# US 10,500,194 B2 · Covalent small molecule DCN1 inhibitors and therapeutic methods using the same

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 10,500,194 B2
- Document ID: US10500194B2
- Status: Granted
- Kind: B2
- Application number: 15/949,799
- Filed: 2018-04-10
- Published: 2018-10-11
- Granted: 2019-12-10
- Earliest claimed: 2017-04-10
- Assignees: The Regents of the University of Michigan
- Applicants: The Regents of the University of Michigan
- Inventors: Shaomeng Wang; Haibin Zhou; Jianfeng Lu; Liu Liu; Jeanne Stuckey; Liangyou Rui; Yi Sun
- Web page: https://patentgrep.com/patent/US10500194B2

## CPC

- A61K 31/428: condensed with carbocyclic rings
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- C07D 277/64: with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- A61K 31/497: containing further heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Small molecule covalent inhibitors of DCN1 and compositions containing the same are disclosed. Methods of using the DCN1 covalent inhibitors in the treatment of diseases and conditions wherein inhibition of DCN1 provides a benefit, like oxidative stress-related diseases and conditions, neurodegenerative diseases and conditions, metabolic disorders, and muscular nerve degeneration, also are disclosed.

## Claims

### Claim 1

A compound having a structural formula (I)
wherein;
Q is C═O, C═S or SO2;
Ar1 is a five or six-membered aromatic or heteroaromatic ring or a bicyclic aromatic or heteroaromatic ring having 8-12 atoms, including up to four heteroatoms chosen from N, O and S, in a chemically stable arrangement, optionally substituted with up to four R2 substituents;
T is halogen, SS—C1-6 lower alkyl, pentafluorophenoxy, tetrafluorophenoxy:
X is selected from a bond, CR7R8, CR7R8NR12, CR7R8NR12CO, CR7R8NR12CONR12, CR7R8NR12SO2, CR7R8O, CR7R8S(O)x CONR12;
Y is selected from C1-6 alkylidyl, C3-6 cycloalkylidyl, C4-7 heterocloalkylidyl, arylene, heteroarylene, aryl(m)ethylene, heteroaryl(m)ethylene, fused C5-8 bicycloalkylidyl or C5-9 spirocycloalkylidyl;
or Y and R9 are taken together with the nitrogen atom to which they are attached to form a heterocyclic or heteroaryl ring of four to seven members, optionally including any chemically stable combination of one to three groups selected from O, C═O, N, NR5 and S;
Z is
R1 is selected from the group consisting of H, C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkylmethylene, NHMe, N(Me)2, NHEt, NH-cyclopropyl, OMe, OEt, O-cyclopropyl;
R2 are independently selected from the group consisting of halo, CN, N3, CF3, NO2, H, C1-6 alkyl, substituted C1-6 alkyl, C2-6 alkenyl, substituted C2-6 alkenyl, C2-6 alkynyl, substituted C2-6 alkynyl, C3-6 cycloalkyl, substituted C3-6 cycloalkyl, C4-6 cycloalkenyl substituted C4-6 cycloalkenyl, C4-7 heterocycloalkyl, phenyl, substituted phenyl, monocyclic heteroaryl, substituted monocyclic heteroaryl, OR5, NR3R4, COOR5, CONR3R4;
R3 and R4, independently, are selected from the group consisting of hydrogen, C1-6 alkyl, allyl, C3-6 cycloalkyl, C4-7 heterocyclyl, aryl, heteroaryl, C1-6 alkyl-C3-6 cycloalkyl, C1-6 alkyl-C4-6 cycloalkenyl, C1-6 alkyl-C4-6 heterocycloalkyl, C1-6 alkaryl, C1-6 alkyl-heteroaryl, C1-6 acyl, C3-6 cycloalkylcarbonyl, C4-7 heterocycloalkylcarbonyl, aroyl, heteroaroyl, or are taken together with the nitrogen atom to which they are attached to form a ring of four to seven members, optionally including any chemically stable combination of one to three O, C═O, NR5 and S;
R5 is selected from the group consisting of hydrogen, CF3, CHF2, C1-6 alkyl, allyl, propargyl, C3-6 cycloalkyl, C1-6 alkyl-C4-6 cycloalkenyl, C4-7 heterocycloalkyl, aryl, heteroaryl, C1-6 alkyl-C3-6 cycloalkyl, C1-6 alkyl-C4-7 heterocycloalkyl, C1-6 alkaryl, C1-6 alkyl-heteroaryl, C1-6 acyl, C3-6 cycloalkylcarbonyl, C4-7 heterocycloalkylcarbonyl, aroyl, heteroaroyl, each optionally substituted with up to three substituents independently selected from halo, hydroxy, oxo, thio, thiono, amino, cyano, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, C1-6 dialkylamino, C4-7 heterocycloalkyl, aryl, and heteroaryl;
R6 is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, C2-6 alkenyl, C4-6 cycloalkenyl, C4-7 heterocycloalkyl, C2-6 alkynyl, C1-6 alkyl-C3-6 cycloalkyl, C1-6 alkyl-C4-6 cycloalkenyl, C1-6 alkyl-C4-7 heterocycloalkyl, aryl, C1-6 alkylaryl, heteroaryl, C1-6 alkyl-heteroaryl, C5-10 bicycloalkyl and C1-6 alkyl-C5-10 bicycloalkyl;
R7 and R8 may be independently H, C1-6 alkyl, substituted C1-6 alkyl, C2-6 alkenyl, substituted C2-6 alkenyl, C2-6 alkynyl, substituted C2-6 alkynyl, or taken together with the C atom to which they are attached, form a carbonyl group, a thionyl group, an oxime, a hydrazone, C3-6 cycloalkyl, substituted C3-6 cycloalkyl, C4-6 cycloalkenyl substituted C4-6 cycloalkenyl or C4-7 heterocycloalkyl:
R9 is selected from the group consisting of H, C1-6 alkyl, substituted C1-6 alkyl, C3-6 alkenyl, substituted C3-6 alkenyl, C3-6 alkynyl, substituted C3-6 alkynyl, C3-6 cycloalkyl, substituted C3-6 cycloalkyl, C4-6 cycloalkenyl substituted C4-6 cycloalkenyl, phenyl, substituted phenyl, monocyclic heteroaryl, substituted monocyclic heteroaryl or C4-7 heterocycloalkyl:
R10 is H, F, Cl, CF3, CHF2, (CH2)nNR3R4, CH2SO2R12, CH2OCOR12, CN or R12;
R11e is H, R12, (CH2)nR2, CF2(CH2)xR2, COR5, CO2R5 or CONR3R4;
R11z is H, F, Cl, CF3, CHF2, CF2R12 or R12;
or R11e and R11z may be taken together with the sp2 carbon atom to which both are bonded to form an alicyclic ring of 4 to 7 members where one of the ring atoms may be NR12, O, or S(O)x, optionally substituted with halogen, oxo, OH, OR5, NR3R4;
or R11e and R11z taken together may be R11eR11zC═, forming an allenyl group;
or R10 and R11e may be taken together with the sp2 C atoms to which they are attached to form a partially saturated carbocyclic or heterocyclic ring of 5-7 atoms, with up to two of the ring atoms being O, S(O)x, NR12, and said ring may be substituted with hydroxy, oxo, C1-6 alkoxy,
R11t is C1-6 alkyl, C3-6 cycloalkyl, aryl, heteroaryl, C4-7 heterocycloalkyl, CH2NR3R4;
R12 is H or C1-6 alkyl, either straight chain or branched;
n is 1, 2 or 3;
x is 0, 1, or 2;
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

### Claim 2 (depends on 1)

The compound of claim 1
wherein;
Q is C═O;
Ar1 is a five or six-membered aromatic or heteroaromatic ring or a bicyclic aromatic or heteroaromatic ring having 8-12 atoms, including up to four heteroatoms chosen from N, O and S, in a chemically stable arrangement, optionally substituted with up to four R2 substituents;
T is halogen:
X is selected from a bond, CR7R8, CR7R8NR12, CR7R8NR12CO, CR7R8NR12CONR12, CR7R8NR12SO2, CR7R8O, CR7R8S(O)x CONR12;
Y is selected from C1-6 alkylidyl, C3-6 cycloalkylidyl, C4-7 heterocloalkylidyl, arylene, heteroarylene, aryl(m)ethylene, heteroaryl(m)ethylene;
or Y and R9 are taken together with the nitrogen atom to which they are attached to form a heterocyclic or heteroaryl ring of four to seven members, optionally including any chemically stable combination of one to three groups selected from O, C═O, N, NR5 and S;
Z is
R1 is selected from the group consisting of H, C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkylmethylene, NHMe, N(Me)2, NHEt, NH-cyclopropyl, OMe, OEt, O-cyclopropyl;
R2 are independently selected from the group consisting of halo, CN, N3, CF3, NO2, H, C1-6 alkyl, substituted C1-6 alkyl, C2-6 alkenyl, substituted C2-6 alkenyl, C2-6 alkynyl, substituted C2-6 alkynyl, C3-6 cycloalkyl, substituted C3-6 cycloalkyl, C4-6 cycloalkenyl substituted C4-6 cycloalkenyl, C4-7 heterocycloalkyl, phenyl, substituted phenyl, monocyclic heteroaryl, substituted monocyclic heteroaryl, OR5, NR3R4, COOR5, CONR3R4;
R3 and R4, independently, are selected from the group consisting of hydrogen, C1-6 alkyl, allyl, C3-6 cycloalkyl, C4-7 heterocyclyl, aryl, heteroaryl, C1-6 alkyl-C3-6 cycloalkyl, C1-6 alkyl-C4-6 cycloalkenyl, C1-6 alkyl-C4-6 heterocycloalkyl, C1-6 alkaryl, C1-6 alkyl-heteroaryl, C1-6 acyl, C3-6 cycloalkylcarbonyl, C4-7 heterocycloalkylcarbonyl, aroyl, heteroaroyl, or are taken together with the nitrogen atom to which they are attached to form a ring of four to seven members, optionally including any chemically stable combination of one to three O, C═O, NR5 and S;
R5 is selected from the group consisting of hydrogen, CF3, CHF2, C1-6 alkyl, allyl, propargyl, C3-6 cycloalkyl, C1-6 alkyl-C4-6 cycloalkenyl, C4-7 heterocycloalkyl, aryl, heteroaryl, C1-6 alkyl-C3-6 cycloalkyl, C1-6 alkyl-C4-7 heterocycloalkyl, C1-6 alkaryl, C1-6 alkyl-heteroaryl, C1-6 acyl, C3-6 cycloalkylcarbonyl, C4-7 heterocycloalkylcarbonyl, aroyl, heteroaroyl, each optionally substituted with up to three substituents independently selected from halo, hydroxy, oxo, thio, thiono, amino, cyano, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, C1-6 dialkylamino, C4-7 heterocycloalkyl, aryl, and heteroaryl;
R6 is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, C2-6 alkenyl, C4-6 cycloalkenyl, C4-7 heterocycloalkyl, C2-6 alkynyl, C1-6 alkyl-C3-6 cycloalkyl, C1-6 alkyl-C4-6 cycloalkenyl, C1-6 alkyl-C4-7 heterocycloalkyl, aryl, C1-6 alkylaryl, heteroaryl, C1-6 alkyl-heteroaryl, C5-10 bicycloalkyl and C1-6 alkyl-C5-10 bicycloalkyl;
R7 and R8 may be independently H, C1-6 alkyl, substituted C1-6 alkyl, C2-6 alkenyl, substituted C2-6 alkenyl, C2-6 alkynyl, substituted C2-6 alkynyl, or taken together with the C atom to which they are attached, form a carbonyl group, a thionyl group, an oxime, a hydrazone, C3-6 cycloalkyl, substituted C3-6 cycloalkyl, C4-6 cycloalkenyl substituted C4-6 cycloalkenyl or C4-7 heterocycloalkyl:
R9 is selected from the group consisting of H, C1-6 alkyl, substituted C1-6 alkyl, C3-6 alkenyl, substituted C3-6 alkenyl, C3-6 alkynyl, substituted C3-6 alkynyl, C3-6 cycloalkyl, substituted C3-6 cycloalkyl, C4-6 cycloalkenyl substituted C4-6 cycloalkenyl, phenyl, substituted phenyl, monocyclic heteroaryl, substituted monocyclic heteroaryl or C4-7 heterocycloalkyl:
R10 is H, F, CF3, CHF2, (CH2)nNR3R4, CN or R12;
R11e is H, R12, (CH2)nR2, CF2(CH2)xR2, COR5, CO2R5 or CONR3R4;
R11z is H, F, Cl, CF3, CHF2;
Or R11e and R11z may be taken together with the sp2 carbon atom to which both are bonded to form an alicyclic ring of 4 to 7 members where one of the ring atoms may be NR12, O, or S(O)x, optionally substituted with halogen, oxo, OH, OR5, NR3R4;
or R10 and R11e may be taken together with the sp2 C atoms to which they are attached to form a partially saturated carbocyclic or heterocyclic ring of 5-7 atoms, with up to two of the ring atoms being O, S(O)x, NR12, and said ring may be substituted with hydroxy, oxo, C1-6 alkoxy,
R11t is C1-6 alkyl, C3-6 cycloalkyl, C4-7 heterocycloalkyl, CH2NR3R4;
R12 is H or C1-6 alkyl, either straight chain or branched;
n is 1, 2 or 3;
x is 0, 1, or 2;
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

### Claim 3 (depends on 1)

The compound of claim 1
wherein;
Ar1 is a five or six-membered aromatic or heteroaromatic ring or a bicyclic aromatic or heteroaromatic ring having 8-12 atoms, including up to four heteroatoms chosen from N, O and S, in a chemically stable arrangement, optionally substituted with up to four R2 substituents;
T is halogen:
X—Y is selected from the group consisting of:
such that Ar2 is monocyclic arylene or heteroarylene;
Z is
R1 is selected from the group consisting of H, C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkylmethylene, NHMe, N(Me)2, NHEt, NH-cyclopropyl, OMe, OEt, O-cyclopropyl;
R2 are independently selected from the group consisting of halo, CN, N3, CF3, NO2, H, C1-6 alkyl, substituted C1-6 alkyl, C2-6 alkenyl, substituted C2-6 alkenyl, C2-6 alkynyl, substituted C2-6 alkynyl, C3-6 cycloalkyl, substituted C3-6 cycloalkyl, C4-6 cycloalkenyl substituted C4-6 cycloalkenyl, C4-7 heterocycloalkyl, phenyl, substituted phenyl, monocyclic heteroaryl, substituted monocyclic heteroaryl, OR5, NR3R4, COOR5, CONR3R4;
R3 and R4, independently, are selected from the group consisting of hydrogen, C1-6 alkyl, allyl, C3-6 cycloalkyl, C4-7 heterocyclyl, aryl, heteroaryl, C1-6 alkyl-C3-6 cycloalkyl, C1-6 alkyl-C4-6 cycloalkenyl, C1-6 alkyl-C4-6 heterocycloalkyl, C1-6 alkaryl, C1-6 alkyl-heteroaryl, C1-6 acyl, C3-6 cycloalkylcarbonyl, C4-7 heterocycloalkylcarbonyl, aroyl, heteroaroyl, or are taken together with the nitrogen atom to which they are attached to form a ring of four to seven members, optionally including any chemically stable combination of one to three O, C═O, NR5 and S;
R5 is selected from the group consisting of hydrogen, CF3, CHF2, C1-6 alkyl, allyl, propargyl, C3-6 cycloalkyl, C1-6 alkyl-C4-6 cycloalkenyl, C4-7 heterocycloalkyl, aryl, heteroaryl, C1-6 alkyl-C3-6 cycloalkyl, C1-6 alkyl-C4-7 heterocycloalkyl, C1-6 alkaryl, C1-6 alkyl-heteroaryl, C1-6 acyl, C3-6 cycloalkylcarbonyl, C4-7 heterocycloalkylcarbonyl, aroyl, heteroaroyl, each optionally substituted with up to three substituents independently selected from halo, hydroxy, oxo, thio, thiono, amino, cyano, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, C1-6 dialkylamino, C4-7 heterocycloalkyl, aryl, and heteroaryl;
R6 is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, C2-6 alkenyl, C4-6 cycloalkenyl, C4-7 heterocycloalkyl, C2-6 alkynyl, C1-6 alkyl-C3-6 cycloalkyl, C1-6 alkyl-C4-6 cycloalkenyl, C1-6 alkyl-C4-7 heterocycloalkyl, aryl, C1-6 alkylaryl, heteroaryl, C1-6 alkyl-heteroaryl, C5-10 bicycloalkyl and C1-6 alkyl-C5-10 bicycloalkyl;
R9 is selected from the group consisting of H, C1-6 alkyl, substituted C1-6 alkyl, C3-6 alkenyl, substituted C3-6 alkenyl, C3-6 alkynyl, substituted C3-6 alkynyl, C3-6 cycloalkyl, substituted C3-6 cycloalkyl, C4-6 cycloalkenyl substituted C4-6 cycloalkenyl, phenyl, substituted phenyl, monocyclic heteroaryl, substituted monocyclic heteroaryl or C4-7 heterocycloalkyl:
R10 is H, (CH2)nNR3R4, CN or R12;
R11e is H, R12, or (CH2)nNR3R4;
R11z is H, F, Cl, CF3, CHF2;
Or R10 and R11e may be taken together with the sp2 C atoms to which they are attached to form a partially saturated carbocyclic or heterocyclic ring of 5-7 atoms, with up to two of the ring atoms being O, S(O)x, NR12, and said ring may be substituted with hydroxy, oxo, C1-6 alkoxy,
R11t is C1-6 alkyl, C3-6 cycloalkyl, C4-7 heterocycloalkyl, CH2NR3R4;
R12 is H or C1-6 alkyl, either straight chain or branched;
l is 2-4;
m is 2-6;
n is 1, 2 or 3;
x is independently 0, 1, or 2;
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

### Claim 4 (depends on 1)

The compound of claim 1
wherein;
Q is C═O;
Ar1 is a five or six-membered aromatic or heteroaromatic ring or a bicyclic aromatic or heteroaromatic ring having 8-12 atoms, including up to four heteroatoms chosen from N, O and S, in a chemically stable arrangement, optionally substituted with up to four R2 substituents;
T is halogen:
X, Y and R9 are taken together with the nitrogen atom to which they are attached to form a ring which selected from the group consisting of:
R1 is selected from the group consisting of H, C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkylmethylene, NHMe, N(Me)2, NHEt, NH-cyclopropyl, OMe, OEt, O-cyclopropyl;
R2 are independently selected from the group consisting of halo, CN, N3, CF3, NO2, H, C1-6 alkyl, substituted C1-6 alkyl, C2-6 alkenyl, substituted C2-6 alkenyl, C2-6 alkynyl, substituted C2-6 alkynyl, C3-6 cycloalkyl, substituted C3-6 cycloalkyl, C4-6 cycloalkenyl substituted C4-6 cycloalkenyl, C4-7 heterocycloalkyl, phenyl, substituted phenyl, monocyclic heteroaryl, substituted monocyclic heteroaryl, OR5, NR3R4, COOR5, CONR3R4;
R3 and R4, independently, are selected from the group consisting of hydrogen, C1-6 alkyl, allyl, C3-6 cycloalkyl, C4-7 heterocyclyl, aryl, heteroaryl, C1-6 alkyl-C3-6 cycloalkyl, C1-6 alkyl-C4-6 cycloalkenyl, C1-6 alkyl-C4-6 heterocycloalkyl, C1-6 alkaryl, C1-6 alkyl-heteroaryl, C1-6 acyl, C3-6 cycloalkylcarbonyl, C4-7 heterocycloalkylcarbonyl, aroyl, heteroaroyl, or are taken together with the nitrogen atom to which they are attached to form a ring of four to seven members, optionally including any chemically stable combination of one to three O, C═O, NR5 and S;
R5 is selected from the group consisting of hydrogen, CF3, CHF2, C1-6 alkyl, allyl, propargyl, C3-6 cycloalkyl, C1-6 alkyl-C4-6 cycloalkenyl, C4-7 heterocycloalkyl, aryl, heteroaryl, C1-6 alkyl-C3-6 cycloalkyl, C1-6 alkyl-C4-7 heterocycloalkyl, C1-6 alkaryl, C1-6 alkyl-heteroaryl, C1-6 acyl, C3-6 cycloalkylcarbonyl, C4-7 heterocycloalkylcarbonyl, aroyl, heteroaroyl, each optionally substituted with up to three substituents independently selected from halo, hydroxy, oxo, thio, thiono, amino, cyano, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, C1-6 dialkylamino, C4-7 heterocycloalkyl, aryl, and heteroaryl;
R6 is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, C2-6 alkenyl, C4-6 cycloalkenyl, C4-7 heterocycloalkyl, C2-6 alkynyl, C1-6 alkyl-C3-6 cycloalkyl, C1-6 alkyl-C4-6 cycloalkenyl, C1-6 alkyl-C4-7 heterocycloalkyl, aryl, C1-6 alkylaryl, heteroaryl, C1-6 alkyl-heteroaryl, C5-10 bicycloalkyl and C1-6 alkyl-C5-10 bicycloalkyl;
R10 is H, (CH2)nNR3R4, CN or R12;
R11e is H, R12, or (CH2)nNR3R4;
R11z is H, F, Cl, CF3, CHF2;
or R10 and R11e may be taken together with the sp2 C atoms to which they are attached to form a partially saturated carbocyclic or heterocyclic ring of 5-7 atoms, with up to two of the ring atoms being O, S(O)x, NR12, and said ring may be substituted with hydroxy, oxo, C1-6 alkoxy,
R11t is C1-6 alkyl, C3-6 cycloalkyl, C4-7 heterocycloalkyl, CH2NR3R4;
R12 is H or C1-6 alkyl, either straight chain or branched;
m is 2-6;
n is 1, 2 or 3;
x is independently 0, 1, or 2;
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

### Claim 5 (depends on 1)

The compound of claim 1
wherein;
Q is C═O;
Ar1 is a five or six-membered aromatic or heteroaromatic ring or a bicyclic aromatic or heteroaromatic ring having 8-12 atoms, including up to four heteroatoms chosen from N, O and S, in a chemically stable arrangement, optionally substituted with up to four R2 substituents;
X—Y is selected from the group consisting of:
such that Ar2 is monocyclic arylene or heteroarylene;
Z is
R1 is selected from the group consisting of H, C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkylmethylene, NHMe, N(Me)2, NHEt, NH-cyclopropyl, OMe, OEt, O-cyclopropyl;
R2 are independently selected from the group consisting of halo, CN, N3, CF3, NO2, H, C1-6 alkyl, substituted C1-6 alkyl, C2-6 alkenyl, substituted C2-6 alkenyl, C2-6 alkynyl, substituted C2-6 alkynyl, C3-6 cycloalkyl, substituted C3-6 cycloalkyl, C4-6 cycloalkenyl substituted C4-6 cycloalkenyl, C4-7 heterocycloalkyl, phenyl, substituted phenyl, monocyclic heteroaryl, substituted monocyclic heteroaryl, OR5, NR3R4, COOR5, CONR3R4;
R3 and R4, independently, are selected from the group consisting of hydrogen, C1-6 alkyl, allyl, C3-6 cycloalkyl, C4-7 heterocyclyl, aryl, heteroaryl, C1-6 alkyl-C3-6 cycloalkyl, C1-6 alkyl-C4-6 cycloalkenyl, C1-6 alkyl-C4-6 heterocycloalkyl, C1-6 alkaryl, C1-6 alkyl-heteroaryl, C1-6 acyl, C3-6 cycloalkylcarbonyl, C4-7 heterocycloalkylcarbonyl, aroyl, heteroaroyl, or are taken together with the nitrogen atom to which they are attached to form a ring of four to seven members, optionally including any chemically stable combination of one to three O, C═O, NR5 and S;
R5 is selected from the group consisting of hydrogen, CF3, CHF2, C1-6 alkyl, allyl, propargyl, C3-6 cycloalkyl, C1-6 alkyl-C4-6 cycloalkenyl, C4-7 heterocycloalkyl, aryl, heteroaryl, C1-6 alkyl-C3-6 cycloalkyl, C1-6 alkyl-C4-7 heterocycloalkyl, C1-6 alkaryl, C1-6 alkyl-heteroaryl, C1-6 acyl, C3-6 cycloalkylcarbonyl, C4-7 heterocycloalkylcarbonyl, aroyl, heteroaroyl, each optionally substituted with up to three substituents independently selected from halo, hydroxy, oxo, thio, thiono, amino, cyano, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, C1-6 dialkylamino, C4-7 heterocycloalkyl, aryl, and heteroaryl;
R6 is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, C2-6 alkenyl, C4-6 cycloalkenyl, C4-7 heterocycloalkyl, C2-6 alkynyl, C1-6 alkyl-C3-6 cycloalkyl, C1-6 alkyl-C4-6 cycloalkenyl, C1-6 alkyl-C4-7 heterocycloalkyl, aryl, C1-6 alkylaryl, heteroaryl, C1-6 alkyl-heteroaryl, C5-10 bicycloalkyl and C1-6 alkyl-C5-10 bicycloalkyl;
R9 is H; or
R10 is H, CN or CH2NR3R4;
R11e and R11z are H or one may be R12;
R12 is H or C1-6 alkyl, either straight chain or branched;
l is 2-4;
m is 2-6;
n is 1, 2 or 3;
x is independently 0, 1, or 2;
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

### Claim 6 (depends on 1)

The compound of claim 1
wherein;
Q is C═O;
Ar1 is a five or six-membered aromatic or heteroaromatic ring or a bicyclic aromatic or heteroaromatic ring having 8-12 atoms, including up to four heteroatoms chosen from N, O and S, in a chemically stable arrangement, optionally substituted with up to four R2 substituents;
X, Y and R9 are taken together with the nitrogen atom to which they are attached to form a ring which selected from the group consisting of:
Z is
R1 is selected from the group consisting of H, C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkylmethylene, NHMe, N(Me)2, NHEt, NH-cyclopropyl, OMe, OEt, O-cyclopropyl;
R2 are independently selected from the group consisting of halo, CN, N3, CF3, NO2, H, C1-6 alkyl, substituted C1-6 alkyl, C2-6 alkenyl, substituted C2-6 alkenyl, C2-6 alkynyl, substituted C2-6 alkynyl, C3-6 cycloalkyl, substituted C3-6 cycloalkyl, C4-6 cycloalkenyl substituted C4-6 cycloalkenyl, C4-7 heterocycloalkyl, phenyl, substituted phenyl, monocyclic heteroaryl, substituted monocyclic heteroaryl, OR5, NR3R4, COOR5, CONR3R4;
R3 and R4, independently, are selected from the group consisting of hydrogen, C1-6 alkyl, allyl, C3-6 cycloalkyl, C4-7 heterocyclyl, aryl, heteroaryl, C1-6 alkyl-C3-6 cycloalkyl, C1-6 alkyl-C4-6 cycloalkenyl, C1-6 alkyl-C4-6 heterocycloalkyl, C1-6 alkaryl, C1-6 alkyl-heteroaryl, C1-6 acyl, C3-6 cycloalkylcarbonyl, C4-7 heterocycloalkylcarbonyl, aroyl, heteroaroyl, or are taken together with the nitrogen atom to which they are attached to form a ring of four to seven members, optionally including any chemically stable combination of one to three O, C═O, NR5 and S;
R5 is selected from the group consisting of hydrogen, CF3, CHF2, C1-6 alkyl, allyl, propargyl, C3-6 cycloalkyl, C1-6 alkyl-C4-6 cycloalkenyl, C4-7 heterocycloalkyl, aryl, heteroaryl, C1-6 alkyl-C3-6 cycloalkyl, C1-6 alkyl-C4-7 heterocycloalkyl, C1-6 alkaryl, C1-6 alkyl-heteroaryl, C1-6 acyl, C3-6 cycloalkylcarbonyl, C4-7 heterocycloalkylcarbonyl, aroyl, heteroaroyl, each optionally substituted with up to three substituents independently selected from halo, hydroxy, oxo, thio, thiono, amino, cyano, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, C1-6 dialkylamino, C4-7 heterocycloalkyl, aryl, and heteroaryl;
R6 is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, C2-6 alkenyl, C4-6 cycloalkenyl, C4-7 heterocycloalkyl, C2-6 alkynyl, C1-6 alkyl-C3-6 cycloalkyl, C1-6 alkyl-C4-6 cycloalkenyl, C1-6 alkyl-C4-7 heterocycloalkyl, aryl, C1-6 alkylaryl, heteroaryl, C1-6 alkyl-heteroaryl, C5-10 bicycloalkyl and C1-6 alkyl-C5-10 bicycloalkyl;
R10 is H, CN or CH2NR3R4;
R11e and R11z are H or one may be R12;
R12 is H or C1-6 alkyl, either straight chain or branched;
m is 2-6;
n is 1, 2 or 3;
x is independently 0, 1, or 2;
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

### Claim 7 (depends on 1)

The compound of claim 1 of Formula (II)
wherein:
Ar1 is a five or six-membered aromatic or heteroaromatic ring or a bicyclic aromatic or heteroaromatic ring having 8-12 atoms, including up to four heteroatoms chosen from N, O and S, in a chemically stable arrangement, optionally substituted with up to four R2 substituents;
R1 is selected from the group consisting of H, C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkylmethylene, NHMe, N(Me)2, NHEt, NH-cyclopropyl, OMe, OEt, O-cyclopropyl;
R2 are independently selected from the group consisting of halo, CN, N3, CF3, NO2, H, C1-6 alkyl, substituted C1-6 alkyl, C2-6 alkenyl, substituted C2-6 alkenyl, C2-6 alkynyl, substituted C2-6 alkynyl, C3-6 cycloalkyl, substituted C3-6 cycloalkyl, C4-6 cycloalkenyl substituted C4-6 cycloalkenyl, C4-7 heterocycloalkyl, phenyl, substituted phenyl, monocyclic heteroaryl, substituted monocyclic heteroaryl, OR5, NR3R4, COOR5, CONR3R4;
R3 and R4, independently, are selected from the group consisting of hydrogen, C1-6 alkyl, allyl, C3-6 cycloalkyl, C4-7 heterocyclyl, aryl, heteroaryl, C1-6 alkyl-C3-6 cycloalkyl, C1-6 alkyl-C4-6 cycloalkenyl, C1-6 alkyl-C4-6 heterocycloalkyl, C1-6 alkaryl, C1-6 alkyl-heteroaryl, C1-6 acyl, C3-6 cycloalkylcarbonyl, C4-7 heterocycloalkylcarbonyl, aroyl, heteroaroyl, or are taken together with the nitrogen atom to which they are attached to form a ring of four to seven members, optionally including any chemically stable combination of one to three O, C═O, NR5 and S;
R5 is selected from the group consisting of hydrogen, CF3, CHF2, C1-6 alkyl, allyl, propargyl, C3-6 cycloalkyl, C1-6 alkyl-C4-6 cycloalkenyl, C4-7 heterocycloalkyl, aryl, heteroaryl, C1-6 alkyl-C3-6 cycloalkyl, C1-6 alkyl-C4-7 heterocycloalkyl, C1-6 alkaryl, C1-6 alkyl-heteroaryl, C1-6 acyl, C3-6 cycloalkylcarbonyl, C4-7 heterocycloalkylcarbonyl, aroyl, heteroaroyl, each optionally substituted with up to three substituents independently selected from halo, hydroxy, oxo, thio, thiono, amino, cyano, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, C1-6 dialkylamino, C4-7 heterocycloalkyl, aryl, and heteroaryl;
R6 is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, C2-6 alkenyl, C4-6 cycloalkenyl, C4-7 heterocycloalkyl, C2-6 alkynyl, C1-6 alkyl-C3-6 cycloalkyl, C1-6 alkyl-C4-6 cycloalkenyl, C1-6 alkyl-C4-7 heterocycloalkyl, aryl, C1-6 alkylaryl, heteroaryl, C1-6 alkyl-heteroaryl, C5-10 bicycloalkyl and C1-6 alkyl-C5-10 bicycloalkyl;
R9 is selected from the group consisting of H, C1-6 alkyl, substituted C1-6 alkyl, C3-6 alkenyl, substituted C3-6 alkenyl, C3-6 alkynyl, substituted C3-6 alkynyl, C3-6 cycloalkyl, substituted C3-6 cycloalkyl, C4-6 cycloalkenyl substituted C4-6 cycloalkenyl, phenyl, substituted phenyl, monocyclic heteroaryl, substituted monocyclic heteroaryl or C4-7 heterocycloalkyl:
R10 is H, F, Cl, CF3, CHF2, (CH2)nNR3R4, CH2SO2R12, CH2OCOR12, CN or R12;
R11e is H, R12, (CH2)nR2, CF2(CH2)xR2, COR5, CO2R5 or CONR3R4;
R11z is H, F, Cl, CF3, CHF2, CF2R12 or R12;
Or R11e and R11z may be taken together with the sp2 carbon atom to which both are bonded to form an alicyclic ring of 4 to 7 members where one of the ring atoms may be NR12, O, or S(O)x, optionally substituted with halogen, oxo, OH, OR5, NR3R4;
or R11e and R11z taken together may be R11eR11zC═, forming an allenyl group;
or R10 and R11e may be taken together with the sp2 C atoms to which they are attached to form a partially saturated carbocyclic or heterocyclic ring of 5-7 atoms, with up to two of the ring atoms being O, S(O)x, NR12, and said ring may be substituted with hydroxy, oxo, C1-6 alkoxy,
R11z is C1-6 alkyl, C3-6 cycloalkyl, aryl, heteroaryl, C4-7 heterocycloalkyl, CH2NR3R4;
R12 is H or C1-6 alkyl, either straight chain or branched;
n is 1, 2 or 3;
x is 0, 1, or 2;
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

### Claim 8 (depends on 1)

The compound of claim 1 of Formula (III)
wherein:
Ar1 is a five or six-membered aromatic or heteroaromatic ring or a bicyclic aromatic or heteroaromatic ring having 8-12 atoms, including up to four heteroatoms chosen from N, O and S, in a chemically stable arrangement, optionally substituted with up to four R2 substituents;
R1 is selected from the group consisting of H, C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkylmethylene, NHMe, N(Me)2, NHEt, NH-cyclopropyl, OMe, OEt, O-cyclopropyl;
R2 are independently selected from the group consisting of halo, CN, N3, CF3, NO2, H, C1-6 alkyl, substituted C1-6 alkyl, C2-6 alkenyl, substituted C2-6 alkenyl, C2-6 alkynyl, substituted C2-6 alkynyl, C3-6 cycloalkyl, substituted C3-6 cycloalkyl, C4-6 cycloalkenyl substituted C4-6 cycloalkenyl, C4-7 heterocycloalkyl, phenyl, substituted phenyl, monocyclic heteroaryl, substituted monocyclic heteroaryl, OR5, NR3R4, COOR5, CONR3R4;
R3 and R4, independently, are selected from the group consisting of hydrogen, C1-6 alkyl, allyl, C3-6 cycloalkyl, C4-7 heterocyclyl, aryl, heteroaryl, C1-6 alkyl-C3-6 cycloalkyl, C1-6 alkyl-C4-6 cycloalkenyl, C1-6 alkyl-C4-6 heterocycloalkyl, C1-6 alkaryl, C1-6 alkyl-heteroaryl, C1-6 acyl, C3-6 cycloalkylcarbonyl, C4-7 heterocycloalkylcarbonyl, aroyl, heteroaroyl, or are taken together with the nitrogen atom to which they are attached to form a ring of four to seven members, optionally including any chemically stable combination of one to three O, C═O, NR5 and S;
R5 is selected from the group consisting of hydrogen, CF3, CHF2, C1-6 alkyl, allyl, propargyl, C3-6 cycloalkyl, C1-6 alkyl-C4-6 cycloalkenyl, C4-7 heterocycloalkyl, aryl, heteroaryl, C1-6 alkyl-C3-6 cycloalkyl, C1-6 alkyl-C4-7 heterocycloalkyl, C1-6 alkaryl, C1-6 alkyl-heteroaryl, C1-6 acyl, C3-6 cycloalkylcarbonyl, C4-7 heterocycloalkylcarbonyl, aroyl, heteroaroyl, each optionally substituted with up to three substituents independently selected from halo, hydroxy, oxo, thio, thiono, amino, cyano, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, C1-6 dialkylamino, C4-7 heterocycloalkyl, aryl, and heteroaryl;
R6 is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, C2-6 alkenyl, C4-6 cycloalkenyl, C4-7 heterocycloalkyl, C2-6 alkynyl, C1-6 alkyl-C3-6 cycloalkyl, C1-6 alkyl-C4-6 cycloalkenyl, C1-6 alkyl-C4-7 heterocycloalkyl, aryl, C1-6 alkylaryl, heteroaryl, C1-6 alkyl-heteroaryl, C5-10 bicycloalkyl and C1-6 alkyl-C5-10 bicycloalkyl;
R9 is selected from the group consisting of H, C1-6 alkyl, substituted C1-6 alkyl, C3-6 alkenyl, substituted C3-6 alkenyl, C3-6 alkynyl, substituted C3-6 alkynyl, C3-6 cycloalkyl, substituted C3-6 cycloalkyl, C4-6 cycloalkenyl substituted C4-6 cycloalkenyl, phenyl, substituted phenyl, monocyclic heteroaryl, substituted monocyclic heteroaryl or C4-7 heterocycloalkyl:
n is 1, 2 or 3;
x is 0, 1, or 2;
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

### Claim 9 (depends on 8)

The compound of claim 8 of Formula (III)
wherein:
Ar1 is benzothiazol-2-yl, benzoxazol-2-yl, naphth-2-yl, 4-methyl-5-phenylthiazole, 4-methyl-5-phenyloxazole and imidazo[1,2-a]pyrid-2-yl, whereby each 6-membered aromatic ring in may be substituted with up to two R2 substituents selected from C1-6 lower alkyl, CF3, and halogen;
R1 is methyl, ethyl, methylamino, cyclopropyl, isopropyl or n-propyl;
R3 and R4, independently, are selected from the group consisting of C1-6 alkyl, allyl, C3-6 cycloalkyl, C4-7 heterocyclyl, or are taken together with the nitrogen atom to which they are attached to form a ring of four to seven members, optionally including any chemically stable combination of one to three O, C═O, NR5 and S;
R5 is C1-4 alkyl, C1-4 acyl, C2-4 hydroxyalkyl, C1-2 alkoxy-C2-4 alkyl, oxetan-3-yl, oxolan-3-yl, oxan-4-yl, N-methylazetidin-3-yl, N-methylpyrrolidin-3-yl or N-methylpiperidin-4-yl;
R6 is benzyl, isopropyl, [R]- or [S]-2-butyl, 3-pentyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, cyclpentylmethyl, 4-tetrahydrofuranyl or isopropyl;
R9 is H, C1-4 alkyl, C2-4 hydroxyalkyl, C1-2 alkoxy-C2-4 alkyl, oxetan-3-yl, oxolan-3-yl, oxan-4-yl, N-methylazetidin-3-yl, N-methylpyrrolidin-3-yl or N-methylpiperidin-4-yl.

### Claim 10 (depends on 1)

The compound of claim 1 wherein Ar1 is selected from benzothiazol-2-yl, benzoxazol-2-yl, naphtha-2-yl, 4-methyl-5-phenylthiazole, 4-methyl-5-phenyloxazole, imidazo[1,2-a]pyrid-2-yl, whereby each 6-membered aromatic ring may be substituted with up to two R2 substituents selected from C1-6 lower alkyl, CF3 and halogen.

### Claim 11 (depends on 5)

The compound of claim 5 wherein Ar1 is selected from benzothiazol-2-yl, benzoxazol-2-yl, naphtha-2-yl, 4-methyl-5-phenylthiazole, 4-methyl-5-phenyloxazole, imidazo[1,2-a]pyrid-2-yl whereby each 6-membered aromatic ring may be substituted with up to two R2 substituents selected from C1-6 lower alkyl, CF3 and halogen.

### Claim 12 (depends on 6)

The compound of claim 6 wherein Ar1 is selected from benzothiazol-2-yl, benzoxazol-2-yl, naphtha-2-yl, 4-methyl-5-phenylthiazole, 4-methyl-5-phenyloxazole, imidazo[1,2-a]pyrid-2-yl whereby each 6-membered aromatic ring may be substituted with up to two R2 substituents selected from C1-6 lower alkyl, CF3 and halogen.

### Claim 13 (depends on 1)

The compound of claim 1 wherein Z is acryloyl, or 2-(aminomethyl)acryloyl, such that the amine is substituted with R3 and R4, and neither is hydrogen.

### Claim 14 (depends on 5)

The compound of claim 5 wherein Z is acryloyl, or 2-(aminomethyl)acryloyl, such that the amine is substituted with R3 and R4, and neither is hydrogen.

### Claim 15 (depends on 6)

The compound of claim 6 wherein Z is acryloyl, or 2-(aminomethyl)acryloyl, such that the amine is substituted with R3 and R4, and neither is hydrogen.

### Claim 16 (depends on 1)

The following compounds of claim 1:
or pharmaceutically acceptable salts, hydrates or solvates thereof.

### Claim 17

A compound of the following structure,
or pharmaceutically acceptable salts, hydrates or solvates thereof.

### Claim 18

A compound of the following structure
or pharmaceutically acceptable salts, hydrates or solvates thereof.

### Claim 19 (depends on 1)

The compound of claim 1 which can form a covalent bond with Cys115 of DCN1.

### Claim 20 (depends on 1)

The compound of claim 1 which can form a covalent bond with Cys115 of DCN1 in vivo, when dosed systemically to a mammal.

### Claim 21 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier vehicle.

### Claim 22 (depends on 1)

A method of treating acetaminophen-induced liver injury comprising administering a therapeutically effective amount of a compound of claim 1 to an individual in need thereof.