# US 2019/0169141 A1 · Small molecules that enable cartilage rejuvanation

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- Number: US 2019/0169141 A1
- Document ID: US20190169141A1
- Status: Published application
- Kind: A1
- Application number: 16/213,958
- Filed: 2018-12-07
- Published: 2019-06-06
- Earliest claimed: 2015-02-27
- Assignees: The Regents of the University of California
- Applicants: The Regents of the University of California
- Inventors: DENIS EVSEENKO; BENJAMIN J. VAN HANDEL; VARGHESE JOHN
- Web page: https://patentgrep.com/patent/US20190169141A1

## CPC

- C07D 277/42: Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
- A61P 19/00: Drugs for skeletal disorders
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

There are provided, inter alia, methods and compounds for activating a proliferative program in competent adult chondrocytes.

## Claims

### Claim at position 1

-21. (canceled)

### Claim 22

A method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (III):
or a pharmaceutically acceptable salt thereof,
wherein:
A is CR14 or N;
B is CR16 or N;
X is O, NR19 or S;
L1 is a bond or substituted or unsubstituted C1-C3 alkylene;
R8 is hydrogen, halogen, —CX8.13, —CHX8.12, —CH2X8.1, —CN, —SOn8R8A, —SOv8NR8BR8C, —NHNR8BR8C, —ONR8BR8C, —NHC(O)NHNR8BR8C, —NHC(O)NR8BR8C, —N(O)m8, —NR8BR8C, —C(O)R8D, —C(O)OR8D, —C(O)NR8BR8C, —OR8A, —NR8BSO2R8A, —NR8BC(O)R8D, —NR8BC(O)OR8D, —NR8BOR8D, —OCX8.13, —OCHX8.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,
R9 is hydrogen, halogen, —CX9.13, —CHX9.12, —CH2X9.1, —CN, —SOn9R9A, —SOv9NR9BR9C, —NHNR9BR9C, —ONR9BR9C, —NHC(O)NHNR9BR9C, —NHC(O)NR9BR9C, —N(O)m9, —NR9BR9C, —C(O)R9D, —C(O)OR9D, —C(O)NR9BR9C, —OR9A, —NR9BSO2R9A, —NR9BC(O)R9D, —NR9BC(O)OR9D, —NR9BOR9D, —OCX9.13, —OCHX9.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R10 is hydrogen, halogen, —CX10.13, —CHX10.12, —CH2X10.1, —CN, —SOn10R10A, —SOv10NR10BR10C, —NHNR10BR10C, —ONR10BR10C, —NHC(O)NHNR10BR10C, —NHC(O)NR10BR10C, —N(O)m10, —NR10BR10C, —C(O)R10D, —C(O)OR10D, —C(O)NR10BR10C, —OR10A, —NR10BSO2R10A, —NR10BC(O)R10D, —NR10BC(O)OR10D, —NR10BOR10D, —OCX10.13, —OCHX10.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R11 is hydrogen, halogen, —CX11.13, —CHX11.12, —CH2X11.1, —CN, —SOn11R11A, —SOv11NR11BR11C, —NHNR11BR11C, —ONR11BR11C, —NHC(O)NHNR11BR11C, —NHC(O)NR11BR11C, —N(O)m11, —NR11BR11C, —C(O)R11D, —C(O)OR11D, —C(O)NR11BR11C, —OR11A, —NR11BSO2R11A, —NR11BC(O)R11D, —NR11BC(O)OR11D, —NR11BOR11D, —OCX11.13, —OCHX11.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R12 is hydrogen, halogen, —CX12.13, —CHX12.12, —CH2X12.1, —CN, —SOn12R12A, —SOv12NR12BR12C, —NHNR12BR12C, —ONR12BR12C, —NHC(O)NHNR12BR12C, —NHC(O)NR12BR12C, —N(O)m12, —NR12BR12C, —C(O)R12D, —C(O)OR12D, —C(O)NR12BR12C, —OR12A, —NR12BSO2R12A, —NR12BC(O)R12D, —NR12BC(O)OR12D, —NR12BOR12D, —OCX12.13, —OCHX12.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R13 is hydrogen, halogen, —CX13.13, —CHX13.12, —CH2X13.1, —CN, —SOn13R13A, —SOv13NR13BR13C, —NHNR13BR13C, —ONR13BR13C, —NHC(O)NHNR13BR13C, —NHC(O)NR13BR13C, —N(O)m13, —NR13BR13C, —C(O)R13D, —C(O)OR13D, —C(O)NR13BR13C, —OR13A, —NR13BSO2R13A, —NR13BC(O)R13D, —NR13BC(O)OR13D, —NR13BOR13D, —OCX13.13, —OCHX13.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R14 is hydrogen, halogen, —CX14.13, —CHX14.12, —CH2X14.1, —CN, —SOn14R14A, —SOv14NR14BR14C, —NHNR14BR14C, —ONR14BR14C, —NHC(O)NHNR14BR14C, —NHC(O)NR14BR14C, —N(O)m14, —NR14BR14C, —C(O)R14D, —C(O)OR14D, —C(O)NR14BR14C, —OR14A, —NR14BSO2R14A, —NR14BC(O)R14D, —NR14BC(O)OR14D, —NR14BOR14D, —OCX14.13, —OCHX14.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R15 is hydrogen, halogen, —CX15.13, —CHX15.12, —CH2X15.1, —CN, —SOn15R15A, —SOv15NR15BR15C, —NHNR15BR15C, —ONR15BR15C, —NHC(O)NHNR15BR15C, —NHC(O)NR15BR15C, —N(O)m15, —NR15BR15C, —C(O)R15D, —C(O)OR15D, —C(O)NR15BR15C, —OR15A, —NR15BSO2R15A, —NR15BC(O)R15D, —NR15BC(O)OR15D, —NR15BOR15D, —OCX15.13, —OCHX15.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R16 is hydrogen, halogen, —CX16.13, —CHX16.12, —CH2X16.1, —CN, —SOn16R16A, —SOv16NR16BR16C, —NHNR16BR16C, —ONR16BR16C, —NHC(O)NHNR16BR16C, —NHC(O)NR16BR16C, —N(O)m16, —NR16BR16C, —C(O)R16D, —C(O)OR16D, —C(O)NR16BR16C, —OR16A, —NR16BSO2R16A, —NR16BC(O)R16D, —NR16BC(O)OR16D, —NR16BOR16D, —OCX16.13, —OCHX16.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R17 is hydrogen, halogen, —CX17.13, —CHX17.12, —CH2X17.1, —CN, —SOn17R17A, —SOv17NR17BR17C, —NHNR17BR17C, —ONR17BR17C, —NHC(O)NHNR17BR17C, —NHC(O)NR17BR17C, —N(O)m17, —NR17BR17C, —C(O)R17D, —C(O)OR17D, —C(O)NR17BR17C, —OR17A, —NR17BSO2R17A, —NR17BC(O)R17D, —NR17BC(O)OR17D, —NR17BOR17D, —OCX17.13, —OCHX17.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R18 is hydrogen, halogen, —CX18.13, —CHX18.12, —CH2X18.1, —CN, —SOn18R18A, —SOv18NR18BR18C, —NHNR18BR18C, —ONR18BR18C, —NHC(O)NHNR18BR18C, —NHC(O)NR18BR18C, —N(O)m18, —NR18BR18C, —C(O)R18D, —C(O)OR18D, —C(O)NR18BR18C, —OR18A, —NR18BSO2R18A, —NR18BC(O)R18D, —NR18BC(O)OR18D, —NR18BOR18D, —OCX18.13, —OCHX18.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R19 is hydrogen, —COR19D, —C(O)NHNR19BR19C, —C(O)OR19D—SO2R19A, C(O)NR19BR19C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
R19A is independently hydrogen, halogen, —CF3, —CCl3, —CBr3, —CI3, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, —NHC(O)NH2, —NHSO2H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF3, —OCCl3, —OCBr3, —OCI3, —OCHF2, —OCHCl2, —OCHBr2, —OCHI2, R19AF-substituted or unsubstituted alkyl, R19AF-substituted or unsubstituted heteroalkyl, R19AF-substituted or unsubstituted cycloalkyl, R19AF-substituted or unsubstituted heterocycloalkyl, R19AF-substituted or unsubstituted aryl, or R19AF-substituted or unsubstituted heteroaryl;
R19B is independently hydrogen, halogen, —CF3, —CCl3, —CBr3, —CI3, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, —NHC(O)NH2, —NHSO2H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF3, —OCCl3, —OCBr3, —OCI3, —OCHF2, —OCHCl2, —OCHBr2, —OCHI2, R19BF-substituted or unsubstituted alkyl, R19BF-substituted or unsubstituted heteroalkyl, R19BF-substituted or unsubstituted cycloalkyl, R19BF-substituted or unsubstituted heterocycloalkyl, R19BF-substituted or unsubstituted aryl, or R19BF-substituted or unsubstituted heteroaryl;
R19C is independently hydrogen, halogen, —CF3, —CCl3, —CBr3, —CI3, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, —NHC(O)NH2, —NHSO2H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF3, —OCCl3, —OCBr3, —OCI3, —OCHF2, —OCHCl2, —OCHBr2, —OCHI2, R19CF-substituted or unsubstituted alkyl, R19CF-substituted or unsubstituted heteroalkyl, R19CF-substituted or unsubstituted cycloalkyl, R19CF-substituted or unsubstituted heterocycloalkyl, R19CF-substituted or unsubstituted aryl, or R19CF-substituted or unsubstituted heteroaryl;
R19D is independently hydrogen, halogen, —CF3, —CCl3, —CBr3, —CI3, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, —NHC(O)NH2, —NHSO2H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF3, —OCCl3, —OCBr3, —OCI3, —OCHF2, —OCHCl2, —OCHBr2, —OCHI2, R19DF-substituted or unsubstituted alkyl, R19DF-substituted or unsubstituted heteroalkyl, R19DF-substituted or unsubstituted cycloalkyl, R19DF-substituted or unsubstituted heterocycloalkyl, R19DF-substituted or unsubstituted aryl, or R19DF-substituted or unsubstituted heteroaryl;
R8A, R8B, R8C, R8D, R9A, R9B, R9C, 9RD, R10A, R10B, R10C, R10D, R11A, R11B, R11C, R11D, R12A, R12B, R12C, R12D, R13A, R13B, R13C, R13D, R14A, R14B, R14C, R14D, R15A, R15B, R15C, R15D, R16A, R16B, R16C, R16D, R17A, R17B, R17C, R17D, R18A, R18B, R18C, R18D, R19AF, R19BF, R19CF, and R19DF are independently hydrogen, halogen, —CF3, —CCl3, —CBr3, —CI3, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, —NHC(O)NH2, —NHSO2H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF3, —OCCl3, —OCBr3, —OCI3, —OCHF2, —OCHCl2, —OCHBr2, —OCHI2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsbstituted or unsubstituted heteroaryl; R8B, R8C, R9B, R9C, R10B, R10C, R11B, R11C, R12B, R13B, R13C, R14B, R14C, R15B, R15C, R16B, R16C, R17B, R17C, R18B, R18C, R19BF and R19CF substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
n8, n9, n10, n11, n12, n13, n14, n15, n16, n17, and n18 is an integer from 0 to 4;
m8, m9, m10, m11, m12, m13, m14, m15, m16, m17, and m18 are independently 1 or 2;
v8, v9,v10, v11, v12, v13, v14, v15, v16, v17, and v18 are independently 1 or 2; and
X8.1, X9.1, X10.1, X11.1, X12.1, X13.1, X14.1, X15.1, X16.1, X17.1 and X18.1 are independently —Cl, —Br, —I or —F.

### Claim at position 3

23-28. (canceled)

### Claim 29

A method of modulating the activity of a gp130 receptor, increasing MYC expression, or increasing pSTAT3 expression in a cell, comprising contacting the cell with a binding site 1 gp130 receptor agonist.

### Claim 30 (depends on 29)

The method of claim 29, wherein the activity of the gp130 receptor is increased.

### Claim 31 (depends on 29)

The method of claim 29, wherein the activity of the gp130 receptor is decreased or inhibited.

### Claim 32 (depends on 30)

The method of claim 30, wherein the activity is homodimerization.

### Claim 33 (depends on 29)

The method of claim 29, wherein the cell is a chondrocyte.

### Claim at position 9

34-36. (canceled)

### Claim 37 (depends on 29)

The method of claim 29, wherein the binding site 1 gp130 receptor agonist is a compound of Formula (III):
or a pharmaceutically acceptable salt thereof,
wherein:
A is CR14 or N;
B is CR16 or N;
X is O, NR19 or S;
L1 is a bond or substituted or unsubstituted C1-C3 alkylene;
R8 is hydrogen, halogen, —CX8.13, —CHX8.12, —CH2X8.1, —CN, —SOn8R8A, —SOv8NR8BR8C, —NHNR8BR8C, —ONR8BR8C, —NHC(O)NHNR8BR8C, —NHC(O)NR8BR8C, —N(O)m8, —NR8BR8C, —C(O)R8D, —C(O)OR8D, —C(O)NR8BR8C, —OR8A, —NR8BSO2R8A, —NR8BC(O)R8D, —NR8BC(O)OR8D, —NR8BOR8D, —OCX8.13, —OCHX8.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,
R9 is hydrogen, halogen, —CX9.13, —CHX9.12, —CH2X9.1, —CN, —SOn9R9A, —SOv9NR9BR9C, —NHNR9BR9C, —ONR9BR9C, —NHC(O)NHNR9BR9C, —NHC(O)NR9BR9C, —N(O)m9, —NR9BR9C, —C(O)R9D, —C(O)OR9D, —C(O)NR9BR9C, —OR9A, —NR9BSO2R9A, —NR9BC(O)R9D, —NR9BC(O)OR9D, —NR9BOR9D, —OCX9.13, —OCHX9.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R10 is hydrogen, halogen, —CX10.13, —CHX10.12, —CH2X10.1, —CN, —SOn10R10A, —SOv10NR10BR10C, —NHNR10BR10C, —ONR10BR10C, —NHC(O)NHNR10BR10C, —NHC(O)NR10BR10C, —N(O)m10, —NR10BR10C, —C(O)R10D, —C(O)OR10D, —C(O)NR10BR10C, —OR10A, —NR10BSO2R10A, —NR10BC(O)R10D, —NR10BC(O)OR10D, —NR10BOR10D, —OCX10.13, —OCHX10.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R11 is hydrogen, halogen, —CX11.13, —CHX11.12, —CH2X11.1, —CN, —SOn11R11A, —SOv11NR11BR11C, —NHNR11BR11C, —ONR11BR11C, —NHC(O)NHNR11BR11C, —NHC(O)NR11BR11C, —N(O)m11, —NR11BR11C, —C(O)R11D, —C(O)OR11D, —C(O)NR11BR11C, —OR11A, —NR11BSO2R11A, ——NR11BC(O)R11D, —NR11BC(O)OR11D, —NR11BOR11D, —OCX11.13, —OCHX11.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R12 is hydrogen, halogen, —CX12.13, —CHX12.12, —CH2X12.1, —CN, —SOn12R12A, —SOv12NR12BR12C, —NHNR12BR12C, —ONR12BR12C, —NHC(O)NHNR12BR12C, —NHC(O)NR12BR12C, —N(O)m12, —NR12BR12C, —C(O)R12D, —C(O)OR12D, —C(O)NR12BR12C, —OR12A, —NR12BSO2R12A, —NR12BC(O)R12D, —NR12BC(O)OR12D, —NR12BOR12D, —OCX12.13, —OCHX12.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R13 is hydrogen, halogen, —CX13.13, —CHX13.12, —CH2X13.1, —CN, —SOn13R13A, —SOv13NR13BR13C, —NHNR13BR13C, —ONR13BR13C, —NHC(O)NHNR13BR13C, —NHC(O)NR13BR13C, —N(O)m13, —NR13BR13C, —C(O)R13D, —C(O)OR13D, —C(O)NR13BR13C, —OR13A, —NR13BSO2R13A, —NR13BC(O)R13D, —NR13BC(O)OR13D, —NR13BOR13D, —OCX13.13, —OCHX13.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R14 is hydrogen, halogen, —CX14.13, —CHX14.12, —CH2X14.1, —CN, —SOn14R14A, —SOv14NR14BR14C, —NHNR14BR14C, —ONR14BR14C, —NHC(O)NHNR14BR14C, —NHC(O)NR14BR14C, —N(O)m14, —NR14BR14C, —C(O)R14D, —C(O)OR14D, —C(O)NR14BR14C, —OR14A, —NR14BSO2R14A, —NR14BC(O)R14D, —NR14BC(O)OR14D, —NR14BOR14D, —OCX14.13, —OCHX14.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R15 is hydrogen, halogen, —CX15.13, —CHX15.12, —CH2X15.1, —CN, —SOn15R15A, —SOv15NR15BR15C, —NHNR15BR15C, —ONR15BR15C, —NHC(O)NHNR15BR15C, —NHC(O)NR15BR15C, —N(O)m15, —NR15BR15C, —C(O)R15D, —C(O)OR15D, —C(O)NR15BR15C, —OR15A, —NR15BSO2R15A, —NR15BC(O)R15D, —NR15BC(O)OR15D, —NR15BOR15D, —OCX15.13, —OCHX15.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R16 is hydrogen, halogen, —CX16.13, —CHX16.12, —CH2X16.1, —CN, —SOn16R16A, —SOv16NR16BR16C, —NHNR16BR16C, —ONR16BR16C, —NHC(O)NHNR16BR16C, —NHC(O)NR16BR16C, —N(O)m16, —NR16BR16C, —C(O)R16D, —C(O)OR16D, —C(O)NR16BR16C, —OR16A, —NR16BSO2R16A, —NR16BC(O)R16D, —NR16BC(O)OR16D, —NR16BOR16D, —OCX16.13, —OCHX16.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R17 is hydrogen, halogen, —CX17.13, —CHX17.12, —CH2X17.1, —CN, —SOn17R17A, —SOv17NR17BR17C, —NHNR17BR17C, —ONR17BR17C, —NHC(O)NHNR17BR17C, —NHC(O)NR17BR17C, —N(O)m17, —NR17BR17C, —C(O)R17D, —C(O)OR17D, —C(O)NR17BR17C, —OR17A, —NR17BSO2R17A, —NR17BC(O)R17D, —NR17BC(O)OR17D, —NR17BOR17D, —OCX17.13, —OCHX17.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R18 is hydrogen, halogen, —CX18.13, —CHX18.12, —CH2X18.1, —CN, —SOn18R18A, —SOv18NR18BR18C, —NHNR18BR18C, —ONR18BR18C, —NHC(O)NHNR18BR18C, —NHC(O)NR18BR18C, —N(O)m18, —NR18BR18C, —C(O)R18D, —C(O)OR18D, —C(O)NR18BR18C, —OR18A, —NR18BSO2R18A, —NR18BC(O)R18D, —NR18BC(O)OR18D, —NR18BOR18D, —OCX18.13, —OCHX18.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R19 is hydrogen, —COR19D, —C(O)NHNR19BR19C, —C(O)OR19D—SO2R19A, C(O)NR19BR19C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
R19A is independently hydrogen, halogen, —CF3, —CCl3, —CBr3, —CI3, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, —NHC(O)NH2, —NHSO2H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF3, —OCCl3, —OCBr3, —OCI3, —OCHF2, —OCHCl2, —OCHBr2, —OCHI2, R19AF-substituted or unsubstituted alkyl, R19AF-substituted or unsubstituted heteroalkyl, R19AF-substituted or unsubstituted cycloalkyl, R19AF-substituted or unsubstituted heterocycloalkyl, R19AF-substituted or unsubstituted aryl, or R19AF-substituted or unsubstituted heteroaryl;
R19B is independently hydrogen, halogen, —CF3, —CCl3, —CBr3, —CI3, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, —NHC(O)NH2, —NHSO2H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF3, —OCCl3, —OCBr3, —OCI3, —OCHF2, —OCHCl2, —OCHBr2, —OCHI2, R19BF-substituted or unsubstituted alkyl, R19BF-substituted or unsubstituted heteroalkyl, R19BF-substituted or unsubstituted cycloalkyl, R19BF-substituted or unsubstituted heterocycloalkyl, R19BF-substituted or unsubstituted aryl, or R19BF-substituted or unsubstituted heteroaryl;
R19C is independently hydrogen, halogen, —CF3, —CCl3, —CBr3, —CI3, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, —NHC(O)NH2, —NHSO2H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF3, —OCCl3, —OCBr3, —OCI3, —OCHF2, —OCHCl2, —OCHBr2, —OCHI2, R19CF-substituted or unsubstituted alkyl, R19CF-substituted or unsubstituted heteroalkyl, R19CF-substituted or unsubstituted cycloalkyl, R19CF-substituted or unsubstituted heterocycloalkyl, R19CF-substituted or unsubstituted aryl, or R19CF-substituted or unsubstituted heteroaryl;
R19D is independently hydrogen, halogen, —CF3, —CCl3, —CBr3, —CI3, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, —NHC(O)NH2, —NHSO2H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF3, —OCCl3, —OCBr3, —OCI3, —OCHF2, —OCHCl2, —OCHBr2, —OCHI2, R19DF-substituted or unsubstituted alkyl, R19DF-substituted or unsubstituted heteroalkyl, R19DF-substituted or unsubstituted cycloalkyl, R19DF-substituted or unsubstituted heterocycloalkyl, R19DF-substituted or unsubstituted aryl, or R19DF-substituted or unsubstituted heteroaryl;
R8A, R8B, R8C, R8D, R9A, R9B, R9C, 9RD, R10A, R10B, R10C, R10D, R11A, R11B, R11C, R11D, R12A, R12B, R12C, R12D, R13A, R13B, R13C, R13D, R14A, R14B, R14C, R14D, R15A, R15B, R15C, R15D, R16A, R16B, R16C, R16D, R17A, R17B, R17C, R17D, R18A, R18B, R18C, R18D, R19AF, R19BF, R19CF, and R19DF are independently hydrogen, halogen, —CF3, —CCl3, —CBr3, —CI3, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, —NHC(O)NH2, —NHSO2H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF3, —OCCl3, —OCBr3, —OCI3, —OCHF2, —OCHCl2, —OCHBr2, —OCHI2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsbstituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R8B, R8C, R9B, R9C, R10B, R10C, R11B, R11C, R12B, R13B, R13C, R14B, R14C, R15B, R15C, R16B, R16C, R17B, R17C, R18B, R18C, R19BF and R19CF substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
n8, n9, n10, n11, n12, n13, n14, n15, n16, n17, and n18 is an integer from 0 to 4;
m8, m9, m10, m11, m12, m13, m14, m15, m16, m17, and m18 are independently 1 or 2;
v8, v9,v10, v11, v12, v13, v14, v15, v16, v17, and v18 are independently 1 or 2; and
X8.1, X9.1, X10.1, X11.1, X12.1, X13.1, X14.1, X15.1, X16.1, X17.1 and X18.1 are independently —Cl, —Br, —I or —F.

### Claim 38 (depends on 37)

The method of claim 37, wherein L1 is a bond and Xis NH.

### Claim at position 12

39-40. (canceled)

### Claim 41 (depends on 37)

The method of claim 37, wherein:
A is CR14; and
B is CR16.

### Claim at position 14

42-43. (canceled)

### Claim 44 (depends on 37)

The method of claim 37, wherein:
A isN;
B is CR16; and
R16 is hydrogen.

### Claim 45

(canceled)

### Claim 46 (depends on 37)

The method of claim 37, wherein:
A and B are independently N; and
R10 is fluorine, chlorine, bromine, or iodine.

### Claim at position 18

47-52. (canceled)

### Claim 53 (depends on 22)

The method of claim 22, wherein the compound is of formula (IIIa):

### Claim 54 (depends on 22)

The method of claim 22, wherein the compound is of formula (IIIb):

### Claim 55 (depends on 22)

The method of claim 22, wherein the compound is of formula (IIIc):

### Claim 56 (depends on 22)

The method of claim 22, wherein the compound is

### Claim 57 (depends on 56)

The method of claim 56, wherein the structure is

### Claim 58 (depends on 22)

The method of claim 22, wherein the disease or disorder is cartilage degenerative disease, joint surface injury or arthritis.

### Claim 59 (depends on 22)

The method of regulating chondrocyte activation, maturation or differentiation, said method comprises contacting a chondrocyte with the compound of claim 22.

### Claim 60 (depends on 59)

The method of claim 59, wherein the chondrocyte activation comprises an increase in proliferation, migration, metabolisn, or any combination thereof.

### Claim 61 (depends on 59)

The method of claim 59, wherein the chondrocyte is an adult chondrocyte.