
5. The compound of claim 4, wherein R1aAnd R1bOne is hydrogen and the other is hydroxyl; and R is4aAnd R4bIs hydrogen.
6. The compound of any one of claims 1-3, wherein R1aAnd R1bIs hydrogen, and R4aAnd R4bOne is hydrogen and the other is hydroxyl or fluorine.
7. The compound of claim 1, wherein R1aAnd R1bOne of and R4aAnd R4bOne of which forms, together with the carbon ring atoms, a cyclopropyl group fused to the bicyclic ring.
8. The compound of any one of claims 1-7, wherein R2Is phenyl, pyridyl, pyrazolyl, thiazolyl or piperidinyl, each of which is unsubstituted or substituted with 1 to 2 substituents independently selected from halo, C1-6Alkyl, halo substituted C1-6Alkyl radical, C1-6Alkoxy, halo substituted C1-6Alkoxy, cyano, C1-6Alkylsulfonyl, unsubstituted phenyl or phenyl substituted with halo.
9. The compound of claim 8, wherein R2Selected from:
phenyl substituted with 3, 4-dichloro, 2-trifluoromethyl, 3-cyano-4-chloro, 2-cyano-4-chloro, 3-fluoro-4-chloro, 3-trifluoromethoxy, 3-fluoro-4-trifluoromethoxy, or 3-fluoro-4- (2-fluorophenyl);
pyridin-4-yl substituted with 6-methoxy or 2-trifluoromethyl;
pyridin-3-yl substituted with 5, 6-dichloro, 6-methoxy, 5-chloro-6-methyl or 5-trifluoromethyl-6-methyl;
pyridin-2-yl substituted with 4, 5-dichloro;
1H-pyrazol-3-yl substituted with 1-methyl;
thiazol-2-yl substituted with 5-methyl; and
piperidin-4-yl substituted with 1-methylsulfonyl.
10. Claim 1-9 wherein R3Is pyridyl, pyrimidyl or pyrazolyl, each of which is unsubstituted or substituted by 1 to 2 substituents independently selected from halo, C1-6Alkyl, halo substituted C1-6Alkyl radical, C1-6Alkoxy or-NR5R6Is substituted with the substituent(s).
11. The compound of claim 10, wherein R3Selected from:
pyridin-4-yl unsubstituted or substituted with 2-methyl, 2-trifluoromethyl, 2-methoxy, 2-amino, 2-fluoro, 2, 3-difluoro, or 2, 5-difluoro;
pyridin-3-yl unsubstituted or substituted with 6-methyl, 6-methoxy, or 5, 6-dichloro;
pyridin-2-yl substituted with 6-trifluoromethyl;
pyrimidin-5-yl unsubstituted or substituted with 2-fluoro, 2-methyl, 2-amino, 2-trifluoromethyl, 2-morpholinyl or 2-di-methylamino;
pyrimidin-4-yl substituted with 2-methyl; and
1H-pyrazol-4-yl or 1H-pyrazolyl-3-yl substituted by 1-methyl.
12. The compound of claim 1, or a pharmaceutically acceptable salt or enantiomer thereof, wherein the compound is selected from compounds 1-181 in table 2.
13. The compound of claim 12, wherein the compound is a monohydrate.
14. A compound having the formula (III)
Wherein Ak is C1-6An alkyl group;
R3is a 5-or 6-membered heteroaryl having 1 to 2 heteroatoms selected from N, O and S; wherein R is3Is not gotSubstituted or substituted by 1-3 substituents independently selected from halo, C1-6Alkyl, halo substituted C1-6Alkyl radical, C1-6Alkoxy or-NR5R6Substituted with the substituent(s);
R1a、R1b、R4aand R4bEach independently is hydrogen, halo, hydroxy, C1-6Alkoxy radical, C1-6Alkyl, -NR7R8or-NR7-(CR9R10)2-4-OR11(ii) a Or wherein R is1aAnd R1bOne and R4aAnd R4bOne of which taken together forms a cyclopropyl group, said R1a、R1b、R4aAnd R4bTwo carbon atoms are attached respectively;
R5、R6、R7、R9、R10and R11Each independently is hydrogen or C1-6An alkyl group;
R8is hydrogen, C3-7Cycloalkyl or a 5-or 6-membered heterocyclyl having 1-3 heteroatoms selected from N, O and S; wherein said R8C of (A)3-7Cycloalkyl or 5-or 6-membered heterocyclyl being unsubstituted or substituted by hydroxy or C1-6Alkyl substitution;
alternatively, R5And R6Or R7And R8To which it is attached at-NR5R6or-NR7R8Form a 5-or 6-membered heterocyclic group having 1-3 heteroatoms selected from N, O and S, respectively;
provided that R is1a、R1b、R4aAnd R4bNot all hydrogen; and is
With the further proviso that when R1a、R1b、R4aOr R4bIs C1-6In the case of alkyl, the other substituents on the same carbon ring atom are not hydrogen.
15. A pharmaceutical composition comprising a compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt or stereoisomer thereof, and one or more pharmaceutically acceptable carriers.
16. A combination comprising a compound of any one of claims 1-13, or a pharmaceutically acceptable salt or stereoisomer thereof, and one or more therapeutically active agents.
17. A compound of any one of claims 1-13, or a pharmaceutically acceptable salt or enantiomer thereof, and optionally in combination with a second therapeutic agent, for use in treating, ameliorating or preventing arthritis or joint injury in a mammal; or for cartilage repair.
18. Use of a compound of any one of claims 1-13, or a pharmaceutically acceptable salt or enantiomer thereof, and optionally in combination with a second therapeutic agent, in the manufacture of a medicament for arthritis or joint injury, or for cartilage repair.
19. A method for treating, ameliorating or preventing arthritis or joint damage or for repairing cartilage in a mammal in need thereof, the method comprising administering a therapeutically effective amount of a compound of any one of claims 1-13, and optionally in combination with a second therapeutic agent; thereby treating, ameliorating or preventing arthritis or joint damage, or repairing cartilage in said mammal.
20. The method of claim 19, wherein the compound is administered orally.
21. A method of inducing hyaline cartilage production or a method of inducing the differentiation of chondrogenic progenitor cells to mature chondrocytes, the method comprising contacting a chondrogenic progenitor cell with a therapeutically effective amount of a compound according to any one of claims 1-16, optionally in combination with a second therapeutic agent; thereby inducing differentiation of chondrocyte progenitor cells into mature chondrocytes producing a hyaline chondrocyte extracellular matrix.
22. The method of claim 21, wherein the contacting step is performed in vitro or in vivo in a mammal; and when performed in vivo, the stem cells are present in a mammal.
23. The method of claim 21 or 22, wherein the contacting step occurs in a matrix or biocompatible scaffold.
Technical Field
The present invention relates to compositions and methods for treating or preventing joint damage caused by joint injury and arthritis.
Background
Osteoarthritis (OA) represents the most common musculoskeletal disorder. Approximately 4000 million americans are affected at present, and due to the aging population and the extended life expectancy, this figure is expected to increase to 6000 million in the next two decades, making osteoarthritis the fourth leading cause of disability. OA is characterized by the slow degenerative destruction of joints, including articular cartilage (containing cells and matrix that produce lubrication and cushioning for the joint) and subchondral bone underlying the articular cartilage. OA can be considered to be the result of a variety of etiologies. For example, osteoarthritis may be caused by abnormal biomechanical stress or genetic or acquired abnormalities of articular cartilage or bone. Current OA treatments include the use of oral NSAIDs or selective cyclooxygenase 2(COX-2) inhibitors, intra-articular (IA) injections of agents such as corticosteroids and hyaluronic acid, and surgical procedures to relieve pain.
Joint damage such as acute joint injury (e.g., meniscal or ligament tears) or intra-articular fractures may also lead to arthritis, such as post-traumatic arthritis. Due to the limited ability of articular cartilage to repair, even small undetectable lesions often deteriorate over time and lead to OA. Current treatments for joint injury may include surgery and other invasive methods focused on regenerating the injured joint, as well as treatment with drugs to reduce pain and inflammation.
Mesenchymal Stem Cells (MSCs) are present in adult articular cartilage and, after isolation, can be programmed in vitro to differentiate into chondrocytes and other mesenchymal cell lineages and can be used for cartilage regeneration. In part, the process is regulated by growth factors (TGF β, BMP), serum conditions, and intercellular contact.
WO 2011/008773 describes peptide compositions and the use of these compositions for the treatment or prevention of arthritis and joint damage and for inducing mesenchymal cells to differentiate into chondrocytes. Furthermore, WO 2012/129562 describes small molecule compounds, compositions and the use of these compositions for ameliorating arthritis and joint damage and for inducing mesenchymal cells to differentiate into chondrocytes.
Although surgical and regenerative techniques have made some progress in cartilage recovery, delaying degeneration, and improving repair of joint damage, there is a continuing need for improved compositions and methods for effective cartilage regeneration, treatment of joint damage, and improvement or prevention of OA.
Disclosure of Invention
The present invention relates to compositions and methods for treating or preventing joint damage caused by joint injury and arthritis.
In one aspect, the present invention provides a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof;
wherein R is0Is hydrogen or C1-6An alkyl group;
R2is phenyl; 5-or 6-membered heteroaryl or 5-or 6-membered heterocyclyl, eachHaving 1 to 3 heteroatoms selected from N, O and S; wherein R is2Is unsubstituted or substituted;
R3is a 5-or 6-membered heteroaryl having 1 to 2 heteroatoms selected from N, O and S; wherein R is3Is unsubstituted or substituted;
R1a、R1b、R4aand R4bEach independently is hydrogen, halo, hydroxy, C1-6Alkoxy radical, C1-6Alkyl, -NR7R8or-NR7-(CR9R10)2-4-OR11(ii) a Or wherein R is1aAnd R1bOne and R4aAnd R4bOne of which taken together forms a cyclopropyl group, said R1a、R1b、R4aAnd R4bTwo carbon atoms are attached respectively;
R5、R6、R7、R9、R10and R11Each independently is hydrogen or C1-6An alkyl group;
R8is hydrogen, C3-7Cycloalkyl or a 5-or 6-membered heterocyclyl having 1-3 heteroatoms selected from N, O and S; wherein said R8C of (A)3-7Cycloalkyl or 5-or 6-membered heterocyclyl is unsubstituted or substituted;
alternatively, R5And R6Or R7And R8To which it is attached at-NR5R6or-NR7R8Form a 5-or 6-membered heterocyclic group having 1-3 heteroatoms selected from N, O and S, respectively;
provided that R is1a、R1b、R4aAnd R4bNot all hydrogen; and is
With the further proviso that when R1a、R1b、R4aOr R4bIs C1-6In the case of alkyl, the other substituents on the same carbon ring atom are not hydrogen.
In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound having formula (I) or a subformula thereof, or a pharmaceutically acceptable salt or stereoisomer thereof; and one or more pharmaceutically acceptable carriers.
In yet another aspect, the present invention provides a combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of a compound having formula (I) or a subformula thereof, or a pharmaceutically acceptable salt or stereoisomer thereof; and one or more therapeutically active agents.
The compounds of the present invention, alone or in combination with one or more therapeutically active agents, are useful for treating, ameliorating or preventing acute joint damage or injury, such as arthritis (osteoarthritis, traumatic arthritis, systemic rheumatoid arthritis) or degenerative disc disease. Furthermore, the compounds of the invention, alone or in combination with one or more therapeutically active agents, can be used to induce hyaline cartilage production or to induce the differentiation of chondrogenic progenitor cells into mature chondrocyte mature chondrocytes producing hyaline cartilage extracellular matrix.
Unless otherwise specified, the term "compounds of the invention" refers to compounds of formula (I) and its subformulae (e.g., formulae (1A), (1B), (1C), (1D), (1E), (1F), (1G), (1H), (1I), (1J), (1K), (1L), (2A), (2B), (2C), (2D), (2E), (2F), (2G), (2H), (2I), (2J), (2K), (2L)) and salts thereof as well as all stereoisomers (including diastereomers and enantiomers), rotamers, tautomers and isotopically labeled compounds (including deuterium substituents) and moieties that are inherently formed.
Detailed Description
The present invention provides novel compounds that stimulate hyaline cartilage production in damaged joints.
In one aspect, the present invention provides novel compounds and compositions for repairing cartilage. Also provided are compositions and methods for treating, preventing or ameliorating arthritis or joint injury by administering a compound or composition of the invention systemically to a joint, cartilage tissue, or tissue adjacent to cartilage. In addition, the present invention provides compositions and methods for inducing the differentiation of chondrogenic progenitor cells into normal hyaline chondrocytes.
Definition of
For the purpose of explaining the present specification, the following definitions will apply and, where appropriate, terms used in the singular will also include the plural and vice versa.
As used herein, the term "C1-6Alkoxy "means having the formula-ORaWherein R isaIs C as generally defined above1-6An alkyl group. C1-6Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, and hexoxy. The alkyl portion of the alkoxy group may be optionally substituted, including those described below for the alkyl group.
As used herein, the term "C1-6Alkyl "refers to a straight or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, with no unsaturation present in the group, having from one to six carbon atoms connected to the rest of the molecule by single bonds. The term "C1-4Alkyl "should be construed accordingly. C1-6Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1, 1-dimethylethyl (tert-butyl). Typical substituents include, but are not limited to, halo, hydroxy, alkoxy, cyano, amino, acyl, aryl, arylalkyl, and cycloalkyl groups or heteroforms (heteroforms) of one of these groups, each of which may be substituted with the appropriate substituent for the particular group in question.
As used herein, "amino" refers to the group-NH2. When an amino group is described as "substituted" or "optionally substituted," the term includes NR 'R "where R' and R" are each independently H, or an alkyl, alkenyl, alkynyl, acyl, aryl, cycloalkyl, arylalkyl, cycloalkylalkyl group or a hetero-type of one of these groups, each of which may be optionally substituted with substituents described herein as appropriate for the respective group. Unless otherwise indicated, compounds of the invention comprising an amino moiety may include protected versions thereofDerivatives of fenpyrad. Suitable protecting groups for the amino moiety include acetyl, t-butyloxycarbonyl, benzyloxycarbonyl and the like.
As used herein, the term "amino C1-6Alkyl "means C as defined above1-6Alkyl radical, wherein C1-6One of the hydrogen atoms of the alkyl group is replaced by a primary amino group. Amino group C1-6Representative examples of alkyl groups include, but are not limited to, amino-methyl, 2-amino-ethyl, 2-amino-propyl, 3-amino-pentyl, and 5-amino-pentyl.
As used herein, the term "C1-4Alkylamino "refers to a compound having the formula-NH-RaWherein R isaIs C as defined above1-4An alkyl group.
"aromatic" as used herein refers to a moiety wherein the constituent atoms form an unsaturated ring system, wherein all atoms in said ring system are sp2Hybridized, the total number of pi electrons equals 4n + 2. The ring atoms in the aromatic ring may be only carbon atoms, or they may comprise carbon and non-carbon atoms (see heteroaryl).
As used herein, "aryl" refers to a monocyclic or polycyclic aromatic ring assembly (assembly) comprising 6 to 14 ring atoms, wherein all ring atoms are carbon atoms. Typically, aryl is a 6-membered (ring atom) monocyclic, 10-12 membered bicyclic, or 14-membered fused tricyclic aromatic ring system. Six to fourteen membered aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, azulenyl (azulenyl) and anthracenyl (anthracenyl). Aryl groups may be unsubstituted or substituted with 1 to 5 (e.g., one or two or three) substituents independently selected from the group consisting of: hydroxy, mercapto, cyano, nitro, C1-4Alkyl radical, C1-4Alkenyl radical, C1-4Alkynyl, C1-4Alkoxy, thio C1-4Alkyl radical, C1-4Alkenyloxy radical, C1-4Alkynyloxy, halogen, C1-4Alkylcarbonyl, carboxyl, C1-4Alkoxycarbonyl, amino, C1-4Alkylamino radical, di-C1-4Alkylamino radical, C1-4Alkylaminocarbonyl, di-C1-4Alkylaminocarbonyl radical, C1-4Alkylcarbonylamino, C1-4Alkylcarbonyl (C)1-4Alkyl) amino, sulfonyl, sulfamoyl, alkylsulfamoyl, C1-4Alkylaminosulfonyl, aryl, heteroaryl, cycloalkyl and heterocyclyl, wherein each of the foregoing substituents may be further substituted with one or more substituents independently selected from halogen, alkyl, hydroxy or C1-4Substituent of alkoxy group. When "aryl" together with another group denotes e.g. "arylalkyl", "aryloxyalkyl", "aryloxycarbonyl", "aryloxy-carbonylalkyl", the aryl moiety shall have the same meaning as described above for the definition of "aryl". As used herein, "bicyclic" or "bicyclic group" refers to a ring component of two rings, wherein the two rings are fused together, connected by a single bond, or connected by two bridging atoms. The ring may be carbocyclyl, heterocyclyl, or a combination thereof.
As used herein, "bridged ring" refers to a polycyclic ring system in which two ring atoms common to both rings are not directly bonded to each other. One or more of the rings in the ring system may also contain heteroatoms as ring atoms. Non-exclusive examples of bridged rings include norbornyl, oxabicyclo [2.2.1] heptanyl, azabicyclo [2.2.1] heptanyl, adamantyl, and the like.
"cycloalkyl" as used herein means a group of non-aromatic, saturated monocyclic, bicyclic, tricyclic, fused, bridged or spiro polycyclic hydrocarbon ring systems containing from 3 to 14 ring members, wherein all ring members are carbon atoms. Exemplary monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Exemplary bicyclic cycloalkyl groups include bicyclo [2.2.1]Heptane, bicyclo [3.2.1]Octyl, bornyl, norbornyl, decahydronaphthyl, bicyclo [2.1.1]Hexyl, bicyclo [2.2.1]Heptyl, bicyclo [3.1.1]Heptyl and bicyclo [2.2.2]And (4) octyl. Exemplary tricyclic cycloalkyl groups include, for example, adamantyl. Cycloalkyl groups may be unsubstituted or substituted with one or two or three or more substituents independently selected from the group consisting of: hydroxy, mercapto, cyano, nitro, oxo, alkylimino, C1-4Alkyl radical, C1-4Alkenyl radical, C1-4Alkynyl, C1-4Alkoxy radical, C1-4Thioalkyl, C1-4Alkenyloxy radical, C1-4Alkynyloxy, halogen, C1-4Alkylcarbonyl, carboxyl, C1-4Alkoxycarbonyl, amino, C1-4Alkylamino radical, di-C1-4Alkylamino radical, C1-4Alkylaminocarbonyl, di-C1-4Alkylaminocarbonyl radical, C1-4Alkylcarbonylamino, C1-4Alkylcarbonyl (C)1-4Alkyl) amino, sulfonyl, sulfamoyl, alkylsulfamoyl, C1-4Alkylaminosulfonyl, wherein each of the above hydrocarbon groups (e.g., alkyl, alkenyl, alkynyl, alkoxy residues) can be further substituted with one or more residues independently selected at each occurrence from halogen, hydroxy, or C1-4An alkoxy group.
As used herein, "cyano" refers to the group-CN.
"EC" as used herein50By "is meant the molar concentration of modulator that produces 50% efficacy.
As used herein, "IC50By "is meant the molar concentration of inhibitor or modulator that produces 50% inhibition.
As used herein, "fused ring" refers to a polycyclic assembly in which the rings comprising the ring assembly are joined such that the ring atoms common to both rings are directly bonded to each other. Fused ring assemblies may be saturated, partially saturated, aromatic, carbocyclic, heterocyclic, and the like. Non-exclusive examples of common fused rings include decalin, naphthalene, anthracene, phenanthrene, indole, benzofuran, purine, quinoline, and the like.
As used herein, "halo" or "halogen" refers to fluorine, chlorine, bromine, and iodine.
"halo-substituted C as used herein1-6Alkyl "means C as defined above substituted with one or more halo groups as defined above1-6An alkyl group. Halogen substituted C1-6Examples of alkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, and trisChloromethyl, 2,2, 2-trifluoroethyl, 1, 3-dibromopropan-2-yl, 3-bromo-2-fluoropropyl and 1,4, 4-trifluorobutan-2-yl.
As used herein, "heteroaryl" refers to a 5-or 6-membered aromatic monocyclic ring group comprising 1,2,3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The heteroaryl group may be bonded via a carbon atom or a heteroatom. Examples of heteroaryl groups include, but are not limited to, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, or pyridyl. Heteroaryl groups may be unsubstituted or substituted with one or more substituents independently selected from hydroxy, mercapto, cyano, nitro, C1-4Alkyl radical, C1-4Alkenyl radical, C1-4Alkynyl, C1-4Alkoxy, thio C1-4Alkyl radical, C1-4Alkenyloxy radical, C1-4Alkynyloxy, halogen, C1-4Alkylcarbonyl, carboxyl, C1-4Alkoxycarbonyl, amino, C1-4Alkylamino radical, di-C1-4Alkylamino radical, C1-4Alkylaminocarbonyl, di-C1-4Alkylaminocarbonyl radical, C1-4Alkylcarbonylamino, C1-4Alkylcarbonyl (C)1-4Alkyl) amino, sulfonyl, sulfamoyl, alkylsulfamoyl, C1-4Alkylaminosulfonyl, wherein each of the above hydrocarbon groups (e.g., alkyl, alkenyl, alkynyl, alkoxy residues) can be further substituted with one or more residues independently selected at each occurrence from halogen, hydroxy, or C1-4An alkoxy group. When heteroaryl together with another group denotes e.g. "heteroaryloxy", "heteroaryloxyalkyl", "heteroaryloxycarbonyl", the heteroaryl part shall have the same meaning as described above for the definition of "heteroaryl".
As used herein, "heteroatom" refers to an atom that is not a carbon atom. Specific examples of heteroatoms include, but are not limited to, nitrogen, oxygen, and sulfur.
"Heterocyclyl" or "heterocyclic" as used herein means containing 1,2 or 3 members independently selected from nitrogen, oxygen and sulfurA stable 5-or 6-membered non-aromatic monocyclic ring group of heteroatoms. The heterocyclyl group may be bonded via a carbon atom or a heteroatom. Examples of heterocyclyl groups include, but are not limited to, azetidinyl, oxetanyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuryl, tetrahydrothienyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, or perhydroazepine
Hydroxyl as used herein refers to the group-OH.
As used herein, "protected derivative" refers to a derivative of an inhibitor in which one or more reactive sites are blocked by a protecting group. The protected derivatives may be used to prepare inhibitors, or they may themselves have inhibitory activity. Examples of protected groups include, but are not limited to, acetyl, tetrahydropyran, methoxymethyl ether, β -methoxyethoxymethyl ether, p-methoxybenzyl, methylthiomethyl ether, pivaloyl, silyl ether, benzyloxycarbonyl, benzyl, t-butoxycarbonyl, p-methoxyphenyl, 9-fluorenylmethyloxycarbonyl, acetal, ketal, acylal, dithiane, methyl ester, benzyl ester, t-butyl ester, and silyl ester. A detailed list of suitable protecting groups can be found in t.w. greene, protectinggroupsin organic synthesis [ protecting groups in organic synthesis ], 3 rd edition, John Wiley & Sons, Inc [ John Wiley daddy ] 1999.
As used herein, "unsubstituted or substituted" or "optionally substituted" means that the substituent is bound to an available valence of the specified group. As used herein, "unsubstituted" means that the specified group has no further non-hydrogen substituents. As used herein, "substituted" or "optionally substituted" means that at least one of the available hydrogen atoms of the indicated group has been (or can be) replaced with a non-hydrogen substituent. Unless otherwise specified, examples of substituents may include, but are not limited to, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, C1-6Alkoxy, 6-to 10-membered aryloxy, 5-to 10-membered heteroaryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino, C1-6Alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, C1-6Alkyl radical, C1-6Haloalkyl, hydroxy C1-6Alkyl, carbonyl C1-6Alkyl, thiocarbonyl C1-10Alkyl, sulfonyl C1-6Alkyl, sulfinyl C1-6Alkyl radical, C1-10Azaalkyl, imino C1-6Alkyl, 3-to 12-membered cycloalkyl C1-6Alkyl, 4-to 15-membered heterocycloalkyl C1-6Alkyl, 6-to 10-membered aryl C1-6Alkyl, 5-to 10-membered heteroaryl C1-6Alkyl, 10-to 12-membered bicyclic aryl C1-6Alkyl, 9-to 12-membered heterobicyclic aryl C1-6Alkyl, 3-to 12-membered cycloalkyl, 4-to 12-membered heterocyclyl, 9-to 12-membered bicycloalkyl, 3-to 12-membered heterobicycloalkyl, 6-to 12-membered aryl and 5-to 12-membered heteroaryl.
"Sulfonyl" as used herein means the group-S (O)2-. It should be noted that the term "sulfonyl" when used in reference to a monovalent substituentMay alternatively refer to a substituted sulfonyl group-S (═ O)2R, wherein R is hydrogen or a non-hydrogen substituent on the sulfur atom, forms various sulfonyl groups including sulfonic acids, sulfonamides, sulfonates, and sulfones.
Any definition herein may be used in combination with any other definition to describe a composite structural group. By convention, any such defined terminal element is an element that is attached to the parent moiety. For example, the complex group alkoxyalkyl represents an alkoxy group attached to the parent molecule through an alkyl group.
As used herein, the term "chondrocyte" refers to a differentiated chondrocyte (cartilagel cell). Chondrocytes produce and maintain a cartilage matrix composed of collagen and proteoglycans. Chondrocytes are derived from the differentiation of Chondrogenic Progenitor Cells (CPC). Differentiation is the process of forming a specialized cell type from a less specialized cell type, for example, the formation of chondrocytes from Chondrogenic Progenitor Cells (CPCs).
As used herein, the term "chondrocyte differentiation agent" refers to an agent that induces chondrogenic cells to differentiate into mature chondrocytes, which synthesize chondrocyte extracellular matrix (ECM).
As used herein, the term "subject" refers to primates (e.g., humans, male or female), dogs, rabbits, guinea pigs, rats, and mice. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.
As used herein, the term "inhibit (inhibition, or inhibiting)" refers to a reduction or inhibition of a given condition, symptom, or disorder, or disease, or a significant decrease in baseline activity of a biological activity or process.
As used herein, the term "treating" of any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or arresting the development of the disease or at least one clinical symptom thereof); or ameliorating or reducing at least one physical parameter or biomarker associated with the disease or disorder, including those physical parameters or biomarkers that may not be discernible by the patient.
As used herein, the term "prevention" of any disease or disorder refers to prophylactic treatment of the disease or disorder; or delay the onset or progression of the disease or disorder.
As used herein, a subject is "in need of" a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
As used herein, the term "therapeutically effective amount" of a compound of the invention refers to an amount of a compound of the invention that will elicit the biological or medical response of a subject (e.g., a reduction or inhibition of enzyme or protein activity, or amelioration of symptoms, alleviation of a disorder, slowing or delaying the progression of a disease or prevention of a disease, etc.). In one non-limiting embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present invention that, when administered to a subject, is effective to (1) at least partially alleviate, inhibit, prevent and/or ameliorate joint damage caused by joint injury and arthritis. In another non-limiting embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present invention that is effective to promote chondrogenesis when administered to a cell, or tissue, or a non-cellular biological material or medium.
As used herein, the terms "treatment" (treatment, treating) plus "improving" (ameliorating) refer to any indication of successful treatment or amelioration of an injury, pathology, disorder, or symptom (e.g., pain), including any objective or subjective parameter, such as reduction; (iii) alleviating; relieving symptoms or making the patient more tolerant to symptoms, damage, pathology or condition; reducing the frequency or duration of occurrence of a symptom or disorder; or in some cases, prevent the onset of symptoms or disorders. Treatment or amelioration of symptoms can be based on any objective or subjective parameter; including, for example, the results of a physical examination.
As used herein, "administration" refers to administration to a particular joint.
The term "pharmaceutical composition" as used herein refers to a compound of the present invention, or a pharmaceutically acceptable salt thereof, in a form suitable for oral or parenteral administration, and at least one pharmaceutically acceptable carrier.
As used herein, the term "pharmaceutically acceptable carrier" refers to a substance that can be used to prepare or use a pharmaceutical composition and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonicity agents, buffers, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, dyes, and combinations thereof, as known to those skilled in the art (see, for example, Remington the science and Practice of Pharmacy, ramiton: pharmaceutical science and Practice, 22 nd edition, pharmaceutical press [ drug press ],2013, page 1049 and 1070).
As used herein, the terms "a", "an", "the" and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.
Description of the preferred embodiments
The present invention relates to compositions and methods for treating or preventing joint damage caused by joint injury and arthritis.
Various illustrative embodiments of the invention are described herein. The features specified in each embodiment may be combined with other specified features to provide further embodiments of the invention.
In one aspect, the present invention provides a compound having formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, as described above.
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