# US 8,785,451 B2 · Compounds for the treatment of proliferative disorders

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 8,785,451 B2
- Document ID: US8785451B2
- Status: Granted
- Kind: B2
- Application number: 12/310,303
- Filed: 2007-08-20
- Published: 2010-04-15
- Granted: 2014-07-22
- Earliest claimed: 2006-08-21
- Assignees: Synta Pharmaceuticals Corp.
- Applicants: Keizo Koya; Lijun Sun; Shoujun Chen; Jun Jiang
- Inventors: Keizo Koya; Lijun Sun; Shoujun Chen; Jun Jiang
- Web page: https://patentgrep.com/patent/US8785451B2

## CPC

- C07C 327/56: having nitrogen atoms of thiocarboxamide groups further bound to another hetero atom
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/08: of the prostate
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 27/02: Ophthalmic agents
- A61P 31/04: Antibacterial agents
- A61P 31/10: Antimycotics
- A61P 31/12: Antivirals
- A61P 33/00: Antiparasitic agents
- A61P 35/00: Antineoplastic agents
- C07C 337/08: the other nitrogen atom being further doubly-bound to a carbon atom, e.g. thiosemicarbazones
- C07D 211/84: with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D 213/53: Nitrogen atoms
- C07D 239/04: having no double bonds between ring members or between ring members and non-ring members
- C07D 263/10: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 271/10: 1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
- C07D 307/52: Radicals substituted by nitrogen atoms not forming part of a nitro radical
- C07D 317/28: Radicals substituted by nitrogen atoms (nitro radicals C07D317/16)
- C07D 333/22: Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
- C07D 339/08: Six-membered rings
- C07D 413/14: containing three or more hetero rings
- C07C 2601/14: The ring being saturated
- C07C 2601/18: with a ring being at least seven-membered
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Disclosed are compounds of formula (IA), formula (IV) or formula (V), wherein the variables are as defined herein, and pharmaceutical compositions containing them which are useful for treating a subject with a proliferative disorder, such as cancer. The disclosed compounds and pharmaceutical compositions are also useful for treating disorders responsive to Hsp70 induction and/or natural killer induction.

## Claims

### Claim 1

A compound represented by the following structural formula:
or a tautomer, or pharmaceutically acceptable salt thereof, wherein:
Q is —(CR14R15)r—, an optionally substituted (C6)aryl group or an optionally substituted heteroaryl group selected from furanyl, benzo[1,3]dioxolyl, benzo[1,4]dioxinyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, a isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, a triazinyl, triazolyl, thiadiazolyl, isoquinolinyl, indazolyl, benzoxazolyl, benzofuryl, indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl, quinazolinyl, purinyl, pyrrolo[2,3]pyrimidinyl, pyrazolo[3,4]pyrimidinyl, imidazo[1,2-a]pyridyl, and benzothienyl;
R1 and R2 are each, independently, —H, a halo, a haloalkyl, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl, wherein the optionally substituted heteroaryl is selected from pyridyl, 1-oxo-pyridyl, benzo[1,3]dioxolyl, benzo[1,4]dioxinyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, a isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, a triazinyl, triazolyl, thiadiazolyl, isoquinolinyl, indazolyl, benzoxazolyl, benzofuryl, indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl, quinazolihyl, purinyl, pyrrolo[2,3]pyrimidinyl, pyrazolo[3,4]pyrimidinyl, imidazo[1,2-a]pyridyl, and benzothienyl;
R3 and R4 are each, independently, —H, a haloalkyl, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl, provided that R3 and R4 are not both —H;
R5 and R6 are each, independently, —H, —NR12R13, —OR9, —SR9, a halo, CN, a haloalkyl, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl;
R9, for each occurrence, is independently, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl;
R12 and R13, for each occurrence, are independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl; or R12 and R13, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R14 and R15, for each occurrence, are independently, —H a lower alkyl optionally substituted with one or more substituents selected from the group consisting of phenyl, benzyl, halo, cyano, nitro, amino, mono(lower alkyl)amino, di(lower alkyl)amino, lower alkoxy, lower haloalkoxy and —OH; phenyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl, halo, cyano, nitro, amino, mono(lower alkyl)amino, di(lower alkyl)amino, lower alkoxy, lower haloalkoxy and —OH; benzyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl, halo, cyano, nitro, amino, mono(lower alkyl)amino, di(lower alkyl)amino, lower alkoxy, lower haloalkoxy and —OH; lower alkoxy; lower haloalkyl; (lower alkoxy)carbonyl; lower alkylcarbonyl; lower alkylcarboxy; cyano; nitro; lower haloalkoxy; amino; mono(lower alkyl)amino; di(lower alkyl)amino; and —OH; or R14 and R15, taken together with the carbon to which they are attached, form C(O), C(S), an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, or an optionally substituted heterocyclyl;
r is an integer from 1 to 6,
or a salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the compound is represented by following structural formula:
or a tautomer, or pharmaceutically acceptable salt thereof, wherein r is 1 or 2, and R14 and R15, for each occurrence, are independently, —H, a lower alkyl, or a benzyl.

### Claim 3 (depends on 1)

The compound of claim 1, wherein the compound is represented by the following structural formula:
or a tautomer, or pharmaceutically acceptable salt thereof, wherein:
X1 and X2 are each, independently, CRR, O, S, S(O)p, or NR;
each R of CRR is, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, a haloalkyl, —C(O)NR33R29, —C(S)NR33R29, —C(NR32)NR33R29, —NR30C(O)R31, —NR30C(S)R31, —NR30C(NR32)R31, halo, —OR30, cyano, nitro, haloalkoxy, —C(O)R30, —C(S)R30, —C(NR32)R30, —NR33R29, —C(O)OR30, —C(S)OR30, —C(NR32)OR30, —OC(O)R30, —OC(S)R30, —OC(NR32)R30, —NR30C(O)NR33R29, —NR30C(S)NR33R29, —NR30C(NR32)NR33R29, —OC(O)NR33R29, —OC(S)NR33R29, —OC(NR32)NR33R29, —NR30C(O)OR31, —NR30C(S)OR31, —NR30C(NR32)OR3, —S(O)hR30, —OS(O)pR30, —NR30S(O)pR30, —S(O)pNR33R29, —OS(O)pNR33R29, or —NR30S(O)pNR33R29, wherein:
R29 and R33, for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl; or R33 and R29 taken together with the nitrogen to which they are attached form an optionally substituted heterocyclyl or optionally substituted heteroaryl;
R30 and R31 for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl; and
R32, for each occurrence is, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, —C(O)R30, —C(O)NR33R29, —S(O)pR30, or —S(O)pNR33R29,
p is 1 or 2; h is 0, 1 or 2;
each R of NR is, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an alkoxy and a haloalkoxy;
R16 and R17, for each occurrence, are independently, —H or lower alkyl optionally substituted with one or more substituents selected from the group consisting of phenyl, benzyl, halo, cyano, nitro, amino, mono(lower alkyl)amino, di(lower alkyl)amino, lower alkoxy, lower haloalkoxy and —OH; phenyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl, halo, cyano, nitro, amino, mono(lower alkyl)amino, di(lower alkyl)amino, lower alkoxy, lower haloalkoxy and —OH; benzyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl, halo, cyano, nitro, amino, mono(lower alkyl)amino, di(lower alkyl)amino, lower alkoxy, lower haloalkoxy and —OH; lower alkoxy; lower haloalkyl; (lower alkoxy)carbonyl; lower alkylcarbonyl; lower alkylcarboxy; cyano; nitro; lower haloalkoxy; amino; mono(lower alkyl)amino; di(lower alkyl)amino; and —OH
q is 2 or 3; and
p is 1 or 2.

### Claim 4 (depends on 3)

The compound of claim 3, wherein:
X1 and X2 are both CRR or both O; and
R, for each occurrence, is independently, —H or a lower alkyl.

### Claim 5 (depends on 1)

The compound of claim 1, wherein Q is an optionally substituted 5-14 membered heteroaryl group selected from furanyl, benzo[1,3]dioxolyl, benzo[1,4]dioxinyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, a isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, a triazinyl, triazolyl, thiadiazolyl, isoquinolinyl, indazolyl, benzoxazolyl, benzofuryl, indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl, quinazolinyl, purinyl, pyrrolo[2,3]pyrimidinyl, pyrazolo[3,4]pyrimidinyl, imidazo[1,2-a]pyridyl, and benzothienyl.

### Claim 6 (depends on 5)

The compound of claim 5, wherein the heteroaryl group represented by Q is selected from the group consisting of:
wherein each of rings A1-J1 independently is optionally substituted.

### Claim 7 (depends on 1)

The compound of claim 1 wherein R5 and R6 are, independently, —H, a lower alkyl, a lower alkoxy, or a lower sulfanyl.

### Claim 8 (depends on 7)

The compound of claim 7, wherein:
R1 and R2 independently are an optionally substituted aryl or an optionally substituted heteroaryl; and
R3 and R4 are each an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, and optionally substituted heterocyclyl.

### Claim 9 (depends on 8)

The compound of claim 8, wherein R1 and R2 are each a substituted or unsubstituted phenyl group; and R3 and R4 are each methyl or ethyl.

### Claim 10 (depends on 7)

The compound of claim 7, wherein R1 and R2 are both an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl.

### Claim 11 (depends on 10)

The compound of claim 10, wherein R1 and R2 are both a C3-C8 cycloalkyl group optionally substituted with at least one alkyl group; R3 and R4 are both an alkyl group.

### Claim 12 (depends on 11)

The compound of claim 11, wherein R1 and R2 are both cyclopropyl or
1-methylcyclopropyl.

### Claim 13 (depends on 1)

The compound of claim 1, wherein:
R1 and R2 are both phenyl, and R3 and R4 are both methyl;
R1 and R2 are both phenyl, and R3 and R4 are both ethyl;
R1 and R2 are both 4-cyanophenyl, and R3 and R4 are both methyl;
R1 and R2 are both 4-methoxyphenyl, and R3 and R4 are both methyl;
R1 and R2 are both 2,5-dimethoxyphenyl, and R3 and R4 are both methyl;
R1 and R2 are both 3-cyanophenyl, and R3 and R4 are both methyl;
R1 and R2 are both 3-fluorophenyl, and R3 and R4 are both methyl;
R1 and R2 are both 4-chlorophenyl, and R3 and R4 are both methyl;
R1 and R2 are both 2-methoxyphenyl, and R3 and R4 are both methyl;
R1 and R2 are both 3-methoxyphenyl, and R3 and R4 are both methyl;
R1 and R2 are both 2,3-dimethoxyphenyl, and R3 and R4 are both methyl;
R1 and R2 are both 2,5-difluorophenyl, and R3 and R4 are both methyl;
R1 and R2 are both 2,5-dichlorophenyl, and R3 and R4 are both methyl;
R1 and R2 are both 2,5-dimethylphenyl, and R3 and R4 are both methyl;
R1 and R2 are both cyclopropyl, and R3 and R4 are both methyl;
R1 and R2 are both cyclopropyl, and R3 and R4 are both ethyl;
R1 and R2 are both 1-methylcyclopropyl, and R3 and R4 are both methyl;
R1 and R2 are both 1-methylcyclopropyl, and R3 and R4 are both ethyl;
R1 and R2 are both 1-methylcyclopropyl, and R3 is methyl, and R4 is ethyl;
R1 and R2 are both 2-methylcyclopropyl, and R3 and R4 are both methyl;
R1 and R2 are both 2-phenylcyclopropyl, and R3 and R4 are both methyl;
R1 and R2 are both 1-phenylcyclopropyl, and R3 and R4 are both methyl;
R1 and R2 are both cyclobutyl, and R3 and R4 are both methyl;
R1 and R2 are both cyclopentyl, and R3 and R4 are both methyl;
R1 and R2 are both cyclohexyl, and R3 and R4 are both methyl;
R1 and R2 are both cyclohexyl, and R3 and R4 are both phenyl;
R1 and R2 are both methyl, and R3 and R4 are both methyl;
R1 and R2 are both methyl, and R3 and R4 are both t-butyl;
R1 and R2 are both methyl, and R3 and R4 are both phenyl;
R1 and R2 are both t-butyl, and R3 and R4 are both methyl;
R1 and R2 are ethyl, and R3 and R4 are both methyl; or
R1 and R2 are both n-propyl, and R3 and R4 are both methyl.

### Claim 14 (depends on 1)

A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of claim 1.

### Claim 15 (depends on 1)

A method of treating a subject having a proliferative disorder, said method comprising administering to the subject an effective amount of a compound of claim 1.

### Claim 16 (depends on 15)

The method of claim 15, wherein the proliferative disorder is psoriasis, Reiter's syndrome, pityriasis rubra pilaris, actinic keratosis, senile keratosis, scleroderma, smooth muscle cell proliferation, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, retinopathy, diabetic retinopathy, cardiac hyperplasia, benign prostatic hyperplasia, ovarian cysts, pulmonary fibrosis, endometriosis, fibromatosis, harmatomas, lymphangiomatosis, sarcoidosis, or desmoid tumors.

### Claim 17 (depends on 15)

The method of claim 15, further comprising administering to the subject a microtubule stabilizer.

### Claim 18 (depends on 17)

The method of claim 17, wherein the microtubule stabilizer is selected from the group consisting of Taxol®, Taxol® analogues, Discodermolide, Epothilone A, Epothilone B, Epothilone C, Epothilone D, Epothilone E, Epothilone F, Epothilone B N-oxide, Epothilone A N-oxide, 16-aza-epothilone B, 21-aminoepothilone B, 21-hydroxyepothilone D, FR-182877, BSF-223651, AC-7739, AC-7700, Fijianolide B, Laulimalide, Caribaeoside, Caribaeolin, Taccalonolide, Eleutherobin, Sarcodictyin; Laulimalide, Dictyostatin-1, and Jatrophane esters.

### Claim 19 (depends on 15)

The method of claim 15, wherein the proliferative disorder is renal cell carcinoma, melanoma, multiple myeloma, myeloma, lymphoma, non-small-cell lung cancer, squamous cell carcinoma, basal cell carcinoma, fibrosarcoma or malignant brain tumors.