# US 11,028,067 B2 · Heteroarylsulfonyl-substituted pyridines and their use in the treatment of cancer

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- Number: US 11,028,067 B2
- Document ID: US11028067B2
- Status: Granted
- Kind: B2
- Application number: 16/484,039
- Filed: 2018-02-07
- Published: 2020-07-16
- Granted: 2021-06-08
- Earliest claimed: 2017-02-07
- Assignees: Oblique Therapeutics AB
- Applicants: Oblique Therapeutics AB
- Inventors: Benjamin Pelcman; Edgars Suna; William Stafford; Martins Priede
- Web page: https://patentgrep.com/patent/US11028067B2

## CPC

- C07D 401/12: linked by a chain containing hetero atoms as chain links
- A61P 35/00: Antineoplastic agents
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

There is provided compounds of formula I (I) or pharmaceutically-acceptable salts thereof, wherein L, R1, R2, R3 and X have meanings provided in the description, which compounds are useful in the treatment of cancers.

## Claims

### Claim 1

A compound of formula I
or a pharmaceutically acceptable salt thereof, wherein:
L represents —S(O)n—;
n represents 2 or 1;
X represents a heteroaryl group, attached to L via a carbon atom, optionally substituted by one or more groups independently selected from Y;
R1, R2 and R3 each independently represent H, halo, Ra1, —CN, -Aa1-C(Qa1)Rb1, -Ab1-C(Qb1)N(Rc1)Rd1, -Ac1-C(Qc1)ORe1, -Ad1-S(O)pRf1, -Ae1-S(O)pN(Rg1)Rh1, -Af1-S(O)pORi1, —N3, —N(Rj1)Rk1, —N(H)CN, —NO2, —ONO2, —ORl1 or —SRm1;
each Aa1 to Af1 independently represents a single bond, —N(Rp1)— or —O—;
each Qa1 to Qc1 independently represents ═O, ═S, ═NRn1 or ═N(ORo1);
each Ra1 and Rf1 independently represents C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl each optionally substituted by one or more groups independently selected from G1a, heterocyclyl optionally substituted by one or more groups independently selected from G1b, aryl optionally substituted by one or more groups independently selected from G1c, or heteroaryl optionally substituted by one or more groups independently selected from G1d;
each Rb1, Rc1, Rd1, Re1, Rg1, Rh1, Ri1, Rj1, Rk1, Rl1, Rm1, Rn1, Ro1 and Rp1 independently represents H, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl each optionally substituted by one or more groups independently selected from G1a, heterocyclyl optionally substituted by one or more groups independently selected from G1b, aryl optionally substituted by one or more groups independently selected from G1c, or heteroaryl optionally substituted by one or more groups independently selected from G1d;
any of Rc1 and Rd1, Rg1 and Rh1 and/or Rj1 and Rk1 are linked together to form, together with the nitrogen atom to which they are attached, a 3-to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from halo, and C1-3 alkyl, C2-3 alkenyl or C2-3 alkynyl each optionally substituted by one or more halo, and ═O;
each G1a and G1b independently represents halo, —CN, —N(Ra2)Rb2, —ORc2, —SRd2 or ═O;
each G1c and G1d independently represents halo, —CN, —N(Ra2)Rb2, —ORc2 or —SRd2;
each Ra2, Rb2, Rc2 and Rd2 independently represents H or C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl each optionally substituted by one or more fluoro; or
Ra2 and Rb2 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from fluoro, C1-3 alkyl, C2-3 alkenyl or C2-3 alkynyl each optionally substituted by one or more fluoro;
each Y independently represents halo, Ra3, —CN, -Aa2-C(Qa2)Rb3, -Ab2-C(Qb2)N(Rc3)Rd3, -Ac2-C(Qc2)ORe3, -Ad2-S(O)qRf3, -Ae2-S(O)qN(Rg3)Rh3, -Af2-S(O)qORi3, —N3, —N(Rj3)Rk3, —N(H)CN, —ONO2, —OR13 or —SRm3;
each Qa2 to Qc2 independently represents ═O, ═S, ═NRn3 or ═N(ORo3);
each Aa2 to Ar2 independently represents a single bond, —N(Rp3)— or —O—;
each Ra3 and Rf1 independently represents C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl each optionally substituted by one or more groups independently selected from G2a, heterocyclyl optionally substituted by one or more groups independently selected from G2b, aryl optionally substituted by one or more groups independently selected from G2c, or heteroaryl optionally substituted by one or more groups independently selected from G2d;
each Rb3, Rc3, Rd3, Re3, Rg3, Rh3Ri3, Rj3, Rk3, Rl3, Rm3, Rn3, Ro3 and Rp3 independently represents H, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl each optionally substituted by one or more groups independently selected from G2a, heterocyclyl optionally substituted by one or more groups independently selected from G2b, aryl optionally substituted by one or more groups independently selected from G2c, or heteroaryl optionally substituted by one or more groups independently selected from G2d; or
any two Rc3 and Rd3, Rg3 and Rh3 and/or Rj3 and Rk3 are linked together to form, along with the nitrogen atom to which they are attached, a 3-to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from heterocyclyl optionally substituted by one or more groups independently selected from G2b, aryl optionally substituted by one or more groups independently selected from G2c, or heteroaryl optionally substituted by one or more groups independently selected from G2d, and ═O;
each G2a independently represents halo, —CN, —N(Rj4)Rk4, —ORl4, —SRm4 or ═O;
each G2b independently represents halo, Ra4, —CN, —N(Rj4)Rk4, —ORl4, —SRm4 or ═O;
each G2C and G2d independently represents halo, Ra4, —CN, -Aa3-C(Qa3)Rb4, -Ab3-C(Qb3)N(Rc4)Rd4, -Ac3-C(Qc3)ORe4, -Ad3-S(O)qRf4, -Ae3-S(O)qN(Rg4)Rh4, -Af3-S(O)qOR14, —N3, —N(Rj4)Rk4, —N(H)CN, —NO2, —ONO2, —OR14 or —SRm4;
each Qa3 to Qc3 independently represents ═O, ═S, ═NRn4 or ═N(ORo4);
each Aa3 to A13 independently represents a single bond, —N(Rp4)— or —O—;
each Ra4 and Rf4 independently represents C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl each optionally substituted by one or more groups independently selected from G3a, heterocyclyl optionally substituted by one or more groups independently selected from G3b, aryl optionally substituted by one or more groups independently selected from G3c, or heteroaryl optionally substituted by one or more groups independently selected from G3d;
each Rb4, Rc4, Rd4, Re4, Rg4, Rh4, Ri4, Rj4, Rk4, Rl4, Rm4, Rn4, Ro4 and Rp4 independently represents H, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl each optionally substituted by one or more groups independently selected from G3a or heterocyclyl optionally substituted by one or more groups independently selected from G3b, aryl optionally substituted by one or more groups independently selected from G3c, or heteroaryl optionally substituted by one or more groups independently selected from G3d; or
any of Rc4 and Rd4, Rg4 and Rh4 and/or Rj4 and Rk4 are linked together to form, together with the nitrogen atom to which they are attached, a 3-to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected G3b;
each G3a and G3b independently represents halo, Ra5, —CN, —N(Rb5)Rc5, —ORd5, —SRe5 or ═O;
each Ra5 independently represents C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl each optionally substituted by one or more groups independently selected from G4;
each Rb5, Rc5, Rd5 and Re5 independently represents H, or C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl each optionally substituted by one or more groups independently selected from G4;
or
each Rb5 and Rc5 are linked together to form, together with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from G4;
each G4 independently represents halo, Ra6, —CN, —N(Rb6)Rc6, —ORd6 or ═O;
each Ra6 independently represents C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl each optionally substituted by one or more fluoro;
each Rb6, Rc6 and Rd6 independently represents H, or C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl each optionally substituted by one or more fluoro; and
each p and q independently represents 1 or 2,
with the provisos that the compound of formula I does not represent:
3-nitro-2-(pyridin-2-ylsulfonyl)pyridine,
2-((3-nitropyridin-2-yl)sulfonyl)pyrimidine, or
N-(6-chloro-2-((5-chloro-3-nitropyridin-2-yl)sulfonyl)pyridin-3-yl)acetamide.

### Claim 2 (depends on 1)

A compound as claimed in claim 1, wherein X is unsubstituted or substituted with one or two Y groups.

### Claim 3 (depends on 1)

A compound as claimed in claim 1, wherein each Y independently represents halo, Ra3, —N(Rj3)Rk3 or —ORl3.

### Claim 4 (depends on 1)

A compound as claimed in claim 1, wherein:
each Ra3 independently represents C1-6 alkyl optionally substituted by one or more fluoro;
and/or
each Rj3, Rk3 and Rl3 independently represents H or C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl each optionally substituted by one or more fluoro.

### Claim 5 (depends on 1)

A compound as claimed in claim 1, wherein:
X is unsubstituted or substituted with one Y; and/or
Y represents halo or C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl each optionally substituted by one or more fluoro.

### Claim 6 (depends on 1)

A compound as claimed in claim 1, wherein the compound of formula I is a compound of formula Ia
wherein:
each of Z1 to Z5 represents CR4 to CR8, respectively, with the exception that one or two of Z1 to Z5 instead represents a heteroatom, which where possible may be substituted with R9, and optionally one of Z1 to Z5 may instead represent a direct bond; and
each of R4 to R9 represents H or Y.

### Claim 7 (depends on 6)

A compound as claimed in claim 6, wherein each of R4, R5, R7, R8 and R9 (where present) represents H and R6 (where present) represents H or Y, wherein Y represents methyl optionally substituted by one or more fluoro.

### Claim 8 (depends on 1)

A compound as claimed in claim 1, wherein R1, R2 and R3 each independently represents H, halo, Ra1, —N(Ri1)Rk1 or —ORl1.

### Claim 9 (depends on 1)

A compound as claimed in claim 1, wherein:
R1, R2 and R3 each independently represent H, halo, Ra1, —N(Rj1)Rk1, —ORl1 or —SRm1; and/or
each of Ra1, Rj1, Rk1, Rl1 and Rm1 independently represents C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl each optionally substituted by one or more fluoro.

### Claim 10 (depends on 1)

A compound as claimed in claim 1, wherein R1, R2 and R3 each independently represent H, halo, —N(Ri1)Rk1 or —ORl1.

### Claim 11 (depends on 1)

A compound as claimed in claim 1, wherein:
R2 and R3 each represent H;
R1 represents H, halo, —N(Rj1)Rk1 or —ORl1; and
each Rj1, Rk1 and Rl1 represents C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl each optionally substituted by one or more fluoro.

### Claim 12 (depends on 1)

A compound as claimed in claim 1, wherein:
R2 and R3 each represent H;
R1 represents halo, —N(Ri1)Rk1 or —ORl1; and
each Rj1, Rk1 and Rl1 represents methyl optionally substituted by one or more fluoro.

### Claim 13 (depends on 1)

A method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound as defined in claim 1 but without the provisos, wherein the cancer is selected from the group consisting of soft tissue cancers, lung cancers, gastrointestinal cancers, breast cancer, genitourinary tract cancers, liver cancers, bone cancers, cancers of the head and/or nervous system, gynecological cancers, hematologic cancers, skin cancers, neurofibromatosis and adrenal gland cancers.

### Claim 14 (depends on 13)

The method of claim 13, wherein the cancer is selected from the group consisting of head and neck cancer, glioblastoma, pharyngeal squamous cell carcinoma, colorectal carcinoma, epidermoid (skin) carcinoma, pancreatic ductal carcinoma, metastatic mammary adenocarcinoma, lung carcinoma, leukemia, non-small cell lung cancer, colon cancer, melanoma, ovarian cancer, renal cancer, and prostate cancer.

### Claim 15 (depends on 1)

A pharmaceutical composition comprising a compound as defined in claim 1 but without the provisos, and optionally one or more pharmaceutically acceptable adjuvant, diluent and/or carrier.

### Claim 16 (depends on 1)

A combination product comprising:
(A) a compound as defined in claim 1, but without the provisos; and
(B) one or more other therapeutic agent that is useful in the treatment of cancer, wherein each of components (A) and (B) is formulated in admixture, optionally with one or more a pharmaceutically-acceptable adjuvant, diluent or carrier.

### Claim 17 (depends on 15)

A kit-of-parts comprising:
(a) a pharmaceutical composition as defined in claim 15; and
(b)one or more other therapeutic agent that is useful in the treatment of cancer, optionally in admixture with one or more pharmaceutically-acceptable adjuvant, diluent or carrier,
which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.

### Claim 18 (depends on 1)

A process for the preparation of a compound as defined in claim 1, including the provisos, which process comprises:
(i) where n represents 2, reaction of a compound of formula IIA
wherein R1, R2 and R3 are as defined in claim 1 and LG1 represents a suitable leaving group, with a compound of formula IIIA
wherein X is as defined in claim 1 and M represents an alkali metal ion, in the presence of a suitable acid and in the presence of a suitable solvent, and optionally in the presence of a suitable phase transfer catalyst;
(ii) where n represents 2, reaction of a compound of formula IIB
wherein R1, R2 and R3 are as defined in claim 1 and M represents an alkali metal ion, with a compound of formula IIIB
wherein X is as defined in claim 1 and LG2 represents a suitable leaving group, in the presence of a suitable acid and in the presence of a suitable solvent, and optionally in the presence of a suitable phase transfer catalyst;
(iii) where n represents 2, reaction of a compound of formula IIA with a compound of formula IIIA, in the presence of a suitable metal halide and in the presence of a suitable solvent;
(iv) where n represents 2, reaction of a compound of formula IIB with a compound of formula IIIB, in the presence of a suitable metal halide and in the presence of a suitable solvent;
(v) reaction of a compound of formula IV
wherein R1 to R3 and X are as defined in claim 1, with a suitable oxidising agent in the presence of a suitable solvent, and optionally in the presence of water;
(vi) where n represents 2, reaction of a compound of formula V
wherein R1, R2 and R3 are as defined in claim 1 and LG3 represents a suitable leaving group with a compound of formula VI
wherein X is as defined in claim 1, in the presence of a suitable Lewis acid and in the presence of a suitable solvent;
(vii) where n represents 2, reaction of a compound of formula V with a compound of formula VI, in the presence of a suitable catalyst and a suitable base, and in the presence of a suitable solvent;
(viii) where n represents 2, reaction of a compound of formula V with a compound of formula VII
wherein X is as defined in claim 1 and LG4 represents a suitable leaving group, in the presence of a suitable catalyst and in the presence of a suitable solvent; or
(ix) where n represents 2, reaction of a compound of formula IIB with (a) a compound of formula VI having at least one Y group, or (b) a compound of formula VI having a group that may be converted to a Y group, wherein the Y group or group that may be converted to a Y group is present in the alpha position relative to the essential H substituent and represents a suitable directing group, in the presence of a suitable catalyst and/or oxidant, and in the presence of a suitable solvent, which step may further comprise conversion of the group that may be converted to a Y group to the required Y group.