PYRAZOLE DERIVATIVES AS ARGININE METHYLTRANSFERASE INHIBITORS AND USES THEREOF
Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds described herein are useful for inhibiting arginine methyltransferase activity. Methods of using the compounds for treating arginine methyltransferase-mediated disorders are also described. Formula (I).
1 .- 150 . (canceled)
151 . A method of inhibiting an arginine methyltransferase (RMT) comprising contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof:
wherein:
X is N, Z is NR 4 , and Y is CR 5 ; or
X is NR 4 , Z is N, and Y is CR 5 ; or
X is CR 5 , Z is NR 4 , and Y is N; or
X is CR 5 , Z is N, and Y is NR 4 ;
R 1 , R 2 , R 6 , R 7 , and R 8 are independently selected from the group consisting of hydrogen, halo, —CN, —NO 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —OR A , —N(R B ) 2 , —SR A , —C(═O)R A , —C(O)OR A , —C(O)SR A , —C(O)N(R B ) 2 , —C(O)N(R B )N(R B ) 2 , —OC(O)R A , —OC(O)N(R B ) 2 , —NR B C(O)R A , —NR B C(O)N(R B ) 2 , —NR B C(O)N(R B )N(R B ) 2 , —NR B C(O)OR A , —SC(O)R A , —C(═NR B )R A , —C(═NNR B )R A , —C(═NOR A )R A , —C(═NR B )N(R B ) 2 , —NR B C(═NR B )R B , —C(═S)R A , —C(═S)N(R B ) 2 , —NR B C(═S)R A , —S(O)R A , —OS(O) 2 R A , —SO 2 R A , —NR B SO 2 R A , or —SO 2 N(R B ) 2 ;
each R A is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom;
each R B is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and a nitrogen protecting group, or two R B groups are taken together with their intervening atoms to form an optionally substituted heterocyclic ring;
R 1 and R 2 are optionally taken together to form an optionally substituted carbocyclic, optionally substituted heterocyclic, or optionally substituted aryl ring; or
R 1 and R 6 are optionally taken together to form an optionally substituted carbocyclic, optionally substituted heterocyclic, or optionally substituted aryl ring; or
R 2 and R 8 are optionally taken together to form an optionally substituted carbocyclic, optionally substituted heterocyclic, or optionally substituted aryl ring; or
R 6 and R 7 are optionally taken together to form an optionally substituted carbocyclic, optionally substituted heterocyclic, or optionally substituted aryl ring;
R 3 is hydrogen, C 1-4 alkyl, or C 3-4 cycloalkyl;
R 4 is hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-7 cycloalkyl, optionally substituted 4- to 7-membered heterocyclyl; or optionally substituted C 1-4 alkyl-Cy;
Cy is optionally substituted C 3-7 cycloalkyl, optionally substituted 4- to 7-membered heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
R 5 is hydrogen, halo, —CN, optionally substituted C 1-4 alkyl, or optionally substituted C 3-4 cycloalkyl;
R x is optionally substituted C 1-4 alkyl or optionally substituted C 3-4 cycloalkyl;
provided that R 2 is not —CF 3 or —CHF 2 ,
provided that R 6 is not —CF 3 or —CHF 2 ;
provided that R 1 is not R y , wherein R y is —NR B C(O)R A , —NR B SO 2 R A , or —(CR z R z ) n C(O)N(R B ) 2 ; wherein each R z is independently hydrogen or fluoro; and n is 0, 1, 2, 3, or 4;
wherein, and unless otherwise specified,
heterocyclyl or heterocyclic refers to a radical of a 3-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur;
carbocyclyl or carbocyclic refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms and zero heteroatoms in the non-aromatic ring system;
aryl refers to a radical of a monocyclic or polycyclic aromatic ring system having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system; and
heteroaryl refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur.
152 . The method of claim 151 , wherein the RMT is PRMT1, PRMT6, PRMT3, PRMT8, or CARM1.
153 .- 156 . (canceled)
157 . A method of modulating gene expression comprising contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof:
wherein:
X is N, Z is NR 4 , and Y is CR 5 ; or
X is NR 4 , Z is N, and Y is CR 5 ; or
X is CR 5 , Z is NR 4 , and Y is N; or
X is CR 5 , Z is N, and Y is NR 4 ;
R 1 , R 2 , R 6 , R 7 , and R 8 are independently selected from the group consisting of hydrogen, halo, —CN, —NO 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —OR A , —N(R B ) 2 , —SR A , —C(═O)R A , —C(O)OR A , —C(O)SR A , —C(O)N(R B ) 2 , —C(O)N(R B )N(R B ) 2 , —OC(O)R A , —OC(O)N(R B ) 2 , —NR B C(O)R A , —NR B C(O)N(R B ) 2 , —NR B C(O)N(R B )N(R B ) 2 , —NR B C(O)OR A , —SC(O)R A , —C(═NR B )R A , —C(═NNR B )R A , —C(═NOR A )R A , —C(═NR B )N(R B ) 2 , —NR B C(═NR B )R B , —C(═S)R A , —C(═S)N(R B ) 2 , —NR B C(═S)R A , —S(O)R A , —OS(O) 2 R A , —SO 2 R A , —NR B SO 2 R A , or —SO 2 N(R B ) 2 ;
each R A is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom;
each R B is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and a nitrogen protecting group, or two R B groups are taken together with their intervening atoms to form an optionally substituted heterocyclic ring;
R 1 and R 2 are optionally taken together to form an optionally substituted carbocyclic, optionally substituted heterocyclic, or optionally substituted aryl ring; or
R 1 and R 6 are optionally taken together to form an optionally substituted carbocyclic, optionally substituted heterocyclic, or optionally substituted aryl ring; or
R 2 and R 8 are optionally taken together to form an optionally substituted carbocyclic, optionally substituted heterocyclic, or optionally substituted aryl ring; or
R 6 and R 7 are optionally taken together to form an optionally substituted carbocyclic, optionally substituted heterocyclic, or optionally substituted aryl ring;
R 3 is hydrogen, C 1-4 alkyl, or C 3-4 cycloalkyl;
R 4 is hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-7 cycloalkyl, optionally substituted 4- to 7-membered heterocyclyl; or optionally substituted C 1-4 alkyl-Cy;
Cy is optionally substituted C 3-7 cycloalkyl, optionally substituted 4- to 7-membered heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
R 5 is hydrogen, halo, —CN, optionally substituted C 1-4 alkyl, or optionally substituted C 3-4 cycloalkyl;
R x is optionally substituted C 1-4 alkyl or optionally substituted C 3-4 cycloalkyl;
provided that R 2 is not —CF 3 or —CHF 2 ,
provided that R 6 is not —CF 3 or —CHF 2 ;
provided that R 1 is not R y , wherein R y is —NR B C(O)R A , —NR B SO 2 R A , or —(CR z R z ) n C(O)N(R B ) 2 ; wherein each R z is independently hydrogen or fluoro; and n is 0, 1, 2, 3, or 4;
wherein, and unless otherwise specified,
heterocyclyl or heterocyclic refers to a radical of a 3-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur;
carbocyclyl or carbocyclic refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms and zero heteroatoms in the non-aromatic ring system;
aryl refers to a radical of a monocyclic or polycyclic aromatic ring system having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system; and
heteroaryl refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur.
158 . A method of modulating transcription comprising contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof:
wherein:
X is N, Z is NR 4 , and Y is CR 5 ; or
X is NR 4 , Z is N, and Y is CR 5 ; or
X is CR 5 , Z is NR 4 , and Y is N; or
X is CR 5 , Z is N, and Y is NR 4 ;
R 1 , R 2 , R 6 , R 7 , and R 8 are independently selected from the group consisting of hydrogen, halo, —CN, —NO 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —OR A , —N(R B ) 2 , —SR A , —C(═O)R A , —C(O)OR A , —C(O)SR A , —C(O)N(R B ) 2 , —C(O)N(R B )N(R B ) 2 , —OC(O)R A , —OC(O)N(R B ) 2 , —NR B C(O)R A , —NR B C(O)N(R B ) 2 , —NR B C(O)N(R B )N(R B ) 2 , —NR B C(O)OR A , —SC(O)R A , —C(═NR B )R A , —C(═NNR B )R A , —C(═NOR A )R A , —C(═NR B )N(R B ) 2 , —NR B C(═NR B )R B , —C(═S)R A , —C(═S)N(R B ) 2 , —NR B C(═S)R A , —S(O)R A , —OS(O) 2 R A , —SO 2 R A , —NR B SO 2 R A , or —SO 2 N(R B ) 2 ;
each R A is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom;
each R B is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and a nitrogen protecting group, or two R B groups are taken together with their intervening atoms to form an optionally substituted heterocyclic ring;
R 1 and R 2 are optionally taken together to form an optionally substituted carbocyclic, optionally substituted heterocyclic, or optionally substituted aryl ring; or
R 1 and R 6 are optionally taken together to form an optionally substituted carbocyclic, optionally substituted heterocyclic, or optionally substituted aryl ring; or
R 2 and R 8 are optionally taken together to form an optionally substituted carbocyclic, optionally substituted heterocyclic, or optionally substituted aryl ring; or
R 6 and R 7 are optionally taken together to form an optionally substituted carbocyclic, optionally substituted heterocyclic, or optionally substituted aryl ring;
R 3 is hydrogen, C 1-4 alkyl, or C 3-4 cycloalkyl;
R 4 is hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-7 cycloalkyl, optionally substituted 4- to 7-membered heterocyclyl; or optionally substituted C 1-4 alkyl-Cy;
Cy is optionally substituted C 3-7 cycloalkyl, optionally substituted 4- to 7-membered heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
R 5 is hydrogen, halo, —CN, optionally substituted C 1-4 alkyl, or optionally substituted C 3-4 cycloalkyl;
R x is optionally substituted C 1-4 alkyl or optionally substituted C 3-4 cycloalkyl;
provided that R 2 is not —CF 3 or —CHF 2 ,
provided that R 6 is not —CF 3 or —CHF 2 ;
provided that R 1 is not R y , wherein R y is —NR B C(O)R A , —NR B SO 2 R A , or —(CR z R z ) n C(O)N(R B ) 2 ; wherein each R z is independently hydrogen or fluoro; and n is 0, 1, 2, 3, or 4;
wherein, and unless otherwise specified,
heterocyclyl or heterocyclic refers to a radical of a 3-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur;
carbocyclyl or carbocyclic refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms and zero heteroatoms in the non-aromatic ring system;
aryl refers to a radical of a monocyclic or polycyclic aromatic ring system having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system; and
heteroaryl refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur.
159 . The method of claim 151 , wherein the cell is in vitro.
160 . The method of claim 151 , wherein the cell is in a subject.
161 . A method of treating an RMT-mediated disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof:
wherein:
X is N, Z is NR 4 , and Y is CR 5 ; or
X is NR 4 , Z is N, and Y is CR 5 ; or
X is CR 5 , Z is NR 4 , and Y is N; or
X is CR 5 , Z is N, and Y is NR 4 ;
R 1 , R 2 , R 6 , R 7 , and R 8 are independently selected from the group consisting of hydrogen, halo, —CN, —NO 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —OR A , —N(R B ) 2 , —SR A , —C(═O)R A , —C(O)OR A , —C(O)SR A , —C(O)N(R B ) 2 , —C(O)N(R B )N(R B ) 2 , —OC(O)R A , —OC(O)N(R B ) 2 , —NR B C(O)R A , —NR B C(O)N(R B ) 2 , —NR B C(O)N(R B )N(R B ) 2 , —NR B C(O)OR A , —SC(O)R A , —C(═NR B )R A , —C(═NNR B )R A , —C(═NOR A )R A , —C(═NR B )N(R B ) 2 , —NR B C(═NR B )R B , —C(═S)R A , —C(═S)N(R B ) 2 , —NR B C(═S)R A , —S(O)R A , —OS(O) 2 R A , —SO 2 R A , —NR B SO 2 R A , or —SO 2 N(R B ) 2 ;
each R A is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom;
each R B is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and a nitrogen protecting group, or two R B groups are taken together with their intervening atoms to form an optionally substituted heterocyclic ring;
R 1 and R 2 are optionally taken together to form an optionally substituted carbocyclic, optionally substituted heterocyclic, or optionally substituted aryl ring; or
R 1 and R 6 are optionally taken together to form an optionally substituted carbocyclic, optionally substituted heterocyclic, or optionally substituted aryl ring; or
R 2 and R 8 are optionally taken together to form an optionally substituted carbocyclic, optionally substituted heterocyclic, or optionally substituted aryl ring; or
R 6 and R 7 are optionally taken together to form an optionally substituted carbocyclic, optionally substituted heterocyclic, or optionally substituted aryl ring;
R 3 is hydrogen, C 1-4 alkyl, or C 3-4 cycloalkyl;
R 4 is hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-7 cycloalkyl, optionally substituted 4- to 7-membered heterocyclyl; or optionally substituted C 1-4 alkyl-Cy;
Cy is optionally substituted C 3-7 cycloalkyl, optionally substituted 4- to 7-membered heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
R 5 is hydrogen, halo, —CN, optionally substituted C 1-4 alkyl, or optionally substituted C 3-4 cycloalkyl;
R x is optionally substituted C 1-4 alkyl or optionally substituted C 3-4 cycloalkyl;
provided that R 2 is not —CF 3 or —CHF 2 ,
provided that R 6 is not —CF 3 or —CHF 2 ;
provided that R 1 is not R y , wherein R y is —NR B C(O)R A , —NR B SO 2 R A , or —(CR z R z ) n C(O)N(R B ) 2 ; wherein each R z is independently hydrogen or fluoro; and n is 0, 1, 2, 3, or 4;
wherein, and unless otherwise specified,
heterocyclyl or heterocyclic refers to a radical of a 3-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur;
carbocyclyl or carbocyclic refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms and zero heteroatoms in the non-aromatic ring system;
aryl refers to a radical of a monocyclic or polycyclic aromatic ring system having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system; and
heteroaryl refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur.
162 . The method of claim 161 , wherein the RMT-mediated disorder is a PRMT1-mediated disorder, a PRMT6-mediated disorder, a PRMT3-mediated disorder, a PRMT8-mediated disorder, or a CARM1-mediated disorder.
163 .- 166 . (canceled)
167 . The method of claim 161 , wherein the disorder is a proliferative disorder, a neurological disorder, amyotrophic lateral sclerosis, a muscular dystrophy, an autoimmune disorder, or a metabolic disorder.
168 . The method of claim 167 , wherein the disorder is cancer.
169 .- 174 . (canceled)
175 . The method of claim 161 , wherein the compound is of Formula (II):
or a pharmaceutically acceptable salt thereof.
176 . The method of claim 161 , wherein the compound is of Formula (I-a):
or a pharmaceutically acceptable salt thereof, wherein R 1 is not hydrogen.
177 . The method of claim 161 , wherein the compound is of Formula (I-b):
or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are not hydrogen.
178 . The method of claim 161 , wherein R 1 is not hydrogen.
179 . The method of claim 161 , wherein R 1 is —OR A .
180 . The method of claim 161 , wherein R 1 is —OR A , wherein R A is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted carbocyclic.
181 . The method of claim 161 , wherein R 1 is —OR A , wherein R A is optionally substituted C 1-6 alkyl.
182 . The method of claim 161 , wherein R 1 is —O-propyl, —O-isopropyl, —O-isobutyl, or —O-isoamyl.
183 . The method of claim 161 , wherein R 1 is —OR A , wherein R A is substituted C 1-6 alkyl.
184 . The method of claim 161 , wherein R 1 is —O—C 1-6 alkyl-O—C 1-6 alkyl or —O—C 1-6 alkyl-carbocyclyl.
185 . The method of claim 161 , wherein R 6 is hydrogen, —OR A .
186 . The method of claim 161 , wherein R 6 is —OR A .
187 . The method of claim 161 , wherein R 6 is hydrogen, —OR A , halo, —CN, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted carbocyclic.
188 . The method of claim 161 , wherein R 6 is halo.
189 . The method of claim 161 , wherein R 6 is fluoro or chloro.
190 . The method of claim 161 , wherein R 2 is hydrogen.
191 . The method of claim 161 , wherein R 7 and R 8 are hydrogen.
192 . The method of claim 161 , wherein R 3 is C 1-4 alkyl.
193 . The method of claim 161 , wherein R 3 is methyl.
194 . The method of claim 161 , wherein R 3 is hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl, or cyclobutyl.
195 . The method of claim 161 , wherein R 4 is hydrogen or optionally substituted C 1-6 alkyl.
195 . The method of claim 161 , wherein R 5 is hydrogen or optionally substituted C 1-4 alkyl.
196 . The method of claim 161 , wherein R x is methyl, ethyl, propyl, butyl, isopropyl, hydroxyethyl methoxyethyl, cyclopropyl, or cyclobutyl.
197 . The method of claim 161 , wherein R x is methyl.
198 . The method of claim 161 , wherein the compound is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
199 . The method of claim 161 , wherein the compound is of Formula (II-a) or (II-b):
or a pharmaceutically acceptable salt thereof;
wherein:
R 1 is optionally substituted alkoxyalkyl, —OR A , —N(R B ) 2 , —OC(O)R A , —OC(O)N(R B ) 2 , —NR B C(O)R A , —NR B C(O)N(R B ) 2 , —NR B C(O)N(R B )N(R B ) 2 , or —NR B C(O)OR A ; and
R 2 is halogen.
200 . The method of claim 161 , wherein R 1 is —OR A , —N(R B ) 2 , or optionally substituted alkoxyalkyl.
201 . The method of claim 161 , wherein the compound is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.