IP Library › Granted Patent US 11,643,388

Granted Patent B2

US 11,643,388 · App. 17/246,014 · Granted May 9, 2023

Inhibitors of alpha 2 beta 1 integrin and methods of use thereof

Inventors: Dean Sheppard (Oakland, CA); William F. DeGrado (San Francisco, CA); Aparna Sundaram (San Francisco, CA); Hyunil Jo (Lafayette, CA); Richard Beresis (San Francisco, CA); Marc Adler (Orinda, CA)

Assignees: The Regents of the University of California; ShangPharma Innovation Inc.

C07C275/26 A61P11/06 C07C275/24 C07D205/04 C07D213/73 C07D217/02 C07D217/06 C07D239/84

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Quick Facts

Patent No.: US 11,643,388
App. No.: 17/246,014
Granted: May 9, 2023
Kind: B2

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Abstract

Disclosed herein, inter alia, are inhibitors of alpha 2 beta 1 integrin and methods of using the same.

Claims (107)

1. A compound, or a pharmaceutically acceptable salt thereof or a prodrug thereof, having the formula:

wherein

Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R 2 is hydrogen or substituted or unsubstituted alkyl;

R 5 is hydrogen or unsubstituted C 1 -C 3 alkyl;

L 5 is a bond or unsubstituted C 1 -C 3 alkylene;

R 10.1 is hydrogen, halogen, —CX 10.1 3 , —CHX 10.1 2 , —CH 2 X 10.1 , —OCX 10.1 3 , —OCH 2 X 10.1 , —OCHX 10.1 2 , —CN, —SO n10.1 R 10.1D , —SO v10.1 NR 10.1A R 10.1B , —NHC(O)NR 10.1A R 10.1B , —N(O) m10.1 , —NR 10.1A R 10.1B , —C(O)R 10.1C , —C(O)OR 10.1C , —C(O)NR 10.1A R 10.1B , —OR 10.1D , —SR 10.1D , —NR 10.1A SO 2 R 10.1D , —NR 10.1A C(O)R 10.1C , —NR 10.1A C(O)OR 10.1C , —NR 10.1A OR 10.1C , —N 3 , 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;

R 10.2 is hydrogen, halogen, —CX 10.2 3 , —CHX 10.2 2 , —CH 2 X 10.2 , —OCX 10.2 3 , —OCH 2 X 10.2 , —OCHX 10.2 2 , —CN, —SO n10.2 R 10.2D , —SO v10.2 NR 10.2A R 10.2B , —NHC(O)NR 10.2A R 10.2B , —N(O) m10.2 , —NR 10.2A R 10.2B , C(O)R 10.2C , —C(O)OR 10.2C , C(O)NR 10.2A R 10.2B , —OR 10.2D , —SR 10.2D , —NR 10.2A SO 2 R 10.2D , —NR 10.2A C(O)R 10.2C , —NR 10.2A C(O)OR 10.2C , —NR 10.2A OR 10.2C , —N 3 , -L 10.2 -R 22 , 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;

R 10.3 is hydrogen, halogen, —CX 10.3 3 , —CHX 10.3 2 , —CH 2 X 10.3 , —OCX 10.3 3 , —OCH 2 X 10.3 , —OCHX 10.3 2 , —CN, —SO n10.3 R 10.3D , —SO v10.3 NR 10.3A R 10.3B , —NHC(O)NR 10.3A R 10.3B , —N(O) m10.3 , —NR 10.3A R 10.3B , —C(O)R 10.3C , —C(O)OR 10.3C , —C(O)NR 10.3A R 10.3B , —OR 10.3D , —SR 10.3D , —NR 10.3A SO 2 R 10.3D , —NR 10.3A C(O)R 10.3C , —NR 10.3A C(O)OR 10.3C , —NR 10.3A OR 10.3C , —N 3 , -L 10.3 -R 23 , 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;

R 10.4 is hydrogen, halogen, —CX 10.4 3 , —CHX 10.4 2 , —CH 2 X 10.4 , —OCX 10.4 3 , —OCH 2 X 10.4 , —OCHX 10.4 2 , —CN, —SO n10.4 R 10.4D , —SO v10.4 NR 10.4A R 10.4B , —NHC(O)NR 10.4A R 10.4B , —N(O) m10.4 , —NR 10.4A R 10.4B , —C(O)R 10.4C , —C(O)OR 10.4C , —C(O)NR 10.4A R 10.4B , —OR 10.4D , —SR 10.4D , —NR 10.4A SO 2 R 10.4D , —NR 10.4A C(O)R 10.4C , —NR 10.4A C(O)OR 10.4C , —NR 10.4A OR 10.4C , —N 3 , -L 10.4 -R 24 , 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;

R 10.5 is hydrogen, halogen, —CX 10.5 , —CHX 10.5 2 , —CH 2 X 10.5 , —OCX 10.5 3 , —OCH 2 X 10.5 , —OCHX 10.5 2 , —CN, —SO n10.5 R 10.5D , —SO v10.5 NR 10.5A R 10.5B , —NHC(O)NR 10.5A R 10.5B , —N(O) m10.5 , —NR 10.5A R 10.5B , —C(O)R 10.5C , —C(O)OR 10.5C , —C(O)NR 10.5A R 10.5B , —OR 10.5D , —SR 10.5D , —NR 10.5A SO 2 R 10.5D , —NR 10.5A C(O)R 10.5C , —NR 10.5A C(O)OR 10.5C , —NR 10.5A OR 10.5C , —N 3 , 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;

R 21 is independently oxo, halogen, —CX 21 3 , —CHX 21 2 , —CH 2 X 21 , —OCX 21 3 , —OCH 2 X 21 , —OCHX 21 2 , —CN, —SO n21 R 21D , —SO v21 NR 21A R 21B , —NHC(O)NR 21A R 21B , —N(O) m21 , —NR 21A R 21B , —C(O)R 21C , —C(O)OR 21C , —C(O)NR 21A R 21B , —OR 21D , SR 21D , —R 21A SO 2 R 21D , —NR 21A C(O)R 21C , —NR 21A C(O)OR 21C , —NR 21A OR 21C , —N 3 , 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;

L 10.2 , L 10.3 , and L 10.4 are independently a bond, —NH—, —S—, —O—, —C(O)—, —C(O)O—, —OC(O)—, —NHC(O)—, —C(O)NH—, —NHC(O)O—, —OC(O)NH—, —NHC(O)NH—, —NHC(NH)NH—, —S(O) 2 —, —NHS(O) 2 —, —S(O) 2 NH—, —C(S)—, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;

R 22 , R 23 , and R 24 are independently substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

L 100 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

R 100 is hydrogen, halogen, —CX 100 3 , —CHX 100 2 , —CH 2 X 100 , —OCX 100 3 , —OCH 2 X 100 , —OCHX 100 2 , —CN, —SO n100 R 100D , —SO v100 NR 100A R 100B , —NHC(O)NR 100A R 100B , —N(O) m100 , —NR 100A R 100B , —C(O)R 100C , —C(O)OR 100C , —C(O)NR 100A R 100B , —OR 100D , —SR 100D , —NR 100A SO 2 R 100D , —NR 100A C(O)R 100C , —NR 100A C(O)OR 100C , —NR 100A OR 100C , —N 3 , 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;

R 10.1A , R 10.1B , R 10.1C , R 10.1D , R 10.2A , R 10.2B , R 10.2C , R 10.2D , R 10.3A , R 10.3B , R 10.3C , R 10.3D , R 10.4A , R 10.4B , R 10.4C , R 10.4D , R 10.5A , R 10.5B , R 10.5C , R 10.5D , R 21A , R 21B , R 21C , R 21D , R 100A , R 100B , R 100C , and R 100D are independently hydrogen, halogen, —CCl 3 , —CBr 3 , —CF 3 , —CI 3 , —CH 2 Cl, —CH 2 Br, —CH 2 F, —CH 2 I, —CHCl 2 , —CHBr 2 , —CHF 2 , —CHI 2 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —OSO 3 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl 3 , —OCBr 3 , —OCF 3 , —OCI 3 , —OCH 2 Cl, —OCH 2 Br, —OCH 2 F, —OCH 2 I, —OCHCl 2 , —OCHBr 2 , —OCHF 2 , —OCHI 2 , —N 3 , 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; R 10.1A and R 10.1B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 10.2A and R 10.2B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 10.3A and R 10.3B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

R 10.4A and R 10.4B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 10.5A and R 10.5B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 21A and R 21B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 100A and R 100B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

n10.1, n10.2, n10.3, n10.4, n10.5, n21, and n100 are independently an integer from 0 to 4;

m10.1, m10.2, m10.3, m10.4, m10.5, m21, m100, v10.1, v10.2, v10.3, v10.4, v10.5, v21, and v100 are independently 1 or 2;

X 10.1 , X 10.2 , X 10.3 , X 10.4 , X 10.5 , X 21 , and X 100 are independently —F, —Cl, —Br, or —I;

z21 is an integer from 0 to 11;

wherein at least one of R 10.1 or R 10.5 is not hydrogen; and

wherein at least one of R 10.2 , R 10.3 , or R 10.4 is -L 10.2 -R 22 , -L 10.3 -R 23 , or -L 10.4 -R 24 respectively.

2. The compound of claim 1 , wherein

L 10.3 is a bond, —NH—, —O—, —C(O)—, —NHC(O)O—, —NHS(O) 2 —, or substituted or unsubstituted 2 to 5 membered heteroalkylene;

and

z33 is an integer from 0 to 10.

3. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof or a prodrug thereof, and a pharmaceutically acceptable excipient.

4. A method of treating asthma, the method comprising administering to a subject in need thereof an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof or a prodrug thereof.

5. A method of treating an inflammatory disease, the method comprising administering to a subject in need thereof an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof or a prodrug thereof.

6. A method of treating an autoimmune disease, the method comprising administering to a subject in need thereof an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof or a prodrug thereof.

7. A compound, or a pharmaceutically acceptable salt thereof or a prodrug thereof, having the formula:

wherein

R 2 is hydrogen or substituted or unsubstituted alkyl;

R 5 is unsubstituted C 1 -C 3 alkyl;

R 10.2 is hydrogen, halogen, —CX 10.2 3 , —CHX 10.2 2 , —CH 2 X 10.2 , —OCX 10.2 3 , —OCH 2 X 10.2 , —OCHX 10.2 2 , —CN, —SO n10.2 R 10.2D , —SO v10.2 NR 10.2A R 10.2B , —NHC(O)NR 10.2A R 10.2B , —N(O) m10.2 , —NR 10.2A R 10.2B , C(O)R 10.2C , —C(O)OR 10.2C , —C(O)NR 10.2A R 10.2B , —OR 10.2D , —SR 10.2D , —NR 10.2A SO 2 R 10.2D , —R 10.2A C(O)R 10.2C , —NR 10.2A C(O)OR 10.2C , —NR 10.2A OR 10.2C , —N 3 , -L 10.2 -R 22 , 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;

R 21 is independently oxo, halogen, —CX 21 3 , —CHX 21 2 , —CH 2 X 21 , —OCX 21 3 , —OCH 2 X 21 , —OCHX 21 2 , —CN, —SO n21 R 21D , —SO v21 NR 21A R 21B , —NHC(O)NR 21A R 21B , —N(O) m21 , —NR 21A R 21B , C(O)R 21C , —C(O)OR 21C , —C(O)NR 21A R 21B , —OR 21D , —SR 21D , —NR 21A SO 2 R 21D , —NR 21A C(O)R 21C , —NR 21A C(O)OR 21C , —NR 21A OR 21C , —N 3 , 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;

L 10.2 , L 10.3 , and L 10.4 are independently a bond, —NH—, —S—, —O—, —C(O)—, —C(O)O—, —OC(O)—, —NHC(O)—, —C(O)NH—, —NHC(O)O—, —OC(O)NH—, —NHC(O)NH—, —NHC(NH)NH—, —S(O) 2 —, —NHS(O) 2 —, —S(O) 2 NH—, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;

R 22 , R 23 and R 24 are independently substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R 100 is hydrogen, halogen, —CX 100 3 , —CHX 100 3 , —CH 2 X 100 , —OCX 100 3 , —OCH 2 X 100 , —OCHX 100 2 , —CN, —SO n100 R 100D , —SO v100 NR 100A R 100B , —NHC(O)NR 100A R 100B , —N(O) m100 , —NR 100A R 100B , —C(O)R 100C , —C(O)OR 100C , —C(O)NR 100A R 100B , —OR 100D , —SR 100D , —NR 100A SO 2 R 100D , —NR 100A C(O)R 100C , —NR 100A C(O)OR 100C , —NR 100A OR 100C , —N 3 , 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;

n10.1, n10.2, n10.3, n10.4, n10.5, n21, and n100 are independently an integer from 0 to 4;

m10.1, m10.2, m10.3, m10.4, m10.5, m21, m100, v10.1, v10.2, v10.3, v10.4, v10.5, v21, and v100 are independently 1 or 2;

X 10.1 , X 10.2 , X 10.3 , X 10.4 , X 10.5 , X 21 , and X 100 are independently —F, —Cl, —Br, or —I;

z21 is an integer from 0 to 5; and

wherein at least one of R 10.1 or R 10.5 is not hydrogen.

8. A compound, or a pharmaceutically acceptable salt thereof or a prodrug thereof, having the formula:

wherein

Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R 2 is hydrogen or substituted or unsubstituted alkyl;

R 5 is hydrogen or unsubstituted C 1 -C 3 alkyl;

L 5 is a bond or unsubstituted C 1 -C 3 alkylene;

R 10.1 is hydrogen, halogen, —CX 10.1 3 , —CHX 10.1 2 , —CH 2 X 10.1 , —OCX 10.1 3 , —OCH 2 X 10.1 , —OCHX 10.1 2 , —CN, —SO n10.1 R 10.1D , —SO v10.1 NR 10.1A R 10.1B , —NHC(O)NR 10.1A R 10.1B , —N(O) m10.1 , —NR 10.1A R 10.1B , C(O)R 10.1C , —C(O)OR 10.1C , —C(O)NR 10.1A R 10.1B , —OR 10.1D , —SR 10.1D , —NR 10.1A SO 2 R 10.1D , —NR 10.1A C(O)R 10.1C , —NR 10.1A C(O)OR 10.1C , —NR 10.1A OR 10.1C , —N 3 , 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;

R 10.3 is hydrogen, halogen, —CX 10.3 3 , —CHX 10.3 2 , —CH 2 X 10.3 , —OCX 10.3 3 , —OCH 2 X 10.3 , —OCHX 10.3 2 , —CN, —SO n10.3 R 10.3D , —SO v10.3 NR 10.3A R 10.3B , —NHC(O)NR 10.3A R 10.3B , —N(O) m10.3 , —NR 10.3A R 10.3B , C(O)R 10.3C , —C(O)OR 10.3C , —C(O)NR 10.3A R 10.3B , —OR 10.3D , —SR 10.3D , —NR 10.3A SO 2 R 10.3D , —NR 10.3A C(O)R 10.3C , —NR 10.3A C(O)OR 10.3C , —NR 10.3A OR 10.3C , —N 3 , -L 10.3 -R 23 , 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;

R 10.5 is hydrogen, halogen, —CX 10.5 3 , —CHX 10.5 2 , —CH 2 X 10.5 , —OCX 10.5 3 , —OCH 2 X 10.5 , —OCHX 10.5 2 , —CN, —SO n10.5 R 10.5D , SO v10.5 NR 10.5A R 10.5B , —NHC(O)NR 10.5A R 10.5B , —N(O) m10.5 , —NR 10.5A R 10.5B , —C(O)R 10.5C , —C(O)OR 10.5C , —C(O)NR 10.5A R 10.5B , —OR 10.5D , —SR 10.5D , —NR 10.5A SO 2 R 10.5D , —NR 10.5A C(O)R 10.5C , —NR 10.5A C(O)OR 10.5C , —NR 10.5A OR 10.5C , —N 3 , 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;

R 10.6 is independently oxo, halogen, —CX 10.6 3 , —CHX 10.6 2 , —CH 2 X 10.6 , —OCX 10.6 3 , —OCH 2 X 10.6 , —OCHX 10.6 2 , —CN, —SO n10.6 R 10.6D , —SO v10.6 NR 10.6A R 10.6B , —NHC(O)NR 10.6A R 10.6B , —N(O) m10.6 , —NR 10.6A R 10.6B , —C(O)R 10.6C , —C(O)OR 10.6C , —C(O)NR 10.6A R 10.6B , —OR 10.6D , —SR 10.6D , —NR 10.6A SO 2 R 10.6D , —NR 10.6A C(O)R 10.6C , —NR 10.6A C(O)OR 10.6C , —NR 10.6A OR 10.6C , —N 3 , 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;

R 21 is independently oxo, halogen, —CX 21 3 , —CHX 21 2 , —CH 2 X 21 , —OCX 21 3 , —OCH 2 X 21 , —OCHX 21 2 , —CN, —SO n21 R 21D , —SO v21 NR 21A R 21B , —NHC(O)NR 21A R 21B , —N(O) m21 , —NR 21A R 21B , —C(O)R 21C , —C(O)OR 21C , —C(O)NR 21A R 21B , —OR 21D , SR 21D , —NR 21A SO 2 R 21D , —NR 21A C(O)R 21C , —NR 21A C(O)OR 21C , —NR 21A OR 21C , —N 3 , 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;

L 10.2 and L 10.3 are independently a bond, —NH—, —S—, —O—, —C(O)—, —C(O)O—, —OC(O)—, —NHC(O)—, —C(O)NH—, —NHC(O)O—, —OC(O)NH—, —NHC(O)NH—, —NHC(NH)NH—, —S(O) 2 —, —NHS(O) 2 —, —S(O) 2 NH—, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;

R 22 and R 23 are independently substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R 10.1A , R 10.1B , R 10.1C , R 10.1D , R 10.2A , R 10.2B , R 10.2C , R 10.2D , R 10.3A , R 10.3B , R 10.3C , R 10.3D , R 10.5A , R 10.5B , R 10.5C , R 10.5D , R 10.6A , R 10.6B , R 10.6C , R 10.6D , R 21A , R 21B , R 21C , R 21D , R 100A , R 100B , R 100C , and R 100D are independently hydrogen, halogen, —CCl 3 , —CBr 3 , —CF 3 , —CI 3 , —CH 2 Cl, —CH 2 Br, —CH 2 F, —CH 2 I, —CHCl 2 , —CHBr 2 , —CHF 2 , —CHI 2 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —OSO 3 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl 3 , —OCBr 3 , —OCF 3 , —OCI 3 , —OCH 2 Cl, —OCH 2 Br, —OCH 2 F, —OCH 2 I, —OCHCl 2 , —OCHBr 2 , —OCHF 2 , —OCHI 2 , —N 3 , 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; R 10.1A and R 10.1B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 10.2A and R 10.2B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 10.3A and R 10.3B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 10.5A and R 10.5B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 10.6A and R 10.6B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 21A and R 21B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 100A and R 100B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

n10.1, n10.2, n10.3, n10.5, n10.6, n21, and n100 are independently an integer from 0 to 4;

m10.1, m10.2, m10.3, m10.5, m10.6, m21, m100, v10.1, v10.2, v10.3, v10.5, v10.6, v21, and v100 are independently 1 or 2;

X 10.1 , X 10.2 , X 10.3 , X 10.5 , X 10.6 , X 21 , and X 100 are independently —F, —Cl, —Br, or —I;

z10.6 is an integer from 0 to 6;

z21 is an integer from 0 to 11; and

wherein at least one of R 10.1 or R 10.5 is not hydrogen.

9. A compound, or a pharmaceutically acceptable salt thereof or a prodrug thereof, having the formula:

wherein

R 2 is hydrogen or substituted or unsubstituted alkyl;

R 5 is hydrogen or unsubstituted C 1 -C 3 alkyl;

R 10.1 is hydrogen, halogen, —CX 10.1 3 , —CHX 10.1 2 , —CH 2 X 10.1 , —OCX 10.1 3 , —OCH 2 X 10.1 , —OCHX 10.1 2 , —CN, —SO n10.1 R 10.1D , —SO v10.1 NR 10.1A R 10.1B , —NHC(O)NR 10.1A R 10.1B , —N(O) m10.1 , —NR 10.1A R 10.1B , C(O)R 10.1C , —C(O)OR 10.1C , —C(O)NR 10.1A R 10.1B , —OR 10.1D , —SR 10.1D , —NR 10.1A SO 2 R 10.1D , —NR 10.1A C(O)R 10.1C , —NR 10.1A C(O)OR 10.1C , —NR 10.1A OR 10.1C , —N 3 , 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;

R 10.2 , R 10.3 , and R 10.4 are independently hydrogen, halogen, or —CF 3 ;

R 10.5 is hydrogen, halogen, —CX 10.5 3 , —CHX 10.5 2 , —CH 2 X 10.5 , —OCX 10.5 3 , —OCH 2 X 10.5 , —OCHX 10.5 2 , —CN, —SO n10.5 R 10.5D , SO v10.5 NR 10.5A R 10.5B , —NHC(O)NR 10.5A R 10.5B , —N(O) m10.5 , —NR 10.5A R 10.5B , —C(O)R 10.5C , —C(O)OR 10.5C , —C(O)NR 10.5A R 10.5B , —OR 10.5D , —SR 10.5D , —NR 10.5A SO 2 R 10.5D , —NR 10.5A C(O)R 10.5C , —NR 10.5A C(O)OR 10.5C , —NR 10.1A OR 10.5C , —N 3 , 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;

R 21 is independently oxo, halogen, —CX 21 3 , —CHX 21 2 , —CH 2 X 21 , —OCX 21 3 , —OCH 2 X 21 , —OCHX 21 2 , —CN, —SO n21 R 21D , —SO v21 NR 21A R 21B , —NHC(O)NR 21A R 21B , —N(O) m21 , —NR 21A R 21B , —C(O)R 21C , —C(O)OR 21C , —C(O)NR 21A R 21B , —OR 21D , —SR 21D , —NR 21A SO 2 R 21D , —NR 21A C(O)R 21C , —NR 21A C(O)OR 21C , —NR 21A OR 21C , —N 3 , 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;

R 100 is hydrogen, halogen, —CX 100 3 , —CHX 100 , —CH 2 X 100 , —OCX 100 3 , —OCH 2 X 100 , —OCHX 100 2 , —CN, —SO n100 R 100D , —SO v100 NR 100A R 100B , —NHC(O)NR 100A R 100B , —N(O) m100 , —NR 100A R 100B , —C(O)R 100C , —C(O)OR 100C , —C(O)NR 100A R 100B , —OR 100D , —SR 100D , —NR 100A SO 2 R 100D , —NR 100A C(O)R 100C , —NR 100A C(O)OR 100C , —NR 100A OR 100C , —N 3 , 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;

R 10.1A , R 10.1B , R 10.1C , R 10.1D , R 10.3A , R 10.3B , R 10.4A , R 10.4B , R 10.5A , R 10.5B , R 10.5C , R 10.5D , R 21A , R 21B , R 21C , R 21D , R 100A , R 100B , R 100C , and R 100D are independently hydrogen, halogen, —CCl 3 , —CBr 3 , —CF 3 , —CI 3 , —CH 2 Cl, —CH 2 Br, —CH 2 F, —CH 2 I, —CHCl 2 , —CHBr 2 , —CHF 2 , —CHI 2 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —OSO 3 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl 3 , —OCBr 3 , —OCF 3 , —OCI 3 , —OCH 2 Cl, —OCH 2 Br, —OCH 2 F, —OCH 2 I, —OCHCl 2 , —OCHBr 2 , —OCHF 2 , —OCHI 2 , —N 3 , 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; R 10.1A and R 10.1B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 10.3A and R 10.3B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 10.4A and R 10.4B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 10.5A and R 10.5B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 21A and R 21B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 100A and R 100B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

n10.1, n10.5, n21, and n100 are independently an integer from 0 to 4;

m10.1, m10.5, m21, m100, v10.1, v10.5, v21, and v100 are independently 1 or 2;

X 10.1 , X 10.5 , X 21 , and X 100 are independently —F, —Cl, —Br, or —I;

z21 is an integer from 0 to 9;

n is an integer from 0 to 3; and

wherein at least one of R 10.1 or R 10.5 is not hydrogen.

10. The compound of claim 1 , wherein

11. The compound of claim 1 , wherein R 2 is hydrogen or unsubstituted C 1 -C 3 alkyl.

12. The compound of claim 1 , wherein R 10.1 is halogen, substituted or unsubstituted C 1 -C 5 alkyl, or substituted or unsubstituted 2 to 5 membered heteroalkyl.

13. The compound of claim 1 , wherein R 10.1 is —Cl.

14. The compound of claim 1 , wherein L 10.3 is a bond, —NH—, —O—, —C(O)—, —NHC(O)O—, —NHS(O) 2 —,

15. The compound of claim 1 , wherein

R 23 is R 33 -substituted or unsubstituted cycloalkyl, R 33 -substituted or unsubstituted heterocycloalkyl, R 33 -substituted or unsubstituted aryl, or R 33 -substituted or unsubstituted heteroaryl; and

R 33 is independently oxo, halogen, —CCl 3 , —CBr 3 , —CF 3 , —CI 3 , —CH 2 Cl, —CH 2 Br, —CH 2 F, —CH 2 I, —CHCl 2 , —CHBr 2 , —CHF 2 , —CHI 2 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —OSO 3 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl 3 , —OCBr 3 , —OCF 3 , —OCI 3 , —OCH 2 Cl, —OCH 2 Br, —OCH 2 F, —OCH 2 I, —OCHCl 2 , —OCHBr 2 , —OCHF 2 , —OCHI 2 , —N 3 , 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.

16. The compound of claim 15 , wherein R 33 is independently halogen, —CF 3 , —OH, —NH 2 , substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted 2 to 5 membered heteroalkyl, or substituted or unsubstituted phenyl.

17. The compound of claim 1 , wherein R 23 is

18. The compound of claim 1 , wherein R 10.5 is hydrogen, halogen, substituted or unsubstituted C 1 -C 5 alkyl, or substituted or unsubstituted 2 to 5 membered heteroalkyl.

19. The compound of claim 1 , wherein R 10.5 is —Cl.

20. The compound of claim 1 , having the formula

Assignments (3)

CONFIRMATORY LICENSE Recorded Nov 14, 2023

From: UNIVERSITY OF CALIFORNIA SAN FRANCISCO

To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT

Reel/Frame 065565/0982 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 23, 2023

From: SHEPPARD, DEAN; DEGRADO, WILLIAM F.; SUNDARAM, APARNA; JO, HYUNIL

To: THE REGENTS OF THE UNIVERSITY OF CALIFORNIA

Reel/Frame 062455/0630 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 23, 2023

From: BERESIS, RICHARD; ADLER, MARC

To: SHANGPHARMA INNOVATION INC.

Reel/Frame 062455/0663 →

Continuity (2)

Provisional Application 63019023 · May 1, 2020

Related Publication 20220411366A1 · Dec 29, 2022