# US 2012/0238570 A1 · Inhibitors of the hedgehog pathway

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- Number: US 2012/0238570 A1
- Document ID: US20120238570A1
- Status: Published application
- Kind: A1
- Application number: 13/487,559
- Filed: 2012-06-04
- Published: 2012-09-20
- Earliest claimed: 2007-03-14
- Assignees: Exelixis Patent Company LLC
- Inventors: Suleyman Bahceci; William Bajjalieh; Jeff Chen; Sergey Epshteyn; Timothy Patrick Forsyth; Tai Phat Huynh; Byung Gyu Kim; James W. Leahy; Matthew Sangyup Lee; Gary L. Lewis; Morrison B. Mac; Grace Mann; Charles K. Marlowe; Brian Hugh Ridgway; Joan C. Sangalang; Xian Shi; Craig Stacy Takeuchi; Yong Wang
- Web page: https://patentgrep.com/patent/US20120238570A1

## CPC

- C07D 239/42: One nitrogen atom (nitro radicals C07D239/30)
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 239/70: condensed with carbocyclic rings or ring systems
- C07D 239/84: Nitrogen atoms
- C07D 239/95: with hetero atoms directly attached in positions 2 and 4
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention is directed to a compound of Formula I or a single isomer thereof; where the compound is optionally as a pharmaceutically acceptable salt, hydrate, solvate or combination thereof, in addition to methods of preparing a Compound of Formula I, and methods of using a Compound of Formula I to treat cancer.

## Claims

### Claim 1

A Compound of Formula I
or a single isomer thereof and optionally as a pharmaceutically acceptable salt thereof, where
R1 is alkyl, cycloalkyl, phenyl, or heteroaryl where the cycloalkyl, phenyl, and heteroaryl are optionally substituted with 1, 2, or 3 R6;
R2 and R3 together with the pyrimidinyl to which they are attached form a quinazolinyl optionally substituted at the 5-, 6-, 7-, and 8-positions with one or two groups independently selected from alkyl, alkoxy, halo, hydroxy, heterocycloalkylalkyloxy, heterocycloalkyl, and heterocycloalkyl substituted with alkyl; or
R2 and R3 together with the pyrimidinyl to which they are attached form a pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, or pyrido[2,3-d]pyrimidinyl, each of which is optionally substituted at a carbon atom at the 5-, 6-, 7-, and 8-positions with one or two groups independently selected from alkyl, alkoxy, halo, hydroxy, heterocycloalkylalkyloxy, heterocycloalkyl, and heterocycloalkyl substituted with alkyl; or
R2 and R3 together with the pyrimidinyl to which they are attached form a 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, 5,6,7,8-tetrahydroquinazolinyl, or 6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidinyl; or
R2 and R3 together with the pyrimidinyl to which they are attached form a 5,6,7,8-tetrahydropyrido[3,2-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidinyl, or 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidinyl, each of which is optionally substituted at the 5-, 6-, 7-, and 8-positions with one or two groups independently selected from alkyl, alkoxycarbonyl, benzyloxycarbonyl, and optionally substituted phenylalkyl;
each R6, when R6 is present, is independently selected from alkyl, alkoxy, amino, alkylamino, dialkylamino, halo, haloalkyl, haloalkoxy, halophenyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl, alkoxycarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminoalkylamino, alkylaminoalkylamino, dialkylaminoalkylamino, alkyloxyalkylamino, heterocycloalkyl, and heterocycloalkylalkyl; where the heterocycloalkyl, either alone or as part of heterocycloalkylalkyl, is optionally substituted with alkyl or alkoxycarbonyl;
R40 is hydrogen or alkyl;
R50 is selected from
n1 is 0, 1, or 2;
each R5, when R5 is present, is independently alkyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, halo, nitro, heterocycloalkyl, heterocycloalkylamino, or heterocycloalkylalkyloxy; where each heterocycloalkyl, either alone or as part of another group in R5, is independently optionally substituted with alkyl or alkoxycarbonyl;
R4a is hydrogen or alkyl;
R4 is heteroaryl substituted with one R8 and additionally substituted with 1 or 2 R8a, wherein heteroaryl is selected from 1,2,3,4-tetrahydroisoquinolinyl or 2,3,4,5-tetrahydro-1,4-benzoxazepinyl; or R4 is phenyl substituted with one R29 and additionally substituted with 1 or 2 R9a;
R17 is cycloalkyl, heterocycloalkyl (optionally substituted with one or two groups selected from alkyl and alkoxycarbonyl), phenylalkylamino, phenylalkyl, or phenyl; where each phenyl, either alone or as part of a group in R17, is substituted with 1, 2, or 3 R9a;
R21 is phenyl substituted with 1, 2, or 3 R9a, or R21 is heteroaryl substituted with 1, 2, or 3 R8a, or R21 is heterocycloalkyl optionally substituted with alkyl or alkoxycarbonyl;
R22 is phenyl substituted with 1, 2, or 3 R9a, or R22 is heteroaryl substituted with 1, 2, or 3 R8a;
each R8 is independently alkyl, cycloalkyl, phenylalkyloxyalkyl, or R9b;
each R8a is independently hydrogen, halo, or R8;
each R9a is independently hydrogen, R9b, or R9c;
R29 is alkyl substituted with —NR15R15a; or alkyl substituted with optionally substituted heterocycloalkyl;
each R9b, when R9b is present, is independently amino, alkylamino, dialkylamino, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyloxy, aminoalkyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, optionally substituted heteroaryl, cyano, —C(O)R14, —CR14a(═NR14b); —C(═NR24)R24a; —S(O)2NR13R13a; —NR23C(O)R23a—C(O)NR12R12a, or alkyl substituted with one or two R11;
each R9c, when R9c is present, is independently alkyl, haloalkyl, hydroxyalkyl, halo, hydroxy, alkoxy, cyano, nitro, or phenylcarbonyl;
each R11 is independently selected from hydroxy, —NR15R15a, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, and optionally substituted cycloalkyl;
R12 is hydrogen or alkyl and R12a is hydrogen, hydroxy, alkoxy, alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, or optionally substituted heteroaryl; or R12 and R12a together with the nitrogen to which they are attached form a heterocycloalkyl optionally substituted with 1, 2, or 3 groups independently selected from alkyl, hydroxyalkyl, haloalkyl, alkylcarbonyl, alkoxycarbonyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted phenyl, and optionally substituted phenylalkyl;
R13 is hydrogen or alkyl;
R13a is alkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl;
each R14 is independently hydrogen, alkyl, hydroxy, alkoxy, optionally substituted heteroarylalkyl, or optionally substituted heterocycloalkylalkyl;
each R14a is hydrogen or alkyl;
R14b is alkoxy, amino, alkylamino, dialkylamino, or optionally substituted heterocycloalkyl;
R15 is hydrogen, alkyl, alkoxyalkyl, hydroxyalkyl, or haloalkyl;
R15a is hydrogen, alkyl, alkoxyalkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, optionally substituted cycloalkyl, or optionally substituted phenylalkyl;
R23 is hydrogen or alkyl;
R23a is hydrogen, alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or optionally substituted heterocycloalkylalkyl;
R24 is hydrogen or alkyl, hydroxy, or alkoxy; and
R24a is hydroxy, alkoxy, amino, alkylamino, or dialkylamino.

### Claim 2 (depends on 1)

The Compound of claim 1 where R40 is hydrogen and R2 and R3 together with the pyrimidinyl to which they are attached form a quinazolinyl optionally substituted at the 5-, 6-, 7-, and 8-positions with one or two groups independently selected from alkyl, alkoxy, halo, and hydroxy; or a single isomer thereof and optionally as a pharmaceutically acceptable salt-thereof.

### Claim 3 (depends on 2)

The Compound of claim 2 where R2 and R3 together with the pyrimidinyl to which they are attached form a quinazolinyl that is not substituted at the 5-, 6-, 7-, or 8-position; or a single isomer thereof and optionally as a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 3)

The Compound of claim 3 where R1 is alkyl; or a single isomer thereof and optionally as a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 3)

The Compound of claim 3 where R1 is heteroaryl optionally substituted with 1, 2, or 3 R6; or a single isomer thereof and optionally as a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 3)

The Compound of claim 3 where R1 is cycloalkyl optionally substituted with 1, 2, or 3 R6; or a single isomer thereof and optionally as a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 3)

The Compound of claim 3 where R1 is phenyl substituted with one or two R6 where each R6 is independently amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, heterocycloalkylalkyl (optionally substituted with alkyl or alkoxycarbonyl), aminoalkylamino, alkylaminoalkylamino, or dialkylaminoalkylamino; or a single isomer thereof and optionally as a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 3)

The Compound of claim 3 where R1 is unsubstituted phenyl; or a single isomer thereof and optionally as a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 1)

The Compound of claim 1 according to Formula Ib
or a single isomer thereof and optionally as a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 9)

The Compound of claim 9 where R4 is heteroaryl substituted with one R8, wherein heteroaryl is selected from 1,2,3,4-tetrahydroisoquinolinyl or 2,3,4,5-tetrahydro-1,4-benzoxazepinyl; or a single isomer thereof and optionally as a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 9)

The Compound of claim 9 where R4 is phenyl substituted with R29 and additionally substituted with 1 or 2 R9a; or a single isomer thereof and optionally as a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 3)

The Compound of claim 3 where R1 is alkyl, cycloalkyl, or heteroaryl, where the cycloalkyl and heteroaryl are optionally substituted with 1, 2, or 3 R6; R50 is
R4 is phenyl substituted with one R29 and additionally substituted with 1 or 2 R9a and each R9a is independently hydrogen or R9c; or a single isomer thereof and optionally as a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 1)

The Compound of claim 1 according to Formula V
wherein R1 is alkyl, cycloalkyl, phenyl, or heteroaryl where the cycloalkyl, phenyl, and heteroaryl are optionally substituted with one or two R6; and R17 is phenyl, phenylalkyl, phenylalkylamino, heterocycloalkyl (optionally substituted with one or two groups selected from alkyl and alkoxycarbonyl), or cycloalkyl; and wherein each phenyl, either alone or as part of a group in R17, is substituted with 1, 2, or 3 R9a; or a single isomer thereof and optionally as a pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 13)

The Compound of claim 13 selected from
N-[(3,4-dichlorophenyl)methyl]-4-[(4-phenylquinazolin-2-
yl)amino]piperidine-1-carboxamide;
4-phenyl-N-[1-(phenylcarbonyl)piperidin-4-yl]quinazolin-2-amine;
4-phenyl-N-[1-(phenylacetyl)piperidin-4-yl]quinazolin-2-amine;
N-{1-[(2,6-dichlorophenyl)acetyl]piperidin-4-yl}-4-
phenylquinazolin-2-amine;
4-phenyl-N-[1-(2-phenylpropanoyl)piperidin-4-yl]quinazolin-2-amine;
N-{1-[(2,6-dichlorophenyl)carbonyl]piperidin-4-yl}-4-
phenylquinazolin-2-amine;
1,1-dimethylethyl 3-({4-[(4-phenylquinazolin-2-yl)amino]piperidin-1-
yl}carbonyl)piperidine-l-carboxylate;
N-[1-(cyclohexylcarbonyl)piperidin-4-yl]-4-phenylquinazolin-2-amine; and
a single isomer thereof and optionally as a pharmaceutically acceptable salt thereof.

### Claim 15 (depends on 1)

The Compound of claim 1 according to Formula IX
wherein R1 is alkyl, cycloalkyl, phenyl, or heteroaryl where the cycloalkyl, phenyl, and heteroaryl are optionally substituted with one or two R6; and R21 is phenyl substituted with 1, 2, or 3 R9a, or R21 is heteroaryl substituted with 1, 2, or 3 R8a; or a single isomer thereof and optionally as a pharmaceutically acceptable salt thereof.

### Claim 16 (depends on 15)

The Compound of claim 15 selected from N-{1-[(3,5-dimethylisoxazol-4-yl)sulfonyl]piperidin-4-yl}-4-phenylquinazolin-2-amine; and a single isomer thereof and optionally as a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 1)

The Compound of claim 1 of Formula X,
wherein R1 is alkyl, cycloalkyl, phenyl, or heteroaryl where the cycloalkyl, phenyl, and heteroaryl are optionally substituted with one or two R6 and R22 is phenyl substituted with 1, 2, or 3 R9a or R22 is heteroaryl substituted with 1, 2, or 3 R8a; or a single isomer thereof and optionally as a pharmaceutically acceptable salt thereof.

### Claim 18 (depends on 17)

The Compound of claim 17 selected from N-[1-(1H-benzimidazol-2-yl)piperidin-4-yl]-4-phenylquinazolin-2-amine; and a single isomer thereof and optionally as a pharmaceutically acceptable salt thereof.

### Claim 19 (depends on 1)

A method of preparing a compound of claim 1 which method comprises
reacting an intermediate of formula 5, or a salt, hydrate, solvate, or combination thereof:
where A is CH or N; with an intermediate of formula R17C(O)OH, R21S(O)2Cl, or R22Cl to yield a Compound of the Invention of Formula 6:
where R is —C(O)R17; —S(O)2R21; or —R22; and optionally separating individual isomers; and optionally modifying any of the R6, R17, R21, and R22 groups; and optionally forming a pharmaceutically acceptable salt thereof; or
reacting an intermediate of formula 8, or a salt, hydrate, solvate, or combination thereof:
where A is CH or N, and D is N; with an intermediate of formula 9:
to yield a Compound of Formula XI:
and optionally separating individual isomers; and optionally modifying any of the R6, R29, and R9a groups; and optionally forming a pharmaceutically acceptable salt thereof; or
reacting an intermediate of formula II, or a salt, hydrate, solvate, or combination thereof:
where A is CH or N, and D is N; with an intermediate of formula NHR12R12a to yield a Compound of formula 8f
and optionally separating individual isomers; and optionally modifying any of the R6, R9a, and R12b groups; and optionally forming a pharmaceutically acceptable salt thereof; or
reacting an intermediate of formula 13, or a salt, hydrate, solvate, or combination thereof:
where A is CH or N, and D is N; with an intermediate of formula NHR15R15a to yield a Compound of Formula XII:
and optionally separating individual isomers; and optionally modifying any of the R6, R9a, and R15 groups; and optionally forming a pharmaceutically acceptable salt thereof; or
reacting an intermediate of formula 15a, or a salt, hydrate, solvate, or combination thereof:
where A is CH or N, and D is N; with an intermediate of formula NH2R15 to yield a Compound of Formula XIII:
and optionally separating individual isomers; and optionally modifying any of the R6, R9a, and R15 groups; and optionally forming a pharmaceutically acceptable salt thereof; or
reacting an intermediate of formula 23, or a salt, hydrate, solvate, or combination thereof:
where A is CH or N, and D is N; with an intermediate of formula R23aC(O)OH or R23aC(O)Cl to yield a Compound of Formula XIV
and optionally separating individual isomers; and optionally modifying any of the R6, R9a, and R23a groups; and optionally forming a pharmaceutically acceptable salt thereof; or
reacting an intermediate of formula 26, or a salt, hydrate, solvate, or combination thereof:
where A is CH or N, and D is N; with an intermediate of formula R″B(OH)2 where R″ is optionally substituted heteroaryl to yield a Compound of Formula XV:
and optionally separating individual isomers; and optionally modifying any of the R6, R9a, and R″ groups; and optionally forming a pharmaceutically acceptable salt thereof;
reacting an intermediate of formula 31, or a salt, hydrate, solvate, or combination thereof:
where R1 is cycloalkyl, and D is N; with an intermediate of formula 9 as defined above to yield a Compound of the Invention of Formula XVI
where R29 and R9a are as defined in the Summary of the Invention for a Compound of Formula I; and optionally separating individual isomers; and optionally modifying any of the R6, R1, R9a, and R29 groups; and optionally forming a pharmaceutically acceptable salt thereof.

### Claim 20 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1 or a single isomer thereof, optionally as a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

### Claim 21 (depends on 1)

A method of treating a disease mediated by a protein in the Hedgehog pathway, the method comprising administering to a patient having the disease a therapeutically effective amount of a compound according to claim 1 or a single isomer thereof, optionally as a pharmaceutically acceptable salt thereof, and optionally with a pharmaceutically acceptable carrier, excipient, or diluent.

### Claim 22 (depends on 21)

The method of claim 21 wherein the disease is a proliferative disease.

### Claim 23 (depends on 21)

The method of claim 21 wherein the disease is cancer.

### Claim 24 (depends on 23)

The method of claim 23 wherein the cancer is selected from basal cell carcinoma, medulloblastoma, rhabdomyosaracoma, pancreatic cancer, breast carcinoma, meningioma, glioblastoma, melanoma, stomach cancer, esophageal cancer, biliary tract cancer, prostate cancer, small cell lung cancer, non-small cell lung cancer, glial cell cancer, multiple myeloma, and colon cancer.