US2019262342A1PendingUtilityA1
Combination therapies for treatment of cancer
Est. expirySep 18, 2034(~8.2 yrs left)· nominal 20-yr term from priority
A61P 43/00A61P 35/00A61P 35/02A61P 1/18A61P 1/00A61P 11/00A61K 31/517A61K 31/337A61K 31/00A61K 31/4745A61K 45/06A61K 31/496
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Claims
Abstract
Combination therapies for treatment of cancers associated with mutations in the KRAS gene are provided. Compositions comprising therapeutic agents for treatment of cancers associated with mutations in the KRAS gene are also provided.
Claims
exact text as granted — not AI-modified1 . A method for treating a KRAS, HRAS or NRAS G12C mutant cancer, the method comprising administering an effective amount of a KRAS, HRAS or NRAS G12C mutant modulating compound and an additional therapeutic agent to a subject in need thereof, wherein the KRAS, HRAS or NRAS G12C mutant modulating compound has the following structure (I):
or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein:
A is CR 1 , CR 2b , NR 7 or S;
B is a bond, CR 1 or CR 2c
G 1 and G 2 are each independently N or CH;
W, X and Y are each independently N, NR 5 or CR 6 ;
Z is a bond, N or CR 6a or Z is NH when Y is C═O;
L 1 is a bond or NR 7 ;
L 2 is a bond or alkylene;
R 1 is H, cyano, halo, heterocyclyl, heteroaryl, aryloxy or aryl;
R 2a , R 2b and R 2C are each independently H, halo, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl or aryl;
R 3a and R 3b are, at each occurrence, independently H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, hydroxylalkly, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl or aminocarbonyl; or R 3a and R 3b join to form a carbocyclic or heterocyclic ring; or R 3a is H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, hydroxylalkly, aminoalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl, and R 3b joins with R 4b to form a carbocyclic or heterocyclic ring;
R 4a and R 4b are, at each occurrence, independently H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, hydroxylalkly, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl or aminocarbonyl; or R 4a and R 4b join to form a carbocyclic or heterocyclic ring; or R 4a is H, —OH, —NH, —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, hydroxylalkly, aminylalkyl, alkylaminoalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl, and R 4b joins with R 3b to form a carbocyclic or heterocyclic ring;
R 5 is, at each occurrence, independently H, C 1 -C 6 alkyl or a bond to L 1 ;
R 6 is, at each occurrence, independently H, oxo, cyano, cyanoalkyl, amino, aminylalkyl, aminylalkylaminyl, aminocarbonyl, alkylaminyl, haloalkylamino, hydroxylalkyamino, amindinylalkyl, amidinylalkoxy, amindinylalkylaminyl, guanidinylalkyl, guanidinylalkoxy, guanidinylalkylaminyl, C 1 -C 6 alkoxy, aminylalkoxy, alkylcarbonylaminylalkoxy, C 1 -C 6 alkyl, heterocyclyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, heteroaryl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, heteroarylalkylamino, aryl, aryloxy, arylamino, arylalkylamino, arylalkyloxy or a bond to L 1 ;
R 6a is H, alkyl or a bond to L 1 ;
R 7 is H or C 1 -C 6 alkyl
m 1 and m 2 are each independently 1, 2 or 3;
indicates a single or double bond such that all valences are satisfied; and
E has the following structure:
wherein:
Q is —C(═O)—, —C(═NR 8′ )—, —NR 8 C(═O)—, —S(═O) 2 — or —NR 8 S(═O) 2 —;
R 8 is H, C 1 -C 6 alkyl or hydroxylalkyl;
R 8 is H, —OH, —CN or C 1 -C 6 alkyl; and
R 9 and R 10 are each independently H, cyano, C 1 -C 6 alkyl, aminylalkyl, alkylaminylalkyl, or hydroxylalkyl or R 9 and R 10 join to form a carbocyclic or heterocyclic ring, and
wherein at least one of W, X, Y or Z is CR 6 where R 6 is a bond to L 1 or at least one of W, X or Y is NR 5 , wherein R 5 is a bond to L 1 .
2 . The method of claim 1 , wherein the additional therapeutic agent is an epidermal growth factor receptor (EGFR) inhibitor, phosphatidylinositol kinase (PI3K) inhibitor, insulin-like growth factor receptor (IGF1R) inhibitor, Janus kinase (JAK) inhibitor, a Met kinase (MET) inhibitor, a SRC family kinase (SFK) inhibitor, a mitogen-activated protein kinase (MEK) inhibitor, an extracellular-signal-regulated kinase (ERK) inhibitor, mechanistic target of rapamycin (mTOR) inhibitor, a topoisomerase inhibitor, a taxane, an anti-metabolite agent, an alkylating agent or a taxane.
3 . The method of claim 1 , wherein the additional therapeutic agent is an epidermal growth factor receptor (EGFR) inhibitor.
4 . The method of claim 3 , wherein the epidermal growth factor receptor (EGFR) inhibitor is Erlotinib, Afatinib or Iressa.
5 . The method of claim 1 , wherein the additional therapeutic agent is a phosphatidylinositol-3 kinase (PI3K) inhibitor.
6 . The method of claim 5 , wherein the phosphatidylinositol kinase (PI3K) inhibitor is GDC0941, MLN1117, BYL719 (Alpelisib) or BKM120 (Buparlisib).
7 . The method of claim 1 , wherein the additional therapeutic agent is an Janus kinase (JAK) inhibitor selected from CYT387, GLPG0634, Baricitinib, Lestaurtinib, momelotinib, Pacritinib, Ruxolitinib, and TG101348.
8 . The method of claim 1 , wherein the additional therapeutic agent is an MET kinase inhibitor selected from Crizotinib, tivantinib, AMG337, cabozantinib, foretinib, and neutralizing monoclonal antibodies to MET such as onartuzumab.
9 . The method of claim 1 , wherein the additional therapeutic agent is an insulin-like growth factor receptor (IGF1R) inhibitor.
10 . The method of claim 9 , wherein the insulin-like growth factor receptor (IGF1R) inhibitor is NVP-AEW541.
11 . The method of claim 1 , wherein the additional therapeutic agent is a non-receptor tyrosine kinase inhibitor.
12 . The method of claim 9 , wherein the non-receptor tyrosine kinase inhibitor is an SFK inhibitor.
13 . The method of claim 12 , wherein the SFK inhibitor is Dasatinib, Ponatinib, saracatinib, or bosutinib.
14 . The method of claim 1 , wherein the additional therapeutic agent is a mitogen-activated protein kinase (MEK) inhibitor.
15 . The method of claim 14 , wherein the mitogen-activated protein kinase (MEK) inhibitor is trametinib, selumetinib, cobimetinib, PD0325901, or RO5126766.
16 . The method of claim 1 , wherein the additional therapeutic agent is a protein kinase inhibitor.
17 . The method of claim 14 , wherein the protein kinase inhibitor is Afatinib, Axitinib, Bevacizumab, Bostutinib, Cetuximab, Crizotinib, Dasatinib, Erlotinib, Fostamatinib, Gefitinib, Imatinib, Lapatinib, Lenvatinib, Ibrutinib, Nilotinib, Panitumumab, Pazopanib, Pegaptanib, Ranibizumab, Ruxolitinib, Sorafenib, Sunitinib, SU6656, Trastuzumab, Tofacitinib, Vandetanib or Vemurafenib.
18 . The method of claim 1 , wherein the additional therapeutic agent is a topoisomerase inhibitor.
19 . The method of claim 18 , wherein the topoisomerase inhibitor is Irinotecan.
20 . The method of claim 1 , wherein the additional therapeutic agent is a taxane.
21 . The method of claim 20 , wherein the taxane is Taxol or Docetaxel.
22 . The method of claim 1 , wherein the additional therapeutic agent is an mTOR inhibitor.
23 . The method of claim 22 , wherein the mTOR inhibitor is Rapamycin or MLN0128.
24 - 32 . (canceled)
33 . The method of claim 1 , wherein the compound is a compound from Table 1.
34 - 36 . (canceled)
37 . The method of claim 1 , wherein the cancer is a hematological cancer, pancreatic cancer, MYH associated polyposis, colorectal cancer or lung cancer.
38 - 40 . (canceled)
41 . A method for inhibiting tumor metastasis in a subject having a KRAS, HRAS or NRAS G12C mutant cancer, the method comprising administering an effective amount of a KRAS, HRAS or NRAS G12C mutant modulating compound and an additional therapeutic agent, wherein the KRAS, HRAS or NRAS G12C mutant modulating compound has the following structure (I):
or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein:
A is CR 1 , CR 2b , NR 7 or S;
B is a bond, CR 1 or CR 2c ;
G 1 and G 2 are each independently N or CH;
W, X and Y are each independently N, NR 5 or CR 6 ;
Z is a bond, N or CR 6a or Z is NH when Y is C═O;
L 1 is a bond or NR 7 ;
L 2 is a bond or alkylene;
R 1 is H, cyano, halo, heterocyclyl, heteroaryl, aryloxy or aryl;
R 2a , R 2b and R 2C are each independently H, halo, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl or aryl;
R 3a and R 3b are, at each occurrence, independently H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkynyl, hydroxylalkly, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl or aminocarbonyl; or R 3a and R 3b join to form a carbocyclic or heterocyclic ring; or R 3a is H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, hydroxylalkly, aminoalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl, and R 3b joins with R 4b to form a carbocyclic or heterocyclic ring;
R 4a and R 4b are, at each occurrence, independently H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkynyl, hydroxylalkly, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl or aminocarbonyl; or R 4a and R 4b join to form a carbocyclic or heterocyclic ring; or R 4a is H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, hydroxylalkly, aminylalkyl, alkylaminoalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl, and R 4b joins with R 3b to form a carbocyclic or heterocyclic ring;
R 5 is, at each occurrence, independently H, C 1 -C 6 alkyl or a bond to L 1 ;
R 6 is, at each occurrence, independently H, oxo, cyano, cyanoalkyl, amino, aminylalkyl, aminylalkylaminyl, aminocarbonyl, alkylaminyl, haloalkylamino, hydroxylalkyamino, amindinylalkyl, amidinylalkoxy, amindinylalkylaminyl, guanidinylalkyl, guanidinylalkoxy, guanidinylalkylaminyl, C 1 -C 6 alkoxy, aminylalkoxy, alkylcarbonylaminylalkoxy, C 1 -C 6 alkyl, heterocyclyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, heteroaryl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, heteroarylalkylamino, aryl, aryloxy, arylamino, arylalkylamino, arylalkyloxy or a bond to L 1 ;
R 6a is H, alkyl or a bond to L 1 ;
R 7 is H or C 1 -C 6 alkyl
m 1 and m 2 are each independently 1, 2 or 3;
indicates a single or double bond such that all valences are satisfied; and
E has the following structure:
wherein:
Q is —C(═O)—, —C(═NR 8′ )—, —NR 8 C(═O)—, —S(═O) 2 — or —NR 8 S(═O) 2 —;
R 8 is H, C 1 -C 6 alkyl or hydroxylalkyl;
R 8 is H, —OH, —CN or C 1 -C 6 alkyl; and
R 9 and R 10 are each independently H, cyano, C 1 -C 6 alkyl, aminylalkyl, alkylaminylalkyl, or hydroxylalkyl or R 9 and R 10 join to form a carbocyclic or heterocyclic ring, and
wherein at least one of W, X, Y or Z is CR 6 where R 6 is a bond to L 1 or at least one of W, X or Y is NR 5 , wherein R 5 is a bond to L 1 .
42 - 46 . (canceled)
47 . A kit comprising a KRAS, HRAS or NRAS G12C mutant modulating compound, an additional therapeutic agent and directions for use of the compound and the additional therapeutic agent for treatment of cancer, wherein the KRAS, HRAS or NRAS G12C mutant modulating compound has the following structure (I):
or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein:
A is CR 1 , CR 2b , NR 7 or S;
B is a bond, CR 1 or CR 2c
G 1 and G 2 are each independently N or CH;
W, X and Y are each independently N, NR 5 or CR 6 ;
Z is a bond, N or CR 6a or Z is NH when Y is C═O;
L 1 is a bond or NR 7 ;
L 2 is a bond or alkylene;
R 1 is H, cyano, halo, heterocyclyl, heteroaryl, aryloxy or aryl;
R 2a , R 2b and R 2C are each independently H, halo, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl or aryl;
R 3a and R 3b are, at each occurrence, independently H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, hydroxylalkly, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl or aminocarbonyl; or R 3a and R 3b join to form a carbocyclic or heterocyclic ring; or R 3a is H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, hydroxylalkly, aminoalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl, and R 3b joins with R 4b to form a carbocyclic or heterocyclic ring;
R 4a and R 4b are, at each occurrence, independently H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, hydroxylalkly, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl or aminocarbonyl; or R 4a and R 4b join to form a carbocyclic or heterocyclic ring; or R 4a is H, —OH, —NH, —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, hydroxylalkly, aminylalkyl, alkylaminoalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl, and R 4b joins with R 3b to form a carbocyclic or heterocyclic ring;
R 5 is, at each occurrence, independently H, C 1 -C 6 alkyl or a bond to L 1 ;
R 6 is, at each occurrence, independently H, oxo, cyano, cyanoalkyl, amino, aminylalkyl, aminylalkylaminyl, aminocarbonyl, alkylaminyl, haloalkylamino, hydroxylalkyamino, amindinylalkyl, amidinylalkoxy, amindinylalkylaminyl, guanidinylalkyl, guanidinylalkoxy, guanidinylalkylaminyl, C 1 -C 6 alkoxy, aminylalkoxy, alkylcarbonylaminylalkoxy, C 1 -C 6 alkyl, heterocyclyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, heteroaryl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, heteroarylalkylamino, aryl, aryloxy, arylamino, arylalkylamino, arylalkyloxy or a bond to L 1 ;
R 6a is H, alkyl or a bond to L 1 ;
R 7 is H or C 1 -C 6 alkyl
m 1 and m 2 are each independently 1, 2 or 3;
indicates a single or double bond such that all valences are satisfied; and
E has the following structure:
wherein:
Q is —C(═O)—, —C(═NR 8′ )—, —NR 8 C(═O)—, —S(═O) 2 — or —NR 8 S(═O) 2 —;
R 8 is H, C 1 -C 6 alkyl or hydroxylalkyl;
R 8 is H, —OH, —CN or C 1 -C 6 alkyl; and
R 9 and R 10 are each independently H, cyano, C 1 -C 6 alkyl, aminylalkyl, alkylaminylalkyl, or hydroxylalkyl or R 9 and R 10 join to form a carbocyclic or heterocyclic ring, and
wherein at least one of W, X, Y or Z is CR 6 where R 6 is a bond to L 1 or at least one of W, X or Y is NR 5 , wherein R 5 is a bond to L 1 .
48 - 49 . (canceled)
50 . The method of claim 1 , wherein R 1 is heteroaryl.
51 . The method of claim 1 , wherein R 1 is thiophenyl, pyridinyl, pyridinonyl, pyrimidinyl, benzooxazolyl, benzoisoxazolyl, benzodioxazolyl, benzoimidazolyl, quinolinyl, quinolinonyl, dihydroquinolinonyl, tetrahydroquinolinyl, quinazolinyl, indazolyl, indolinonyl, benzothiophenyl or dihydrobenzodioxinyl.
52 . The method of claim 51 , wherein R 1 is substituted with one or more substituents selected from halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 2 -C 6 alkenylcarbonylaminyl.
53 . The method of claim 52 , wherein the substituents are selected from fluoro, chloro, amino and methyl.
54 . The method of claim 1 , wherein R 1 is indazolyl optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy and halo.
55 . The method of claim 1 , wherein R 1 has one of the following structures:
56 . The method of claim 1 , wherein R 2a , R 2b and R 2C are each independently H or halo.
57 . The method of claim 56 , wherein halo is chloro or fluoro.
58 . The method of claim 1 , wherein Q is —C(═O)—.
59 . The method of claim 1 , wherein each of R 9 and R 10 are H.
60 . The method of claim 1 , wherein E has one of the following structures:
61 . The method of claim 1 , wherein R 3a , R 3b , R 4a and R 4b are each independently H or C 1 -C 6 alkyl.Join the waitlist — get patent alerts
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