IP Library › Granted Patent US 12,522,606

Granted Patent B2

US 12,522,606 · App. 17/758,577 · Granted Jan 13, 2026

Modified pyrrolo- and pyrazolo-pyrimidines for prostate cancer therapy

Inventors: Wesley C. Van Voorhis (Seattle, WA); Dustin James Maly (Seattle, WA); Kayode K. Ojo (Seattle, WA); Gayani Perera (Seattle, WA); Stephen R. Plymate (Seattle, WA); Cynthia Sprenger (Seattle, WA); Takuma Uo (Seattle, WA); Rama Subba Rao Vidadala (Seattle, WA)

Assignees: UNIVERSITY OF WASHINGTON; UNITED STATES GOVERNMENT AS REPRESENTED BY THE DEPARTMENT OF VETERANS AFFAIRS

C07D487/04 A61P35/00

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Quick Facts

Patent No.: US 12,522,606
App. No.: 17/758,577
Granted: Jan 13, 2026
Kind: B2

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Abstract

This disclosure relates to compounds, pharmaceutical compositions comprising them, and methods of using the compounds and compositions for treating diseases affected by glycolytic generation of adenosine triphosphate (ATP). More particularly, this disclosure relates to compounds and pharmaceutical compositions thereof, methods of selectively inhibiting glycolysis with these compounds, and methods of treating diseases that benefit from selective glycolysis inhibition, such as cancer.

Claims (86)

1 . A compound of formula

or a pharmaceutically acceptable salt thereof, wherein

X and Y are independently CH or N;

Z is O or N—R 2 ,

wherein R 2 is hydrogen or C 1 -C 6 alkyl optionally substituted with one or more of R 5 groups;

R 1 is C 1 -C 6 alkyl optionally substituted with one or more of R 5 groups, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —(C 0 -C 4 alkyl)-C 3 -C 8 cycloalkyl optionally substituted with one or more of R 6 groups, —(C 0 -C 4 alkyl)-aryl optionally substituted with one or more of R 6 groups, —(C 0 -C 4 alkyl)-heteroaryl optionally substituted with one or more of R 6 groups, —(C 0 -C 4 alkyl)-heterocyclyl optionally substituted with one or more of R 6 groups, or polyethylene glycol moiety;

R 3 is selected from:

(a) one of the formulas:

wherein

n is 0, 1, or 2; and

Q is —O—, —S—, or —N(R′)—; and

b) the formula

and

R 4 is C 1 -C 6 alkyl optionally substituted with one or more of R 8 groups, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl optionally substituted with one or more of R 7 groups, aryl optionally substituted with one or more of R 7 groups, heteroaryl optionally substituted with one or more of R 7 groups, or heterocyclyl optionally substituted with one or more of R 7 groups;

wherein

each R 5 is independently halogen, cyano, nitro, —OR′, —SR′, —N(R′) 2 , —C(O)R′, —C(O)OR′, —C(O)N(R′) 2 , —S(O) 2 N(R′) 2 , —S(O) 2 R′, —OC(O)R′, —OC(O)OR′, —OC(O)N(R′) 2 , —N(R′)C(O)R′, —N(R′)C(O)OR′, —N(R′)C(O)N(R′) 2 , aryl, heteroaryl, C 3-8 cycloalkyl, or heterocyclyl;

each R 6 is independently halogen, cyano, nitro, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OR′, —SR′, —N(R′) 2 , —C(O)R′, —C(O)OR′, —C(O)N(R′) 2 , —S(O) 2 N(R′) 2 , —S(O) 2 R′, —OC(O)R′, —OC(O)OR′, —OC(O)N(R′) 2 , —N(R′)C(O)R′, —N(R′)C(O)OR′, —N(R′)C(O)N(R′) 2 , aryl, heteroaryl, C 3-8 cycloalkyl, or heterocyclyl;

each R 7 is independently halogen, cyano, nitro, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OR′, —SR′, —N(R′) 2 , —C(O)R′, —C(O)OR′, —C(O)N(R′) 2 , —S(O) 2 N(R′) 2 , —S(O) 2 R′, —OC(O)R′, —OC(O)OR′, —OC(O)N(R′) 2 , —N(R′)C(O)R′, —N(R′)C(O)OR′, —N(R′)C(O)N(R′) 2 , aryl, heteroaryl, C 3 -C 8 cycloalkyl, or heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted by one, two, or three groups that are each independently halogen, cyano, nitro, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —OR″, —SR″, —N(R″) 2 , —C(O)R″, —C(O)OR″, —C(O)N(R″) 2 , —S(O) 2 R″, —OC(O)R″, —OC(O)OR″, —OC(O)N(R″) 2 , —N(R″)C(O)R″, —N(R″)C(O)OR″, or —N(R″)C(O)N(R″) 2 ;

each R 8 is independently halogen, cyano, nitro, —OR′, —SR′, —N(R′) 2 , —C(O)R′, —C(O)OR′, —C(O)N(R′) 2 , —S(O) 2 N(R′) 2 , —S(O) 2 R′, —OC(O)R′, —OC(O)OR′, —OC(O)N(R′) 2 , —N(R′)C(O)R′, —N(R′)C(O)OR′, —N(R′)C(O)N(R′) 2 , aryl, heteroaryl, C 3 -C 8 cycloalkyl, or heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted by one, two, or three groups that are each independently halogen, cyano, nitro, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —OR″, —SR″, —N(R″) 2 , —C(O)R″, —C(O)OR″, —C(O)N(R″) 2 , —S(O) 2 R″, —OC(O)R″, —OC(O)OR″, —OC(O)N(R″) 2 , —N(R″)C(O)R″, —N(R″)C(O)OR″, or —N(R″)C(O)N(R″) 2 ;

each R′ and R″ is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 haloalkyl, —(C 0 -C 4 alkyl)-C 3 -C 8 cycloalkyl, —(C 0 -C 4 alkyl)-aryl, —(C 0 -C 4 alkyl)-heteroaryl, and —(C 0 -C 4 alkyl)-heterocyclyl, wherein the alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are optionally substituted with one, two, three, or four groups that are each independently halogen, cyano, nitro, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OR 0 , —SR 0 , —N(R 0 ) 2 , —C(O)R 0 , —C(O)OR 0 , —C(O)N(R 0 ) 2 , —S(O) 2 R 0 , —OC(O)R 0 , —OC(O)OR 0 , —OC(O)N(R 0 ) 2 , —N(R 0 )C(O)R 0 , —N(R 0 )C(O)OR 0 , or —N(R 0 )C(O)N(R 0 ) 2 , wherein each R 0 is independently hydrogen or C 1 -C 6 alkyl.

2 . The compound according to claim 1 , wherein X is CH and Y is N.

3 . The compound according to claim 2 , wherein the compound is of formula:

4 . The compound according to claim 2 , wherein the compound is of formula:

5 . The compound according to claim 1 , wherein X is N and Y is N.

6 . The compound according to claim 5 , wherein the compound is of formula:

7 . The compound according to claim 5 , wherein the compound is of formula:

8 . The compound according to claim 1 , wherein R 2 is hydrogen or C 1 -C 6 alkyl.

9 . The compound according to claim 1 , wherein R 1 is C 1 -C 6 alkyl optionally substituted with one or more of R 5 groups, C 3 -C 8 cycloalkyl optionally substituted with one or more of R 6 groups, aryl optionally substituted with one or more of R 6 groups, heteroaryl optionally substituted with one or more of R 6 groups, or heterocyclyl optionally substituted with one or more of R 6 groups.

10 . The compound according to claim 1 , wherein R 1 is methyl, 2-ethoxyethyl, 3-(dimethylamino)propyl, 2-aminoethyl, 2-hydroxyethyl, 2-(2-aminoethoxy)ethyl, 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl, or 2-(2-(((cyclooct-4-en-1-yloxy)carbonyl)amino)ethoxy)ethyl.

11 . The compound according to claim 1 , wherein R 4 is C 1 -C 6 alkyl optionally substituted with one or more of R 8 groups.

12 . A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, solvent, adjuvant or diluent.

13 . A method for treating cancer comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 1 , wherein the cancer is selected from the group consisting of androgen receptor positive prostate cancer, castrate resistant prostate cancer, testicular, breast, lung, liver, kidney, and colon cancer.

14 . The method of claim 13 , wherein the cancer is testicular, breast, lung, liver, kidney, or colon cancer.

15 . The method of claim 13 , wherein the cancer is prostate cancer selected from androgen receptor (AR) positive prostate cancer and castrate resistant prostate cancer (CRPC).

16 . The method of claim 13 , wherein the therapeutically effective amount of a compound is administered with a secondary therapeutic agent.

17 . The compound of claim 1 , wherein R 3 is one of the formulas:

wherein

n is 0, 1, or 2; and

Q is —O—, —S—, or —N(R′)—.

18 . The compound of claim 1 , wherein R 3 is the formula

19 . A compound selected from:

1-(3-(6-cyclopropoxynaphthalen-2-yl)-4-(methylamino)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-2-methylpropan-2-ol

1-(5-(6-cyclopropoxynaphthalen-2-yl)-4-(2-methoxyethoxy)- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol

1-(5-(6-ethoxynaphthalen-2-yl)-4-(2-methoxyethoxy)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol

1-(5-(biphenyl-4-yl)-4-(2-methoxyethoxy)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol

1-(4-ethoxy-5-(6-ethoxynaphthalen-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol

1-(5-(6-cyclopropoxynaphthalen-2-yl)-4-ethoxy-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol

1-(4-(2-methoxyethoxy)-5-(naphthalen-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol

1-(4-(2-ethoxyethylamino)-5-(naphthalen-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol

trans-cyclooct-4-enyl 2-(5-(6-cyclopropoxynaphthalen-2-yl)-7- (2-hydroxy-2-methylpropyl)-7H-pyrrolo[2,3-d]pyrimidin-4- ylamino)ethylcarbamate

2-(3-(but-3-ynyl)-3H-diazirin-3-yl)ethyl 2-(5-(6-ethoxynaphthalen-2- yl)-7-(2-hydroxy-2-methylpropyl)-7H-pyrrolo[2,3-d]pyrimidin-4- ylamino)ethylcarbamate

1-(5-(6-ethoxynaphthalen-2-yl)-4-(methylamino)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol

1-(3-(biphenyl-4-yl)-4-(methylamino)-1H-pyrazolo[3,4-d]pyrimidin-1- yl)-2-methylpropan-2-ol

1-(5-(biphenyl-4-yl)-4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)-2-methylpropan-2-ol

1-(3-(6-ethoxynaphthalen-2-yl)-4-(methylamino)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-2-methylpropan-2-ol

1-(5-(6-cyclopropoxynaphthalen-2-yl)-4-(methylamino)- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol

1-(3-(3-isopropylphenyl)-4-(methylamino)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-2-methylpropan-2-ol

1-(5-(6-cyclopropoxynaphthalen-2-yl)-4-(cyclopropylamino)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol

5-(6-ethoxynaphthalen-2-yl)-7-(2-methoxy-2-methylpropyl)-N- methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

1-(3-(biphenyl-3-yl)-4-(methylamino)-1H-pyrazolo[3,4-d]pyrimidin-1- yl)-2-methylpropan-2-ol

1-(3-(3-fluorobiphenyl-4-yl)-4-(methylamino)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-2-methylpropan-2-ol

5-(3-isopropylphenyl)-7-(2-methoxy-2-methylpropyl)-N-methyl- 7H-pyrrolo[2,3-d]pyrimidin-4-amine

5-(3-chlorophenyl)-7-(2-methoxy-2-methylpropyl)-N-methyl-7H- pyrrolo[2,3-d]pyrimidin-4-amine

1-(4-(2-aminoethylamino)-5-(6-ethoxynaphthalen-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol

1-(4-(2-aminoethylamino)-5-(6-cyclopropoxynaphthalen-2-yl)- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol

1-(5-(6-ethoxynaphthalen-2-yl)-4-(2-hydroxyethylamino)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol

1-(5-(6-cyclopropoxynaphthalen-2-yl)-4-(2-hydroxyethylamino)- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol

1-(4-(2-(2-aminoethoxy)ethylamino)-5-(6-cyclopropoxynaphthalen- 2-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol

1-(4-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethylamino)-5-(6- cyclopropoxy naphthalen-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)-2-methylpropan-2-ol

trans-cyclooct-4-enyl 2-(2-(5-(6-cyclopropoxynaphthalen-2-yl)-7- (2-hydroxy-2-methylpropyl)-7H-pyrrolo[2,3-d]pyrimidin-4- ylamino)ethoxy)ethylcarbamate

1-(5-(biphenyl-4-yl)-4-(2-hydroxyethylamino)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol

1-(4-(2-ethoxyethylamino)-5-(6-ethoxynaphthalen-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol

5-(6-isopropoxynaphthalen-2-yl)-7-(2-methoxy-2-methylpropyl)-N- methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

5-(4′-bromobiphenyl-4-yl)-7-(2-methoxy-2-methylpropyl)-N-methyl- 7H-pyrrolo[2,3-d]pyrimidin-4-amine

5-(4′-ethylbiphenyl-4-yl)-7-(2-methoxy-2-methylpropyl)-N-methyl- 7H-pyrrolo[2,3-d]pyrimidin-4-amine

1-(5-(6-cyclopropoxynaphthalen-2-yl)-4-(2-ethoxyethylamino)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol

1-(4-(2-ethoxyethylamino)-5-(6-isopropoxynaphthalen-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol

1-(5-(biphenyl-4-yl)-4-(2-ethoxyethylamino)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol

1-(4-(2-ethoxyethylamino)-5-(4′-methoxybiphenyl-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol

1-(4-(2-ethoxyethylamino)-5-(4′-ethylbiphenyl-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol

1-(5-(4′-bromobiphenyl-4-yl)-4-(2-ethoxyethylamino)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol

1-(4-(cyclopropylamino)-5-(6-ethoxynaphthalen-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol

1-(4-(cyclopropylamino)-5-(6-methoxynaphthalen-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol

1-(5-(6-cyclopropoxynaphthalen-2-yl)-4-(isopropylamino)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol

1-(5-(6-ethoxynaphthalen-2-yl)-4-(isopropylamino)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol

1-(4-(isopropylamino)-5-(6-methoxynaphthalen-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol

Assignments (3)

CONFIRMATORY LICENSE Recorded Jun 1, 2026

From: UNIVERSITY OF WASHINGTON

To: THE GOVERNMENT OF THE UNITED STATES, AS REPRESENTED BY THE DIRECTOR OF THE DEFENSE HEALTH AGENCY

Reel/Frame 074805/0286 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 16, 2022

From: VAN VOORHIS, WESLEY C.; MALY, DUSTIN JAMES; OJO, KAYODE K.; PERERA, GAYANI; SPRENGER, CYNTHIA; UO, TAKUMA; VIDADALA, RAMA SUBBA RAO

To: UNIVERSITY OF WASHINGTON

Reel/Frame 060825/0001 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 16, 2022

From: PLYMATE, STEPHEN R.

To: UNIVERSITY OF WASHINGTON; UNITED STATES GOVERNMENT AS REPRESENTED BY THE DEPARTMENT OF VETERANS AFFAIRS

Reel/Frame 060825/0066 →

Continuity (2)

Provisional Application 62958826 · Jan 9, 2020

Related Publication 20230125057A1 · Apr 20, 2023

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The International Search Report (ISR) for PCT/US2016/014996, dated Mar. 4, 2016, pp. 1-3. [cited by applicant]

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