# US 11,306,108 B2 · Chemical compounds

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- Number: US 11,306,108 B2
- Document ID: US11306108B2
- Status: Granted
- Kind: B2
- Application number: 17/133,515
- Filed: 2020-12-23
- Published: 2021-06-24
- Granted: 2022-04-19
- Earliest claimed: 2019-05-13
- Assignees: Borah, Inc.
- Applicants: Boragen, Inc.
- Inventors: Yasheen Zhou; Chunliang Liu; Yong-Kang Zhang; Marissa Aubrey; Chun Yu Liu
- Web page: https://patentgrep.com/patent/US11306108B2

## CPC

- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07F 5/02: Boron compounds
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07F 5/025: {Boronic and borinic acid compounds}
- 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)
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention describes novel compounds, or their pharmaceutically acceptable salts, pharmaceutical compositions containing them, and their medical uses. The compounds of the invention have activity as Janus kinase (JAK) inhibitors and are useful in the in the treatment or control of inflammation, auto-immune diseases, cancer, and other disorders and indications where modulation of JAK would be desirable. Also described herein are methods of treating inflammation, auto-immune diseases, cancer, and other conditions susceptible to inhibition of JAK by administering a compound herein described.

## Claims

### Claim 1

A compound of formula (II):
wherein:
Z is selected from the group consisting of hydrogen, fluorine, and CH3;
Y is selected from the group consisting of hydrogen, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, and (CH2)3OH, or Y and the oxygen atom depicted as OH together form a 6 to 8 membered ring;
each R1 independently is selected from the group consisting of unsubstituted or substituted:
(i) C1-C15 alkyl,
(ii) C2-15 alkenyl,
(iii) C2-15 alkynyl,
(iv) C1-C15 alkyl, wherein one or more carbon atom, including the carbon atom attached to the depicted ring, is replaced with a heteroatom selected from O, N, S, or Si, and wherein each N, S, or Si may be oxidized, and wherein the N may be quarternized,
(v) C2-15 alkenyl, wherein one or more carbon atom, including the carbon atom attached to the depicted ring, is replaced with a heteroatom selected from O, N, S, or Si, and wherein each N, S, or Si may be oxidized, and wherein the N may be quarternized,
(vi) C2-15 alkynyl, wherein one or more carbon atom, including the carbon atom attached to the depicted ring, is replaced with a heteroatom selected from O, N, S, or Si, and wherein each N, S, or Si may be oxidized, and wherein the N may be quarternized,
(vii) C3-15 cycloalkyl,
(viii) heterocyclyl,
(ix) aryl, and
(x) heteroaryl,
or a stereoisomer, enantiomer, or tautomer thereof, or a veterinary or pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein Y is hydrogen.

### Claim 3 (depends on 1)

The compound of claim 1, wherein Z is hydrogen.

### Claim 4 (depends on 1)

The compound of claim 1, wherein Y is hydrogen and Z is hydrogen.

### Claim 5 (depends on 1)

The compound of claim 1, wherein R1 is (a) unsubstituted or substituted C3-15 cycloalkyl, or (b) unsubstituted or substituted heterocyclyl.

### Claim 6 (depends on 5)

The compound of claim 5, wherein R1 individually is unsubstituted or substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, adamantyl, or heterocyclyl.

### Claim 7 (depends on 5)

The compound of claim 5 wherein each R1 is a substituted 3- to 6-membered heterocyclyl, wherein at least one heteroatom is a N.

### Claim 8 (depends on 5)

The compound of claim 5, wherein R1 is pyrrolidinyl, piperidinyl, or tetrahydropyranyl.

### Claim 9 (depends on 1)

The compound of claim 1, wherein each R1 individually is substituted with one or more substituent selected from the group consisting of halogen, haloalkyl, R′, OR′, OH, SH, SR′, NO2, CN, C(O)R′, C(O)(alkyl substituted with one or more of halogen, haloalkyl, NH2, OH, SH, CN, and NO2), C(O)OR′, OC(O)R′, CON(R′)2, OC(O)N(R′)2, NH2, NHR′, N(R′)2, NHCOR′, NHCOH, NHCONH2, NHCONHR′, NHCON(R′)2, NR′CON(R′)2, NR′COR′, NR′COH, NHCO2H, NHCO2R′, NR′CO2R′, NHC(S)NH2, NHC(S)NHR′, NHC(S)N(R′)2, NR′C(S)N(R′)2, CO2R′, CO2H, CHO, CONH2, CONHR′, CON(R′)2, S(O)2H, S(O)2R′, SO2NH2, S(O)H, S(O)R′, SO2NHR′, SO2N(R′)2, NHS(O)2H, NR′S(O)2H, NHS(O)2R′, NR′S(O)2R′, N(R′)SO2N(R′)2, and ═O,
wherein each of the preceding may be linked to R1 through an alkylene linker, (CH2)x,
where x is 1, 2, or 3, and
wherein each R′ is the same or different and is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, cycloalkyl, cycloalkyl substituted by one or more halogens, cycloalkylalkyl, aryl, aryl substituted with one or more halogen, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

### Claim 10 (depends on 9)

The compound of claim 9, wherein each R1 is substituted
a) with one substitutent; or
b) substituted with two substituents, each of which may be substituted from the same or different atoms, as valency allows.

### Claim 11 (depends on 9)

The compound of claim 9, wherein the alkylene linker, (CH2)x, where x is 1, 2, or 3, may itself be further substituted with one or more of alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl.

### Claim 12 (depends on 1)

The compound of claim 1, wherein R1 is substituted with NHSO2H, NHS(O)2(C1-C6 alkyl), NHS(O)2(C1-C6 partially or fully fluorinated alkyl), NHS(O)2(C1-C6 alkenyl), NHS(O)2(C1-C6 partially or fully fluorinated alkenyl), NHS(O)2(C1-C6 alkynyl), NHS(O)2(C1-C6 partially or fully fluorinated alkynyl), NHS(O)2(C1-C6 cycloalkyl), NHS(O)2(C1-C6 partially or fully fluorinated cycloalkyl), NHSO2(aryl), NHSO2(heterocyclyl), NHSO2(heteroaryl), OH, CH2S(O)2NH(C1-C6 alkyl), CH2S(O)2NH(C1-C6 partially or fully fluorinated alkyl), CH2S(O)2N(C1-C6 alkyl)2, CH2S(O)2N(C1-C6 partially fluorinated alkyl)2, N(C1-C6 alkyl)2, or N(C1-C6 partially fluorinated alkyl)2.

### Claim 13 (depends on 1)

The compound of claim 1, wherein R1 is substituted with NHSO2R′, wherein R′ is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl.

### Claim 14 (depends on 13)

The compound of claim 13, wherein R′ is C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl.

### Claim 15 (depends on 1)

The compound of claim 1, wherein R1 is R1a-L-R1b, wherein
R1a is independently any R1 group as defined,
L is a polar linking group, and
R1b is independently any R1 group as defined.

### Claim 16 (depends on 15)

The compound of claim 15, wherein
(i) R1a is C3-15 cycloalkyl,
L is —(CH2)p-L1-,
wherein p is 0, 1, or 2,
L1 is selected from the group consisting of —O—, —C(O)—, —C(O)O—, —OC(O)—, —C(O)N(R′)—, —OC(O)N(R′)—, —N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(S)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)O—, —SO2—, —S(O)—, —SO2N(R′)—, —N(R′)SO2—,
and —N(R′)SO2(NR′)—; and
R1b is selected from the group consisting of unsubstituted or substituted C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-15 cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl;
or
(ii) R1a is heterocyclyl;
L is —(CH2)p-L1-,
wherein p is 0, 1, or 2,
L1 is selected from the group consisting of —O—, —C(O)—, —C(O)O—, —OC(O)—, —C(O)N(R′)—, —OC(O)N(R′)—, —N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(S)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)O—, —SO2—, —S(O)—, —SO2N(R′)—, —N(R′)SO2—,
and —N(R′)SO2(NR′)—; and
R1b is selected from the group consisting of unsubstituted or substituted C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-15 cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl,
wherein each R′ individually is the same or different and is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, cycloalkyl, cycloalkyl substituted by one or more halogens, cycloalkylalkyl, aryl, aryl substituted with one or more halogen, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

### Claim 17 (depends on 16)

The compound of claim 16, wherein L1 is selected from the group consisting of —O—, —C(O)—, —C(O)O—, —C(O)N(R′)—, —NR′C(O)—, —NR′C(O)O—, —SO2—, —SO2N(R′)—, —N(R′)C(O)N(R′)—, and —N(R′)SO2—.

### Claim 18 (depends on 16)

The compound of claim 16, wherein R1a is selected from the group consisting of unsubstituted or substituted cyclobutyl, cyclohexyl, bicyclo[1.1.1]pentyl, pyrrolidinyl, and piperidinyl.

### Claim 19 (depends on 16)

The compound of claim 16, wherein R1b is (a) unsubstituted or (b) substituted.

### Claim 20 (depends on 19)

The compound of claim 19, wherein R1b is substituted with at least one of fluorine, OCH3, or CN.

### Claim 21 (depends on 16)

The compound of claim 16, wherein Z and Y are both hydrogen.

### Claim 22

A compound selected from the group consisting of:
wherein each X independently is selected from the group consisting of O and NRa;
each Ra independently is selected from the group consisting of hydrogen, C1-C15 alkyl, C2-15 alkenyl, C2-15 alkynyl, C3-15 cycloalkyl, and aryl; and
R1 is selected from the group consisting of unsubstituted or substituted:
(i) C1-C15 alkyl,
(ii) C2-15 alkenyl,
(iii) C2-15 alkynyl,
(iv) C1-C15 alkyl, wherein one or more carbon atom, including the carbon atom attached to the depicted ring, is replaced with a heteroatom selected from O, N, S, or Si, and wherein each N, S, or Si may be oxidized, and wherein the N may be quarternized,
(v) C2-15 alkenyl, wherein one or more carbon atom, including the carbon atom attached to the depicted ring, is replaced with a heteroatom selected from O, N, S, or Si, and wherein each N, S, or Si may be oxidized, and wherein the N may be quarternized,
(vi) C2-15 alkynyl, wherein one or more carbon atom, including the carbon atom attached to the depicted ring, is replaced with a heteroatom selected from O, N, S, or Si, and wherein each N, S, or Si may be oxidized, and wherein the N may be quarternized,
(vii) C3-15 cycloalkyl,
(viii) heterocyclyl,
(ix) aryl, and
(x) heteroaryl,
or a stereoisomer, enantiomer, or tautomer thereof, or a veterinary or pharmaceutically acceptable salt thereof.

### Claim 23 (depends on 22)

The compound of claim 22, wherein X is oxygen.

### Claim 24 (depends on 1)

The compound of claim 1, wherein R1 is selected from the group consisting of:
or a stereoisomer, enantiomer, or tautomer thereof, or a veterinary or pharmaceutically acceptable salt thereof.

### Claim 25 (depends on 1)

A compound of claim 1, selected from the group consisting of:
or a stereoisomer, enantiomer, or tautomer thereof, or a veterinary or pharmaceutically acceptable salt thereof.

### Claim 26

A compound of formula (III), (IV), or (V):
wherein
each Y independently is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
each Z independently is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-6 alkenyl, and C2-6 alkynyl; and
each L independently is selected from the group consisting of —NR′SO2—, —CH2SO2NR′—, —NR′C(O)—, and —NR′C(O)NR′—,
where each R′ and R1b independently is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, aryl, aryl-C1-C6 alkyl, aryl-C2-C6 alkenyl, aryl-C1-C6 alkynyl, heteroaryl, C1-C6 alkyl-heteroaryl, C2-C6 alkenyl-heteroaryl, C2-C6 alkynyl-heteroaryl, heteroaryl-C1-C6 alkyl, heteroaryl-C2-C6 alkenyl, heteroaryl-C1-C6 alkynyl, heterocyclyl-C1-C6 alkyl, heterocyclyl-C2-C6 alkenyl, and heterocyclyl-C1-C6 alkynyl,
or a stereoisomer, enantiomer, or tautomer thereof, or a veterinary or pharmaceutically acceptable salt thereof.

### Claim 27 (depends on 26)

The compound of claim 26, selected from formula (III′), (IV′), or (V′):

### Claim 28 (depends on 1)

The compound of claim 1, selected from the group consisting of:
wherein
each R′ independently is selected from the group consisting of hydrogen, substituted or unsubstituted C1-C15 alkyl, substituted or unsubstituted C2-15 alkenyl, substituted or unsubstituted C2-15 alkynyl, substituted or unsubstituted C3-15 cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted aryl,
or a stereoisomer, enantiomer, or tautomer thereof,
or a veterinary or pharmaceutically acceptable salt thereof.

### Claim 29 (depends on 21)

The compound of claim 21, wherein R′ is H.

### Claim 30

A compound selected from the group consisting of:
or a stereoisomer, enantiomer, or tautomer thereof, or a veterinary or pharmaceutically acceptable salt thereof.