	US 11,896,589 B2
	Diazinyl amino acridines and medical uses thereof
Lars-Gunnar Olof Larsson, Stockholm (SE); and Alina Andrea Viktoria Castell, Stockholm (SE)
Assigned to MyCural Therapeutics AB, Uppsala (SE)
Appl. No. 16/962,620
Filed by Lars-Gunnar Olof Larsson, Stockholm (SE); and Alina Andrea Viktoria Castell, Stockholm (SE)
PCT Filed Jan. 23, 2019, PCT No. PCT/EP2019/051664 § 371(c)(1), (2) Date Jul. 16, 2020, PCT Pub. No. WO2019/145375, PCT Pub. Date Aug. 1, 2019.
Claims priority of application No. 1801102 (GB), filed on Jan. 23, 2018.
Prior Publication US 2020/0405707 A1, Dec. 31, 2020
Int. Cl. A61K 31/473 (2006.01); A61P 35/00 (2006.01); C07D 215/42 (2006.01); C07D 401/12 (2006.01); C07D 495/04 (2006.01)

CPC A61K 31/473 (2013.01) [A61P 35/00 (2018.01); C07D 215/42 (2013.01); C07D 401/12 (2013.01); C07D 495/04 (2013.01)]

12 Claims

1. A method of treating a cancer characterised by increased MYC activity comprising administering to a patient in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt and/or detectably labelled derivative thereof, wherein the compound is represented by formula I:

wherein:

R¹represents aryl optionally substituted by one or more groups independently selected from G^1c, and heteroaryl optionally substituted by one or more groups independently selected from G^1d;

R²and R³each represent H;

m represents 0, 1, 2, 3 or 4;

n represents 0, 1, 2 or 3;

each X independently represents —OR¹²or H;

each Y independently represents halo, R^a3, —CN, -A^a2-C(O)R^b3, -A^b2-C(O)N(R^c3)R^d3, -A^c2-C(O)OR^e3, -A^d2-S(O)_pR^f3, -A^e2-S(O)_pN(R^g3)R^h3, -A^f2-S(O)_pORⁱ³, —N(R^j3)R^k3, —OR^l3or —SR^m3;

each A^a2, A^b2, A^c2, A^d2, A^e2, and A^f2independently represents a single bond, —N(Rⁿ³)— or —O—;

each G^1cand G^1dindependently represents halo, R^a4, —CN, -A^a3-C(Q^a2)R^b4, -A^b3-C(Q^b2)N(R^c4)R^d4, -A^c3-C(Q^c2)OR^e4, -A^d3-S(O)_pR^f4, -A^e3-S(O)_pN(R^g4)R^h4, -A^f3-S(O)_pORⁱ⁴, —N₃, —N(R^j4)R^k4, —N(H)CN, —NO₂, —ONO₂, —OR^l4, —SR^m4—B(ORⁿ⁴)₂, —P(O)(N(R^o4)R^p4)₂, —P(O)(N(R^o4)R^p4)(OR^q4), —P(O)(OR^r4)₂, or =Q^d2;

each A^a3, A^b3, A^c3, A^d3, A^e3, and A^f3independently represents a single bond, —C(O)N(R^s4)—, —N(R^t4)— or —O—;

each Q^a2, Q^b2, Q^c2, and Q^d2independently represents ═O, ═S, ═C(H)NO₂, ═N(CN), ═NR^u4, ═NN(R^v4)R^w4, ═N(OR^x4), or ═NS(O)_pN(R^v4)R^w4;

each R¹²independently represents H, C_1-12alkyl, C_2-12alkenyl or C_2-12alkynyl each optionally substituted by one or more groups independently selected from G^3aand heterocyclyl optionally substituted by one or more groups independently selected from G^3b;

each R^a3and R^f3independently represents C_1-6alkyl optionally substituted by one or more F;

each R^b3, R^c3, R^d3, R^e3, R^g3, R^h3, Rⁱ³, R^j3, R^k3, R^l3, R^m3and Rⁿ³independently represents H or C_1-6alkyl optionally substituted by one or more F, or alternatively

any of R^c3and R^cd, R^fgand R^h3and/or R^j3and R^k3, 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 F, C_1-3alkyl optionally substituted by one or more F, and ═O;

each R^a4and R^f4independently represents C_1-8alkyl, C_2-8alkenyl or C_2-8alkynyl each optionally substituted by one or more groups independently selected from G^4a, heterocyclyl optionally substituted by one or more groups independently selected from G^4b, aryl optionally substituted by one or more groups independently selected from G⁴, and heteroaryl optionally substituted by one or more groups independently selected from G^4d;

each R^b4, R^c4, R^d4, R^e4, R^g4, R^h4, Rⁱ⁴, R^j4, R^k4, R^l4, R^m4, Rⁿ⁴, R^o4, R^p4, R^q4, R^r4, R^s4, R^t4, R^u4, R^v4, R^w4and R^x4independently represents H or C_1-8alkyl, C_2-8alkenyl or C_2-8alkynyl each optionally substituted by one or more groups independently selected from G^4a, heterocyclyl optionally substituted by one or more groups independently selected from G^4b, aryl optionally substituted by one or more groups independently selected from G^4c, and heteroaryl optionally substituted by one or more groups independently selected from G^4d, or alternatively

any of R^c4and R^d4, R^g4and R^h4, R^j4and R^k4, R^o4and R^p4and/or R^v4and R^w4are 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, C_1-3alkyl, C_2-3alkenyl and C_2-3alkynyl each optionally substituted by one or more halo, and ═O, or alternatively

two Rⁿ⁴are linked together to form, along with the boron, and the oxygen atoms to which they are attached, a 5- to 8-membered heterocyclic ring, which ring optionally contains one or more further heteroatoms and which ring optionally is substituted by one or more groups independently selected from halo, C_1-3alkyl optionally substituted by one or more halo, and ═O, or alternatively

two R^r4are linked together to form, along with the phosphorus, and the oxygen atoms to which they are attached, a 5- to 8-membered heterocyclic ring, which ring optionally contains one or more further heteroatoms and which ring optionally is substituted by one or more groups independently selected from halo, C_1-3alkyl optionally substituted by one or more halo, and ═O;

each R^v6and R^x6idenpendently represents H or C_1-6alkyl optionally substituted by one or more F;

each G^3aand G^3bindependently represents halo, R^a6, -CN, -A^a5-C(Q^a4)R^b6, -A^b5-C(Q^b4)N(R^c6)R^d6, -A^c5-C(Q^c4)OR^e6, -A^d5-S(O)_pR^f6, -A^e5-S(O)_pN(R^g6)R^h6, -A^f5-S(O)_pORⁱ⁶, -N₃, -N(R^k6, -N(H)CN, -NO₂, -ONO₂, -OR¹⁶, -SR^m6-B(ORⁿ⁶)₂, -P(O)(N(R^o6)R^P6)₂, -P(O)(N(R^o6)R^p6)(OR^q6), -P(O)(OR^r6)₂, or =Q^d4;

each A^a5, A^b5, A^c5, A^d5, A^e5, and A^f5independently represents a single bond, -C(O)N(R^s6)-, -N(R^t6)—or -O-;

each Q^a4, Q^b4, Q^c4, and Q^d4independently represents =0, =S, =C(H)NO₂, =N(CN), =NR^u6, =NN(R^v6)R^w6, =N(OR^x6), or =NS(O)_pN(R^v6)R^w6;

each R^v6and R^x6independently represents H or C_1-6alkyl optionally substituted by one or more F;

each R^a6and R^f6independently represents C_1-6alkyl, C_2-6alkenyl or C_2-6alkynyl, each optionally substituted by one or more groups independently selected from G^5a, heterocyclyl optionally subtituted by one or more groups independently selected from G^5b, aryl optionally substituted by one or more groups independently selected from G^5c, and heteroaryl optionally substituted by one or more groups independently selected from G^5d;

each R^b6, R^c6, R^d6, R^e6, R^g6, R^h6, Rⁱ⁶, R^j6, R^k6, R^l6, R^m6, Rⁿ⁶, R^o6, R^p6, R^q6, R^r6, R^s6, R^t6, R^u6, R^v6, R^w6and R^x6, independently represents H or independently represents C_1-6alkyl, C_2-6alkenyl or C_2-6alkynyl, each optionally substituted by one or more groups independently selected from G^5a, heterocyclyl optionally substituted by one or more groups independently selected from G^5b, aryl optionally substituted by one or more groups independently selected from G^5c, and heteroaryl optionally substituted by one or more groups independently selected from G^5d, or alternatively any of R^c6and R^d6, R^g6and R^h6, R^j6and R^k6, R^o6and R^p6and/or R^v6and R^w6, 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 F, C_1-3alkyl optionally substituted by one or more F, and ═O;

each G^4a, G^4b, G^4cand G^4dindependently represents halo, R^a7, —CN, -A^a6-C(Q^a5)R^b7, -A^b6-C(Q^b5)N(R^c7)R^d7, -A^c6-C(Q^c5)OR^e7, -A^d6-S(O)_pR^f7, -A^e6-S(O)_pN(R^g7)R^h7, -A^f6-S(O)_pORⁱ⁷, —N₃, —N(R^j7)R^k7, —N(H)CN, —NO₂, —ONO₂, —OR^l7, —SR^m7—B(ORⁿ⁷)₂, —P(O)(N(R^o7)R^p7)₂, —P(O)(N(R^o7)R^p7)(OR^q7) —P(O)(OR^r7)₂or =Q^d5;

each A^a6, A^b6, A^c6, A^d6, A^e5, and A^f6independently represents a single bond, —C(O)N(R^s7)—, —N(R^t7) or —O—;

each Q^a5, Q^b5, Q^c5, and Q^d5independently represents ═O, ═S, ═C(H)NO₂, ═N(CN), ═NR^u7, ═NN(R^v7)R^w7or ═N(OR^x7), or ═NS(O)_pN(R^v7)R^w7;

each R^a7and R^f7independently represents C_1-6alkyl, C_2-6alkenyl or C_2-6alkynyl, each optionally substituted by one or more groups independently selected from G^6a, heterocyclyl optionally substituted by one or more groups independently selected from G^6b, aryl optionally substituted by one or more groups independently selected from G^6c, and heteroaryl optionally substituted by one or more groups independently selected from G^6d;

each R^b7, R^c7, R^d7, R^e7, R^g7, R^h7, Rⁱ⁷, R^j7, R^k7, R^l7, R^m7, Rⁿ⁷, R^o7, R^p7, R^q7, R^r7, R^s7, R^t7, R^u7, R^v7, R^w7and and R^x7independently represents H or C_1-6alkyl, C_2-6alkenyl or C_2-6, alkynyl, each optionally substituted by one or more groups independently selected from G^6a, heterocyclyl optionally substituted by one or more groups independently selected from G^6b, aryl optionally substituted by one or more groups independently selected from G^6C, and heteroaryl optionally substituted by one or more groups independently selected from G^6d, or alternatively

any of R^c7and R^d7, R^g7and , R^h7, R^j7and R^k7, Rⁿ⁷and R^o7and/or R^v7, R^w7, 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 F, C_1-3alkyl optionally substituted by one or more F, and ═O;

each G^5a, G^5b, G^5cand G^5dindependently represents halo, R^a8, —CN, -A^a7-C(Q^a6)R^b8, -A^b7-C(Q^b6)N(R^c8)R^d8, -A^c7-C(Q^c6)OR^e8, -A^d7-S(O)_pR^f8, -A^e7-S(O)_pN(R^g8)R^h8, -A^f7-S(O)_pORⁱ⁸, —N₃, —N(R^j8)R^k8, —N(H)CN, —NO₂, —ONO₂, —OR^l8, —SR^m8—B(ORⁿ⁸)₂, —P(O)(N(R^o8)R^p8)₂, —P(O)(N(R^o8)R^p8)(OR^q8) —P(O)(OR^r8)₂or =Q^d6;

each A^a7, A^b7, A^c7, A^d7, A^e7, and to A^f7independently represents a single bond, —C(O)N(R^s8)—, —N(R^t8)— or —O—;

each Q^a6, Q^b6, Q^c6, and Q^d6independently represents ═O, ═S, ═C(H)NO₂, ═N(CN), ═NR^u8, ═NN(R^v8)R^w8, ═N(OR^x8), or ═NS(O)_pN(R^v8)R^w8;

each G^6a, G^6b, G^6cand G^6dindependently represents halo, R^a9, —CN, -A^a8-C(Q^a7)R^b9, -A^b8-C(Q^b7)N(R^c9)R^d9, -A^c8-C(Q^c7)OR^e9, -A^d8-S(O)_pR^f9, -A^e8-S(O)_pN(R^g9)R^h9, -A^f8-S(O)_pORⁱ⁹, —N₃, —N(R^j9)R^k9, —N(H)CN, —NO₂, —ONO₂, —OR^l9, —SR^m9—B(ORⁿ⁹)₂, —P(O)(N(R^o9)R^p9)₂, —P(O)(N(R^o9)R^p9)(OR^q9) or —P(O)(OR^r9)₂or =Q^d7;

each A^a8, A^b8, A^c8, A^d8, A^e8, and A^f8independently represents a single bond, —C(O)N(R^s9)—, —N(R^t9)— or —O—;

each Q^a7, Q^b7, Q^c7, and Q^d7independently represents ═O, ═S, ═C(H)NO₂, ═N(CN), ═NR^u9, ═NN(R^v9)R^w9, ═N(OR^x9), or ═NS(O)_pN(R^v9)R^w9;

each R^a8and R^f8independently represents H or C_1-6alkyl optionally substituted by one or more F;

each R^b8, R^c8, R^d8, R^e8, R^g8, R^h8, Rⁱ⁸, R^j8, R^k8, R^l8, R^m8, Rⁿ⁸, R^o8, R^p8, R^q8, R^r8, R^s8, R^t8, R^u8, R^v8, R^w8and R^x8independently represents H or C_1-6alkyl optionally substituted by one or more F, or alternatively

any of R^c8and R^d8, R^g8and R^h8, R^j8and R^k8, Rⁿ⁸and R^o8and/or R^v8and R^w8, 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 F, C_1-3alkyl optionally substituted by one or more F, and ═O;

each R^a9and R^f9independently represents H or C_1-6alkyl optionally substituted by one or more F;

each R^b9, R^c9, R^d9, R^e9, R^g9, R^h9, Rⁱ⁹, R^j9, R^k9, R^l9, R^m9, Rⁿ⁹, R^o9, R^p9, R^q9, R^r9, R^s9, R^t9, R^u9, R^v9, R^w9and R^x9independently represents H or C_1-6alkyl optionally substituted by one or more F, or alternatively

any of R^c9and R^dg, R^g9and R^h9, R^j9and R^k9, Rⁿ⁹and R^o9and/or R^v9and R^w9, 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 F, C_1-3alkyl optionally substituted by one or more F, and ═O; and

each p independently represents 1 or 2,

wherein a cancer is characterised by increased MYC activity when:

(1) there is an at least 50% increase in the copy number of a MYC gene in a cancer cell from the patient compared to a corresponding non-cancerous cell from the patient; or

(2) there is an at least 50% increase in MYC mRNA or protein levels in a cancer cell from the patient compared to a corresponding non-cancerous cell from the patient; or

(3) there is an at least 50% increase in activity of a MYC pathway in a cancer cell from the patient compared to a corresponding non-cancerous cell from the patient, and

wherein the cancer characterised by increased MYC activity is selected from Burkitt's lymphoma, ovarian cancer, basel-like breast cancer, esophageal squamous cell carcinoma, colon cancer, endometrial cancer, neuroblastoma, small cell lung carcinoma, medulloblastoma, pancreatic cancer, head and neck cancer, prostate cancer, and hepatocellular carcinomas.