Methods of using SCD1 antagonists

1. A method of treating a cancer cell in an individual wherein the cancer cell is a kidney cancer cell, a pancreatic cancer cell, an urinary cancer cell, or a bladder cancer cell comprising administering to the individual an effective amount of (i) a compound of formula (I):

wherein: x and y are each independently 1 , 2 or 3; W is —C(O)N(R 1 )—; —C(O)N[C(O)R 1a ]—, —N(R 1 )C(O)N(R 1 )— or —N(R 1 )C(O)—; V is —C(O)—, —C(S)—, or —C(R 10 )H; each R 1 is independently selected from the group consisting of hydrogen; C 1 -C 6 alkyl optionally substituted with one or more substituents selected from the group consisting of halo, methyl or trifluoromethyl; and C 2 -C 6 alkyl optionally substituted with one or more substituents selected from the group consisting of methoxy and hydroxyl; R 1a is selected from the group consisting of hydrogen, C 1 -C 6 alkyl and cycloalkyl; R 2 is selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 hydroxyalkyl, C 2 -C 12 hydroxyalkenyl, C 1 -C 12 alkoxy, C 2 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 12 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl, and C 3 -C 12 heteroarylalkyl; or R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other; R 3 is selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 hydroxyaIkyl, C 2 -C 12 hydroxyalkenyl, C 1 C 12 alkoxy, C 2 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 12 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl and C 3 -C 12 heteroarylalkyl; or R 3 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other; R 4 and R 5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or —N(R 12 ) 2 ; R 6 , R 6a , R 7 , R 7a , R 8 . R 8a , R 9 . and R 9a are each independently selected from hydrogen or C 1 -C 3 alkyl; or R 6 and R 6a together, or R 7 R 7a together, or R 8 and R 8a together, or R 9 and R 9a together are an oxo group, provided that when V is —C(O)—, R 7 and R 7a together or R 8 and R 8a together do not form an oxo group, while the remaining R 6 ,R 6a , R 7 R 7a , R 8 ,R 8a ,R 9 , and R 9a are each independently selected from hydrogen or C 1 -C 3 alkyl; or one of R 6 , R 6a , R 7 and R 7a together with one of R 8 , R 8a , R 9 and R 9a form an alkylene bridge, while the remaining R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 9 , and R 9a are each independently selected from hydrogen or C 1 -C 3 alkyl; R 10 is hydrogen or C 1 -C 3 alkyl; and each R 12 is independently selected from hydrogen or C 1 -C 6 alkyl

(ii) G01522403 (A37062),

(iii) G0244 7171, or

a pharmaceutically acceptable salt thereof derivatives thereof.

2. The method of claim 1 , wherein the cancer cell expresses elevated levels of one or more biomarkers compared to a reference sample, reference cell, reference tissue, control sample, control cell, control tissue, or internal control (e.g., housekeeping gene).

3. A method of treating cancer in an individual wherein the cancer is kidney cancer, pancreatic cancer, urinary cancer, or bladder cancer comprising administering to the individual an effective amount of (i) a compound of formula (I):

wherein: x and y are each independently 1 , 2 or 3; W is —C(O)N(R 1 )—; —C(O)N[C(O)R 1a ]—, —N(R 1 )C(O)N(R 1 )— or —N(R 1 )C(O)—; V is —C(O)—,—C(S)—or —C(R 10 )H; each R 1 is independently selected from the group consisting of hydrogen; C 1 -C 6 alkyl optionally substituted with one or more substituents selected from the group consisting of halo, methyl or trifluoromethyl; and C 2 -C 6 alkyl optionally substituted with one or more substituents selected from the group consisting of methoxy and hydroxyl; R 1a is selected from the group consisting of hydrogen, C 1 -C 6 alkyl and cycloalkyl; R 2 is selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 hydroxyalkyl, C 2 -C 12 hydroxyalkellyl, C 1 C 12 alkoxy, C 2 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 12 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl, and C 3 -C 12 heteroarylalkyl; or R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other; R 3 is selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 hydroxyaIkyl, C 2 -C 12 hydroxyalkenyl, C 1 -C 12 alkoxy, C 2 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 12 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl and C 3 -C 12 heteroarylalkyl; or R 3 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other; R 4 and R 5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or —N(R 12 ) 2 ; R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 9 , and R 9a are each independently selected from hydrogen or C 1 -C 3 alkyl; or R 6 and R 6a together, or R 7 and R 7a together, or R 8 and R 8a together, or R 9 and R 9a together are an oxo group, provided that when V is —C(O)—,and R 7 and R 7a together or R 8 and R 8a together do not form an oxo group, while the remaining R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 9 , and R 9a are each independently selected from hydrogen or C 1 -C 3 alkyl; or one of R 6 ,R 6a , R 7 and R 7a together with one of R 8 , R 8a , R 9 and R 9a form an alkylene bridge, while the remaining R 6 , R 6a ,R 7 , R 7a , R 8 , R 8a , R 9 , and R 9a are each independently selected from hydrogen or C 1 -C 3 alkyl; R 10 is hydrogen or C 1 -C 3 alkyl; and each R 12 is independently selected from hydrogen or C 1 -C 6 alkyl

(ii) G01522403(A37062),

(iii) G0244 7171, or

a pharmaceutically acceptable salt thereof.

4. The method of claim 3 , wherein the cancer in the individual expresses elevated levels of one or more biomarkers compared to a reference sample, reference cell, reference tissue, control sample, control cell, control tissue, or internal control (e.g., housekeeping gene).

5. A method of treating cancer wherein the cancer is kidney cancer, pancreatic cancer, urinary cancer, or bladder cancer in an individual comprising administering to the individual an effective amount of (i) a compound of formula (I):

wherein: x and y are each independently 1 , 2 or 3; W is —C(O)N(R 1 )—; —C(O)N[C(O)R 1a ]—, —N(R 1 )C(O)N(R 1 )— or —N(R 1 )C(O)—; V is —C(O)—, —C(S)—, or —C(R 10 )H; each R 1 is independently selected from the group consisting of hydrogen; C 1 -C 6 alkyl optionally substituted with one or more substituents selected from the group consisting of halo, methyl or trifluoromethyl; and C 2 -C 6 alkyl optionally substituted with one or more substituents selected from the group consisting of methoxy and hydroxyl; R 1a is selected from the group consisting of hydrogen, C 1 -C 6 alkyl and cycloalkyl; R 2 is selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 hydroxyalkyl, C 2 -C 12 hydroxyalkenyl, C 1 -C 12 alkoxy, C 2 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 12 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl, and C 3 -C 12 heteroarylalkyl; or R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other; R 3 is selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 hydroxyaIkyl, C 2 -C 12 hydroxyalkenyl, C 1 -C 12 alkoxy, C 2 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 12 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl and C 3 -C 12 heteroarylalkyl; or R 3 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other; R 4 and R 5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or —N(R 12 ) 2 ; R 6 , R 6a , R 7 , R 7a , R 8 . R 8a , R 9 . and R 9a are each independently selected from hydrogen or C 1 -C 3 alkyl; or R 6 and R 6a together, or R 7 and R 7a together, or R 8 and R 8a together, or R 9 and R 9a together are an oxo group, provided that when V is —C(O)—, R 7 and R 7a together or R 8 and R 8a together do not form an oxo group, while the remaining R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 9 , and R 9a are each independently selected from hydrogen or C 1 -C 3 alkyl; or one of R 6 ,R 6a , R 7 and R 7a together with one of R 8 , R 8a , R 9 and R 9a form an alkylene bridge, while the remaining R 6 , R 6a , R 7 , R 7a , R 8 , R 8 a, R 9 , and R 9a are each independently selected from hydrogen or C 1 -C 3 alkyl; R 10 is hydrogen or C 1 -C 3 alkyl; and each R 12 is independently selected from hydrogen or C 1 -C 6 alkyl

(ii) GO 1 522403 (A37062),

(iii) G0244 7171, or

(iv) a stereoisomer thereof, an enantiomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof derivatives thereof, wherein treatment is based upon the individual having cancer expressing elevated levels of one or more biomarkers compared to a reference sample, reference cell, reference tissue, control sample, control cell, control tissue, or internal control (e.g., housekeeping gene).

6. The method of claim 5 , wherein the cancer is bladder cancer.

7. The method of claim 5 , wherein the biomarkers is FGFR3.

8. The method of claim 5 , wherein the biomarkers is phosphorylated FGFR3.

9. The method of claim 5 , wherein the biomarkers is one or more genes of the FGFR3-regulated lipogenic signature.

10. The method of claim 9 , wherein the signature comprises one or more genes selected from the group consisting of SREBF1, G6PD, ACOT7, PTPLA, PCCB, FADS1, RDH11, ACER3, PDSS1, MVD, AGPAT5, HSD17B2, ACSL4, EBP, PIGW, LBR, ACLY, ADORA2B, GPCPD1, CYP24A1, ACSL3, MVK, ACSS2, FDPS, ELOVL5, HMGCR, LIPG, ME1, DHCR7, LSS, ACAT2, FASN, CYP51A1, IDI1, FDFT1, FAR2, HMGCS1, SDR16C5, LDLR, MSMO1, INSIG1, DHRS9, LRPS, SQLE, PCSK9, SCD1, and FABP4, or combinations thereof.

11. The method of claim 9 , wherein the signature comprises one or more genes selected from the group consisting of ELOVL5, HMGCR, LIPG, ME1, DHCR7, LSS, ACAT2, FASN, CYP51A1, IDI1, FDFT1, FAR2, HMGCS1, SDR16C5, LDLR, MSMO1, INSIG1, DHRS9, LRPS, SQLE, PCSK9, SCD1, and FABP4, or combinations thereof.

12. The method of claim 9 , wherein the signature comprises one or more genes selected from the group consisting of CYP51A1, IDI1, FDFT1, FAR2, HMGCS1, SDR16C5, LDLR, MSMO1, INSIG1, DHRS9, LRPS, SQLE, PCSK9, SCD1, and FABP4, or combinations thereof.

13. The method of claim 9 , wherein the signature comprises one or more genes selected from the group consisting of LDLR, MSMO1, INSIG1, DHRS9, LRPS, SQLE, PCSK9, SCD1, and FABP4, or combinations thereof.

14. The method of claim 9 , wherein the signature comprises one or more genes selected from the group consisting of SQLE, PCSK9, SCD1, and FABP4, or combinations thereof.

15. The method of claim 5 , wherein the biomarkers is mature SREBP1.

16. The method of claim 5 , wherein the biomarkers is Δ9 monounsaturaturated fatty acids.

17. The method of claim 5 , wherein the biomarkers is ratio of Δ9 monounsaturaturated fatty acids:saturated fatty acids.

18. The method of claim 5 , wherein the biomarkers is PI3K signaling, mTOR signaling, MEK signaling.

19. The method of claim 5 , wherein the biomarkers is one or more polymorphism in genes selected from the group consisting of PI3K, PTEN, p85, TSC½, and AKT.

20. The method of claim 5 , wherein the biomarkers is phosphorylated AKT.

21. The method of claim 5 , wherein the expression level of the one or more biomarkers is elevated by greater than about 1.5 fold, about 1.75 fold, about 2 fold, about 2.25 fold, about 2.5 fold, about 2.75 fold, about 3.0 fold, or about 3.25 fold as compared to a reference sample, reference cell, reference tissue, control sample, control cell, control tissue, or internal control (e.g., housekeeping gene).

22. The method of claim 1 , wherein the SCD1 antagonist is G01522403(A37062), G0244 7171, or pharmaceutically acceptable salt thereof derivatives thereof.

23. The method of claim 3 , wherein the method further comprises an additional therapeutic agent.