US 12,338,440 B2
Intracellular kinase associated with resistance against anti-tumour immune responses, and uses thereof
Antonio Sorrentino, Heidelberg (DE); Philipp Beckhove, Regensburg (DE); Tillmann Michels, Heidelberg (DE); Nisit Khandelwal, Martinsried (DE); Michael Boutros, Heidelberg (DE); Marco Breinig, Schriesheim (DE); Peter Sennhenn, Martinsried (DE); Sebastian Meier-Ewert, Martinsried (DE); Valentina Volpin, Regensburg (DE); and Ayse Nur Menevse, Regensburg (DE)
Assigned to IOMX THERAPEUTICS AG, Martinsried (DE)
Appl. No. 16/316,298
Filed by iOmx Therapeutics AG, Martinsried (DE)
PCT Filed Apr. 20, 2018, PCT No. PCT/EP2018/060172
§ 371(c)(1), (2) Date Jan. 8, 2019,
PCT Pub. No. WO2018/193084, PCT Pub. Date Oct. 25, 2018.
Claims priority of application No. 17167295 (EP), filed on Apr. 20, 2017.
Prior Publication US 2021/0040486 A1, Feb. 11, 2021
Int. Cl. C12N 15/113 (2010.01); A61K 31/506 (2006.01); A61K 31/7088 (2006.01); A61K 45/06 (2006.01); A61P 35/00 (2006.01); C07D 417/12 (2006.01); C07D 417/14 (2006.01); G01N 33/50 (2006.01); G01N 33/574 (2006.01); A61B 10/00 (2006.01)
CPC C12N 15/1137 (2013.01) [A61K 31/506 (2013.01); A61K 31/7088 (2013.01); A61K 45/06 (2013.01); A61P 35/00 (2018.01); C07D 417/12 (2013.01); C07D 417/14 (2013.01); G01N 33/5047 (2013.01); G01N 33/57492 (2013.01); A61B 10/0041 (2013.01); C12N 2310/122 (2013.01); C12N 2320/31 (2013.01)] 33 Claims
 
1. A method of treating cancer in a subject, the treatment comprising exposing cancer cells in a solid tumor within the subject to Tumor Necrosis Factor (TNF) and/or an agonist of TNFR1-signalling and inhibiting SIK3 in the solid tumor cancer cells, wherein the cancer cells express SIK3 and are resistant to an anti-tumor immune response and wherein inhibiting SIK3 in the solid tumor cancer cells comprises:
(i) administering a therapeutically effective amount of a SIK3 inhibitor effective to directly inhibit the SIK3 in the cancer cells, wherein the SIK3 inhibitor comprises an inhibitory nucleic acid that specifically targets a nucleic acid encoding SIK3 or is complementary to a SIK3 mRNA or
(ii) administering a therapeutically effective amount of a SIK3 inhibitor effective to inhibit the SIK3 in the cancer cells, wherein the SIK3 inhibitor is a small molecule, and wherein the small molecule comprises a cyclic compound of the following formula I, and salts, prodrugs, solvates, complexes, polymorphs, crystalline forms, tautomers, isotopically labelled forms or combinations thereof, and stereoisomers thereof:

OG Complex Work Unit Chemistry
where Q is:
(1) a 5-membered heteroaryl ring;
(2) a 6-membered heteroaryl ring; or
(3) an aryl ring;
optionally substituted with one or more groups R1;
Z is:
(1) a single bond;
(2) —R16C═CH—; or
(3) —(CH2)m—, where m is 1 to 2;
X1 and X2 are each hydrogen, or together form ═O or ═S;
R1 is:
(1) hydrogen or R6,
where R6 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, heterocyclo, or heterocycloalkyl, each of which is unsubstituted or substituted with Z1, Z2 and one or more groups Z3;
(2) —OH or —OR6;
(3) —SH or —SR6;
(4) —C(O)2H, —C(O)qR6, or —O—C(O)qR6, where q is 1 or 2;
(5) —SO3H or —S(O)qR6;
(6) halo;
(7) cyano;
(8) nitro;
(9) —Z4—NR7R8;
(10) —Z4—N(R9)—Z5—NR10R11;
(11) —Z4—N(R12)—Z5—R6;
(12) —P(O)(OR6)2;
R2 and R3 are each independently:
(1) hydrogen or R6;
(2) —Z4—R6; or
(3) —Z13—NR7R8;
R4 and R5:
(1) are each independently hydrogen or R6;
(2) —Z4—N(R9)—Z5—NR10R11;
(3) —N(R9) Z4R6; or
(4) together with the nitrogen atom to which they are attached complete a 3- to 8-membered saturated or unsaturated heterocyclic ring which is unsubstituted or substituted with Z1, Z2 and Z3, which heterocyclic ring may optionally have fused to it a benzene ring itself unsubstituted or substituted with Z1, Z2 and Z3;
R7, R8, R9, R10, R11 and R12:
(1) are each independently hydrogen or R6;
(2) R7, and R8 may together be alkylene, alkenylene or heteroalkyl, completing a 3- to 8-membered saturated or unsaturated ring with the nitrogen atom to which they are attached, which ring is unsubstituted or substituted with Z1, Z2 and Z3; or
(3) any two of R9, R10 and R11 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z1, Z2 and Z3;
R13 is:
(1) cyano;
(2) nitro;
(3) —NH2;
(4) —NHOalkyl;
(5) —OH;
(6) —NHOaryl;
(7) —NHCOOalkyl;
(8) —NHCOOaryl;
(9) —NHSO2alkyl;
(10) —NHSO2aryl;
(11) aryl;
(12) heteroaryl;
(13) —Oalkyl; or
(14) —Oaryl;
R14 is:
(1) —NO2;
(2) —COOalkyl; or
(3) —COOaryl;
R15 is:
(1) hydrogen;
(2) alkyl;
(3) aryl;
(4) arylalkyl; or
(5) cycloalkyl;
Z1, Z2 and Z3 are each independently:
(1) hydrogen or Z6, where Z6 is (i) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl; (ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or (iii) a group (i) or (ii) which is substituted by one or more of the following groups (2) to (16) of the definition of Z1, Z2 and Z3;
(2) —OH or —OZ6;
(3) —SH or —SZ6;
(4) —C(O)qH, —C(O)qZ6, or —O—C(O)qZ6;
(5) —SO3H, —S(O)qZ6; or S(O)qN(Z9)Z6;
(6) halo;
(7) cyano;
(8) nitro;
(9) —Z4—NZ7Z8;
(10) —Z4—N(Z9)—Z5—NZ7Z8;
(11) —Z4—N(Z10)—Z5-Z6;
(12) —Z4—N(Z10)—Z5—H;
(13) oxo;
(14) —O—C(O)—Z6;
(15) any two of Z1, Z2, and Z3 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached; or
(16) any two of Z1, Z2, and Z3 may together be —O—(CH2)r—O—, where r is 1 to 5, completing a 4- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached;
Z4 and Z5 are each independently:
(1) a single bond;
(2) —Z11—S(O)q—Z12—;
(3) —Z11—C(O)—Z12;
(4) —Z11—C(S)—Z12—;
(5) —Z11—O—Z12—;
(6) —Z11—S—Z12—;
(7) —Z11—O—C(O)—Z12; or
(8) —Z11—C(O)—O—Z12—;
Z7, Z8, Z9 and Z10:
(1) are each independently hydrogen or Z6;
(2) Z7 and Z8, or Z6 and Z10, may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with Z1, Z2 and Z3; or
(3) Z7 or Z8, together with Z9, may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z1, Z2 and Z3;
Z11 and Z12 are each independently:
(1) a single bond;
(2) alkylene;
(3) alkenylene; or
(4) alkynylene; and
Z13 is:
(1) a single bond;
(2) —Z11—S(O)q—Z12—;
(3) —Z11—C(O)—Z12;
(4) —Z11—C(S)—Z12—;
(5) —Z11—O—Z12—;
(6) —Z11—S—Z12—;
(7) —Z11—O—C(O)—Z12—;
(8) —Z11—C(O)—O—Z12—;
(9) —C(NR13)—;
(10) —C(CHR14)—; or
(11) —C(C(R14)2)—;
wherein:
Q is thiazole;
Z is a single bond;
R1 is hydrogen;
X1 and X2 together form-O;
R2 is hydrogen;
R3 is —Z4—R6, wherein Z4 is a single bond and R6 is aryl or heteroaryl which is unsubstituted or substituted with Z1, Z2 and one, two or more groups Z3; and
R4 is hydrogen,
wherein, the cyclic compound of formula I has the following formula II:

OG Complex Work Unit Chemistry
where n is 1;
A is nitrogen;
B is sulphur;
X3 is oxygen;
R1 is hydrogen;
R2 is hydrogen;
R4 is hydrogen; and
R3 is Rx, where Rx has the following formula X:

OG Complex Work Unit Chemistry
wherein Z1, Z2 and Z3 of formula X are each independently:
(1) hydrogen or Z6, where Z6 is (i) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl; (ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or (iii) a group (i) or (ii) which is substituted by one or more of the following groups (2) to (16) of the definition of Z1, Z2 and Z3;
(2) —OH or —OZ6;
(3) —SH or —SZ6;
(4) —C(O)qH, —C(O)qZ6, or —O—C(O)qZ6;
(5) —SO3H, —S(O)qZ6; or S(O)qN(Z9)Z6;
(6) halo;
(7) cyano;
(8) nitro;
(9) —Z4—NZ7Z8;
(10) —Z4—N(Z9)—Z5—NZ7Z8;
(11) —Z4—N(Z10)—Z5-Z6;
(12) —Z4—N(Z10)—Z5—H;
(13) oxo;
(14) —O—C(O)—Z6;
(15) any two of Z1, Z2, and Z3 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached; or
(16) any two of Z1, Z2, and Z3 may together be —O—(CH2)r—O—, where r is 1 to 5, completing a 4- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached.