Therapeutic compounds and methods
The invention provides a compound of formula (I): or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 have any of the values described in the specification, as well as compositions comprising a compound of formula (I) or a prodrug thereof, or a pharmaceutically acceptable salt thereof. The compounds are agonists of glycolytic enzyme phosphofructokinase-1 liver type and are useful for treating diseases associated with the activity of glycolytic enzyme phosphofructokinase-1 liver type, such as cancer, diabetes, sepsis, and septic shock.
1 . A method for treating a symptom of a disease associated with the activity of glycolytic enzyme phosphofructokinase-1 liver type in an animal, comprising administering to the animal a compound of formula (I):
or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —NR a R b or a 5-10 membered heteroaryl that is optionally substituted with one or more groups R c ;
R 2 is a 6-10 membered aryl that is optionally substituted with one or more groups R r ; or R 2 is a 5-10 membered heteroaryl that is that is optionally substituted with one or more groups R s ; or R 2 is a 3-10 membered heterocycle that is that is optionally substituted with one or more groups R 2 ;
R a is (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkanoyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, (C 2 -C 6 )alkynylcarbonyl, 3-6 membered heterocycle, or a 5-6 membered heteroaryl that is optionally substituted with one or more groups R f ; wherein each (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkanoyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, (C 2 -C 6 )alkynylcarbonyl, and 3-6 membered heterocycle is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, cyano, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, C(═O)NR m R n , and (C 1 -C 6 )alkyl that is optionally substituted with one or more groups independently selected form the group consisting of halo, hydroxy, cyano, —NR m R n , and —C(═O)NR m R n ;
R b is H or (C 1 -C 6 )alkyl;
each R c is independently selected from the group consisting of cyano, —NR d R e , —C(═O)NR d R e , (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and (C 1 -C 6 )alkanoyl, wherein each (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy and (C 1 -C 6 )alkanoyl is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, carboxy, and cyano;
R d and R e are each independently selected from the group consisting of H and (C 1 -C 6 )alkyl; or R d and R e taken together with the nitrogen to which they are attached form a 3-6 membered heterocyclic ring that is optionally substituted with one or more groups independently selected from the group consisting of halo and (C 1 -C 6 )alkyl;
each R f is independently selected from the group consisting of halo, hydroxy,
cyano, —NR g R h , —C(═O)N g R h , and (C 1 -C 6 )alkyl that is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, carboxy, —NR g R h , —C(═O)NR g R h , and cyano;
R g and R h are each independently selected from the group consisting of H and (C 1 -C 6 )alkyl; or R g and R h taken together with the nitrogen to which they are attached form a 3-6 membered heterocyclic ring that is optionally substituted with one or more groups independently selected from the group consisting of halo and (C 1 -C 6 )alkyl;
R m is H or (C 1 -C 6 )alkyl that is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, carboxy, cyano, and oxo;
R n is H or (C 1 -C 6 )alkyl that is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, carboxy, cyano, and oxo;
each R r is independently selected from the group consisting of halo, hydroxy, cyano, —NR t R u , —C(═O)NR t R u , —S(O) 2 NR t R u , (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, —N(H)S(O) 2 R x , —S(O) 2 R x , (C 2 -C 6 )alkenyl, and (C 2 -C 6 )alkynyl, wherein each (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, (C 2 -C 6 )alkenyl, and (C 2 -C 6 )alkynyl is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, carboxy, —NR t R u , —C(═O)NR t R u , —S(O) 2 NR t R u , —S(O) 2 R x , and cyano;
each R s is independently selected from the group consisting of halo,
cyano, —NR v R w , —C(═O)NR v R w , —S(O) 2 NR v R w , (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkylthio, 3-6 membered heterocycle, and —S(O) 2 R y , wherein each (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, 3-6 membered heterocycle, and (C 1 -C 6 )alkylthio, is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, carboxy, —NR t R u , —C(═O)NR t R u , S(O) 2 NR v R w , —S(O) 2 R y , and cyano;
R t and R u are each independently selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, and (C 2 -C 6 )alkynylcarbonyl; or R t and R u taken together with the nitrogen to which they are attached form a 3-6 membered heterocyclic ring that is optionally substituted with one or more groups independently selected from the group consisting of halo and (C 1 -C 6 )alkyl;
R v and R w are each independently selected from the group consisting of H, (C 1 -C 6 )alkyl, and (C 1 -C 6 )alkanoyl; or R y and R w taken together with the nitrogen to which they are attached form a 3-6 membered heterocyclic ring that is optionally substituted with one or more groups independently selected from the group consisting of halo and (C 1 -C 6 )alkyl;
R x is H or (C 1 -C 6 )alkyl that is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, carboxy, cyano, and oxo;
R y is H or (C 1 -C 6 )alkyl that is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, carboxy, cyano, and oxo; and
each R z is independently selected from the group consisting of oxo, halo, hydroxy, and (C 1 -C 6 )alkyl that is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, carboxy, —NR t R u , —C(═O)NR t R u , S(O) 2 NR v R w , —S(O) 2 R y , cyano, and oxo;
provided the compound is not:
wherein the disease associated with the activity of glycolytic enzyme phosphofructokinase-1 liver type is cancer, diabetes, a caspase-associated auto-inflammatory condition, pulmonary disease, a systemic autoimmune disease, atherosclerosis, thrombosis, multiple sclerosis, Alzheimer's disease, psoriasis, or pulmonary fibrosis.
2 . The method of claim 1 , wherein:
R 1 is —NR a R b or a 5-10 membered heteroaryl that is optionally substituted with one or more groups R c ;
R 2 is a phenyl that is optionally substituted with one or more groups R r ; or R 2 is a 5-9 membered heteroaryl that is that is optionally substituted with one or more groups R s ; or R 2 is a 9-membered heterocycle that is that is optionally substituted with one or more groups R 2 ;
R a is (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkanoyl, (C 2 -C 6 )alkynylcarbonyl, 3-6 membered heterocycle, or a 5-membered heteroaryl that is optionally substituted with one or more groups R f ; wherein each (C 1 -C 6 )alkyl and (C 3 -C 6 )cycloalkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, cyano, (C 2 -C 6 )alkynyl, C(═O)NR m R n , and (C 1 -C 6 )alkyl that is optionally substituted with one or more hydroxy;
R b is H or (C 1 -C 6 )alkyl;
each R c is independently selected from the group consisting of cyano, —NR d R e , and (C 1 -C 6 )alkyl that is optionally substituted with one or more cyano;
R d and R e are each H;
each R f is independently selected from the group consisting of halo, hydroxy, cyano, —C(═O)NR g R h , and (C 1 -C 6 )alkyl that is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy and carboxy;
R d and R e are each H;
R m is H;
R n is H;
each R r is independently selected from the group consisting of halo, hydroxy,
cyano, —NR t R u , —C(═O)NR t R u , —S(O) 2 NR t R u , (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, —N(H)S(O) 2 R x , —S(O) 2 R x , and (C 2 -C 6 )alkynyl, wherein each (C 1 -C 6 )alkyl and (C 2 -C 6 )alkynyl, is optionally substituted with one or more groups independently selected from the group consisting of hydroxy, —NR t R u , —C(═O)NR t R u , and cyano;
each R g is independently selected from the group consisting of halo,
cyano, —NR v R w , —C(═O)NR v R w , (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkylthio, 3-6 membered heterocycle, and —S(O) 2 R y , wherein each (C 1 -C 6 )alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo and —NR t R u ;
R t and R u are each independently selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, and (C 2 -C 6 )alkynylcarbonyl; or R t and R u taken together with the nitrogen to which they are attached form a 3-6 membered heterocyclic ring that is optionally substituted with one or more groups independently selected from the group consisting of halo and (C 1 -C 6 )alkyl;
R v and R w are each independently selected from the group consisting of H, (C 1 -C 6 )alkyl, and (C 1 -C 6 )alkanoyl;
R x is (C 1 -C 6 )alkyl;
R y is (C 1 -C 6 )alkyl; and
each R z is independently selected from the group consisting of oxo and (C 1 -C 6 )alkyl;
or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
3 . The method of claim 1 , wherein R 1 is —NR a R b .
4 . The method of claim 1 , wherein R a is acetyl.
5 . The method of claim 1 , wherein R a is selected from the group consisting of
6 . The method of claim 1 , wherein R 1 is a 5-membered heteroaryl that is optionally substituted with one or more groups R c .
7 . The method of claim 1 , wherein R 1 is selected from the group consisting of:
8 . The method of claim 1 , wherein R 2 is a 5-9 membered heteroaryl that is that is optionally substituted with one or more groups R s .
9 . The method of claim 1 , wherein R 2 is selected from the group consisting of
10 . The method of claim 1 , wherein R 2 is:
R r (C 2 -C 6 )alkynyl that is substituted with hydroxy.
11 . The method of claim 1 , wherein R 2 is selected from the group consisting of:
12 . The method of claim 1 , wherein the compound, prodrug, or pharmaceutically acceptable salt is selected from the group consisting of:
and prodrugs and pharmaceutically acceptable salts thereof.
13 . The method of claim 1 , wherein the prodrug is a compound of formula (I) that comprises a hydroxy group that has been converted to a prodrug group that increases the aqueous solubility of the compound; or a pharmaceutically acceptable salt thereof.
14 . The method of claim 13 , wherein the hydroxy group has been converted to a prodrug group selected from the group consisting of: a phosphate,
15 . The method of claim 1 , wherein the prodrug or pharmaceutically acceptable salt is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
16 . A method for treating a symptom of a disease associated with the activity of glycolytic enzyme phosphofructokinase-1 liver type in an animal, comprising administering to the animal a compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof, wherein the disease associated with the activity of glycolytic enzyme phosphofructokinase-1 liver type is cancer, diabetes, a caspase-associated auto-inflammatory condition, pulmonary disease, a systemic autoimmune disease, atherosclerosis, thrombosis, multiple sclerosis, Alzheimer's disease, psoriasis, or pulmonary fibrosis.
17 . The method of claim 1 , wherein the caspase-associated auto-inflammatory condition is sepsis or septic shock.
18 . The method of claim 1 , wherein the pulmonary disease is acute respiratory distress syndrome ARDS, chronic obstructive pulmonary disease COPD, or bronchiectasis.
19 . The method of claim 1 , wherein the disease or condition is thrombosis.
20 . The method of claim 1 , wherein the cancer is selected from the group consisting of brain, breast, lung, urinary bladder, cervical, skin, oral cavity, pharynx, colon, liver, cecum, stomach, pancreatic, prostate, oesophageal, hematologic, thyroid, uterine, and head and neck cancer.