WO2017059434A1

WO2017059434A1 - Use of tetrahydroindazolylbenzamide and tetrahydroindolylbenzamide derivatives for the treatment of cancer

Info

Publication number: WO2017059434A1
Application number: PCT/US2016/055181
Authority: WO
Inventors: Everardus O. M. ORLEMANS
Original assignee: Esanex, Inc.
Priority date: 2015-10-02
Filing date: 2016-10-03
Publication date: 2017-04-06

Abstract

Provided are methods of treating cancer having at least one null-type mutation of the TP53 gene, comprising administering to a patient in need thereof a compound of formula (I) in a therapeutically effective amount: Formula (I).

Description

USE OF TETRAHYDROINDAZOLYLBENZAMIDE AND TETRAHYDRO- INDOLYLBENZAMIDE DERIVATIVES FOR THE TREATMENT OF CANCER

Cross-Reference To Related Applications

This application claims priority to U.S. Provisional Application No. 62/236,580, fifed October 2, 2015, the disclosure of which is hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

Field of the invention

The invention relates to therapies useful in treating cancer, wherein the cancer cells comprise at least one null-type mutation of the Tumor Protein P53 (TP53) gene.

Description of the Related Art

Cancer is characterized by abnormal cellular proliferation. Cancer cells exhibit a number of properties that make them dangerous to the host, typically including an ability to invade other tissues and to induce capillary ingrowth, which assures that the proliferating cancer cells have an adequate supply of blood. A hallmark of cancerous cells is their abnormal response to control mechanisms that regulate cell division in normal cells and continue to divide until they ultimately kill the host.

The tumor suppressor gene TP53 codes for a central regulator of the DNA- damage-response pathway, and its activation leads to cell-cycle arrest and DNA repair, apoptosis, or senescence through both transcription-dependent and transcriptional-independent activities. The prevalence of TP53 mutations differs considerably between tumor types and stages of cancer, and approximately 50% of all tumors present mutations associated with TP53. In contrast to other tumor suppressor genes that are mainly altered by truncating mutations, the majority of TP53 mutations are missense substitutions (75%). Other alterations include frameshift insertions and deletions (9%), nonsense mutations (7%), silent mutations (5%) and other infrequent alterations (Petitjean et ai. (2007) Oncogene, 26(15):2157- 65).

In chronic lymphocytic leukemia (CLL), mutations in TP53 correlate with unfavorable prognosis and chemotherapy resistance, especially when located in DNA binding domain. Furthermore, a strong correlation between 17p deletions and TP53 mutations has been shown in CLL Deletion of 17p is the strongest independent adverse prognostic factor for survival, and is associated with the shortest median treatment-free survival in patients with CLL. This deletion involves the loss of the TP53 tumor suppressor gene and is found in 5-7% of CLL cases in 5 early stages, while it is present in 25-40% of patients with advanced refractory disease (Shanafelt et ai. (2006) Journal Clinical Oncology 24(28):4634-41 ). In multiple myeloma, deletion of the TP53 gene (located at 17p13) was present in 7% of the patients and negatively impacted both the event free survival and the overall survival (Lode et al. (2010) Haematologica. 95(1 1 ):1973-76.). Loss of TP53, i o observed in 8% of diffuse large B-cell lymphoma was significantly associated with a shorter survival even after treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (Jardin et al. (2010) Blood 1 16(7):1092-104). In non- small cell lung cancer, 9% of TP53 alterations include frameshift insertions and deletions. In smokers, however, TP53 deletion has been detected in about 20% of

15 patients and was associated with poor prognosis (Mogi A. and Kuwano H. (2011 ) Journal of Biomedicine and Biotechnology, 201 1 :1-9.) 7P53 mutation is a predictive marker for resistance to chemotherapy and radiotherapy and for poor prognoses in head and neck squamous cell carcinomas (HNSCCs). A relatively high incidence of null-type mutations of 7P53 in HNSCC (48%) compared to 32% of HNSCCs in the

20 International Agency for Research on Cancer database was reported by Ebihara et al. (2014 Journal of Cancer Therapy, 5:664-671 ).

SUMMARY OF THE INVENTION

The inventors have discovered that the compounds of the disclosure have

25 unexpected activity against cancer, particularly cancer having at least one null-type mutation of the TP53 gene. Data from various cancer cell lines that have either TP53 wild type or TP53 mutation without concurrent TP53 gene deletion show that neither TP53 wild type nor TP53 mutation alone confers sensitivity to the compounds of the disclosure. Unexpectedly, the compounds of the disclosure retain activity in

30 cancers with loss of the TP53 gene activity from at least one of the alleles. The compound of the disclosure displayed good activity in cancer cell lines with TP53 null/TP53 wild type (TP53^NULLWT) and TP53 null/TP53 mutation (TP53^NULL/MUT). Even when TP53 activity is lost from both alleles (TP53^NULL/NULL), the compound of the disclosure retains activity. Because patients having cancers with at least one nuil-type mutation of the TP53 gene have adverse prognostic factors for both the event free survival and the overall survival, the compounds of the disclosure are useful as therapeutic agents for these patients.

Thus, in one aspect, the disclosure encompasses methods of treating cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I), wherein the cancer cells comprise at least one null-type mutation of the TP53 gene, and wherein the formula (I) is:

or a pharmaceutically acceptable salt thereof.

In one aspect, the disclosure encompasses methods for treating cancer in a patient in need thereof, the method comprising:

determining that the patient has a tumor comprising cancer cells that comprise at least one null-type mutation of the TP53 gene; and

administering to the patient a therapeutically effective amount of a compound of formula (I).

In another aspect, the disclosure encompasses methods of causing cancer cells to undergo apoptosis, the method comprising:

determining that cancer cells comprise at least one null-type mutation of the TP53 gene; and

contacting the cells with a compound of formula (I).

The invention also provides the use of compounds described herein for the manufacture of a medicament for use in treating cancer, wherein the cancer cells comprise at least one null-type mutation of the TP53 gene.

DETAILED DESCRIPTION OF THE INVENTION

Before the disclosed methods are described, it is to be understood that the aspects described herein are not limited to specific embodiments, or compositions, and as such can, of course, vary, !t is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and, unless specifically defined herein, is not intended to be limiting.

Throughout this specification, unless the context requires otherwise, the word "comprise" and "include" and variations (e.g., "comprises," "comprising," "includes," "including") will be understood to imply the inclusion of a stated component, feature, element, or step or group of components, features, elements or steps but not the exclusion of any other integer or step or group of integers or steps.

As used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise.

The term "pharmaceutical composition" is used in its widest sense, encompassing all pharmaceutically applicable compositions containing at least one active substance, and optional carriers, adjuvants, constituents etc. The term "pharmaceutical composition" also encompasses a composition comprising the active substance in the form of derivative or pro-drug, such as pharmaceutically acceptable salts and esters. The manufacture of pharmaceutical compositions for different routes of administration falls within the capabilities of a person skilled in medicinal chemistry.

In view of the present disclosure, the methods described herein can be configured by the person of ordinary skill in the art to meet the desired need. In general, the disclosed methods provide improvements in the treatment and/or inhibition of cancer. For example, in particular embodiments, the compounds of the disclosure (e.g., 4-(6,6-Dimethyl-4-oxo-3-trifiuoromethyl-4,5,6,7-tetrahydro-indazol-1 - yl)-2-(trans-4-hydroxy-cyclohexylamino)-benzamide) effectively treat cancer wherein the cancer cells comprise at least one null-type mutation of the TP53 gene.

For example, a null-type mutation is a change in genetic sequence that causes the complete loss of the protein encoded by the gene (i.e., no protein is actually synthesized). One of skill in the art will recognize that null-type mutation may be caused by deletions, truncating mutations, missense substitutions, frameshift insertions and deletions, nonsense mutations, silent mutations, and other infrequent alterations. In certain embodiments, the cancers have null-type mutation in one allele (e.g., null/wt or null/mut). In another embodiment, the null-type mutation is in both alleles (e.g., null/null). The null-type mutation of the TP53 gene in cancer cells may be determined by direct sequencing (Lode et al. (2010); Stuhmer et al. (2005) Blood 106(10):3609-17; Ebihara et al. (2014)) or by Fluorescence in situ hybridization (FISH) analysis (Shanafelt et al. (2006); Dewald et al (2003) Br. J Haematol. 121 :287-295).

The cancers that may be treated by the methods of the disclosure include tumors, leukemias, neoplasms, carcinomas, proliferative disorders, and other malignant diseases. In some embodiments, the cancer is lung cancer, adenocarcinoma, leukemia, lymphoma, multiple myeloma, melanoma, ovarian cancer, breast cancer, renal cell carcinoma, neuroendocrine cancer, central nervous system cancer, prostate cancer, colon cancer, osteosarcoma, liver cancer, glioblastoma, or head and neck squamous cell carcinoma. In one embodiment, the cancer is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), muitiple myeloma, diffuse large B-celi lymphoma, head and neck squamous cell carcinomas, or nonsmall cell lung cancer (NSCLC).

The methods of the disclosure require compounds of formula (I) or a pharmaceutically acceptable salt thereof. Some of these compounds are disclosed in, for example, International Publication Nos. WO 2006/091963, WO 2007/101 156, and WO 2008/130879, all incorporated herein by reference.

In one embodiment, the compound useful in the methods and compositions of the disclosure is of formula (I):

(I)

or a pharmaceutically acceptable salt thereof, wherein

R3 and R₄ are independently

(a) H,

(b) halo, or

(c) a C1-C15 alkyl group where up to six of the carbon atoms in said alkyl group are optionally replaced independently by R22, carbonyl, ethenyl, ethynyl or a moiety selected from N, O, S, SO2, or SO, with the proviso that two O atoms, two S atoms, or an O and S atom are not immediately adjacent each other, wherein

R22 is

(i) heteroaryl,

(ii) aryl,

(iii) saturated or unsaturated C3-C10 cycloaikyi, or

(iv) saturated or unsaturated C2-C10 heterocycloalkyl, wherein each aryl, heteroaryi, saturated or unsaturated cycloaikyi, or saturated or unsaturated heterocycloalkyl, independently, is optionally substituted with at least one group, which independently is hydroxy, halo, amino, cyano, carboxy, carboxamido, nitro, oxo, -S-(Ci-C6)alkyl, -S02-(Ci-C6)aikyi, -S0₂-aryl, -SO-(Ci-C₆)alkyl, -SO-aryl, -SO2NH2, -S0₂NH-(Ci-C6)alkyl, -S0₂NH-aryl, (Ci-C₆)alkoxy, or mono- or di-(Ci-Cio)alkylamino; and

each R₂₂ is optionally fused to a Ce-Cio aryl group, Cs-Cs saturated cyclic group, or a C5-C10 heterocycloalkyl group;

wherein each (c) moiety is optionally substituted at any available position with C1-C10 alkyl, C1-C10 haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino, cyano, nitro, -SH, -S-(Ci- C₆)alkyl, -S0₂-(Ci-C₆)alkyl, -S0₂NH_2! -S0₂NH-(Ci-C₆)alkyl, -SO2NH- aryl, -S0₂-aryl, -SO-(CrC₆)alkyl, -S0₂-aryi, Ci-C₆ alkoxy, C₂-Cio alkenyloxy, C₂-C o alkynyloxy, mono- or di-(C -Cio)alkylamino, -OC1- C10 alkyl-Z, or R₂3, wherein

Z is ORo or -N(R3o)₂, wherein

each R30 is independently -H or C1-C6 alkyl, or N(R3o)₂ represents pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, 1 ,3- or 1 ,4-diazepanyl, or morpholinyl, each of which is optionally substituted with hydroxy, amino, aminoalkyl, C1-C6 alkyl, mono- or di(CrC6)alkylamino, C1-C6 alkoxy, or halogen; Ro is -H, -C1-C10 alkyl, -C2-C10 alkenyl, -C2-C10 alkynyl, aryl, heteroaryl, or -Ci-Ce acyl;

R23 is (1) heteroaryl,

(2) aryl,

(3) saiurated or unsaturated C5-C10 cycloaikyi, or

(4) saturated or unsaturated C5-C10 heterocycioalkyl, and the R23 groups are optionally substituted with at least one group which independently is hydroxy, oxo, halo, amino, cyano, nitro, -SH, -S-(Ci-C₆)alkyl, -S02-(Ci-C₆)alkyl, -SC -aryS, -SO-(Ci- C₆)alkyl, -SO-aryl, -SO2NH2, -S0₂NH-(C -C₆)alkyl, -S0₂NH-aryl, (C -C6)alkoxy, or mono- or di-(Ci-Cio)alkylamino; and wherein one or both of R3 and R₄ is optionally substituted with a group R50 where R50 is:

wherein

d and k are integers independently selected from 1 and 2;

R201 is (C -Ce)alkyl where the alkyl is optionally substituted with (C3-

C7)cycloalkyl, (C2-C6) alkenyl, (C₂-C6)alkynyl, hydroxy, halogen, nitro, or cyano; and

T is O or NR202 where R202 is hydrogen or (Ci-C6)alkyl; and

R301 and R302 are independently hydrogen or (Ci-Ce)alkyl, and R303 is absent, hydrogen, or (C -C6)alkyl;

R₇ is O, S, NH, N-OH, N-NH₂, N-NHR₂2, N-NH-(Ci-C₆ alkyl), N-O-(C₀-C₆)alkyl- R22, N-(Ci-C6 alkenoxy);or N-(Ci-C6 aikoxy optionally substituted with carboxy);

Y is N or CRc, wherein

each Rc independently is hydrogen, halogen, cyano, nitro, -C(0)Re, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 haloalkyl, C3-C7 cycloaikyi, C3-C7 cycioalkyi(Ci-Cio)alkyl, heterocycioalkyl, aryl, or heteroaryl, wherein

each alkyl, aryl, cycloaikyi, heterocycioalkyl, and heteroaryl group is optionally substituted with from 1-4 groups that are independently C1-C6 aikyi, Ci-Ce alkoxy, halogen, hydroxy, amino, mono- or di-(Ci-Ce) alkyiamino, cyano, nitro, halo(Ci- C6)alkyl, halo(Ci-C6)alkoxy, carboxamide, heterocycloalkyl, aryl, or heteroaryl, wherein

the aryi and heteroaryl groups are optionally substituted with from 1-4 groups that are independently Ci-Ce alkyl, C1-C6 alkoxy, halogen, hydroxy, amino, mono- or di-(Ci- C6) alkyiamino, halo(Ci-C6)alkyl, or carboxamide;

Rc^! is -Ci-Ce alkyl, -ORc-, or -N(RcN)2, wherein

Re- is -H, C1-C10 alkyl, C1-C10 haloalkyl, C3-C7 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each RCN is independently -H, -C1-C10 alkyl, -C1-C10 -aloalkyl, -C3-C7 cycloalkyl, -heterocycloalkyl, -C1-C6 acyl, -aryl, or -heteroaryl, wherein

each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is optionally substituted with from 1-4 groups that are independently Ci-Ce alkyl, Ci- Ce alkoxy, halogen, hydroxy, amino, mono- or di- (C1-C6) alkyiamino, nitro, halo(Ci-C6)alkyl, halo(C - C6)alkoxy, or carboxamide;

Xi is N or CRc;

Q , Q₂, and Q3 are independently N or CRQ , wherein one and only one of Q ,

Q2, and Q3 is C-R21 , and wherein

each RQ is independently hydrogen, halogen, -N(RCN)2, Ci-Ce alkyl, Ci- Ce haloalkyl, C3-C7 cycloalkyl, aryi, or heteroaryl, or R2 , wherein each alkyl, cycloalkyl, aryl, and heteroaryl group is optionally substituted with from 1-4 groups that are independently C1-C6 alkyl, Ci- Ce alkoxy, halogen, hydroxy, amino, mono- or di-(C -Ce) alkyiamino, halo(Ci-C6)alkyl, halo(Ci-Ce)alkoxy, or carboxamide;

R21 is cyano, -C(0)OH, -C -0(Ci-C₆ alkyl), or a group of the formula

wherein

R and R₂ are independently H, hydroxy, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, heteroaryl, aryl, C3-C8 cycloalkyl, heterocycloalkyl, wherein

each alkyl, cycloalkyl, heterocycloaikyi, aryl, and heteroaryl group is optionally substituted with from 1-4 groups that are independently C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, amino, mono- or di-(d-Cs) alkylamino, nitro, halo(Ci-C6)alkyl, halo(Ci-C6)alkoxy, or carboxamide;

or R and R₂ together with the nitrogen to which they are both attached, form a heterocycloalkyl which optionally contains one or more additional heteroatoms which are, independently, O, N, S, or N(RCN); and

X₄ is O, S, NH, NOH, N-NH₂, N-NHaryl, N-NH-(Ci-C₆ alkyl), or N-(Ci-

Ce alkoxy);

X₂ and X3 are independently C, O, N, or S(0)_p wherein

p is 0, 1 , or 2; and

n is 0, 1 , 2, 3, or 4;

provided that when

(i) X₂ is C, then

Rs and Rs are independently H, C1-C6 alkyl, or aryl, wherein the aryi is optionally substituted with from 1-4 groups that are independently Ci- Ce alkyl, C1-C6 alkoxy, halogen, hydroxy, amino, mono- or di-(Ci-Ce) alkylamino, nitro, halo(Ci-C6)alkyl, halo(CrC6)alkoxy, or carboxamide, wherein any two adjacent substituted aryl positions, together with the carbon atoms to which they are attached, form an unsaturated cycloalkyl or heterocycloalkyl; or

Rs and R6 together with the carbon to which they are attached form a 3-8 membered ring;

(ii) X₂ is N, thenRe is absent and R5 is H or C1-C6 alkyl;

(iii) X3 is C, then it is substituted with two groups that are independently H, Ci-

Ce alkyl, or mono- or di-(Ci-C6)alkylamino(Ci-C6)alkyl; and

(iv) X₂ is O or S(0)_p, then R6 and R5 are absent. In Formula I, R3 and R₄ are, as noted above, independently (a) hydrogen, (b) haio, or (c) an alkyi group having from 1-15 carbon atoms. All, but no more than about six, of the carbon atoms in the alkyi group may be replaced independently by the various groups listed above in connection with Formula I.

Thus, when the alkyi group is methyl, i.e., a one carbon atom alkyi group, replacement of that carbon atom with, for example, nitrogen or sulfur, the resulting group will not be an alkyi group but instead will be an amino or thio group, respectively. Similarly, when the carbon atom being replaced terminates the alkyi group, the terminal group will become another moiety such as pyrimidinyl, amino, phenyl, or hydroxy.

Replacement of a carbon atom with a group such as, for example, oxygen, nitrogen, or sulfur will require appropriate adjustment of the number of hydrogens or other atoms required to satisfy the replacing atom's valency. Thus, when the replacement is N or O, the number of groups attached to the atom being replaced will be reduced by one or two to satisfy the valency of the nitrogen or oxygen respectively. Similar considerations will be readily apparent to those skilled in the art with respect to replacement by ethenyi and ethynyl.

Thus, replacement as permitted herein results in the term "C1-C15 alkyi" as defined in connection with Formula I encompassing groups such as, but not limited to:

amino, hydroxy, phenyl, benzyl, propylaminoethoxy, butoxyethylamino, pyrid- 2-ylpropyl, diethylaminomethyl, pentylsulfonyl, methylsulfonamidoethyl, 3-[4- (butylpyrimidin-2-yl)ethyl]phenyl, butoxy, dimethylamino, 4-(2- (benzylamino)ethyl)pyridyl, but-2-enylamino, 4-(1-(methylamino)pent-3-en-2- ylthio)phenyl, 2-(N-methyl-hexanamido)ethoxy)methyl, and 4-(((3-methoxy-4- (4-methyl-1 H-imidazol-2-yi)but-1-enyl)(methyi)amino)-methyl)phenyl.

Preferred compounds of Formula I include those where Xi is carbon optionally substituted with Ci-Cs alkyi, more preferably C1-C3 alkyi. Other preferred compounds of Formula I are those where Xi is carbon optionally substituted with Ci - Ce alkyi and Y is CRc wherein Rc is -H, Ci-Ce alkyi, C1-C3 haloalkyl, C3-C7 cycloalkyl, or C3-C7 cycloalkyl(Ci-C6)alkyl. More preferably, in compounds of Formula I, Xi is carbon optionally substituted with C1-C2 alkyi and Y is CRc wherein Rc is -H, Ci-C₄ alkyi, C1-C3 haloalkyl, cyclopropyl, or cyclopropyl(Ci-C2)alkyl. Still more preferred compounds of Formula I are those where Xi is CH. Other more preferred compounds of Formula I are those where Xi is CH and Y is CRc wherein Rc is -H, C1-C3 alkyl, C1-C3 haloalkyl, C3-C5 cycloalkyl, or C3-C5 cycloalkyl(Ci -C2)alkyl. Even more preferred compounds of Formula I are those where Xi is CH and Y is CRc wherein Rc is -H, methyl, ethyl, trifiuoromethyl, cyclopropyl, or cyclopropyimethyl. Particularly preferred compounds of Formula I are those where Xi is CH and Y is CRc wherein Rc is methyl, ethyl, or cyclopropyl. Other particularly preferred compounds of Formula ! are those where Xi is CH and Y is CRc wherein Rc is trifiuoromethyl. Other particularly preferred compounds of Formula I are those where Xi is CH and Y is CRc wherein Rc is methyl. Other particularly preferred compounds of Formula I are those where X is CH and Y is CRc wherein Rc is ethyl. Other particularly preferred compounds of Formula I are those where X is CH and Y is CRc wherein Rc is cyclopropyl.

Still more preferred compounds of Formula I are those where Xi is N. Other more preferred compounds of Formula I are those where Xi is N and Y is CRc wherein Rc is -H, C1-C3 alkyl, C1 -C3 haloalkyl, C3-C5 cycloalkyl, or C3-C5 cycloalkyl(Ci-C2)alkyl. Even more preferred compounds of Formuia I are those where X is N and Y is CRc wherein Rc is -H, methyl, ethyl, trifiuoromethyl, cyclopropyl, or cyclopropyimethyl. Particularly preferred compounds of Formula I are those where Xi is N and Y is CRc wherein Rc is methyl, ethyl, or cyclopropyl. Other particularly preferred compounds of Formula I are those where Xi is N and Y is CRc wherein Rc is trifiuoromethyl. Other particularly preferred compounds of Formuia I are those where X is N and Y is CRc wherein Rc is methyl. Other particularly preferred compounds of Formula I are those where Xi is N and Y is CRc wherein Rc is ethyl. Other particularly preferred compounds of Formula I are those where X is N and Y is CRc wherein Rc is cyclopropyl.

Other preferred compounds of Formula I are those where

Q3 is CR21 , wherein

R21 is a group of the formula,

R7 is O; and Y is CRc, wherein Rc is hydrogen, C1-C3 alkyl, C3-C5 cycloaikyl, trifiuoromethyl, or C3-C5 cycloalkyl(Ci-C2)alkyl. Such compounds are compounds of Formula II herein.

Other preferred compounds of Formula I are those where

Qs is CR21. wherein

R21 is a group of the formula,

X3 is C substituted with Rg_a and Rgb, wherein Rg_a and Rgb are independently H or Ci- C₆ alkyl.

Such compounds are hereinafter compounds of Formula III.

Other preferred compounds of Formula I are those where

Q3 is CR21 , wherein

R21 is a group of the formula,

Qi and Q₂ are independently C substituted with Rio_a and Riob respectively, wherein R oa and R o are independently H or C1-C6 alkyl. Such compounds are hereinafter compounds of Formula IV.

Other preferred compounds of Formula I are those where

Q3 is CR21 , wherein

R21 is a group of the formula,

Xi is C substituted with Rn where Rn hydrogen, halogen, cyano, nitro, - C(0)Rc\ C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 haloalkyl, C3-C7 cycloaikyl, C3-C7 cycloaikyi(Ci-Cio)alkyl, heterocycioalkyl, aryi, or heteroaryl, wherein

Rc is -d-Cs alkyl, -ORc, or -N(RcN)2, wherein

Rc- is -H, C1-C10 alkyl, C1-C10 haloalkyl, C3-C7 cycloaikyl, heterocycioalkyl, aryi, or heteroaryl; each RCN is independently -H, -C1-C10 alkyl, -C1-C10 -haloalkyl, -C3-C7 cycloalkyl, -heterocycloalkyl, -C1-C6 acyl, -aryl, or -heteroaryl. Such compounds are hereinafter compounds of Formula V.

Preferred compounds of Formula V are those where Rn is hydrogen, halogen, C1-C10 alkyl, C1-C10 haloalkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl (Ci- Cio)alkyl, aryl, or heteroaryl.

More preferred compounds of Formula V are those where R-n is H or C1-C6 alkyl.

Other preferred compounds of Formula I are those where

Q3 is CR21 , wherein

R21 is a group of the formul

Xi is N. Such compounds are hereinafter compounds of Formula Va.

Other preferred compounds of Formula I are those where

Q3 is CR21 , wherein

R21 is a group of the formula,

X₄ Ri

^R2 ; and

X2 is C substituted with R5 and Re, wherein R5 and R6 are independently H or Ci-C₄ alkyl. Such compounds are hereinafter compounds of Formula VI.

More preferred compounds of the invention are those of Formula I wherein Ch is CR21 , wherein

More preferred compounds of the invention are those of Formula I wherein Ri and R2 are independently H or Ci-C₄ alkyl;

X2 is C substituted with two independently selected Ci-C₄ alkyl groups; and n is 1.

Other preferred compounds of the invention include those having the formula

VII

VII

wherein Xi and Rc are as defined in Formula I;

R5 and Re are independently H or C1-C4 alkyl;

R11 is H or Ci-Ce alkyl;

Rioa and Riob are independently H or Ci-Cs alkyl;

Rg_a and Rgb are independently H or C1-C6 alkyl.

Preferred compounds of Formula VII include those where

Ri and R₂ are independently H or C1-C4 alkyl;

Rioa and Riob are both H; and

R5 and Re are independently C1-C4 alkyl.

Other preferred compounds of Formula VII include those where

Xi is N.

Other preferred compounds of Formula VII include those where Xi is CRc, wherein Rc is hydrogen, methyl, ethyl, cyciopropyl, cyclopropyimethyi, fluoromethyl, difluoromethyl, or trifluoromethyl. In a preferred embodiment of this aspect, the R_c group derived from Xi is hydrogen, methyl, or trifluoromethyl, and the R_c group derived from Y carries the definition given in connection with Formula I.

Other preferred compound de those of formula VIM,

VIII wherein Rc is H, C1-C6 alkyl, trifluoromeihyi, or cyclopropyl; and

R1-R6, Xi,and X₄ carry the same definitions as for Formula I.

Preferred compounds of Formula VIII include those where X is N.

Preferred compounds of Formula VIII include those where Xi is CRc, wherein Rc is hydrogen, methyl, ethyl, cyclopropyl, cyclopropylmethyl, fiuoromethyl, difluoromethyl, or trifluoromethyi. In a preferred embodiment of this aspect, the R_c group derived from X is hydrogen, methyl, or trifluoromethyi, and the R_c group derived from Y carries the definition given in connection with Formula I.

Other preferred compoun ose of Formula IX:

IX

where R is hydrogen or methyl, preferably hydrogen;

Rc is H, C1-C2 alkyl, trifluoromethyi, or cyclopropyl; and

R3, R₄, and X₄ carry the same definitions as for Formula I. Preferred compounds of Formula IX include those where Rc is C1-C2 alkyl, trifluoromethyi, or cyclopropyl.

Other preferred compounds of Formula I are those where R21 is cyano, R₇ is O, and Y is CRc, wherein Rc is H, methyl, ethyl, trifluoromethyi, or cyclopropyl.

Other preferred compounds of Formula I are those where,

R21 is cyano; R₇ is O; and Y is CRc, wherein Rc is H, methyl, trifluoromethyi, or cyclopropyl.

Yet other preferred compounds of Formula I are those where R21 is cyano, and X3 is C substituted with two groups that are independently H or Ci-Ce alkyl.

More preferred compounds of Formula I are those where R21 is cyano, and Q and Q₂ are independently C substituted with H or C1-C6 alkyl.

Yet other preferred compounds of Formula I are those where R21 is cyano, and Xi is C substituted with H or Ci-Cs alkyl. Still other preferred compounds of Formula I are those where R21 is cyano, and X2 is C substituted with two groups that are independently H or C1-C4 aikyi.

Yet other preferred compounds of Formula I include those of Formula X,

X

wherein X1-X4, Qi , Q2, Rc, and R1-R4 are as defined in Formula I.

Preferred compounds of formula X are those where Qi and Q₂ are each independently hydrogen or Ci-Ce aikyi.

Other preferred compounds of formula X are those where R_c is d-Cealkyl, C3- C?cycloalkyl, Ci-Ce haloaiky!, C3-C7cycloaikyi(Ci-C6)alkyl, or heterocycloalkyl.

More preferred compounds of Formula X include those where R_c is C3- C7cycloalkyi, C -C6 haloaikyl, heterocycloalkyl, or C3-C7cycloaikyi(Ci-C6)alkyl.

Particularly preferred compounds of Formula X include those where R_c is Ci- C₃alkyl, Cs-Cscycloalkyl, C3-C5cycloalkyl(Ci-C₃)alkyl, or C -C₂ haloaikyl.

Preferred compounds of Formula X are those where X is N. Such compounds are referred to herein as compounds of Formula XI.

Preferred compounds of any of Formulas l-X include those wherein R3 is substituted with Rso, and R50 is

Other preferred compounds of any of Formulas l-X include those wherein Q3 is CR2 , wherein

R21 is a group of the formula,

R₇ is O; and

Y is CRc, wherein

Rc is -H, -CH3, ethyl, cyciopropyl, or -CF3.

Other preferred compounds of any of Formulas l-X include those wherein Q3 is CR21 , wherein

R21 is a group of the formula,

and X₂ is C substituted with two groups that are independently H or Ci- C₆ aikyi.

Other preferred compounds of any of Formulas l-X include those wherein Q3 , wherein

R21 is a group of the formula,

and Qi and Q₂ are independently C substituted with H or Ci-Ce alkyl.

Other preferred compounds of any of Formuias l-X include those wherein Xi

Other preferred compounds of any of Formulas l-X include those wherein Xi

R21 is a group a,

^■

and Xi is C substituted with H or Ci-Ce alkyl. Other preferred compounds of any of Formulas l-X include those wherein Q3, wherein

R21 is a group of the formula,

X₄ R,

and X2 is C substituted with two groups that are independently H or Ci- C₄ alkyl.

Other preferred compounds of any of Formulas l-X include those wherein R21up of the formula,

R3 is -ZiRzi , wherein

Zi is -O- or -NH-; and

Rzi is a saturated or unsaturated C3-C10 cycloalkyl, each of which is

(a) substituted with R50, where R50 is

(b) optionally substituted at any available position with C1-C10 alkyl, C1-C10 haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino, cyano, nitro, -SH, -S-(Ci-C₆)alkyl, -S0₂-(Ci-C₆)alkyl, -SO2NH2, - S0₂NH-(C -C₆)alkyl, -S0₂NH-aryl, -S0₂-aryl, -SO-(Ci- C6)aikyi, -S02-aryl, C1-C6 aikoxy, C2-C10 alkenyloxy, C2- Cio alkynyloxy, mono- or di-(Ci-Cio)alkylamino, -OC1-C10 alkyl-Z, or R23; and

R₄ is H or halogen. Other preferred compounds of any of Formulas l-X include those wherein Rzi is a saturated C5-C7 cycioalkyl.

Other preferred compounds of any of Formulas l-X include those wherein wherein Rz is a unsaturated C5-C7 cycioalkyl.

Other preferred compounds of any of Formulas l-X include those wherein Xi is N.

Other preferred compounds of any of Formulas l-X include those wherein X

Other preferred compounds of any of Formulas l-X include those wherein Xi is CH.

Other preferred compounds of any of Formulas l-X include those wherein Ri and R₂ are independently H or C1-C4 alkyl;

X₂ is C substituted with two independently selected Ci-C₄ aikyi groups; and

n is 1.

Other preferred compounds of any of Formulas l-X include those of the formula,

wherein

RQI is H or halogen; and

RQ₂ is H or halogen.

Other preferred compounds of any of Formulas l-X include those wherein R3 is cyclohexyi which is

(a) substituted with R50, where R50 is

; and

(b) optionally substituted at any available position with C1-C10 alkyl, C1-C10 haloalkyl, C2-C10 alkenyi, C2-C10 alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino, cyano, nitro, -SH, -S- (C -C₆)alkyl, -S0₂-(Ci-Ce)alkyl, -SO2NH2, -S0₂NH-(Ci-C₆)alkyl, - S0₂NH-aryl, -S0₂-aryl, -SO-(C -C₆)alkyl, -S0₂-aryl, Ci-C₆ alkoxy, C2-C10 alkenyloxy, C2-C10 alkynyloxy, mono- or di-(Ci- Cio)alkylamino, -OC1-C10 alkyl-Z, or R23; and

R₄ is H or fluoro.

In some embodiments, the compound of formula (I) is 4-(6,6-dimethyl-4-oxo- 3-trifiuoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(trans-4-hydroxy- cyclohexylamino)-benzamide:

trans-4-({2-(aminocarbonyi)-5-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4, 5,6,7- tetrahydro-1 H-indazol-1-yl]phenyl}amino)cyclohexyl glycinate:

or pharmaceutical iy acceptable salts thereof. Synthesis and characterization data for these compounds are described in U.S. Patent No. 7,358,370, which is incorporated by reference in its entirety.

Examples of compounds of formula (I) suitable for use in the methods and compositions of the disclosure include, but are not limited to compounds listed in Table 1.

Table 1

2-(allylamino)-4-(3-methyl-4-oxo-4,5,6,7-tetrahydroindol-1-yl)benzamide;

2-(cyclopropylamino)-4-(3-methyl-4-oxo-4,5,6,7-tetrahydroindol-1-yl)benzamide; 2-(2-methoxyethylamino)-4-(3-methyl-4-oxo-4,5,6,7-tetrahydroindol-1-yl)benzamide; 4-(3-methyl-4-oxo-4,5,6,7-tetrahydroindol-1-yl)benzamide;

4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindol-1-yl)benzamide;

4-(3-methyl-4-oxo-4,5,6,7-tetrahydroindoi-1-yl)-2-(phenylamino)benzamide;

2-(trans-4-hydroxycyclohexylamino)-4-(3-methyl-4-oxo-4,5,6,7-tetrahydroindol-1- yl)benzamide;

4-(3-methyl-4-oxo-4,5,6,7-tetrahydroindol-1-yl)-2-(3,4,5- trimethoxyphenylamino)benzamide;

2-(2-(dimethylamino)ethylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindol-1- yl)benzamide;

2-(2-(dimethylamino)ethylamino)-4-(3-methyl-4-oxo-4,5,6,7-tetrahydroindol-1- yl)benzamide;

2-(pyridin-4-ylmethylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindol-1- yl)benzamide;

4-(3-methyl-4-oxo-4,5,6,7-tetrahydroindol-1-yl)-2-(pyridin-3- ylmethylamino)benzamide;

tert-butyl 4-(2-carbamoyl-5-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindol-1- yl)phenylamino)piperidine-1-carboxylate;

2-amino-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindol-1-yi)benzamide;

2-(allylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindol-1-yl)benzamide;

2-(1-methylpiperidin-4-ylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindol-1- yl)benzamide;

2-(piperidin-4-ylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindol-1- yl)benzamtde;

-butoxy-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindol-1-yl)benzamide;

-(2_!3-dihydro-1 H-inden-1-ylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6_>7-tetrahydroindol- 1-yl)benzamide;

1- (2-carbamoyl-5-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindol-1-yl)phenyl)urea - Benzylamino-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indoi-1-yl)-benzamide; - Prop-2-ynyloxy-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-ietrahydro-indol-1-yl)-benzamide; -Ethynyl-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indoi-1-yl)-benzamide;

-(4-Methoxy-phenylamino)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)- benzamide;

-Cyclohexyiamino-4-(2_>6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yi)- benzamide;

- (butylamino)-4-(2,6,6-trimeihyl-4-oxo-4,5,6,7-tetrahydroindol-1-yi)benzamide; - ethyl-3-(2,6_>6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzamide;

3- (3-thienyl)-4-{2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 2-methyl-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1 H-indol-1-yl)benzamide; 2-[(3-ethynyiphenyl)amino]-4-(2,6,6-trimethyi-4-oxo-4,5,67-tetrahydro-1 H-indol-1- yl)benzamide;

2-[(4-chlorophenyl)amino]-4-(2,6,6-trimeihyi-4-oxo-4,5,6,7-tetrahydro-1H-indol-1 - yi)benzamide;

2- anilino-4-(2-methyl-4-oxo-4,5,6,7-ietrahydro-1 H-indol-1-yl)benzamide;

3- anilino-5-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1 H-indol-1-yl)pyridine-2- carboxamide;

2-[(3,4,5-trimethoxyphenyl)amino]-4-(2,6_J6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1 H- indol-1-yl)benzamide;

2-pyridin-4-yl-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-teirahydro-1H-indol-1-yl)benzamide; N-[2-(aminocarbonyl)-5-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- y!)phenyl]-L-valine;

2-morpholin-4-yi-4-(2,6,6-trimethyi-4-oxo-4,5,6,7-ietrahydro-1 H-indol-1- yl)benzamide;

2-(1 H-imidazol-1-yl)-4-(2,6,6-trimeihyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide;

4- (3-chioro-2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yi)-2-[(3,4,5- trimethoxyphenyi)amino]benzamide; -[(4-hydroxyphenyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1 H-indol-1- y!)benzamide;

-[(1 -ethyl- 1 H-pyrazol-5-yl)amino]-4-(2,6,6-trimethyl-4-oxo-4_>5,6,7-tetrahydro-1 H- indol-1 -yl)benzamide;

-[(5-methylisoxazol-3-yl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1 H- indol-1 -yl)benzamide;

-{[4-(aminocarbonyl)phenyl]amino}-4-(2-methyl-4-oxo-4,5_>6,7-tetrahydro-1 H-indoi-

1-yi)benzamide;

-(4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-[(3,4,5- trimethoxyphenyl)amino]benzamide;

-[{6-methoxypyridtn-3-yl)amino}-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1 H- indol-1 -yl)benzamide;

- (allyiamino)-4-(4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yi)benzamide;

-(2,3-dimethyl-4-oxo-4,5,6,7-tetrahydro-1 H-indol-1-yl)benzamide;

- bromo-4-(2,3-dimethyl-4-oxo-4,5,6,7-tetrahydro-1 H-indol-1-yl)benzamide;

-(allylamino)-4-(2,3-dimethyi-4-oxo-4,5,6,7-tetrahydro-1 H-indol-1-yl)benzamide;- (2,3-dimethyl-4-oxo-4,5,6,7-tetrahydro-1 H-indol-1-yl)-2-[(2- methoxyethy I )a mi no] be nza m i de ;

-({3-[3-(dimethyiamino)propoxy]-4-methoxyphenyl}amino)-4-(2,6,6-trimethyl-4-oxo-

4,5,6, 7-tetrahydro-1 H-indol-1 -yl)benzamide;

-(morpholin-4-ylamino)-4-(2,6,6-trimethyi-4-oxo-4,5,6,7-tetrahydro-1 H-indol-1- yl)benzamide;

-[(2-methoxyethyi)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1 H-indazol-1- yi)benzamide;

-[(2-morpholin-4-yiethyl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indol-1 -yl)benzamide;

-(pyridin-4-ylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1 H-indol-1 - yl)benzamide;

-(acetylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1 H-indol-1 -yl)benzamide;-(4-methylpiperazin-1 -yl)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1 H-indol-1 - yi)benzamide; -[(cyclopropylmethyl)amino]-4-(3,6,6-trimethyl -4-0X0-4, 5,6 J-tetrahydro-1 H-indazol- 1-yl)benzamide;

-[(methoxyaceiyl)amino]-4-(3,6,6-trimeihyl-4-oxo-4,5,6,7-tetrahydro-1 H-indoi-1- yi)benzamide;

-ethyl-4-(3,6,6-trimethyi-4-oxo-4,5,6,7-tetrahydro-1 H-indazol-1-yl)benzamide;

-(butylthio)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide;-({3-[2-(dimeihylamino)ethoxy]-4-methoxyphenyl}amino)-4-(3,6,6-trimethyl-4-oxo-

4,5,6,7-tetrahydro-1 H-indol-1-yl)benzamide;

-(pyridin-4-ylthio)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide;

-{[(1 R)-1 -phenyiethylJaminoH-iS.e.S-trimethyM-oxo^.S.ej-tetrahydro-l H-indazol- 1-yi)benzamide;

-[6,6-dimeihyl-4-oxo-3-(irifluoromeihyl)-4,5,6,7-ietrahydro-1 H-indazol-1-yl]-2-

[(3,4,5-trimethoxyphenyl)amino]benzamide;

-({2-[2-(dimeihyiamino)ethoxy]pyridin-4-yl}amino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7- tetrahydro-1 H-indol-1 -yl)benzamide;

-{[1-(N,N-dimethylglycyi)piperidin-4-yl]amino}-4-(3,6_!6-trimethyl-4-oxo-4, 5,6,7- tetrahydro-1 H-indol-1 -yl)benzamide;

-(6,6-dimethyl-4-oxo-3-phenyl-4,5,6,7-ietrahydro-1 H-indol-1-yl)benzamide;

-[(2-{[2-(aminocarbonyi)-5-(3,6,6-trimethyi-4-oxo-4,5,6,7-tetrahydro-1 H-indol-1 - yi)phenyl]amino}ethyl)amino]-2-oxoethyl acetate;

-{[2-(glycoloylamino)ethyl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indol-1 -yl)benzamide;

-{[2-(methylsulfonyi)ethyl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1 H- indazol-1 -yl)benzamide;

-[(4-methoxyphenyl)amino]-4-(3,6, 6-trimethyl-4-oxo-4, 5,6, 7-tetrahydro-1 H-indazol-

1-yi)benzamide;

-[(6-oxo-1 ,6-dihydropyridin-3-yi)amino]-4-(3,6,6-trimethyl -4-oxo-4,5, 6, 7-tetrahydro-

1 H-indazol-1 -yl)benzamide;

-(cyciopent-3-en-1-ylamino)-4-[3-(difluoromethyl)-6,6-dimethyl-4-oxo-4, 5,6,7- tetrahydro-1 H-indazol-1 -yljbenzamide;

-(cyclobutylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1 H-indazol-1 - yi)benzamide; -[trans-4-(2-Hydroxy-ethoxy)-cyclohexylamino3-4-(3,6,6-irimethyl-4-oxo-4,5,6,7- tetrahydro-indazol-1-yl)-benzamide;

-(trans-4-Hydroxy-cyclohexylamino)-4-(3,6,6-trimethyl-4-oxo-4,5_>6,7-tetrahydro- indazoi-1-yl)-benzamide;

-(2- ethoxy-1 -methoxymethyl-ethylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7- teirahydro-indazol-1-yl)-benzamide;

-{[3-hydroxy-1-(2-hydroxyethyl)propyl]amino}-4-(3,6,6-trimethyl-4-oxo-4, 5,6,7- tetrahydro-1 H-indazol-1 -yi)benzamide;

-[6,6-dimethyi-4-oxo-3-(trifluoromethyi)-4,5,6,7-tetrahydro-1 H-indazol-1-yl]-2-{[2- methoxy-1-(methoxymethyl)ethyl]amino}benzamide;

-{[3-(methylsulfinyl)phenyl]amino}-4-(3,6_>6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1 H- indazoi-1 -yl)benzamide;

-[6,6-dimeihyl-4-oxo-3-(irifluoromeihyl)-4,5,6,7-ietrahydro-1 H-indazol-1-yl]-2-{[1-

(methylsulfonyi)piperidin-4-yl]amino}benzamide;

-(6,6-Dimethyl-4-oxo-3-trifiuoromethyl-4,5,6,7-tetrahydro-indazol-1 -yi)-2-(trans-4- hyd roxy-cyclohexyl amino)-benza mide ;

-(6,6-Dimethyl-4-oxo-3-trifiuoromethyi-4,5,6,7-ietrahydro-indazol-1-yl)-2-[trans-4-(2- hydroxy-ethoxy)-cyciohexylamino]-benzamide;

-{[1 -(3-morphoiin-4-yipropanoyl)piperidin-4-yl]amino}-4-(3,6,6-trimethyl-4-oxo-

4, 5,6, 7-tetrahydro-1 H-indazol-1 -yl)benzamide;

-[trans-4-(2-Amino-ethoxy)-cyclohexylamino]-4-(6,6-dimethyl-4-oxo-3- trifiuoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide;

-[(1-glycylpiperidin-4-yl)amino]-4-(3,6,6-trimethyi-4-oxo-4,5,6,7-tetrahydro-1 H- indazol-1 -yl)benzamide;

-[trans-4-(2-Amino-ethoxy )-cydohexylamino]-4-(3,6,6-trimethyl-4-oxo-4, 5,6,7- tetrahydro-indazol-1-yl)-benzamtde;

-{[1 -(methylsulfonyl)azetidin-3-yl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-

1 H-indazol-1 -yl)benzamide;

-{[3-(methylsulfonyl)propyl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-ietrahydro-1 H- indazol-1-yl)benzamide;

-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1-yl]-2-({2-

[(methylsulfonyl)amino]ethyl}amino)benzamide;

-(3-bui-3-en-1-yl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide; 2-{[<3S)-1-(methylsulfonyl)pyrrolidin-3-y^

tetrahydro-1 H-indazol-1 -yl)benzamide;

2-({2-[(dimethylamino)sulfonyl]ethyl}amino)-4-[6,6-dim^

4, 5,6, 7-tetrahydro-1 H-indazol-1 -yljbenzamide;

4-[3-(2-Amino-ethyl)-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl]-benzamide; or pharmaceutically acceptable salts thereof.

The synthesis and characterization data of the above-listed compounds is described in U.S. Patent No. 7,358,370.

Pharmaceutical Compositions

In some embodiments, the method comprises the administration of the compound of formula (I) in a pharmaceutical composition having at least one pharmaceutically acceptable carrier, solvent, adjuvant or diluent.

The compounds described herein may be administered orally, topically, parenterally, by inhalation or spray or rectaily in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes percutaneous, subcutaneous, intravascular (e.g., intravenous), intramuscular, or intrathecal injection or infusion techniques and the like. The pharmaceutical compositions described herein may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservative agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques. In some cases such coatings may be prepared by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Formulations for oral use may also be presented as lozenges.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally- occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. Pharmaceutical compositions of the invention may also be in the form of oil-in- water emulsions. The oily phase may be a vegetable oil or a mineral oil or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxy ethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol, glucose or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1 ,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The compositions disclosed herein may also be administered in the form of suppositories, e.g., for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols.

The compositions disclosed herein may be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.

Alternatively, the active ingredients may be formulated in a cream with an oil- in-water cream base. If desired, the aqueous phase of the cream base may include, for example at least 30% w/w of a polyhydric alcohol such as propylene glycol, butane-1 ,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof. The topical formulation may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs. The compounds of this invention can also be administered by a transdermal device. Preferably topical administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. In either case, the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient. In the case of microcapsules, the encapsulating agent may also function as the membrane. The transdermal patch may include the compound in a suitable solvent system with an adhesive system, such as an acrylic emulsion, and a polyester patch. The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make-up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span

80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate, among others. The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low. Thus, the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di- isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyi palmitate, butyl stearate, 2-ethylhexyl paimitate or a blend of branched chain esters may be used. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.

Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanoi, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.

Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient. The daily dose can be administered in one to four doses per day. In the case of skin conditions, it may be preferable to apply a topical preparation of compounds of this invention to the affected area two to four times a day.

in the methods of the disclosure the compound of formula (I) is administered in an amount of about 50 mg/m² to about 150 mg/m², or about 50 mg/m² to about 100 mg/m², or about 75 mg/m² to about 100 mg/m², or about 75 mg/m² to about 125 mg/m², or about 90 mg/m² to about 110 mg/m². In one embodiment, the compound of formula (I) is administered in an amount that gradually increases from about 50 mg/m² to about 100 mg/m². In another embodiment, the compound of formula (I) is administered in an amount of about 100 mg/m². In another embodiment, the compound of formula (I) is administered in an amount of about 75 mg/m². In another embodiment, the compound of formula (I) is administered in an amount of about 50 mg/m².

In other methods of the disclosure, the compound of formula (I) is administered according to the dosage schedule. In one embodiment, the dosage schedule comprises one, or two, or three, or four, or five, or six or more 28-day treatment cycles. In another embodiment, the compound of formula (I) is administered every other day for at least 21 days (i.e., starting on day 1 and continuing for at least 21 days) during each 28-day treatment cycle.

It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, genera! health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

The compounds of the present invention may be administered alone or in combination with at least one anti-cancer therapeutic. In some embodiments, the composition includes at least one anti-cancer therapeutic, or a pharmaceutically acceptable sa!t thereof. In some embodiments, the compounds of the present invention may be combined with one or more anti-cancer therapeutic simultaneously or sequentially. Suitable anti-cancer therapeutics include, but are not limited to the therapeutics listed in Table 2.

Table 2

Anti-cancer Therapeutics

Generic IPUAC Name

Name

Everolimus dihydroxy-12-[(2R)-1 -[(1 S,3R,4R)-4-(2-hydroxyethoxy)-3- methoxycyclohexyl]propan-2-yl]-19,30-dimethoxy-

15, 17,21 ,23,29,35-hexamethyl-11 ,36-dioxa-4-azatricycio[30.3.1.0 hexatriaconta-16,24,26,28-tetraene-2,3, 10, 14,20-pentone

Erlotinib A/-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy) quinazolin-4-amine

Generic IPUAC Name

Name

Abiraterone [(3S.8R.9S, 10R, 13S, 14S)-10,13-dimethyl-17-pyridin-3-yl- acetate 2,3,4,7,8,9,11 , 12,14,

cyclopenta[a]phenant

Bleomycin (3-{[(2'-{(5S,8S,9S, 10R, 13S)-15-{6-amino-2- [(1 S)-3-amino-1 - {[(2S)-2,3-diamino-3-oxopropyl]amino}-3-oxopropyl]-5- methylpyrimidin-4-yl}-13-[{[(2R,3S,4S,5S,6S)-3- {[(2R,3S,4S,5/?,6R)-4-(carbamoyloxy)-3,5-dihydroxy-6- (hydroxymethyi)tetrahydro-2/-/-pyran-2-yl]oxy}-4,5-dihydroxy-6- (hydroxymethy!)tetrahydro-2H-pyran-2-yl]oxy} (1 H-imidazol-5- yl)methyl]-9-hydroxy-5-[(1 R)-1-hydroxyethyl]-8,10-dimethyl- 4,7,12,15-tetraoxo-3 ,6 , 11 ,14-tetraazapentadec- 1 -yl}-2 ,4'-bi- 1 , 3- thiazol-4-yl)carbonyi3amino}propyl)(dimethy])sulfonium

Siroiimus (3S,6R,7£,9/?, 10/?, 12R, 14S, 15E, 17E, 195,21 S,23S,

26R,27 ?,34aS)-

9,10,12,13,14,21 ,22,23,24,25,26,27,32,33,34,34a- hexadecahydro-9,27-dihydroxy-3-[(1 R)-2-[(1S,3f?,4R)-4-hydroxy- 3-methoxycy cl oh exy I]-

1 -methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl- 23,27-epoxy-3H-pyrido[2, 1 -c][1 ,4]-oxaazacyclohentriacontine- 1 ,5,11 ,28,29

(4H,6H,31H)-pentone Generic IPUAC Name

Name

Arsenic 2,4,5-trioxa-1 ,3-diarsabicycio[1.1.1]peniane

irioxide

Temsirolimus (1 R,2R,4S)-4-{(2R)-2-

[(3S,6R,7£,9R, 10R, 12R, 14S.15E, 17£, 19£,21 S, 23S,26R,27R,34aS)-9,27-dihydroxy-10,21 -dimethoxy- 6,8,12,14,20,26-hexamethyl-1,5,11 ,28,29-pentaoxo- 1 ,4,5,6,9,10,11 ,12,13,14,21 ,22,23,

24,25,26,27,28,29,31 , 32,33,34,34a-tetracosahydro-3H-23,27- epoxy-pyrido[2,1-c][1 ,4]oxazacyclohentriacontin-3-yl]propyl}-2- methoxycyclo-hexyl 3-hydroxy-2-(hydroxymeihyl)-2- methylpropanoate

Imaiinib 4-[(4-methylpiperazin-1-yl)methyl]-A/-(4-methyl-3-{[4-(pyridin-3- yl)pyrimidin-2-yl]amino}phenyl)benzamide Generic IPUAC Name Name

in some embodiments, the composition includes a compound selected from Table 1 , or a pharmaceutically acceptable salt thereof, and everolimus, erlotinib, abiraterone, bleomycin, siroiimus, arsenic trioxide, temsiroiimus, imatinib, dasatinib, carboplatin, vandetanib, Iomustine, or cisplattn, or a pharmaceutically acceptable salt thereof.

Definitions

The term "alkoxy" represents an alkyl group of indicated number of carbon atoms attached to the parent molecular moiety through an oxygen bridge. Examples of alkoxy groups include, for example, methoxy, ethoxy, propoxy and isopropoxy.

As used herein, the term "alkyl" includes those alkyl groups of a designated number of carbon atoms. Aikyi groups may be straight, or branched. Examples of "alkyl" include methyl, ethyl, propyl, isopropyl, butyl, iso-, sec- and tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl, and the like.

The term "alkenyl" as used herein, means a straight or branched chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbon- carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyi, 2-propenyl, 2-methyl-2- propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3- decenyl.

The term "alkenoxy" refers to an alkenyl group attached to the parent group through an oxygen atom.

The term "alkynyl" as used herein, means a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited, to acetylenyl, 1-propynyl, 2-propynyi, 3-butynyl, 2-pentynyi, and 1 -butynyl.

The term "aryl" refers to an aromatic hydrocarbon ring system containing at least one aromatic ring. The aromatic ring may optionally be fused or otherwise attached to other aromatic hydrocarbon rings or non-aromatic hydrocarbon rings. Examples of aryl groups include, for example, phenyl, naphthyl, 1 ,2,3,4- tetrahydronaphthalene and biphenyi. Preferred examples of aryl groups include phenyl, naphthyl, and anthracenyl. More preferred aryl groups are phenyl and naphthyl. Most preferred is phenyl. The aryl groups of the invention may be substituted with various groups as provided herein. Thus, any carbon atom present within an ary! ring system and available for substitution may be further bonded to a variety of ring substituents, such as, for example, halogen, hydroxy, nitro, cyano, amino, Ci-dalkyl, d-Csalkoxy, mono- and di(Ci-Csalkyl)amino, C3-Ciocycloalkyl, (C3-C ocycloalkyl)alkyl, (C3-Ciocycloalkyl)alkoxy, C2-C9heterocycloalkyl, Cr da!kenyl, d-dalkynyl, halo(Ci-d)alkyl, halo(Ci-d)alkoxy, oxo, amino(Ci-C8)alkyl, mono- and di(Ci-C8alkyl)amino(Ci-Cs)alkyl, Ci-dacyl, C -Csacyloxy, d-dsulfonyl, Ci-Csthio, Ci-Cssulfonamido, d-daminosulfonyl .

The term "carboxy" as used herein, means a -CO2H group.

The term "cycioalkyi" refers to a d-d cyclic hydrocarbon. Examples of cycioalkyi include cyciopropyl, cyciobutyl, cyclopentyi, cyclohexyl, cyciohepty! and cyclooctyl. More preferred are d-d cycioalkyi groups. The cycioalkyi groups of the invention may be substituted with various groups as provided herein. Thus, any carbon atom present within a cycioalkyi ring system and available for substitution may be further bonded to a variety of ring substituents, such as, for example, halogen, hydroxy, nitro, cyano, amino, d-dalkyl, d-da!koxy, mono- and di(Ci- dalkyl)amino, d-C ocycloalkyl, (d-C ocycloalkyl)alkyl, (C3-Ciocycloalkyl)alkoxy, C₂- Cgheterocycloalkyl, Ci-dalkenyl, d-dalkynyl, haio(Ci-d)alkyl, halo(C -d)alkoxy, oxo, amino(Ci-C8)alkyl and mono- and di(Ci-C8alkyl)amino(Ci-C8)alkyl.

The terms "halogen" or "halo" indicate fluorine, chlorine, bromine, and iodine.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more haiogen atoms, where each halogen is independently F, CI, Br or I. Preferred halogens are F and CI. Preferred haloalkoxy groups contain 1-6 carbons, more preferably 1-4 carbons, and still more preferably 1-2 carbons. "Haloalkoxy" includes perhaloalkoxy groups, such as OCF3 or OCF2CF3. A preferred haloalkoxy group is trifluoromethoxy.

The term "haloalkyl" refers to an alkyl group substituted with one or more haiogen atoms, where each halogen is independently F, CI, Br or I. Preferred halogens are F and Ci. Preferred haloalkyl groups contain 1-6 carbons, more preferably 1 -4 carbons, and still more preferably 1-2 carbons. "Haloalkyl" includes perhaloalkyl groups, such as CF3 or CF2CF3. A preferred haloalkyl group is trifluoromethyl. The term "heterocycioalkyl" refers to a ring or ring system containing at least one heteroatom selected from nitrogen, oxygen, and sulfur, wherein said heteroatom is in a non-aromatic ring. The heterocycloaikyi ring is optionally fused to or otherwise attached to other heterocycioalkyl rings and/or non-aromatic hydrocarbon 5 rings and/or phenyl rings. Preferred heterocycioalkyl groups have from 3 to 7 members. More preferred heterocycioalkyl groups have 5 or 6 members. Examples of heterocycioalkyl groups include, for example, 1 ,2,3,4-tetrahydroisoquinolinyl, piperazinyl, morpholinyl, piperidinyl, tetrahydrofuranyl, pyrrolidinyl, pyridinonyl, and pyrazolidinyl. Preferred heterocycioalkyl groups include piperidinyl, piperazinyl, i o morpholinyl, pyrrolidinyl, pyridinonyl, dihydropyrrolidinyl, and pyrrolidinonyl. The heterocycioalkyl groups of the invention may be substituted with various groups as provided herein. Thus, any atom present within a heterocycioalkyl ring and available for substitution may be further bonded to a variety of ring substituents, such as, for example, halogen, hydroxy, nitro, cyano, amino, d-Csalkyl, d-Csalkoxy, mono- and

15 di(C -C8alkyl)amino, C3-Ciocycloalkyl, (C3-Ciocycioalkyl)aikyl, (C3- Ciocycloalkyl)alkoxy, C2-C9heterocycloalkyl, d-Csalkenyl, Ci-Csa!kyny!, halo(Ci- C8)alkyl, halo(C -Cs)alkoxy, oxo, amino(Ci-Cs)alkyl and mono- and di(C - C8alkyl)amino(Ci-C8)alkyl.

The term "heteroaryl" refers to an aromatic ring system containing at least one

20 heteroatom selected from nitrogen, oxygen, and sulfur. The heteroaryl ring may be fused or otherwise attached to one or more heteroaryl rings, aromatic or non- aromatic hydrocarbon rings or heterocycioalkyl rings. Examples of heteroaryl groups include, for example, pyridine, furan, thienyl, 5,6,7,8-tetrahydroisoquinoline and pyrimidines. The heteroaryl groups of the invention may be substituted with various

25 groups as provided herein. Thus, any carbon atom present within an heteroaryl ring system and available for substitution may be further bonded to a variety of ring substituents, such as, for example, halogen, hydroxy, nitro, cyano, amino, Ci- Csaikyi, Ci-Cealkoxy, mono- and di(C -C8alkyl)amino, C3-Ciocycloalkyi, (C3- Ciocycloalkyl)alkyl, (C3-C ocycloalkyl)alkoxy, C2-C9heterocycloalkyl, Ci-Csalkenyl,

30 Ci-Cealkynyl, halo(C -Cs)alkyl, halo(d-Cs)alkoxy, oxo, amino(d-Cs)alkyl and mono- and di(Ci-C8alkyl)amino(C -C8)alkyl.

Preferred examples of heteroaryl groups include thienyl, benzothienyl, pyridyl, quinolyl, pyrazolyl, pyrimidyl, imidazolyl, benzimidazolyl, furanyl, benzofuranyl, dibenzofuranyi, thiazoiyl, benzothiazolyl, isoxazoiyl, oxadiazoiyl, isothiazolyl, benzisothiazolyl, triazolyl, pyrrolyl, indolyl, pyrazolyl, and benzopyrazolyl.

The compounds of this invention may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. These compounds can be, for example, racemates, chiral non-racemic or diastereomers. In these situations, the single enantiomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent; chromatography, using, for example a chiral HPLC column; or derivatizing the racemic mixture with a resolving reagent to generate diastereomers, separating the diastereomers via chromatography, and removing the resolving agent to generate the original compound in enantiomerically enriched form. Any of the above procedures can be repeated to increase the enantiomeric purity of a compound.

When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, it is intended that the compounds include the cis, trans, Z- and E- configurations. Likewise, all tautomeric forms are also intended to be included.

As used here, the terms "treatment" and "treating" means:

(i) inhibiting the progression the disease;

(ii) prophylactic use for example, preventing or limiting development of a disease, condition or disorder in an individual who may be predisposed or otherwise at risk to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease;

(iii) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder;

(iv) ameliorating the referenced disease state, for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing or improving the pathology and/or symptomatology) such as decreasing the severity of disease; or

(v) eliciting the referenced biological effect. EXAMPLES

Example 1. General procedure

The 50% inhibition concentration (IC50) of compound of invention on ceil viability of cancer cell lines was determined using CellTiter-Glo luminescent cell viability assay after incubation at various concentrations. All the cells were cultured in media supplemented with 10% Fetal Bovine Serum, at a temperature of 37 °C, 5% CO2 and 95% humidity. Culture medium was purchased from GIBCO or Sigma, USA. Cisplatin was used as reference control.

Ceils were harvested during the logarithmic growth period and cell numbers were counted using Count-star. The cell concentrations were adjusted to 5.56*10⁴ cells/ml with respective culture medium. 90 μΙ_ cell suspensions were added to two 96-weli piates (plates A and B) with the final cell density of 5x10³ cells/weli.

Plate A was incubated overnight in humidified incubator at 37 °C with 5% CO2. 10 μ!_ of culture medium was added to each well of plate A for To reading. The plate and its contents were equilibrated at room temperature for approximately 30 minutes. A black sticker was placed on bottom of plates to block light. 50 μΙ_ CellTiter-Glo was added to each well. The contents were mixed for 2 mins on an orbital shaker to induce cell iysis. The plate was allowed to incubate at room temperature for 10 mins to stabilize luminescent signal. Luminescence (To) was recorded using EnVision Multi Label Reader.

Plate B was incubated overnight in humidified incubator at 37 °C with 5% C0₂. 500xsolution (Top Concentration: 1.0 mM) of 4-(6,6-Dimethyl-4-oxo-3- trifiuoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(trans-4-hydroxy-cyclohexylamino)- benzamide was prepared in DMSO with 4-fold dilution. Then, DMSO solution was diluted with culture medium (50-fold) to achieve 10* solutions (Highest test concentration: 2.0 μΜ). 10^χ cisplatin drug solutions (Top working concentrate on: 100 μΜ) was prepared with Phosphate Buffered Saline (PBS). 10 pL (10^χ) drug solution of both test articles and reference control were dispensed in each well (triplicate for each drug concentration) of the plates B (final DMSO concentration in culture medium: 0.2% [v/v]). The test piates were incubated for 72 hrs in the humidified incubator at 37 °C with 5% CO2, and then measured by means of CTG assay. The plate and its contents were equilibrated at room temperature for approximately 30 minutes. A black sticker was placed on bottom of plates to block light, and 50 μί CellTiter-Glo was added to each well. The contents were mixed for 2 mins on an orbital shaker to induce cell lysis. The plate was allowed to incubate at room temperature for 10 mins to stabilize luminescent signal, followed by recording of the luminescence.

Data Analysis

The data was displayed graphically using GraphPad Prism 5.0. A dose- response curve was fitted using noniinear regression model with a sigmoidal dose response to calculate absolute !Cso (EC50). The formula for calculating surviving rate is shown below and the absolute IC50 (EC50) was calculated according to the dose- response curve generated by GraphPad Prism 5.0.

Example 2. Results

Tables 3-5 show !Cso values after treatment with 4-(6,6-Dimethyl-4-oxo-3- trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(trans-4-hydroxy-cyclohexylamino)- benzamide. Table 3 illustrates the results from various ceil lines that have TP53 wild type (not null):

Table 3

TP53 Wild Type (not NULL)

NCI-H209 SCLC >2,000

NCI-H82 SCLC 7

Table 4 illustrates the results after treatment with 4-(6,6-Dimethyl-4-oxo-3- trtfluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(trans-4-hydroxy-cyclohexylamino)- benzamide in various cell lines that have TP53 mutation (not null):

Table 4

TP53 mutation (not NULL)

Table 5 illustrates the results after treatment with 4-(6,6-Dimethyl-4-oxo-3- trifiuoromethyl-4,5,6,7-tetrahydro-indazol-1 -yl)-2-(trans-4-hydroxy-cyclohexylamino)- benzamide in various cell lines that have at least one null-type TP53 mutation:

Table 5

TP53 Null

It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be incorporated within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated herein by reference for all purposes.

Claims

What is claimed is:

1. A method for treating cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I), wherein the cancer cells comprise at least one null-type mutation of the TP53 gene, and wherein the formula I) is:

(I)

or a pharmaceutically acceptable salt thereof, wherein

R3 and R₄ are independently

(a) H,

(b) halo, or

(c) a C1-C15 alkyl group where up to six of the carbon atoms in said alky! group are optionally replaced independently by R22, carbonyl, ethenyl, ethynyl or a moiety selected from N, O, S, SO2, or SO, with the proviso that two O atoms, two S atoms, or an O and S atom are not immediately adjacent each other, wherein

R22 is

(i) heteroaryl,

(ii) aryl,

(iii) saturated or unsaturated C3-C10 cycloalkyl, or

(iv) saturated or unsaturated C2-C10 heterocycloalkyl, wherein each aryl, heteroaryl, saturated or unsaturated cycloalkyl, or saturated or unsaturated heterocycloalkyl, independently, is optionally substituted with at least one group, which independently is hydroxy, halo, amino, cyano, carboxy, carboxamido, nitro, oxo, -S-(Ci-C6)alkyl, -S0₂-(Ci-C6)alkyl, -S0₂-aryl, -SO-(Ci-C₆)alkyl, -SO-aryl, -SO2NH2, -S0₂NH-(Ci- C6)alkyl, -S02N H-aryl, (Ci-C6)aikoxy, or mono- or di-(Ci - C o)alkylamino; and

each R22 is optionally fused to a C6-C10 aryl group, Cs-Ce saturated cyclic group, or a C5-C10 heterocycloalkyl group;

wherein each (c) moiety is optionally substituted at any available position with C1-C10 alkyl, C1-C10 haloaikyi, C2-C10 alkenyl, C2-C10 alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino, cyano, nitro, -SH, -S-(Ci- C₆)alkyl, -S0₂-(Ci -C₆)alkyl, -SO2NH2, -S0₂NH-(Ci-C₆)alkyl, -SO2NH- aryl, -S0₂-aryl, -SO-(CrC₆)alkyl, -S0₂-aryl, C -C₆ alkoxy, C2-C10 alkenyloxy, C2-C10 alkynyloxy, mono- or di-(C -Cio)alkylamino, -OC1- C10 alkyl-Z, or R₂3, wherein

Z is ORo or -N(R3o)2, wherein

each R30 is independently -H or C1-C6 alkyl, or N(R3o)2 represents pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, 1 ,3- or 1 ,4-diazepanyl, or morpholinyl, each of which is optionally substituted with hydroxy, amino, aminoalkyl, Ci -Cs alkyl, mono- or di(C i-C6)alkylamino, Ci-Cs alkoxy, or halogen; Ro is -H, -C1-C10 alkyl, -C2-C10 alkenyl, -C2-C10 alkynyl, aryl, heteroaryl, or -Ci-Ce acyl;

(1) heteroaryl,

(2) aryl,

(3) saturated or unsaturated C5-C10 cycloalkyl, or

(4) saturated or unsaturated C5-C10 heterocycloalkyl, and the R23 groups are optionally substituted with at least one group which independently is hydroxy, oxo, halo, amino, cyano, nitro, -SH, -S-(Ci-C₆)alkyl, -S02-(Ci-C₆)alkyl, -S0₂-aryl, -SO-(Ci- C₆)alkyl, -SO-aryl, -SO2NH2, -S0₂NH-(C -C₆)alkyl, -S0₂NH-aryl, (C -C6)alkoxy, or mono- or di-(Ci-Cio)alkylamino; and wherein one or both of R3 and R4 is optionally substituted with a group R50 where R50 is:

wherein

d and k are integers independently selected from 1 and 2;

R201 is (Ci-Ce)aikyi where the alkyl is optionally substituted with (C3- C7)cycloalkyl, (C2-C6) alkenyl, (C2-C6)alkynyl, hydroxy, halogen, nitro, or cyano; and

T is O or NR202 where R202 is hydrogen or (Ci-Ce)alkyl; and

R301 and R302 are independently hydrogen or (Ci-C6)alkyl, and R303 is absent, hydrogen, or (Ci-C6)alkyl;

R₇ is O, S, NH, N-OH, N-NH₂, N-NHR22, N-NH-(Ci-C₆ alkyl), N-O-(C₀-C₆)alkyl-

R22, N-(Ci-C6 alkenoxy);or N-(Ci-C6 aikoxy optionally substituted with carboxy);

Y is N or CRc, wherein

each Rc independently is hydrogen, halogen, cyano, nitro, -C(0)Rc,

C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 haloalkyl, C3-C7 cycloalkyl, C3-C₇ cycloalkyl(C -Cio)alkyl, heterocycloalkyl, aryl, or heteroaryl, wherein

each alkyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl group is optionally substituted with from 1-4 groups that are independently Ci-Ce alkyl, Ci-Ce aikoxy, halogen, hydroxy, amino, mono- or di-(Ci-Ce) alkylamino, cyano, nitro, halo(Ci- Ce)alkyl, halo(C -C6)alkoxy, carboxamide, heterocycloalkyl, aryl, or heteroaryl, wherein

the aryl and heteroaryl groups are optionally substituted with from 1-4 groups that are independently C i-Ce alkyl, C1-C5 aikoxy, halogen, hydroxy, amino, mono- or di-(Ci- Ce) alkylamino, halo(Ci-C6)alkyl, or carboxamide;

-Ci-Ce alkyl, -ORc", or -N(R_CN)2, wherein

Rc is -H, C1-C10 alkyl, C1-C10 haloalkyl, C₃-C₇ cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each RCN is independently -H, -C1-C10 alkyl, -C1-C10 aloaikyi, -C3-C7 cycloalkyl, -heterocycloalkyl, -C1-C6 acyl, -aryi, or -heteroaryl, wherein

each aikyi, cycloalkyl, heterocycloalkyl, aryl, and heteroaryi group is optionally substituted with from 1-4 groups that are independently Ci-Ce aikyi, Ci- C6 alkoxy, halogen, hydroxy, amino, mono- or di- (Ci-Ce) aikylamino, nitro, halo(Ci-C6)alkyl, halo(Ci- C6)alkoxy, or carboxamide;

Xi is N or CRc;

Qi , Q2, and Cb are independently N or CRQ , wherein one and only one of Qi,

Q2, and Q3 is C-R21 , and wherein

each RQ is independently hydrogen, halogen, -N(RCN)₂, C Ce alkyl, Ci- Ce haloalkyl, C3-C7 cycloalkyl, aryl, or heteroaryi, or R21, wherein each aikyi, cycloalkyl, aryi, and heteroaryi group is optionaliy substituted with from 1-4 groups that are independently C Ce alkyl, Ci- C6 alkoxy, halogen, hydroxy, amino, mono- or di-(Ci-C6) alkylamino, halo(Ci-C6)alkyl, halo(C -C6)aikoxy, or carboxamide;

R21 is cyano, -C(0)OH, -C -0(Ci-C6 alkyl), or a group of the formula

wherein

R and R2 are independently H, hydroxy, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, heteroaryi, aryl, C3-C8 cycloalkyl, heterocycloalkyl, wherein

each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryi group is optionally substituted with from 1-4 groups that are independently C Ce alkyl, C Ce alkoxy, halogen, hydroxy, amino, mono- or di-(d-Cs) alkylamino, nitro, haio(Ci-C6)alkyl, halo(Ci-C6)alkoxy, or carboxamide; or and R₂ together with the nitrogen to which they are both attached, form a heterocycloalkyl which optionally contains one or more additional heteroatoms which are, independently, O, N, S, or N(RCN); and

X₄ is O, S, NH, NOH, N-NH₂, N-NHaryl, N-NH-(Ci-C₆ alkyl), or N-(C - C6 alkoxy);

X₂ and X3 are independently C, O, N, or S(0) wherein

p is 0, 1 , or 2; and

n is 0, 1 , 2, 3, or 4;

provided that when

(i) X₂ is C, then

Rs and R6 are independently H, C1-C6 alkyl, or aryl, wherein the aryl is optionally substituted with from 1-4 groups that are independently Ci- Ce alkyl, C1-C6 alkoxy, halogen, hydroxy, amino, mono- or di-(Ci-Ce) alkylamino, nitro, halo(Ci-Ce)alkyl, halo(Ci-C6)alkoxy, or carboxamide, wherein any two adjacent substituted aryl positions, together with the carbon atoms to which they are attached, form an unsaturated cycloalkyl or heterocycloalkyl; or Rs and R6 together with the carbon to which they are attached form a 3-8 membered ring;

(ii) X₂ is N, thenR6 is absent and R5 is H or C -C6 alkyl;

Ce alkyl, or mono- or di-(Ci-C6)alkylamino(C -C6)alkyl; and

(iv) X₂ is O or S(0) , then Re and R5 are absent.

2. A method for treating cancer in a patient in need thereof, the method comprising:

administering to the patient a therapeutically effective amount of a compound of formula (I):

(I)

or a pharmaceutically acceptable salt thereof, wherein

R3 and R4 are independently

(a) H,

(b) halo, or

R22 is

(i) heteroaryl,

(ii) aryl,

(iii) saturated or unsaturated C3-C10 cycloaikyi, or

(iv) saturated or unsaturated C2-C10 heterocycloalkyl, wherein each aryl, heteroaryl, saturated or unsaturated cycloaikyi, or saturated or unsaturated heterocycloalkyl, independently, is optionally substituted with at least one group, which independently is hydroxy, halo, amino, cyano, carboxy, carboxamido, nitro, oxo, -S-(Ci-Cs)alkyl, -S0₂-(C -C6)aikyi, -S0₂-aryl, -SO-(Ci-C₆)alkyl, -SO-aryl, -SO2NH2, -S0₂NH-(C - Ce)alky!, -S0₂NH-aryl ,

or mono- or di-(Ci- Cio)alkylamino; and

each R22 is optionally fused to a C6-C10 aryl group, Cs-Cs saturated cyclic group, or a C5-C10 heterocycloalkyl group;

wherein each (c) moiety is optionally substituted at any available position with C1-C10 alkyl, C1-C10 haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, hydroxy, carboxy, carboxamido, oxo, haio, amino, cyano, nitro, -SH, -S-(Ci - Ce)alkyl, -S0₂-(Ci-C₆)alkyl, -SO2NH2, -S0₂NH-(Ci-C₆)alkyl, -SO2NH- aryl, -S0₂-aryi, -SO-(Ci-C₆)aikyl, -S0₂-aryi, Ci-Ce alkoxy, C2-C10 alkenyioxy, C2-C10 alkynyloxy, mono- or di-(C -Cio)alkylamino, -OC1- C10 alkyl-Z, or R23, wherein

Z is ORo or -N(R3o)2, wherein

each R30 is independently -H or C1-C6 alkyl, or N(R3o)₂ represents pyrrolidinyl, piperidinyl, piperazinyl, azepanyi, 1,3- or 1,4-diazepanyl, or morpholinyl, each of which is optionally substituted with hydroxy, amino, aminoalkyl, Ci-Cs alkyl, mono- or di(Ci-C6)alkylamino, d-Ce alkoxy, or halogen;

Ro is -H, -C1-C10 alkyl, -C2-C10 alkenyl, -C2-C10 alkynyl, aryl, heteroaryl, or -Ci-Ce acyl;

(1) heteroaryl,

(2) aryl,

(3) saturated or unsaturated C5-C10 cycloaikyi, or

(4) saturated or unsaturated C5-C10 heterocycioalkyl, and the R23 groups are optionally substituted with at least one group which independently is hydroxy, oxo, halo, amino, cyano, nitro, -SH, -S-(C -C₆)alkyl, -S0₂-(C -C₆)alkyl, -SC -aryi, -SO-(Ci - C₆)alkyl, -SO-aryl, -SO2NH2, -S0₂NH-(C -C₆)alkyl, -S0₂NH-aryl, (Ci-C6)alkoxy, or mono- or di-(Ci-Cio)alkylamino; and wherein one or both of R3 and R₄ is optionally substituted with a group R50 where R50 is:

wherein

d and k are integers independently selected from 1 and 2; R201 is (C -C6)aikyi where the alkyl is optionally substituted with (C3- C7)cycloalkyl, (C2-C6) alkenyl, (C2-C6)alkynyl, hydroxy, halogen, nitro, or cyano; and

T is O or NR202 where R202 is hydrogen or (Ci-Ce)alkyl; and

R₇ is O, S, NH, N-OH, N-NH₂, N-NHR22, N-NH-(Ci-C₆ alkyl), N-O-(C₀-C₆)alkyl- R22, N-(Ci-C6 alkenoxy);or N-(Ci-C6 aikoxy optionally substituted with carboxy);

Y is N or CRc, wherein

each Rc independently is hydrogen, halogen, cyano, nitro, -C(0)Rc , C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 haloalkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl(Ci-Cio)alkyl, heterocycloalkyl, aryl, or heteroaryl, wherein

each alkyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl group is optionally substituted with from 1-4 groups that are independently Ci-Ce alkyl, Ci-Ce aikoxy, halogen, hydroxy, amino, mono- or di-(Ci-Ce) alkylamino, cyano, nitro, halo(Ci- Ce)alkyl, halo(Ci-C6)aikoxy, carboxamide, heterocycloalkyl, aryl, or heteroaryl, wherein

the aryl and heteroaryl groups are optionally substituted with from 1-4 groups that are independently C-i-Ce alkyl, Ci-Ce aikoxy, halogen, hydroxy, amino, mono- or di-(Ci- Ce) alkylamino, halo(Ci-C6)alkyl, or carboxamide;

Rc 1S -C1-C6 alkyl, -ORc-, or -N(RcN)2, wherein

Rc- is -H, C1-C10 alkyl, C1-C10 haloalkyl, C3-C7 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each RCN is independently -H, -C1-C10 alkyl, -C1-C10 aloalkyl, -C3-C7 cycloalkyl, -heterocycloalkyl, -C1-C6 acyl, -aryl, or -heteroaryl, wherein

each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is optionally substituted with from 1-4 groups that are independently Ci-Ce alkyl, Ci- Ce aikoxy, halogen, hydroxy, amino, mono- or di- (Ci-Ce) aikylamino, nitro, halo(Ci-C6)alkyl, halo(Ci- C6)alkoxy, or carboxamide;

Xi is N or CRc;

Qi , Q₂, and Q3 are independently N or CRQ , wherein one and only one of Qi ,

Q2, and Cb is C-R21 , and wherein

each RQ is independently hydrogen, halogen, -N(RCN)2, C Ce alkyl, Ci- Ce haloalkyl, C3-C7 cycloalkyl, aryl, or heteroaryl, or R21 , wherein each aikyi, cycloalkyl, aryi, and heteroaryl group is optionally substituted with from 1-4 groups that are independently C1-G3 alkyl, Ci - C6 alkoxy, halogen, hydroxy, amino, mono- or di-(Ci-Ce) alkyiamino, halo(C -C6)alkyi, halo(Ci-C6)alkoxy, or carboxamide;

R21 is cyano, -C(0)OH, - -0(Ci-C6 alkyl), or a group of the formula

wherein

R and R2 are independently H, hydroxy, C1 -G5 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, heteroaryl, aryl, C3-C8 cycloalkyl, heterocycloalkyl, wherein

each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is optionally substituted with from 1-4 groups that are independently Ci-Ce alkyl, Ci-Ce alkoxy, halogen, hydroxy, amino, mono- or di-(Ci-Cs) alkyiamino, nitro, halo(Ci-C6)alkyl, halo(Ci-C6)alkoxy, or carboxamide;

or R and R2 together with the nitrogen to which they are both attached, form a heterocycloalkyl which optionally contains one or more additional heteroatoms which are, independently, O, N, S, or N(RCN); and

X₄ is O, S, NH, NOH, N-NH₂, N-NHaryl, N-NH-(Ci -Ce alkyl), or N-(Ci- C6 alkoxy);

X2 and X3 are independently C, O, N, or S(0) wherein

p is 0, 1 , or 2; and n is 0, 1 , 2, 3, or 4;

provided that when

(i) X₂ is C, then

Rs and e are independently H, C1-C6 alkyi, or aryl, wherein the aryl is optionally substituted with from 1-4 groups that are independently Ci- C6 alkyi, C1-C6 alkoxy, halogen, hydroxy, amino, mono- or di-(Ci-Ce) alkylamino, nitro, halo(Ci-C6)alkyl, halo(Ci-C6)alkoxy, or carboxamide, wherein any two adjacent substituted aryl positions, together with the carbon atoms to which they are attached, form an unsaturated cycloalkyl or heterocycloalkyl; or

(ii) X₂ is N, thenR6 is absent and R5 is H or Ci-Ce alkyi;

Ce alkyi, or mono- or di-(Ci-C6)alkylamino(C -Ce)alkyl; and

(iv) X₂ is O or S(0) , then Re and R5 are absent.

3. A method of causing cancer cells to undergo apoptosis, the method comprising:

contacting the cells with a com ound of formula (I):

(I)

or a pharmaceutically acceptable salt thereof, wherein

R3 and R₄ are independently

(a) H,

(b) halo, or (c) a C1-C15 alkyl group where up to six of the carbon atoms in said alky! group are optionaily replaced independently by R22, carbonyl, ethenyl, ethynyl or a moiety selected from N, O, S, SO2, or SO, with the proviso that two O atoms, two S atoms, or an O and S atom are not immediateiy adjacent each other, wherein

R22 is

(i) heteroaryl,

(ii) aryi,

(iii) saturated or unsaturated C3-C10 cycloalkyl, or

(iv) saturated or unsaturated C2-C10 heterocycloaikyi, wherein each aryi, heteroaryl, saturated or unsaturated cycloalkyl, or saturated or unsaturated heterocycloaikyi, independently, is optionally substituted with at least one group, which independently is hydroxy, halo, amino, cyano, carboxy, carboxamido, nitro, oxo, -S-(Ci-C6)alkyl, -S02-(Ci-C6)alkyl, -S0₂-aryl, -SO-(Ci-C₆)alkyl, -SO-aryl, -SO2NH2, -S0₂NH-(Ci - C6)alkyl, -S02N H-aryl, (Ci-C6)aikoxy, or mono- or di-(Ci- Cio)aikyiamino; and

each R22 is optionally fused to a C6-C10 aryi group, Cs-Cs saturated cyclic group, or a C5-C10 heterocycloaikyi group;

wherein each (c) moiety is optionaily substituted at any available position with C1-C10 alkyl, C1-C10 haloaikyi, C2-C10 alkenyi, C2-C10 alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino, cyano, nitro, -SH, -S-(Ci - C₆)alkyl, -S0₂-(CrC₆)alkyl, -SO2NH2, -S0₂NH-(Ci-C₆)alkyl, -SO2NH- aryl, -S0₂-aryi, -SO-(Ci-C₆)aikyl, -S0₂-aryl, C -C₆ alkoxy, C2-C10 alkenyioxy, C2-C10 alkynyloxy, mono- or di-(C -Cio)alkylamino, -OC1- C10 alkyl-Z, or R23, wherein

Z is ORo or -N(R3o)₂, wherein

each R30 is independently -H or Ci-Ce alkyl, or N(R3o)2 represents pyrrolidinyl, piperidinyl, piperazinyl, azepanyi, 1 ,3- or 1 ,4-diazepanyl, or morpholinyl, each of which is optionaily substituted with hydroxy, amino, aminoalkyl, Ci-Cs alkyl, mono- or di(Ci-C6)alkylamino, d-Ce alkoxy, or halogen; Ro is -H, -C1-C10 aikyl, -C2-C10 alkenyl, -C2-C10 alkynyl, aryl, heteroaryl, or -C1-C6 acyl;

(1 ) heteroaryl,

(2) aryl,

(3) saturated or unsaturated C5-C10 cycloalkyl, or

(4) saturated or unsaturated C5-C10 heterocycloalkyl, and the R23 groups are optionally substituted with at least one group which independently is hydroxy, oxo, halo, amino, cyano, nitro, -SH, -S-(Ci-C₆)alkyl, -S02-(Ci-Ce)alkyl, -S0₂-aryl, -SO-(Ci- Ce)alkyl, -SO-aryl, -S0₂NH₂₎ -S0₂NH-(Ci-C6)alkyl, -S0₂NH-aryl, (Ci-C6)aikoxy, or mono- or di-(Ci-Cio)alkylamino; and wherein one or both of R3 and R₄ is optionally substituted with a group R50 where R50 is:

wherein

d and k are integers independently selected from 1 and 2;

R201 is (Ci-C6)alkyl where the alkyl is optionally substituted with (C3-

C7)cycloalkyl, (C2-C6) alkenyl, (C2-C6)alkynyl, hydroxy, halogen, nitro, or cyano; and

T is O or NR202 where R202 is hydrogen or (Ci-Ce)alkyl; and

R₇ is O, S, NH, N-OH, N-NH₂, N-NHR22, N-NH-(Ci-C₆ alkyl), N-O-(C₀-C₆)alkyl- 22, N-(Ci-Ce alkenoxy);or N-(Ci-C6 aikoxy optionally substituted with carboxy);

Y is N or CRc, wherein

each Rc independently is hydrogen, halogen, cyano, nitro, -C(0)Rc , C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 haloalkyl, C3-C7 cycioalkyl, C3-C7 cycloalkyi(Ci-Cio)alkyl, heterocycloaikyi, aryl, or heteroaryl, wherein

each aikyi, aryi, cycloaikyi, heterocycloaikyi, and heteroaryl group is optionally substituted with from 1-4 groups that are independently C1-C6 aikyi, C -C6 aikoxy, halogen, hydroxy, amino, mono- or di-(Ci-Ce) alkyiamino, cyano, nitro, haio(Ci- Ce)alkyl, halo(C -C6)aikoxy, carboxamide, heterocycloaikyi, aryl, or heteroaryl, wherein

the aryl and heteroaryl groups are optionally substituted with from 1-4 groups that are independently C1-C6 aikyi, Ci-Ce aikoxy, halogen, hydroxy, amino, mono- or di-(Ci- Ce) alkyiamino, haio(Ci-C6)alkyl, or carboxamide;

Re is -C1-C6 alkyl, -ORc, or -N(RCN)2, wherein

Re- is -H, C1-C10 aikyi, C1-C10 haloaikyi, C3-C7 cycioalkyl, heterocycloaikyi, aryl, or heteroaryi; each RCN is independently -H, -C1-C10 aikyi, -C1-C10 aloaikyi, -C3-C7 cycioalkyl, -heterocycloaikyi, -C1-C6 acyl, -aryi, or -heteroaryl, wherein

each alkyl, cycioalkyl, heterocycloaikyi, aryl, and heteroaryi group is optionally substituted with from 1-4 groups that are independently Ci-Ce aikyi, Ci- Ce aikoxy, halogen, hydroxy, amino, mono- or di- (Ci-Ce) alkyiamino, nitro, halo(Ci-C6)alkyl, halo(Ci- C6)alkoxy, or carboxamide;

Xi is N or CRc;

Qi , Q2, and Q3 are independently N or CRQ , wherein one and only one of Qi,

Q2, and Q3 is C-R21 , and wherein

each RQ is independently hydrogen, halogen, -N(RCN)₂, C1-C6 alkyl, Ci- Ce haloaikyi, C3-C7 cycioalkyl, aryl, or heteroaryi, or R21, wherein each alkyl, cycioalkyl, aryl, and heteroaryl group is optionally substituted with from 1-4 groups that are independently C1-C6 aikyi, Ci- Ce aikoxy, halogen, hydroxy, amino, mono- or di-(Ci-Ce) alkyiamino, halo(C -Ce)alkyl, halo(Ci-C6)alkoxy, or carboxamide;

R21 is cyano, -C(0)OH, -C(0)-0(Ci-C6 alkyl), or a group of the formula

wherein

R and R₂ are independeniiy H, hydroxy, Ci-Ce aikyi, C2-C6 alkenyl, C2-C6 alkynyl, heteroaryl, aryi, C3-C8 cyc!oalkyl, heterocycloaikyl, wherein

each alkyl, cycioalkyl, heterocycloaikyl, aryi, and heteroaryl group is optionally substituted with from 1-4 groups that are independently C -C6 aikyi, C -C6 aikoxy, halogen, hydroxy, amino, mono- or di-(Ci-Ce) alkylamino, nitro, halo(Ci-C6)alkyl, halo(Ci-C6)alkoxy, or carboxamide;

or Ri and R₂ together with the nitrogen to which they are both attached, form a heterocycloaikyl which optionally contains one or more additional heteroatoms which are, independently, O, N, S, or N(RCN); and

X₄ is O, S, NH, NOH, N-NH₂, N-NHaryl, N-NH-(Ci-C₆ alkyl), or N-(Ci- C6 alkoxy);

X₂ and X3 are independently C, O, N, or S(0)_p wherein

p is 0, 1 , or 2; and

n is 0, 1 , 2, 3, or 4;

provided that when

(i) X₂ is C, then

Rs and R6 are independently H, C1-C6 alkyl, or aryi, wherein the aryi is optionally substituted with from 1-4 groups that are independently C- Ce alkyl, C1-C6 alkoxy, halogen, hydroxy, amino, mono- or di-(Ci-Ce) alkylamino, nitro, halo(Ci-C6)aikyi, halo(Ci-Ce)alkoxy, or carboxamide, wherein any two adjacent substituted aryi positions, together with the carbon atoms to which they are attached, form an unsaturated cycioalkyl or heterocycloaikyl; or

Rs and R6 together with the carbon to which they are attached form a 3-8 membered ring; (ii) X₂ is N, thenR6 is absent and Rs is H or C1-C6 alkyl;

C6 alkyl, or mono- or di-(Ci-C6)alkylamino(Ci-C6)alkyl; and

(iv) X₂ is O or S(0)p, then R6 and R5 are absent.

4. The method of any one of claims 1-3, wherein the cancer cells comprise null- type mutation of the TP53 gene in one allele.

5. The method of any one of claims 1-3, wherein the cancer cells comprise null- type mutation of the TP53 gene in both alleles.

6. The method of any one of claims 1-5, wherein cancer is lung cancer, adenocarcinoma, leukemia, lymphoma, multiple myeloma, melanoma, ovarian cancer, breast cancer, renal cell carcinoma, neuroendocrine cancer, central nervous system cancer, prostate cancer, colon cancer, osteosarcoma, liver cancer, glioblastoma, or head and neck squamous cell carcinoma.

7. The method of any one of claims 1 -5, wherein cancer is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), multiple myeloma, diffuse large B-cell lymphoma, head and neck squamous cell carcinomas, or nonsmaii cell lung cancer (NSCLC).

8. The method of any one of claims 1 , 2, or 4-7, wherein the patient has adverse prognosis for event free survival and/or overall survival.

9. The method of any one of claims 1-8, wherein the compound of formula (I) is selected from group consisting of:

2-(allylamino)-4-(3-methyl-4-oxo-4,5,6,7-tetrahydroindol-1-yl)benzamide;

2-(cyclopropylamino)-4-(3-methyi-4-oxo-4,5,6,7-tetrahydroindol-1-yl)benzamide;

2-(2-methoxyethylamino)-4-(3-methyl-4-oxo-4,5,6,7-tetrahydroindol-1- yl)benzamide;

4-(3-methyl-4-oxo-4,5,6,7-tetrahydroindol-1-yi)benzamide; 4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroinc!ol-1-yl)benzamide;

4-(3-methyi-4-oxo-4,5,6,7-tetrahydroindol-1-yl)-2-(phenyiamino)benzamide;

2-(trans-4-hydroxycyclohexylamino)-4-(3-meihyi-4-oxo-4,5,6,7-tetrahydroindol-1- yl)benzamide;

4-(3-methyi-4-oxo-4,5,6,7-tetrahydroindol-1-yl)-2-(3,4,5- trimethoxyphenylamino)benzamide;

2-(2-(dimethylamino)ethy!amino)-4-(3,6_!6-trimethyl-4-oxo-4,5,6,7-tetrahydroindol- 1 -yl)benzamide;

2-(2-(dimethylamino)ethylamtno)-4-(3-methyl-4-oxo-4,5,6,7-tetrahydroindoi-1- yl)benzamide;

2-(pyridin-4-ylmethylamino)-4-(3,6,6-trimethyi-4-oxo-4,5,6_>7-tetrahydroindol-1- yl)benzamide;

4-(3-meihyl-4-oxo-4,5,6,7-tetrahydroindol-1-yl)-2-(pyridin-3- ylmethylamino)benzamide;

tert-buiyl 4-(2-carbamoyl-5-{3,6,6-trtmethyl-4-oxo-4,5,6,7-tetrahydroindol-1- yl)phenylamino)piperidine-1-carboxylate;

2-amino-4-(3,6_>6-trimethyl-4-oxo-4,5,6,7-tetrahydroindol-1-yl)benzamide;

2-(allylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindol-1-yl)benzamide;

2-(1-meihylpiperidin-4-ylamino)-4-(3,6, 6-trimethyl-4 -oxo-4, 5,6,7-tetrahydroindol-1- yl)benzamide;

2- (piperidin-4-ylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindol-1- yl)benzamide;

3- buioxy-4-(3 , 6 , 6-tri m ethy I -4-0X0-4 ,5 , 6 , 7-ietra hyd rot n do i- 1 -yi )benza m id e ;

2-(2,3-dihydro-1H-inden-1-ylamino)-4-(3,6,6-trimeihyl-4-oxo-4,5,6,7- tetrahydroindoi-1-yl)benzamide;

1- (2-carbamoyl-5-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindoi-1-yi)phenyl)urea

2- Benzylamino-4-(2,6,6-trimeihyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzamide;

3- Prop-2-ynyioxy-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)- benzamide;

2-Ethynyi-4-(2,6,6-trimethyi-4-oxo-4,5,6,7-ietrahydro-indol-1-yl)-benzamide; 2-(4-Methoxy-phenyiamino)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-inclol-1-yi)- benzamide;

2-Cyciohexylamino-4-(2,6,6-trimeihyi-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)- benzamide;

2- (butylamino)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindol-1-yl)benzamide; 4-Meihyi-3-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzamide;

3- (3-thienyl)-4-(2,6_J6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1 H-indol-1-yl)benzamide;

2-meihyi-4-(2,6,6-trimethyi-4-oxo-4,5,6,7-tetrahydro-1 H-indoi-1-yl)benzamtde;

2-[(3-ethynylphenyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide;

2-[(4-chlorophenyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-teirahydro-1 H-indol-1- yl)benzamide;

2- anilino-4-(2-meihyl-4-oxo-4,5,6,7-tetrahydro-1 H-indoi-1-yi)benzamide;

3- anilino-5-(2,6,6-trimethyl-4-oxo-4,5,6,7-teirahydro-1 H-indol-1-yl)pyridine-2- carboxamide;

2-[(3,4,5-trimethoxyphenyi)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,67-ietrahydro-1 H- indol-1 -yl)benzamide;

2-pyridin-4-yl-4-(2,6_J6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1 H-indol-1-yl)benzamide;

N-[2-(aminocarbonyl)-5-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1 H-indol-1- yl)phenyl]-L-valine;

2-morpholin-4-yl-4-(2,6,6-trimeihyl-4-oxo-4,5_>6,7-tetrahydro-1 H-indoi-1- yl)benzamide;

2-(1H-imidazol-1-yl)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1 H-indol-1- yl)benzamide;

4- (3-chioro-2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1 H-indol-1-yl)-2-[(3,4_l5- trimethoxypheny!)amino]benzamide;

2-[(4-hydroxyphenyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-teirahydro-1H-indol-1- yl)benzamide;

2-[(1-ethyl-1 H-pyrazol-5-yi)amino]-4-(2,6,6-inmethyl-4-oxo-4,5,6,7-tetrahydro-1 H- indol-1 -yl)benzamide; 2-[(5-methylisoxazol-3-yl)amino]-4-(2,6,6-trimethy]-4-oxo-4,5,6,7-tetrahyc!ro-1 H- indol-1 -yl)benzamide;

2-{[4-(aminocarbonyi)phenyi]amino}-4-(2-methyi-4-oxo-4,5,6,7-tetrahydro-1 H-tndol- 1 -yl)benzamide;

4-(4-oxo-4,5,6,7-tetrahydro-1 H-indol-1 -yl)-2-[(3 ,4,5- trimethoxyphenyi)amino]benzamide;

2-[(6-methoxypyridin-3-yl)amino]-4-(2,6,6-trimethyi-4-oxo-4,5,6,7-tetrahydro-1 H- indoi-1 -yi)benzamide;

2- (ailylamino)-4-(4-oxo-4, 5,6, 7-teirahydro-1 H-indol-1 -yl)benzamide;

4-(2,3-dimethyl-4-oxo-4,5,6,7-teirahydro-1H-indol-1-yl)benzamide;

3- bromo-4-(2,3-dimethyl-4-oxo-4,5,6,7-tetrahydro-1 H-indol-1 -yl)benzamide;

2-(ailylamino)-4-(2,3-dimethyl-4-oxo-4, 5, 6,7-tetrahydro-1 H-indol-1 -yl)benzamide;

4- (2,3-dimethyl-4-oxo-4,5,6,7-tetrahydro-1 H-indol-1-yl)-2-[(2- methoxyethyl)amino]benzamide;

2-({3-[3-(dimethyiamino)propoxy]-4-methoxyphenyl}amino)-4-(2,6,6-trimethyl-4- oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide;

2-(morpholin-4-ylamino)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-teirahydro-1 H-indol-1- yl)benzamide;

2-[(2-methoxyethyi)amino]-4-(3,6,6-trimethyi-4-oxo-4,5,6,7-ietrahydro-1 H-indazol- 1 -yl)benzamide;

2-[(2-morpholin-4-ylethyl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1 H- indol-1 -yl)benzamide;

2-(pyridin-4-ylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1 H-indol-1- yl)benzamide;

2-(acetylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1 H-indol-1 - yl)benzamide;

2-(4-methyipiperazin-1-yl)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1 H-indol-1 - yl)benzamide;

2-[(cyclopropylmethyl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indazol-1 -yl)benzamide; -[(methoxyacetyl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,67-tetrahydro-1 H-indol-1- yl)benzamide;

-ethyl-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yi)benzamide;-(butylthio)-4-(3,6,6-trimethyl-4-oxo-4,5,6J-tetrahydro-1 H-indazol-1 -yl)benzamide;-({3-[2-(dimethyiamino)eihoxy]-4-methoxyphenyl}amino)-4-(3,6,6-trimethyl-4-oxo- 4,5,6,7-tetrahydro-1 H-indol-1-yl)benzamide;

-(pyridin-4-yithio)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-teirahydro-1 H-indol-1- yl)benzamide;

-{[(1 R)-1 -phenylethyl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1 H- indazol-1 -yi)benzamide;

-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-ietrahydro-1 H-indazol-1-yl]-2- [(3,4,5-trimeihoxyphenyl)amino]benzamide;

-({2-[2-(dimeihylamino)ethoxy]pyridin-4-yl}amino)-4-(3,6,6-trimethyl-4-oxo-4, 5,6,7- tetrahydro-1 H-indol-1-yl)benzamide;

-{[1-(N,N-dimethylglycyl)piperidin-4-yl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7- tetrahydro-1 H-indol-1-yl)benzamide;

-(6,6-dimethyl-4-oxo-3-phenyl-4,5,6,7-ietrahydro-1 H-indoi-1-yl)benzamide;

-[(2-{[2-(aminocarbonyl)-5-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)phenyl]amino}ethyl)amino]-2-oxoethyl acetate;

-{[2-(methylsulfonyl)ethyl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1 H- indazol-1 -yi)benzamide;

-[(4-methoxyphenyl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1 H- indazol-1 -yi)benzamide;

-[(6-oxo-1 ,6-dihydropyridin-3-yi)amino]-4-(3,6,6-trimethyl-4 -oxo-4,5,6,7- tetrahydro-1 H-indazol-1 -yi)benzamide;

-(cyclopent-3-en-1-ylamino)-4-[3-(difluoromethyl)-6,6-dimethyl-4-oxo-4, 5,6,7- tetrahydro-1 H-indazol-1 -yljbenzamide;

-(cyclobutylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1 H-indazol-1 - yl)benzamide; -[trans-4-(2-Hydroxy-ethoxy)-cyclohexylamino3-4-(3,6,6-trimethyl-4-oxo-4,5,6,7- tetrahydro-indazoi-1-yl)-benzamide;

-(irans-4-Hydroxy-cyciohexyiamino)-4-(3,6,6-trimethyi-4-oxo-4,5,6,7-ietrahydro- indazol-1 -yl)-benzamide;

-(2-Meihoxy-1-methoxymethyl-ethylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7- tetrahydro-indazoi-1-yl)-benzamide;

-{[3-hydroxy-1-(2-hydroxyethyl)propyl]amino}-4-(3,6,6-trimethyi-4-oxo-4,5,6,7- tetrahydro-1 H-indazol-1 -yl)benzamide;

-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1-yl]-2-{[2- methoxy-1 -(methoxymethyl)ethyl]amino}benzamide;

-{[3-(meihylsulfinyl)phenyl]amino}-4-(3,6_>6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indazol-1 -yi)benzamide;

-[6,6-dimethyl-4-oxo-3-(trifiuoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1-yl]-2-{[1- (methyisulfonyl)piperidin-4-yi]amino}benzamide;

-(6,6-Dimethyl-4-oxo-3-trtfluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(trans-4- hydroxy-cyciohexylamino)-benzamide;

-(6,6-Dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-[trans-4- (2-hydroxy-ethoxy)-cyclohexylamino]-benzamide;

-{[1-(3-morpholin^-ylpropanoyl)piperidin-4-y!]amino}-4-(3,6,6-trimethyl-4-oxo- 4,5,6,7-tetrahydro-l H-indazol-1 -yi)benzamide;

-[trans-4-(2-Amino-ethoxy)-cyciohexyiamino]-4-(6,6-dimethyl-4-oxo-3- trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide;

-[(1-glycyipiperidin-4-yl)amino]-4-(3,6,6-trimethyi-4-oxo-4,5,6,7-tetrahydro-1H- indazol-1 -yi)benzamide;

-[trans-4-(2-Amino-ethoxy )-cyciohexylamino]-4-(3,6,6-trimethyl-4-oxo-4, 5,6,7- tetrahydro-indazoi-1-yl)-benzamide;

-{[1-(methylsulfonyl)azetidin-3-yl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7- tetrahydro-1 H-indazol-1 -yl)benzamide;

-{[3-(methylsulfonyl)propyl]amtno}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-ietrahydro-1 H- indazol-1 -yl)benzamide; 4-[6,6-dtmethyl-4-oxo-3-(trifluoromethyl)-4,5,6J-tetrahyclro-1 H-indazol-1-yl]-2-({2- [(methylsulfonyi)amino]ethyl}amino)benzamide;

4-(3-but-3-en-1 -yl-6,6-dimethyl-4-oxo-4,5,6,7-ietrahydro-1 H-indazol-1- yl)benzamide;

2-{[(3S)-1-(methylsulfonyl)pyrrolidin-3-yl]^^

tetrahydro-1 H-indazol-1 -yl)benzamide;

2-({2-[(dimethylamino)sulfonyl]ethyl}amino)-4-[6,6-dimethyi-4-oxo-3-

(trifluoromethyl)-4, 5, 6, 7-teirahydro-1 H-indazol-1 -yljbenzamide; or

4-[3-(2-Amino-ethyl)-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl]- benzamide;

or a pharmaceutically acceptable salt thereof.

10. The method of any one of claims 1-8, wherein the compound of formula (I) is:

4-(6,6-Dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(trans-4- hydroxy-cyclohexylamino)-benzamide,

or a pharmaceutically acceptable salt thereof.

11. The method of any one of claims 1-8, wherein the compound of formula (l)is:

trans-4-({2-(aminocarbonyi)-5-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4, 5,6,7- tetrahydro-1 H-indazol-1 -yl]phenyl}amino)cyclohexyl g!ycinate,

or a pharmaceutically acceptable salt thereof.

12. The method of any one of claims 1-11 further comprising administering a therapeutically effective amount of at least one other anti-cancer therapeutic.

13. The method of claim 12, wherein the anti-cancer therapeutic is selected from the group consisting of everolimus, erlotinib, abiraterone, bleomycin, sirolimus, arsenic trioxide, temsirolimus, imatinib, dasatinib, carboplatin, vandetanib, lomustine, and cisplatin.

14. The method of any one of claims 1-13, wherein the therapeutically effective amount of compound of formula (I) comprises a dosage of between about 0.1 mg to about 140 mg/kg per day.

15. The method of any one of claims 1-13, wherein the therapeutically effective amount of compound of formula (I) is administered in an amount of about 50 mg/m² to about 150 mg/m², or about 50 mg/m² to about 100 mg/m², or about 75 mg/m² to about 125 mg/m², or about 90 mg/m² to about 110 mg/m², or about or about 50 mg/m², or about 75 mg/m², or about 100 mg/m².

16. The method of any one of claims 1-15, wherein the therapeutically effective amount of compound of formula (I) is administered to the patient on a dosage schedule, wherein the dosage schedule comprises at least one 28-day treatment cycles, and wherein the compound of formula (I) is administered every other day starting on day 1 and continuing for at least 21 days of each 28-day treatment cycle.