NZ753264B2 - Magl inhibitors - Google Patents
Magl inhibitors Download PDFInfo
- Publication number
- NZ753264B2 NZ753264B2 NZ753264A NZ75326417A NZ753264B2 NZ 753264 B2 NZ753264 B2 NZ 753264B2 NZ 753264 A NZ753264 A NZ 753264A NZ 75326417 A NZ75326417 A NZ 75326417A NZ 753264 B2 NZ753264 B2 NZ 753264B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- compound
- formula
- pharmaceutically acceptable
- solvate
- acceptable salt
- Prior art date
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- 231100000486 side effect Toxicity 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000001187 sodium carbonate Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 235000011044 succinic acid Nutrition 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 230000004083 survival Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- WZWYJBNHTWCXIM-UHFFFAOYSA-N tenoxicam Chemical compound O=C1C=2SC=CC=2S(=O)(=O)N(C)C1=C(O)NC1=CC=CC=N1 WZWYJBNHTWCXIM-UHFFFAOYSA-N 0.000 description 1
- 229960002871 tenoxicam Drugs 0.000 description 1
- IELBUWARMJVXDU-UHFFFAOYSA-N tert-butyl 2,4-dibromobutanoate Chemical compound CC(C)(C)OC(=O)C(Br)CCBr IELBUWARMJVXDU-UHFFFAOYSA-N 0.000 description 1
- QYOBADYUAJGOKM-UHFFFAOYSA-N tert-butyl 4-(benzylamino)butanoate Chemical compound CC(C)(C)OC(=O)CCCNCC1=CC=CC=C1 QYOBADYUAJGOKM-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran THF Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000005985 thienyl[1,3]dithianyl group Chemical group 0.000 description 1
- 229960001017 tolmetin Drugs 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M toluenesulfonate group Chemical group C=1(C(=CC=CC1)S(=O)(=O)[O-])C LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- 230000000699 topical Effects 0.000 description 1
- 229940026752 topical Sulfonamides Drugs 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N trans-L-hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 239000011778 trisodium citrate Substances 0.000 description 1
- 125000005455 trithianyl group Chemical group 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000005019 zein Substances 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 235000016804 zinc Nutrition 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- 235000014692 zinc oxide Nutrition 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/195—Radicals derived from nitrogen analogues of carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D295/205—Radicals derived from carbonic acid
Abstract
Provided herein are piperazine carbamates of Formula (I) and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful as modulators of MAGL. Furthermore, the subject compounds and compositions are useful for the treatment of pain.
Description
MAGL INHIBITORS
CROSS-REFERENCE
This application claims benefit of U.S. Provisional Application No. 62/423,099, filed on
November 16, 2016, which is herein incorporated by reference in its entirety.
BACKGROUND
Monoacylglycerol lipase (MAGL) is an enzyme responsible for hydrolyzing
endocannabinoids such as 2-AG (2-arachidonoylglycerol), an arachidonate based lipid, in the
nervous system.
BRIEF SUMMARY OF THE INVENTION
This disclosure provides, for example, compounds and compositions which are modulators
of MAGL, and their use as medicinal agents, processes for their preparation, and pharmaceutical
compositions that include disclosed compounds as at least one active ingredient. The disclosure also
provides for the use of disclosed compounds as medicaments and/or in the manufacture of
medicaments for the inhibition of MAGL activity in warm-blooded animals such as humans.
In one aspect is a compound of Formula (I):
Formula (I);
wherein:
1 14 3 4 4 4 5 4’ 6 7 8
R is -R , -OR , -SR , -S(O) R , -N(R )(R ), -NH(R ), or -C C-(CR R )-R ;
each R is independently selected from C1-6alkyl, halogen, -CN, C1-6haloalkyl, -C1-
17 18 19
6alkyl(heterocycloalkyl), -OR , and -C(O)NR R ;
3 6 7 8 6 7 6 7 8 6 7 8
R is -(CR R ) -R , -(CR R ) -Y-(CR R ) -R , or -(CR R ) -C cycloalkyl-R ;
m p q t 3-6
4 6 7 8’ 6 7 6 7 6 7 8
R is -(CR R )m-R , -(CR R )v-C(O)OH, or -(CR R )p-Y-(CR R )q-R ;
4’ 6 7 8’ 6 7 6 7 8
R is -(CR R )m-R , -(CR R )p-Y-(CR R )q-R , -C4-6alkyl-C(O)OH, -C3-6cycloalkyl-C(O)OH,
or -C alkyl-C cycloalkyl-C(O)OH;
1-6 3-6
Y is -O- or -N(R )-;
R is C1-6alkyl or -CH2-phenyl optionally substituted with one, two, or three groups
independently selected from halogen, C alkyl, C haloalkyl, and C alkoxy;
1-6 1-6 1-6
6 7 6 7
each R and R is each independently selected from H, F, and C1-6alkyl; or R and R , together
with the carbon to which they are attached, form a C cycloalkyl ring;
8 9 10 12 13 11
R is -C(O)OR , -C(O)R , or -C(O)O-(CR R )-OC(O)R ;
8’ 9’ 10’ 12 13 11
R is -C(O)OR , -C(O)R , or -C(O)O-(CR R )-OC(O)R ;
R is H or C alkyl;
R is C alkyl;
21
R is C1-6alkyl or -NHSO2R ;
’ 21
R is C alkyl or -NHSO R ;
2-6 2
R is C alkyl or C alkoxy;
1-6 1-6
12 13
R and R is each independently H or C1-6alkyl;
14 15 16 8 6 7 6 7 8
R is -(CR R )m-R or -(CR R )p-Y-(CR R )q-R ;
16
each R and R is each independently selected from H, F, and C alkyl;
each R is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl;
18 19
each R and R is each independently selected from H, C1-6alkyl, C3-6cycloalkyl, aryl, and
18 19
heteroaryl; or R and R , together with the nitrogen to which they are attached, form a
heterocycloalkyl ring optionally substituted with one, two, or three R ;
each R is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, oxo, -CN, and C3-
cycloalkyl;
R is C alkyl or C cycloalkyl;
1-6 3-6
22 23
R is H, C1-6alkyl, or -SO2R ;
R is C1-6alkyl;
m is 1, 2, 3 or 4;
n is 0, 1, 2, 3, or 4;
p is 2, 3, or 4;
q is 1, 2, or 3;
t is 0, 1, or 2; and
v is 3 or 4;
or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt
or solvate thereof, wherein R is -OR . In some embodiments is a compound of Formula (I), or a
3 6 7 8
pharmaceutically acceptable salt or solvate thereof, wherein R is -(CR R )m-R . In some
embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,
wherein m is 1, 2, or 3. In some embodiments is a compound of Formula (I), or a pharmaceutically
acceptable salt or solvate thereof, wherein m is 1. In some embodiments is a compound of Formula
(I), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 2. In some embodiments is
a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 3.
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate
3 6 7 6 7 8
thereof, wherein R is -(CR R )p-Y-(CR R )q-R . In some embodiments is a compound of Formula
(I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -O-. In some embodiments
is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -
N(R )-. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt
22 23
or solvate thereof, wherein R is -SO R . In some embodiments is a compound of Formula (I), or a
pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some embodiments is a
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2. In
some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate
1 6 7 8
thereof, wherein R is -C C-(CR R )-R . In some embodiments is a compound of Formula (I), or
3 6 7 8
a pharmaceutically acceptable salt or solvate thereof, wherein R is -(CR R )t-C3-6cycloalkyl-R . In
some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate
thereof, wherein t is 1. In some embodiments is a compound of Formula (I), or a pharmaceutically
acceptable salt or solvate thereof, wherein t is 0. In some embodiments is a compound of Formula
(I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R and R is each
independently selected from H and C alkyl. In some embodiments is a compound of Formula (I),
or a pharmaceutically acceptable salt or solvate thereof, wherein each R and R is H. In some
embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,
wherein R and R , together with the carbon to which they are attached, form a C3-6cycloalkyl ring.
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate
thereof, wherein R is -C(O)OR . In some embodiments is a compound of Formula (I), or a
pharmaceutically acceptable salt or solvate thereof, wherein R is H. In some embodiments is a
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is C
alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or
8 10
solvate thereof, wherein R is -C(O)R . In some embodiments is a compound of Formula (I), or a
21
pharmaceutically acceptable salt or solvate thereof, wherein R is -NHSO R . In some
embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,
8 12 13 11
wherein R is -C(O)O-(CR R )-OC(O)R . In some embodiments is a compound of Formula (I), or
a pharmaceutically acceptable salt or solvate thereof, wherein R is C1-6alkyl. In some embodiments
is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is
C1-6alkoxy. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable
1 4 5
salt or solvate thereof, wherein R is -N(R )(R ). In some embodiments is a compound of Formula
(I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -CH3. In some
embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,
wherein R is -CH2-phenyl optionally substituted with one, two, or three groups independently
selected from halogen, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy. In some embodiments is a
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
SR . In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or
solvate thereof, wherein R is -S(O)2R . In some embodiments is a compound of Formula (I), or a
4 6 7
pharmaceutically acceptable salt or solvate thereof, wherein R is -(CR R ) -C(O)OH. In some
embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,
wherein v is 3. In some embodiments is a compound of Formula (I), or a pharmaceutically
acceptable salt or solvate thereof, wherein v is 4. In some embodiments is a compound of Formula
4 6 7 8’
(I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -(CR R ) -R . In some
embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,
wherein m is 1, 2, or 3. In some embodiments is a compound of Formula (I), or a pharmaceutically
acceptable salt or solvate thereof, wherein m is 1. In some embodiments is a compound of Formula
(I), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 2. In some embodiments is
a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 3.
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate
8’ 9’
thereof, wherein R is -C(O)OR . In some embodiments is a compound of Formula (I), or a
8’ 10’
pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)R . In some embodiments
is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R
is -NHSO R . In some embodiments is a compound of Formula (I), or a pharmaceutically
8’ 12 13 11
acceptable salt or solvate thereof, wherein R is -C(O)O-(CR R )-OC(O)R . In some
embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,
wherein R is C alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically
acceptable salt or solvate thereof, wherein R is C alkoxy. In some embodiments is a compound of
4 6 7
Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R is -(CR R )p-
6 7 8
Y-(CR R ) -R . In some embodiments is a compound of Formula (I), or a pharmaceutically
acceptable salt or solvate thereof, wherein Y is -O-. In some embodiments is a compound of
Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -N(R )-. In some
embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,
22 23
wherein R is -SO R . In some embodiments is a compound of Formula (I), or a pharmaceutically
acceptable salt or solvate thereof, wherein q is 1. In some embodiments is a compound of Formula
(I), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2. In some embodiments is
a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
C(O)OR . In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable
salt or solvate thereof, wherein R is H. In some embodiments is a compound of Formula (I), or a
pharmaceutically acceptable salt or solvate thereof, wherein R is C1-6alkyl. In some embodiments is
a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
C(O)R . In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt
21
or solvate thereof, wherein R is -NHSO2R . In some embodiments is a compound of Formula (I),
8 12 13 11
or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)O-(CR R )-OC(O)R .
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate
thereof, wherein R is C1-6alkyl. In some embodiments is a compound of Formula (I), or a
pharmaceutically acceptable salt or solvate thereof, wherein R is C1-6alkoxy. In some embodiments
is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is
-NH(R ). In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt
4’ 6 7 8’
or solvate thereof, wherein R is -(CR R )m-R . In some embodiments is a compound of Formula
(I), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1, 2, or 3. In some
embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,
wherein m is 1. In some embodiments is a compound of Formula (I), or a pharmaceutically
acceptable salt or solvate thereof, wherein m is 2. In some embodiments is a compound of Formula
(I), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 3. In some embodiments is
a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
C(O)OR . In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable
8’ 10’
salt or solvate thereof, wherein R is -C(O)R . In some embodiments is a compound of Formula
’ 21
(I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -NHSO2R . In some
embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,
8’ 12 13 11
wherein R is -C(O)O-(CR R )-OC(O)R . In some embodiments is a compound of Formula (I),
or a pharmaceutically acceptable salt or solvate thereof, wherein R is C alkyl. In some
embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,
wherein R is C alkoxy. In some embodiments is a compound of Formula (I), or a
4’ 6 7 6 7 8
pharmaceutically acceptable salt or solvate thereof, wherein each R is -(CR R ) -Y-(CR R ) -R .
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate
thereof, wherein Y is -O-. In some embodiments is a compound of Formula (I), or a
pharmaceutically acceptable salt or solvate thereof, wherein Y is -N(R )-. In some embodiments is
a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
SO2R . In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt
or solvate thereof, wherein q is 1. In some embodiments is a compound of Formula (I), or a
pharmaceutically acceptable salt or solvate thereof, wherein p is 2. In some embodiments is a
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
C(O)OR . In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable
salt or solvate thereof, wherein R is H. In some embodiments is a compound of Formula (I), or a
pharmaceutically acceptable salt or solvate thereof, wherein R is C alkyl. In some embodiments is
a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
C(O)R . In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt
21
or solvate thereof, wherein R is -NHSO R . In some embodiments is a compound of Formula (I),
8 12 13 11
or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)O-(CR R )-OC(O)R .
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate
thereof, wherein R is C alkyl. In some embodiments is a compound of Formula (I), or a
pharmaceutically acceptable salt or solvate thereof, wherein R is C1-6alkoxy. In some embodiments
is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each
R and R is each independently selected from H and C alkyl. In some embodiments is a
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R
and R is H. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable
salt or solvate thereof, wherein R and R , together with the carbon to which they are attached, form
a C cycloalkyl ring. In some embodiments is a compound of Formula (I), or a pharmaceutically
acceptable salt or solvate thereof, wherein R is -C4-6alkyl-C(O)OH. In some embodiments is a
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
C cycloalkyl-C(O)OH. In some embodiments is a compound of Formula (I), or a pharmaceutically
acceptable salt or solvate thereof, wherein R is -C1-6alkyl-C3-6cycloalkyl-C(O)OH. In some
embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,
1 14
wherein R is -R . In some embodiments is a compound of Formula (I), or a pharmaceutically
14 15 16 8
acceptable salt or solvate thereof, wherein R is -(CR R ) -R . In some embodiments is a
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
16 8
(CR R ) -R and m is 1. In some embodiments is a compound of Formula (I), or a
14 15 16 8
pharmaceutically acceptable salt or solvate thereof, wherein R is -(CR R ) -R and m is 2. In
some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate
14 15 16 8
thereof, wherein R is -(CR R )m-R and m is 3. In some embodiments is a compound of Formula
14 15 16 8
(I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -(CR R ) -R and m is
4. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or
14 15 16 8 8 9
solvate thereof, wherein R is -(CR R )m-R and R is -C(O)OR . In some embodiments is a
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
16 8 8 9 9
(CR R ) -R , R is -C(O)OR , and R is H. In some embodiments is a compound of Formula (I),
14 15 16 8 8
or a pharmaceutically acceptable salt or solvate thereof, wherein R is -(CR R )m-R , R is -
C(O)OR , and R is C1-6alkyl. In some embodiments is a compound of Formula (I), or a
pharmaceutically acceptable salt or solvate thereof, wherein each R is independently selected from
C alkyl, halogen, -CN, and C haloalkyl. In some embodiments is a compound of Formula (I), or a
1-6 1-6
pharmaceutically acceptable salt or solvate thereof, wherein each R is independently selected from
C alkyl, halogen, and C haloalkyl. In some embodiments is a compound of Formula (I), or a
1-6 1-6
pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R
is -Cl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or
solvate thereof, wherein each R is -CF .
In another aspect is a compound selected from:
, , ,
, , ,
, , ,
, , ,
, , ,
and ;
or a pharmaceutically acceptable salt or solvate thereof.
In another aspect is a compound selected from:
O CF
NO CF
O CF
O CF
3 N O CF
O CF
N O CF
NO CF
ONH OO S
OO S
, , , ,
O CF
N O CF
, , ,
, , ,
, , ,
, , ,
, , ,
, , ,
, , ,
O CF
N O CF
OO S
, , ,
, , , and
or a pharmaceutically acceptable salt or solvate thereof.
In another embodiment is a pharmaceutical composition comprising a compound of
Formula (I) described herein, or a pharmaceutically acceptable salt or solvate thereof, and at least
one pharmaceutically acceptable excipient.
In another embodiment is a method of treating pain in a patient in need thereof comprising
administering to the patient a therapeutically effective amount of a compound of Formula (I)
described herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the
pain is neuropathic pain. In some embodiments, the pain is inflammatory pain.
In another embodiment is a method of treating a disease or disorder in a patient in need
thereof comprising administering to the patient a therapeutically effective amount of a compound of
Formula (I) described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein the
disease or disorder is selected from the group consisting of epilepsy/seizure disorder, multiple
sclerosis, neuromyelitis optica (NMO), Tourette syndrome, Alzheimer’s disease, and abdominal pain
associated with irritable bowel syndrome. In some embodiments, the disease or disorder is
epilepsy/seizure disorder. In some embodiments, the disease or disorder is multiple sclerosis. In
some embodiments, the disease or disorder is neuromyelitis optica (NMO). In some embodiments,
the disease or disorder is Tourette syndrome. In some embodiments, the disease or disorder is
Alzheimer’s disease. In some embodiments, the disease or disorder is abdominal pain associated
with irritable bowel syndrome.
In another embodiment is a method of treating attention deficit and hyperactivity disorder
(ADHD) in a patient in need thereof comprising administering to the patient a therapeutically
effective amount of a compound of Formula (I) described herein, or a pharmaceutically acceptable
salt or solvate thereof.
DETAILED DESCRIPTION OF THE INVENTION
This disclosure is directed, at least in part, to compounds capable of inhibiting MAGL.
As used herein and in the appended claims, the singular forms "a," "and," and "the" include
plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an
agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or
more cells (or to a plurality of cells) and equivalents thereof. When ranges are used herein for
physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all
combinations and subcombinations of ranges and specific embodiments therein are intended to be
included. The term "about" when referring to a number or a numerical range means that the number
or numerical range referred to is an approximation within experimental variability (or within
statistical experimental error), and thus the number or numerical range varies between 1% and 15%
of the stated number or numerical range. The term "comprising" (and related terms such as
"comprise" or "comprises" or "having" or "including") is not intended to exclude that which in other
certain embodiments, for example, an embodiment of any composition of matter, composition,
method, or process, or the like, described herein, may "consist of" or "consist essentially of" the
described features.
Definitions
As used in the specification and appended claims, unless specified to the contrary, the
following terms have the meaning indicated below.
As used herein, C -C includes C -C , C -C . . . C -C . C -C refers to the number of
1 x 1 2 1 3 1 x 1 x
carbon atoms that make up the moiety to which it designates (excluding optional substituents).
"Amino" refers to the -NH radical.
"Cyano" refers to the -CN radical.
"Nitro" refers to the -NO2 radical.
"Oxa" refers to the -O- radical.
"Oxo" refers to the =O radical.
"Thioxo" refers to the =S radical.
"Imino" refers to the =N-H radical.
"Oximo" refers to the =N-OH radical.
"Alkyl" or "alkylene" refers to a straight or branched hydrocarbon chain radical consisting
solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon
atoms (e.g., C1-C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms
(e.g., C -C alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C -
1 13 1
C alkyl). In other embodiments, an alkyl comprises one to six carbon atoms (e.g., C -C alkyl). In
8 1 6
other embodiments, an alkyl comprises one to five carbon atoms (e.g., C1-C5 alkyl). In other
embodiments, an alkyl comprises one to four carbon atoms (e.g., C -C alkyl). In other embodiments,
an alkyl comprises one to three carbon atoms (e.g., C -C alkyl). In other embodiments, an alkyl
comprises one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, an alkyl comprises one
carbon atom (e.g., C1 alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms
(e.g., C -C alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C -C
15 5 8
alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C2-C5 alkyl). In
other embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-C5 alkyl). In other
embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl
(iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl),
1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is attached to the rest of the molecule
by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is
optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo,
a a a a a a a
imino, oximo, trimethylsilanyl, -OR , -SR , -OC(O)R , -N(R )2, -C(O)R , -C(O)OR , -C(O)N(R )2, -
a f a f a f a f a
N(R )C(O)OR , -OC(O)-NR R , -N(R )C(O)R , -N(R )S(O)tR (where t is 1 or 2), -S(O)tOR (where t
f a a
is 1 or 2), -S(O) R (where t is 1 or 2) and -S(O) N(R ) (where t is 1 or 2) where each R is
t t 2
independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or
heteroarylalkyl, and each R is independently alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl,
heterocycloalkyl, heteroaryl or heteroarylalkyl.
"Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where
alkyl is an alkyl chain as defined above.
"Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely
of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from
two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon
atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is
attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), propenyl
(i.e., allyl), butenyl, pentenyl, penta-1,4-dienyl, and the like. Unless stated otherwise
specifically in the specification, an alkenyl group is optionally substituted by one or more of the
following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR , -
a f a a a a a f a f a
SR , -OC(O)-R , -N(R ) , -C(O)R , -C(O)OR , -C(O)N(R ) , -N(R )C(O)OR , -OC(O)- NR R , -N(R
f a f a f
)C(O)R , -N(R )S(O)tR (where t is 1 or 2), -S(O)tOR (where t is 1 or 2), -S(O)tR (where t is 1 or 2)
and -S(O)tN(R )2 (where t is 1 or 2) where each R is independently hydrogen, alkyl, fluoroalkyl,
cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each R is independently
alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.
"Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely
of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to
twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In
other embodiments, an alkynyl has two to four carbon atoms. The alkynyl is attached to the rest of
the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the
like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally
substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino,
a a a a a a a
oximo, trimethylsilanyl, -OR , -SR , -OC(O)R , -N(R )2, -C(O)R , -C(O)OR , -C(O)N(R )2, -
a f a f a f a f a
N(R )C(O)OR , -OC(O)-NR R , -N(R )C(O)R , -N(R )S(O) R (where t is 1 or 2), -S(O) OR (where t
f a a
is 1 or 2), -S(O) R (where t is 1 or 2) and -S(O) N(R ) (where t is 1 or 2) where each R is
t t 2
independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or
heteroarylalkyl, and each R is independently alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl,
heterocycloalkyl, heteroaryl or heteroarylalkyl.
"Aryl" refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon
ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or
multicyclic hydrocarbon ring system contains only hydrogen and carbon from six to eighteen carbon
atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic,
delocalized (4n+2) –electron system in accordance with the Hückel theory. The ring system from
which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene,
indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the
term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals optionally
substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo,
fluoroalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl,
b a b a b a b a b a b
heteroarylalkyl, -R -OR , -R -OC(O)-R , -R -OC(O)-OR , -R -OC(O)-N(R ) , -R -N(R ) , -R -C(O)
a b a b a b c a b a a b a a
R , -R -C(O)OR , -R -C(O)N(R )2, -R -O-R -C(O)N(R )2, -R -N(R )C(O)OR , -R -N(R )C(O)R , -R
b a a b a b a
-N(R )S(O)tR (where t is 1 or 2), -R -S(O)tOR (where t is 1 or 2), -R -S(O)tR (where t is 1 or 2)
b a a
and -R -S(O) N(R ) (where t is 1 or 2), where each R is independently hydrogen, alkyl, fluoroalkyl,
cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl,
heterocycloalkyl, heteroaryl or heteroarylalkyl, each R is independently a direct bond or a straight or
branched alkylene or alkenylene chain, and R is a straight or branched alkylene or alkenylene chain.
"Aryloxy" refers to a radical bonded through an oxygen atom of the formula –O-aryl, where
aryl is as defined above.
"Aralkyl" refers to a radical of the formula -R -aryl where R is an alkylene chain as
defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl
radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl
radical is optionally substituted as described above for an aryl group.
"Aralkyloxy" refers to a radical bonded through an oxygen atom of the formula –O-aralkyl,
where aralkyl is as defined above.
"Aralkenyl" refers to a radical of the formula –R -aryl where R is an alkenylene chain as
defined above. The aryl part of the aralkenyl radical is optionally substituted as described above for
an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined
above for an alkenylene group.
"Aralkynyl" refers to a radical of the formula -R -aryl, where R is an alkynylene chain as
defined above. The aryl part of the aralkynyl radical is optionally substituted as described above for
an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined
above for an alkynylene chain.
"Cycloalkyl " refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical
consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems,
having from three to fifteen carbon atoms. In certain embodiments, a cycloalkyl comprises three to
ten carbon atoms. In other embodiments, a cycloalkyl comprises five to seven carbon atoms. The
cycloalkyl is attached to the rest of the molecule by a single bond. Cycloalkyls are saturated, (i.e.,
containing single C-C bonds only) or partially unsaturated (i.e., containing one or more double bonds
or triple bonds.) Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In certain embodiments, a cycloalkyl
comprises three to eight carbon atoms (e.g., C3-C8 cycloalkyl). In other embodiments, a cycloalkyl
comprises three to seven carbon atoms (e.g., C -C cycloalkyl). In other embodiments, a cycloalkyl
comprises three to six carbon atoms (e.g., C -C cycloalkyl). In other embodiments, a cycloalkyl
comprises three to five carbon atoms (e.g., C3-C5 cycloalkyl). In other embodiments, a cycloalkyl
comprises three to four carbon atoms (e.g., C3-C4 cycloalkyl). A partially unsaturated cycloalkyl is
also referred to as "cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g.,
cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic cycloalkyl radicals
include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl,
7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the
specification, the term "cycloalkyl" is meant to include cycloalkyl radicals optionally substituted by
one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,
cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl,
b a b a b a b a b a b
heteroarylalkyl, -R -OR , -R -OC(O)-R , -R -OC(O)-OR , -R -OC(O)-N(R ) , -R -N(R ) , -R -C(O)
a b a b a b c a b a a b a a
R , -R -C(O)OR , -R -C(O)N(R ) , -R -O-R -C(O)N(R ) , -R -N(R )C(O)OR , -R -N(R )C(O)R , -R
b a a b a b a
-N(R )S(O)tR (where t is 1 or 2), -R -S(O)tOR (where t is 1 or 2), -R -S(O)tR (where t is 1 or 2)
b a a
and -R -S(O) N(R ) (where t is 1 or 2), where each R is independently hydrogen, alkyl, fluoroalkyl,
cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl,
heterocycloalkyl, heteroaryl or heteroarylalkyl, each R is independently a direct bond or a straight or
branched alkylene or alkenylene chain, and R is a straight or branched alkylene or alkenylene chain.
"Halo" or "halogen" refers to bromo, chloro, fluoro or iodo substituents.
"Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more
halo radicals, as defined above.
"Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more
fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl,
2,2,2-trifluoroethyl, 1-fluoromethylfluoroethyl, and the like. The alkyl part of the fluoroalkyl
radical are optionally substituted as defined above for an alkyl group.
"Haloalkoxy" refers to an alkoxy radical, as defined above, that is substituted by one or
more halo radicals, as defined above.
"Heterocycloalkyl" refers to a stable 3- to 18-membered non-aromatic ring radical that
comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen,
oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl
radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which include fused, spiro, or
bridged ring systems. The heteroatoms in the heterocycloalkyl radical are optionally oxidized. One
or more nitrogen atoms, if present, are optionally quaternized. The heterocycloalkyl radical is
partially or fully saturated. In some embodiments, the heterocycloalkyl is attached to the rest of the
molecule through any atom of the ring(s). Examples of such heterocycloalkyl radicals include, but
are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,
imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl,
2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl,
4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl,
tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and
1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term
"heterocycloalkyl" is meant to include heterocycloalkyl radicals as defined above that are optionally
substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo,
thioxo, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl,
b a b a b a b a b a b
heteroarylalkyl, -R -OR , -R -OC(O)-R , -R -OC(O)-OR , -R -OC(O)-N(R )2, -R -N(R )2, -R -C(O)
a b a b a b c a b a a b a a
R , -R -C(O)OR , -R -C(O)N(R ) , -R -O-R -C(O)N(R ) , -R -N(R )C(O)OR , -R -N(R )C(O)R , -R
b a a b a b a
-N(R )S(O) R (where t is 1 or 2), -R -S(O) OR (where t is 1 or 2), -R -S(O) R (where t is 1 or 2)
t t t
b a a
and -R -S(O)tN(R )2 (where t is 1 or 2), where each R is independently hydrogen, alkyl, fluoroalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each R is
independently a direct bond or a straight or branched alkylene or alkenylene chain, and R is a
straight or branched alkylene or alkenylene chain.
"Heteroaryl" refers to a radical derived from a 5- to 18-membered aromatic ring radical that
comprises one to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen,
oxygen and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic or
tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it
contains a cyclic, delocalized (4n+2) –electron system in accordance with the Hückel theory.
Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is
optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The
heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Unless stated
otherwise specifically in the specification, the term "heteroaryl" is meant to include heteroaryl
radicals as defined above that are optionally substituted by one or more substituents selected from
alkyl, alkenyl, alkynyl, halo, haloalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl,
b a b a b a
cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -R -OR , -R -OC(O)-R , -R -OC(O)-OR , -
b a b a b a b a b a b c a
R -OC(O)-N(R ) , -R -N(R ) , -R -C(O)R , -R -C(O)OR , -R -C(O)N(R ) , -R -O-R -C(O)N(R ) , -
2 2 2 2
b a a b a a b a a b a
R -N(R )C(O)OR , -R -N(R )C(O)R , -R -N(R )S(O)tR (where t is 1 or 2), -R -S(O)tOR (where t is
b a b a a
1 or 2), -R -S(O)tR (where t is 1 or 2) and -R -S(O)tN(R )2 (where t is 1 or 2), where each R is
independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,
heterocycloalkyl, heteroaryl or heteroarylalkyl, each R is independently a direct bond or a straight or
branched alkylene or alkenylene chain, and R is a straight or branched alkylene or alkenylene chain.
"N-heteroaryl" refers to a heteroaryl radical as defined above containing at least one
nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is
through a nitrogen atom in the heteroaryl radical. An N-heteroaryl radical is optionally substituted as
described above for heteroaryl radicals.
"C-heteroaryl" refers to a heteroaryl radical as defined above and where the point of
attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the
heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl
radicals.
"Heteroaryloxy" refers to radical bonded through an oxygen atom of the formula -O-
heteroaryl, where heteroaryl is as defined above.
"Heteroarylalkyl" refers to a radical of the formula –R -heteroaryl, where R is an alkylene
chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is
optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the
heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The
heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a
heteroaryl group.
"Heteroarylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O-
R -heteroaryl, where R is an alkylene chain as defined above. If the heteroaryl is a
nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the
nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as
defined above for an alkylene chain. The heteroaryl part of the heteroarylalkoxy radical is optionally
substituted as defined above for a heteroaryl group.
In some embodiments, the compounds disclosed herein contain one or more asymmetric
centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are
defined, in terms of absolute stereochemistry, as (R)- or (S)-. Unless stated otherwise, it is intended
that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure.
When the compounds described herein contain alkene double bonds, and unless specified otherwise,
it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans.)
Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric
forms are also intended to be included. The term "geometric isomer" refers to E or Z geometric
isomers (e.g., cis or trans) of an alkene double bond. The term "positional isomer" refers to structural
isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.
A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to
another atom of the same molecule is possible. In certain embodiments, the compounds presented
herein exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium
of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including
physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:
O OH
OH O
O OH
NH NH
NH NH N N
N NH
N HN N
"Optional" or "optionally" means that a subsequently described event or circumstance may
or may not occur and that the description includes instances when the event or circumstance occurs
and instances in which it does not. For example, "optionally substituted aryl" means that the aryl
radical are or are not substituted and that the description includes both substituted aryl radicals and
aryl radicals having no substitution.
"Pharmaceutically acceptable salt" includes both acid and base addition salts. A
pharmaceutically acceptable salt of any one of the pyrazole compounds described herein is intended to
encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable
salts of the compounds described herein are pharmaceutically acceptable acid addition salts and
pharmaceutically acceptable base addition salts.
"Pharmaceutically acceptable acid addition salt" refers to those salts which retain the
biological effectiveness and properties of the free bases, which are not biologically or otherwise
undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the
like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic
acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids,
aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid,
propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric
acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,
ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include
sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates,
dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates,
trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates,
fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,
phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates,
methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates,
and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical
Science, 66:1-19 (1997). Acid addition salts of basic compounds are prepared by contacting the free base
forms with a sufficient amount of the desired acid to produce the salt.
"Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological
effectiveness and properties of the free acids, which are not biologically or otherwise undesirable.
These salts are prepared from addition of an inorganic base or an organic base to the free acid. In some
embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines, such as
alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are
not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper,
manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited
to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring
substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine,
trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine,
2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,
caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine,
ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine,
purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al.,
supra.
As used herein, "treatment" or "treating " or "palliating" or "ameliorating" are used
interchangeably herein. These terms refers to an approach for obtaining beneficial or desired results
including but not limited to therapeutic benefit and/or a prophylactic benefit. By "therapeutic
benefit" is meant eradication or amelioration of the underlying disorder being treated. Also, a
therapeutic benefit is achieved with the eradication or amelioration of one or more of the
physiological symptoms associated with the underlying disorder such that an improvement is
observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder.
For prophylactic benefit, the compositions are administered to a patient at risk of developing a
particular disease, or to a patient reporting one or more of the physiological symptoms of a disease,
even though a diagnosis of this disease has not been made.
Compounds
The compounds of Formula (I), (Ia), or (Ib) described herein which are modulators of
MAGL. These compounds, and compositions comprising these compounds, are useful for the
treatment of pain. In some embodiments, the compounds of Formula (I), (Ia), or (Ib) described
herein are useful for treating epilepsy/seizure disorder, multiple sclerosis, neuromyelitis optica
(NMO), Tourette syndrome, Alzheimer’s disease, or abdominal pain associated with irritable bowel
syndrome.
In some embodiments is a compound of Formula (I):
Formula (I);
wherein:
1 14 3 4 4 4 5 4’ 6 7 8
R is -R , -OR , -SR , -S(O) R , -N(R )(R ), -NH(R ), or -C C-(CR R )-R ;
each R is independently selected from C1-6alkyl, halogen, -CN, C1-6haloalkyl, -C1-
17 18 19
6alkyl(heterocycloalkyl), -OR , and -C(O)NR R ;
3 6 7 8 6 7 6 7 8 6 7 8
R is -(CR R ) -R , -(CR R ) -Y-(CR R ) -R , or -(CR R ) -C cycloalkyl-R ;
m p q t 3-6
4 6 7 8’ 6 7 6 7 6 7 8
R is -(CR R )m-R , -(CR R )v-C(O)OH, or -(CR R )p-Y-(CR R )q-R ;
4’ 6 7 8’ 6 7 6 7 8
R is -(CR R )m-R , -(CR R )p-Y-(CR R )q-R , -C4-6alkyl-C(O)OH, -C3-6cycloalkyl-C(O)OH,
or -C alkyl-C cycloalkyl-C(O)OH;
1-6 3-6
Y is -O- or -N(R )-;
R is C1-6alkyl or -CH2-phenyl optionally substituted with one, two, or three groups
independently selected from halogen, C alkyl, C haloalkyl, and C alkoxy;
1-6 1-6 1-6
6 7 6 7
each R and R is each independently selected from H, F, and C alkyl; or R and R , together
with the carbon to which they are attached, form a C3-6cycloalkyl ring;
8 9 10 12 13 11
R is -C(O)OR , -C(O)R , or -C(O)O-(CR R )-OC(O)R ;
8’ 9’ 10’ 12 13 11
R is -C(O)OR , -C(O)R , or -C(O)O-(CR R )-OC(O)R ;
R is H or C1-6alkyl;
R is C1-6alkyl;
21
R is C alkyl or -NHSO R ;
1-6 2
’ 21
R is C alkyl or -NHSO R ;
2-6 2
R is C1-6alkyl or C1-6alkoxy;
12 13
R and R is each independently H or C alkyl;
14 15 16 8 6 7 6 7 8
R is -(CR R )m-R or -(CR R )p-Y-(CR R )q-R ;
16
each R and R is each independently selected from H, F, and C alkyl;
each R is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl;
18 19
each R and R is each independently selected from H, C1-6alkyl, C3-6cycloalkyl, aryl, and
18 19
heteroaryl; or R and R , together with the nitrogen to which they are attached, form a
heterocycloalkyl ring optionally substituted with one, two, or three R ;
each R is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, oxo, -CN, and C3-
cycloalkyl;
R is C alkyl or C cycloalkyl;
1-6 3-6
22 23
R is H, C1-6alkyl, or -SO2R ;
R is C1-6alkyl;
m is 1, 2, 3 or 4;
n is 0, 1, 2, 3, or 4;
p is 2, 3, or 4;
q is 1, 2, or 3;
t is 0, 1, or 2; and
v is 3 or 4;
or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt
1 4’
or solvate thereof, wherein R is -NH(R ). In some embodiments is a compound of Formula (I), or a
1 4’ 4’ 6 7 8’
pharmaceutically acceptable salt or solvate thereof, wherein R is -NH(R ) and R is -(CR R )m-R .
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate
1 4’ 4’ 6 7 8’ 6 7
thereof, wherein R is -NH(R ), R is -(CR R )m-R , and each R and R is each independently
selected from H and C1-6alkyl. In some embodiments is a compound of Formula (I), or a
1 4’ 4’ 6 7 8’
pharmaceutically acceptable salt or solvate thereof, wherein R is -NH(R ), R is -(CR R ) -R ,
and each R and R is H. In some embodiments is a compound of Formula (I), or a pharmaceutically
acceptable salt or solvate thereof, wherein m is 1, 2, or 3. In some embodiments is a compound of
Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1. In some
embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,
wherein m is 2. In some embodiments is a compound of Formula (I), or a pharmaceutically
acceptable salt or solvate thereof, wherein m is 3. In some embodiments is a compound of Formula
(I), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 4. In some embodiments is
a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
C(O)OR . In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable
8’ 9’ 9’
salt or solvate thereof, wherein R is -C(O)OR and R is -CH3. In some embodiments is a
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
9’ 9’
C(O)OR and R is -CH2CH3. In some embodiments is a compound of Formula (I), or a
8’ 10’
pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)R . In some embodiments
is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is
’ 10’ 21
-C(O)R and R is -NHSO R . In some embodiments is a compound of Formula (I), or a
8’ 10’ 10’ 21
pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)R , R is -NHSO2R , and
R is C alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically
8’ 10’ 10’ 21 21
acceptable salt or solvate thereof, wherein R is -C(O)R , R is -NHSO R , and R is C
2 3-
6cycloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable
8’ 12 13 11
salt or solvate thereof, wherein R is -C(O)O-(CR R )-OC(O)R . In some embodiments is a
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
12 13 11 11
C(O)O-(CR R )-OC(O)R and R is C1-6alkyl. In some embodiments is a compound of Formula
8’ 12 13
(I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)O-(CR R )-
11 11
OC(O)R and R is C alkoxy. In some embodiments is a compound of Formula (I), or a
1 4’ 4’
pharmaceutically acceptable salt or solvate thereof, wherein R is -NH(R ) and R is -
CH2CH2C(O)OCH3. In some embodiments is a compound of Formula (I), or a pharmaceutically
1 4’ 4’
acceptable salt or solvate thereof, wherein R is -NH(R ) and R is -CH CH C(O)OCH CH . In
2 2 2 3
some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate
1 4’ 4’
thereof, wherein R is -NH(R ) and R is -CH2CH2C(O)OC(CH3)3. In some embodiments is a
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
4’ 4’
NH(R ) and R is -CH CH CH C(O)OCH . In some embodiments is a compound of Formula (I), or
2 2 2 3
1 4’ 4’
a pharmaceutically acceptable salt or solvate thereof, wherein R is -NH(R ) and R is -
CH2CH2CH2C(O)OCH2CH3. In some embodiments is a compound of Formula (I), or a
1 4’ 4’
pharmaceutically acceptable salt or solvate thereof, wherein R is -NH(R ) and R is -
CH CH CH C(O)OC(CH ) .
2 2 2 3 3
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt
1 4’ 4’ 6 7 6 7 8
or solvate thereof, wherein R is -NH(R ) and R is -(CR R ) -Y-(CR R ) -R . In some
embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,
1 4’ 4’ 6 7 6 7 8 6 7
wherein R is -NH(R ), R is -(CR R )p-Y-(CR R )q-R , and each R and R is each independently
selected from H and C1-6alkyl. In some embodiments is a compound of Formula (I), or a
1 4’ 4’ 6 7
pharmaceutically acceptable salt or solvate thereof, wherein R is -NH(R ), R is -(CR R ) -Y-
6 7 8 6 7
(CR R )q-R , and each R and R is H. In some embodiments is a compound of Formula (I), or a
1 4’ 4’ 6 7
pharmaceutically acceptable salt or solvate thereof, wherein R is -NH(R ), R is -(CR R )p-Y-
6 7 8
(CR R )q-R , and Y is -O-. In some embodiments is a compound of Formula (I), or a
1 4’ 4’ 6 7
pharmaceutically acceptable salt or solvate thereof, wherein R is -NH(R ), R is -(CR R ) -Y-
6 7 8 22
(CR R )q-R , and Y is -N(R )-. In some embodiments is a compound of Formula (I), or a
1 4’ 4’ 6 7
pharmaceutically acceptable salt or solvate thereof, wherein R is -NH(R ), R is -(CR R )p-Y-
6 7 8 22 22 23
(CR R ) -R , Y is -N(R )-, and R is -SO R . In some embodiments is a compound of Formula
(I), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some embodiments is
a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2.
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate
thereof, wherein R is -C(O)OR . In some embodiments is a compound of Formula (I), or a
8 9 9
pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)OR and R is H. In some
embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,
8 9 9
wherein R is -C(O)OR and R is C alkyl. In some embodiments is a compound of Formula (I), or
8 9 9
a pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)OR and R is -CH3. In
some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate
8 9 9
thereof, wherein R is -C(O)OR and R is -CH CH . In some embodiments is a compound of
8 10
Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)R . In
some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate
8 10 10 21
thereof, wherein R is -C(O)R and R is -NHSO R . In some embodiments is a compound of
8 10 10
Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)R , R is -
21 21
NHSO2R , and R is C1-6alkyl. In some embodiments is a compound of Formula (I), or a
8 10 10 21
pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)R , R is -NHSO2R , and
R is C cycloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically
8 12 13 11
acceptable salt or solvate thereof, wherein R is -C(O)O-(CR R )-OC(O)R . In some
embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,
8 12 13 11 11
wherein R is -C(O)O-(CR R )-OC(O)R and R is C alkyl. In some embodiments is a
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
12 13 11 11
C(O)O-(CR R )-OC(O)R and R is C1-6alkoxy. In some embodiments is a compound of
1 4’ 4’
Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -NH(R ) and R
is -CH CH OCH C(O)OH. In some embodiments is a compound of Formula (I), or a
2 2 2
1 4’ 4’
pharmaceutically acceptable salt or solvate thereof, wherein R is -NH(R ) and R is -
CH2CH2N(SO2CH3)CH2C(O)OH. In some embodiments is a compound of Formula (I), or a
1 4’ 4’
pharmaceutically acceptable salt or solvate thereof, wherein R is -NH(R ) and R is -
CH2CH2CH2C(O)OCH(CH3)OC(O)OCH2CH3. In some embodiments is a compound of Formula (I),
1 4’ 4’
or a pharmaceutically acceptable salt or solvate thereof, wherein R is -NH(R ) and R is -
CH2CH2CH2C(O)OCH(CH3)OC(O)OCH(CH3)2. In some embodiments is a compound of Formula
1 4’ 4’
(I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -NH(R ) and R is -
CH2CH2CH2C(O)OCH2OC(O)OC(CH3)3. In some embodiments is a compound of Formula (I), or a
1 4’ 4’
pharmaceutically acceptable salt or solvate thereof, wherein R is -NH(R ) and R is -
CH CH CH C(O)OCH(CH )OC(O)CH(CH ) .
2 2 2 3 3 2
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt
1 4’ 4’
or solvate thereof, wherein R is -NH(R ) and R is -C4-6alkyl-C(O)OH. In some embodiments is a
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
4’ 4’
NH(R ) and R is -CH CH CH CH C(O)OH. In some embodiments is a compound of Formula (I),
2 2 2 2
1 4’ 4’
or a pharmaceutically acceptable salt or solvate thereof, wherein R is -NH(R ) and R is -
CH2CH(CH3)CH2C(O)OH.
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt
1 4’ 4’
or solvate thereof, wherein R is -NH(R ) and R is -C3-6cycloalkyl-C(O)OH. In some embodiments
is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is
4’ 4’
-NH(R ) and R is -C alkyl-C cycloalkyl-C(O)OH.
1-6 3-6
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt
1 4 5
or solvate thereof, wherein R is -N(R )(R ). In some embodiments is a compound of Formula (I), or
1 4 5 5
a pharmaceutically acceptable salt or solvate thereof, wherein R is -N(R )(R ) and R is C alkyl.
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate
1 4 5 5
thereof, wherein R is -N(R )(R ) and R is -CH3. In some embodiments is a compound of Formula
1 4 5 5
(I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -N(R )(R ) and R is -CH2-
phenyl optionally substituted with one, two, or three groups independently selected from halogen, C
6alkyl, C1-6haloalkyl, and C1-6alkoxy. In some embodiments is a compound of Formula (I), or a
1 4 5 5
pharmaceutically acceptable salt or solvate thereof, wherein R is -N(R )(R ) and R is -CH2-phenyl
optionally substituted with one or two groups independently selected from halogen, C alkyl, C
1-6 1-
haloalkyl, and C alkoxy. In some embodiments is a compound of Formula (I), or a
6 1-6
1 4 5 5
pharmaceutically acceptable salt or solvate thereof, wherein R is -N(R )(R ) and R is -CH2-phenyl
optionally substituted with one group selected from halogen, C alkyl, C haloalkyl, and C alkoxy.
1-6 1-6 1-6
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate
1 4 5 4 6 7 8’
thereof, wherein R is -N(R )(R ) and R is -(CR R )m-R . In some embodiments is a compound of
1 4 5 4
Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -N(R )(R ), R is
6 7 8’ 6 7
-(CR R ) -R , and each R and R is each independently selected from H and C alkyl. In some
m 1-6
embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,
1 4 5 4 6 7 8’ 6 7
wherein R is -N(R )(R ), R is -(CR R )m-R , and each R and R is H. In some embodiments is a
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1, 2,
or 3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or
solvate thereof, wherein m is 1. In some embodiments is a compound of Formula (I), or a
pharmaceutically acceptable salt or solvate thereof, wherein m is 2. In some embodiments is a
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 3.
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate
thereof, wherein m is 4. In some embodiments is a compound of Formula (I), or a pharmaceutically
8’ 9’
acceptable salt or solvate thereof, wherein R is -C(O)OR . In some embodiments is a compound of
8’ 9’
Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)OR and
R is -CH3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable
8’ 9’ 9’
salt or solvate thereof, wherein R is -C(O)OR and R is -CH2CH3. In some embodiments is a
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
C(O)R . In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt
8’ 10’ 10’ 21
or solvate thereof, wherein R is -C(O)R and R is -NHSO2R . In some embodiments is a
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
’ 10’ 21 21
C(O)R , R is -NHSO R , and R is C alkyl. In some embodiments is a compound of Formula
2 1-6
8’ 10’ 10’
(I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)R , R is -
21 21
NHSO R , and R is C cycloalkyl. In some embodiments is a compound of Formula (I), or a
2 3-6
8’ 12 13 11
pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)O-(CR R )-OC(O)R . In
some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate
8’ 12 13 11 11
thereof, wherein R is -C(O)O-(CR R )-OC(O)R and R is C1-6alkyl. In some embodiments is a
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
12 13 11 11
C(O)O-(CR R )-OC(O)R and R is C1-6alkoxy. In some embodiments is a compound of
1 4 5 5
Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -N(R )(R ), R is
-CH or -CH -phenyl optionally substituted with one, two, or three groups independently selected
from halogen, C alkyl, C haloalkyl, and C alkoxy, and R is -CH CH C(O)OCH . In some
1-6 1-6 1-6 2 2 3
embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,
1 4 5 5
wherein R is -N(R )(R ), R is -CH or -CH -phenyl optionally substituted with one, two, or three
groups independently selected from halogen, C alkyl, C haloalkyl, and C alkoxy, and R is -
1-6 1-6 1-6
CH2CH2C(O)OCH2CH3. In some embodiments is a compound of Formula (I), or a pharmaceutically
1 4 5 5
acceptable salt or solvate thereof, wherein R is -N(R )(R ), R is -CH3 or -CH2-phenyl optionally
substituted with one, two, or three groups independently selected from halogen, C alkyl, C
1-6 1-
6haloalkyl, and C1-6alkoxy, and R is -CH2CH2C(O)OC(CH3)3. In some embodiments is a compound
1 4 5 5
of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -N(R )(R ), R
is -CH3 or -CH2-phenyl optionally substituted with one, two, or three groups independently selected
from halogen, C alkyl, C haloalkyl, and C alkoxy, and R is -CH CH CH C(O)OCH . In some
1-6 1-6 1-6 2 2 2 3
embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,
1 4 5 5
wherein R is -N(R )(R ), R is -CH3 or -CH2-phenyl optionally substituted with one, two, or three
groups independently selected from halogen, C alkyl, C haloalkyl, and C alkoxy, and R is -
1-6 1-6 1-6
CH CH CH C(O)OCH CH . In some embodiments is a compound of Formula (I), or a
2 2 2 2 3
1 4 5 5
pharmaceutically acceptable salt or solvate thereof, wherein R is -N(R )(R ), R is -CH3 or -CH2-
phenyl optionally substituted with one, two, or three groups independently selected from halogen, C
alkyl, C haloalkyl, and C alkoxy, and R is -CH CH CH C(O)OC(CH ) .
6 1-6 1-6 2 2 2 3 3
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt
1 4 5 5
or solvate thereof, wherein R is -N(R )(R ), R is -CH3 or -CH2-phenyl optionally substituted with
one, two, or three groups independently selected from halogen, C alkyl, C haloalkyl, and C
1-6 1-6 1-
4 6 7 6 7 8
6alkoxy, and R is -(CR R )p-Y-(CR R )q-R . In some embodiments is a compound of Formula (I),
1 4 5 5
or a pharmaceutically acceptable salt or solvate thereof, wherein R is -N(R )(R ), R is -CH3 or -
CH -phenyl optionally substituted with one, two, or three groups independently selected from
4 6 7 6 7 8 6
halogen, C alkyl, C haloalkyl, and C alkoxy, and R is -(CR R ) -Y-(CR R ) -R , and each R
1-6 1-6 1-6 p q
and R is each independently selected from H and C1-6alkyl. In some embodiments is a compound of
1 4 5 5
Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -N(R )(R ), R is
-CH or -CH -phenyl optionally substituted with one, two, or three groups independently selected
4 6 7 6 7 8
from halogen, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy, and R is -(CR R )p-Y-(CR R )q-R , and each
R and R is H. In some embodiments is a compound of Formula (I), or a pharmaceutically
1 4 5 5
acceptable salt or solvate thereof, wherein R is -N(R )(R ), R is -CH or -CH -phenyl optionally
substituted with one, two, or three groups independently selected from halogen, C1-6alkyl, C1-
4 6 7 6 7 8
6haloalkyl, and C1-6alkoxy, and R is -(CR R )p-Y-(CR R )q-R , and Y is -O-. In some embodiments
is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is
4 5 5
-N(R )(R ), R is -CH or -CH -phenyl optionally substituted with one, two, or three groups
4 6 7
independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy, and R is -(CR R )p-
6 7 8 22
Y-(CR R ) -R , and Y is -N(R )-. In some embodiments is a compound of Formula (I), or a
1 4 5 5
pharmaceutically acceptable salt or solvate thereof, wherein R is -N(R )(R ), R is -CH or -CH -
phenyl optionally substituted with one, two, or three groups independently selected from halogen, C1-
4 6 7 6 7 8 22 22
6alkyl, C1-6haloalkyl, and C1-6alkoxy, and R is -(CR R )p-Y-(CR R )q-R , Y is -N(R )-, and R is -
SO R . In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt
or solvate thereof, wherein q is 1. In some embodiments is a compound of Formula (I), or a
pharmaceutically acceptable salt or solvate thereof, wherein p is 2. In some embodiments is a
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
C(O)OR . In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable
8 9 9
salt or solvate thereof, wherein R is -C(O)OR and R is H. In some embodiments is a compound of
8 9 9
Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)OR and R
is C alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable
8 9 9
salt or solvate thereof, wherein R is -C(O)OR and R is -CH . In some embodiments is a
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
C(O)OR and R is -CH CH . In some embodiments is a compound of Formula (I), or a
8 10
pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)R . In some embodiments is
a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
10 21
C(O)R and R is -NHSO2R . In some embodiments is a compound of Formula (I), or a
8 10 10 21
pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)R , R is -NHSO R , and
R is C1-6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically
8 10 10 21 21
acceptable salt or solvate thereof, wherein R is -C(O)R , R is -NHSO2R , and R is C3-
cycloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable
8 12 13 11
salt or solvate thereof, wherein R is -C(O)O-(CR R )-OC(O)R . In some embodiments is a
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
12 13 11 11
C(O)O-(CR R )-OC(O)R and R is C alkyl. In some embodiments is a compound of Formula
8 12 13
(I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)O-(CR R )-
11 11
OC(O)R and R is C1-6alkoxy. In some embodiments is a compound of Formula (I), or a
1 4 5 5
pharmaceutically acceptable salt or solvate thereof, wherein R is -N(R )(R ), R is -CH3 or -CH2-
phenyl optionally substituted with one, two, or three groups independently selected from halogen, C
6alkyl, C1-6haloalkyl, and C1-6alkoxy, and R is -CH2CH2OCH2C(O)OH. In some embodiments is a
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
4 5 5
N(R )(R ), R is -CH or -CH -phenyl optionally substituted with one, two, or three groups
independently selected from halogen, C alkyl, C haloalkyl, and C alkoxy, and R is -
1-6 1-6 1-6
CH2CH2N(SO2CH3)CH2C(O)OH. In some embodiments is a compound of Formula (I), or a
1 4 5 5
pharmaceutically acceptable salt or solvate thereof, wherein R is -N(R )(R ), R is -CH or -CH -
phenyl optionally substituted with one, two, or three groups independently selected from halogen, C
6alkyl, C1-6haloalkyl, and C1-6alkoxy, and R is is -CH2CH2CH2C(O)OCH(CH3)OC(O)OCH2CH3. In
some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate
1 4 5 5
thereof, wherein R is -N(R )(R ), R is -CH or -CH -phenyl optionally substituted with one, two, or
three groups independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy, and R is
-CH2CH2CH2C(O)OCH(CH3)OC(O)OCH(CH3)2. In some embodiments is a compound of Formula
1 4 5 5
(I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -N(R )(R ), R is -CH3 or -
CH -phenyl optionally substituted with one, two, or three groups independently selected from
halogen, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy, and R is -
CH2CH2CH2C(O)OCH2OC(O)OC(CH3)3. In some embodiments is a compound of Formula (I), or a
1 4 5 5
pharmaceutically acceptable salt or solvate thereof, wherein R is -N(R )(R ), R is -CH or -CH -
phenyl optionally substituted with one, two, or three groups independently selected from halogen, C
6alkyl, C1-6haloalkyl, and C1-6alkoxy, and R is -CH2CH2CH2C(O)OCH(CH3)OC(O)CH(CH3)2.
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt
1 4 5 4 6 7
or solvate thereof, wherein R is -N(R )(R ) and R is -(CR R ) -C(O)OH. In some embodiments is
a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
4 5 5 4 6 7
N(R )(R ), R is -CH3, and R is -(CR R )v-C(O)OH. In some embodiments is a compound of
1 4 5 5
Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -N(R )(R ), R is
4 6 7
-CH3, R is -(CR R )v-C(O)OH, and v is 3. In some embodiments is a compound of Formula (I), or a
1 4 5 5 4
pharmaceutically acceptable salt or solvate thereof, wherein R is -N(R )(R ), R is -CH3, R is -
(CR R ) -C(O)OH, and v is 4. In some embodiments is a compound of Formula (I), or a
1 4 5 5
pharmaceutically acceptable salt or solvate thereof, wherein R is -N(R )(R ), R is -CH -phenyl
optionally substituted with one, two, or three groups independently selected from halogen, C1-6alkyl,
4 6 7
C haloalkyl, and C alkoxy, and R is -(CR R ) -C(O)OH. In some embodiments is a compound
1-6 1-6 v
1 4 5 5
of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -N(R )(R ), R
is -CH2-phenyl optionally substituted with one, two, or three groups independently selected from
4 6 7
halogen, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy, R is -(CR R )v-C(O)OH, and v is 3. In some
embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,
1 4 5 5
wherein R is -N(R )(R ), R is -CH2-phenyl optionally substituted with one, two, or three groups
4 6 7
independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy, R is -(CR R )v-
C(O)OH, and v is 4. In some embodiments is a compound of Formula (I), or a pharmaceutically
1 4 5 5 4
acceptable salt or solvate thereof, wherein R is -N(R )(R ), R is -CH , and R is -
CH2CH2CH2C(O)OH. In some embodiments is a compound of Formula (I), or a pharmaceutically
1 4 5 5
acceptable salt or solvate thereof, wherein R is -N(R )(R ), R is -CH -phenyl optionally substituted
with one, two, or three groups independently selected from halogen, C alkyl, C haloalkyl, and C
1-6 1-6 1-
6alkoxy, and R is -CH2CH2CH2C(O)OH. In some embodiments is a compound of Formula (I), or a
1 4 5 5 4
pharmaceutically acceptable salt or solvate thereof, wherein R is -N(R )(R ), R is -CH3, and R is -
CH CH CH CH C(O)OH. In some embodiments is a compound of Formula (I), or a
2 2 2 2
1 4 5 5
pharmaceutically acceptable salt or solvate thereof, wherein R is -N(R )(R ), R is -CH2-phenyl
optionally substituted with one, two, or three groups independently selected from halogen, C1-6alkyl,
C1-6haloalkyl, and C1-6alkoxy, and R is -CH2CH2CH2CH2C(O)OH. In some embodiments is a
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
4 5 5 4
N(R )(R ), R is -CH3, and R is -CH2CH(CH3)CH2C(O)OH. In some embodiments is a compound
1 4 5 5
of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -N(R )(R ), R
is -CH -phenyl optionally substituted with one, two, or three groups independently selected from
halogen, C alkyl, C haloalkyl, and C alkoxy, and R is -CH CH(CH )CH C(O)OH.
1-6 1-6 1-6 2 3 2
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt
or solvate thereof, wherein R is -OR . In some embodiments is a compound of Formula (I), or a
1 3 3 6 7 8
pharmaceutically acceptable salt or solvate thereof, wherein R is -OR and R is -(CR R ) -R . In
some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate
thereof, wherein R is -C(O)OR . In some embodiments is a compound of Formula (I), or a
8 9 9
pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)OR and R is H. In some
embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,
8 9 9
wherein R is -C(O)OR and R is C1-6alkyl. In some embodiments is a compound of Formula (I), or
8 9 9
a pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)OR and R is -CH . In
some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate
8 9 9
thereof, wherein R is -C(O)OR and R is -CH2CH3. In some embodiments is a compound of
8 10
Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)R . In
some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate
8 10 10 21
thereof, wherein R is -C(O)R and R is -NHSO2R . In some embodiments is a compound of
8 10 10
Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)R , R is -
21 21
NHSO R , and R is C alkyl. In some embodiments is a compound of Formula (I), or a
2 1-6
8 10 10 21
pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)R , R is -NHSO2R , and
R is C3-6cycloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically
8 12 13 11
acceptable salt or solvate thereof, wherein R is -C(O)O-(CR R )-OC(O)R . In some
embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,
8 12 13 11 11
wherein R is -C(O)O-(CR R )-OC(O)R and R is C1-6alkyl. In some embodiments is a
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
12 13 11 11
C(O)O-(CR R )-OC(O)R and R is C alkoxy. In some embodiments is a compound of
1 3 3
Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -OR and R is -
CH2C(O)OH. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable
1 3 3
salt or solvate thereof, wherein R is -OR and R is -CH CH C(O)OH. In some embodiments is a
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
OR and R is . In some embodiments is a compound of Formula (I), or a
1 3 3
pharmaceutically acceptable salt or solvate thereof, wherein R is -OR and R is . In
some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate
1 3 3
thereof, wherein R is -OR and R is -CH CH CH C(O)OH. In some embodiments is a compound
2 2 2
1 3 3
of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -OR and R is
-CH2CH(CH3)CH2C(O)OH. In some embodiments is a compound of Formula (I), or a
1 3 3
pharmaceutically acceptable salt or solvate thereof, wherein R is -OR and R is -
CH CH C(O)OCH . In some embodiments is a compound of Formula (I), or a pharmaceutically
2 2 3
1 3 3
acceptable salt or solvate thereof, wherein R is -OR and R is -CH2CH2C(O)OCH2CH3. In some
embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,
1 3 3
wherein R is -OR and R is -CH CH C(O)OC(CH ) . In some embodiments is a compound of
2 2 3 3
1 3 3
Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -OR and R is -
CH2CH2CH2C(O)OCH3. In some embodiments is a compound of Formula (I), or a pharmaceutically
1 3 3
acceptable salt or solvate thereof, wherein R is -OR and R is -CH CH CH C(O)OCH CH . In
2 2 2 2 3
some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate
1 3 3
thereof, wherein R is -OR and R is -CH2CH2CH2C(O)OC(CH3)3.
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt
1 3 3 6 7 6 7 8
or solvate thereof, wherein R is -OR and R is -(CR R ) -Y-(CR R ) -R . In some embodiments is
a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
3 3 6 7 6 7 8 6 7
OR , R is -(CR R )p-Y-(CR R )q-R , and each R and R is each independently selected from H and
C alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt
1 3 3 6 7 6 7 8 6 7
or solvate thereof, wherein R is -OR , R is -(CR R )p-Y-(CR R )q-R , and each R and R is H. In
some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate
1 3 3 6 7 6 7 8
thereof, wherein R is -OR , R is -(CR R ) -Y-(CR R ) -R , and Y is -O-. In some embodiments is
a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
3 3 6 7 6 7 8 22
OR , R is -(CR R )p-Y-(CR R )q-R , and Y is -N(R )-. In some embodiments is a compound of
1 3 3
Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -OR , R is -
6 7 6 7 8 22 22 23
(CR R ) -Y-(CR R ) -R , Y is -N(R )-, and R is -SO R . In some embodiments is a compound of
p q 2
Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some
embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,
wherein p is 2. In some embodiments is a compound of Formula (I), or a pharmaceutically
acceptable salt or solvate thereof, wherein R is -C(O)OR . In some embodiments is a compound of
8 9 9
Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)OR and R
is H. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or
8 9 9
solvate thereof, wherein R is -C(O)OR and R is C1-6alkyl. In some embodiments is a compound of
8 9 9
Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)OR and R
is -CH . In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt
8 9 9
or solvate thereof, wherein R is -C(O)OR and R is -CH2CH3. In some embodiments is a
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
C(O)R . In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt
8 10 10 21
or solvate thereof, wherein R is -C(O)R and R is -NHSO2R . In some embodiments is a
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
10 21 21
C(O)R , R is -NHSO R , and R is C alkyl. In some embodiments is a compound of Formula
2 1-6
8 10 10
(I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)R , R is -
21 21
NHSO2R , and R is C3-6cycloalkyl. In some embodiments is a compound of Formula (I), or a
8 12 13 11
pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)O-(CR R )-OC(O)R . In
some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate
8 12 13 11 11
thereof, wherein R is -C(O)O-(CR R )-OC(O)R and R is C1-6alkyl. In some embodiments is a
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
12 13 11 11
C(O)O-(CR R )-OC(O)R and R is C alkoxy. In some embodiments is a compound of
1 3 3
Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -OR and R is -
CH2CH2OCH2C(O)OH. In some embodiments is a compound of Formula (I), or a pharmaceutically
1 3 3
acceptable salt or solvate thereof, wherein R -OR and R is -CH CH N(SO CH )CH C(O)OH. In
2 2 2 3 2
some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate
1 3 3
thereof, wherein R is -OR and R is -CH2CH2CH2C(O)OCH(CH3)OC(O)OCH2CH3. In some
embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,
1 3 3
wherein R is -OR and R is -CH CH CH C(O)OCH(CH )OC(O)OCH(CH ) . In some
2 2 2 3 3 2
embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,
1 3 3
wherein R is -OR and R is -CH CH CH C(O)OCH OC(O)OC(CH ) . In some embodiments is a
2 2 2 2 3 3
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
OR and R is -CH2CH2CH2C(O)OCH(CH3)OC(O)CH(CH3)2.
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt
1 3 3 6 7 8
or solvate thereof, wherein R is -OR and R is -(CR R ) -C cycloalkyl-R . In some embodiments
t 3-6
is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is
3 3 6 7 8
-OR , R is -(CR R )t-C3-6cycloalkyl-R , and t is 0. In some embodiments is a compound of Formula
1 3 3 6 7
(I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -OR , R is -(CR R )t-C3-
cycloalkyl-R , and t is 1. In some embodiments is a compound of Formula (I), or a
1 3 3 6 7
pharmaceutically acceptable salt or solvate thereof, wherein R is -OR , R is -(CR R )t-C3-
6cycloalkyl-R , and t is 2. In some embodiments is a compound of Formula (I), or a
1 3 3
pharmaceutically acceptable salt or solvate thereof, wherein R is -OR and R is -cyclopropyl-
C(O)OH. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt
1 3 3
or solvate thereof, wherein R is -OR and R is -cyclobutyl-C(O)OH. In some embodiments is a
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
OR and R is -cyclopentyl-C(O)OH.
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt
1 14
or solvate thereof, wherein R is -R . In some embodiments is a compound of Formula (I), or a
1 14 14 15 16 8
pharmaceutically acceptable salt or solvate thereof, wherein R is -R and R is -(CR R ) -R . In
some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate
14 15 16 8
thereof, wherein R is -(CR R )m-R and m is 1. In some embodiments is a compound of Formula
14 15 16 8
(I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -(CR R ) -R and m is
2. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or
14 15 16 8
solvate thereof, wherein R is -(CR R )m-R and m is 3. In some embodiments is a compound of
14 15 16 8
Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -(CR R ) -R
and m is 4. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable
salt or solvate thereof, wherein R is -C(O)OR . In some embodiments is a compound of Formula
8 9 9
(I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)OR and R is H. In
some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate
8 9 9
thereof, wherein R is -C(O)OR and R is C1-6alkyl. In some embodiments is a compound of
8 9 9
Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)OR and R
is -CH . In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt
8 9 9
or solvate thereof, wherein R is -C(O)OR and R is -CH CH . In some embodiments is a
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
C(O)R . In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt
8 10 10 21
or solvate thereof, wherein R is -C(O)R and R is -NHSO R . In some embodiments is a
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
10 21 21
C(O)R , R is -NHSO2R , and R is C1-6alkyl. In some embodiments is a compound of Formula
8 10 10
(I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)R , R is -
21 21
NHSO2R , and R is C3-6cycloalkyl. In some embodiments is a compound of Formula (I), or a
8 12 13 11
pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)O-(CR R )-OC(O)R . In
some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate
8 12 13 11 11
thereof, wherein R is -C(O)O-(CR R )-OC(O)R and R is C alkyl. In some embodiments is a
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
12 13 11 11
C(O)O-(CR R )-OC(O)R and R is C1-6alkoxy. In some embodiments is a compound of
1 14 14
Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -R and R is -
CH C(O)OH. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable
1 14 14
salt or solvate thereof, wherein R is -R and R is -CH2CH2C(O)OH. In some embodiments is a
1 14
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -R
and R is -CH CH CH C(O)OH. In some embodiments is a compound of Formula (I), or a
2 2 2
1 14 14
pharmaceutically acceptable salt or solvate thereof, wherein R is -R and R is -
CH2CH2CH2CH2C(O)OH. In some embodiments is a compound of Formula (I), or a
1 14 14
pharmaceutically acceptable salt or solvate thereof, wherein R is -R and R is -
CH2CH(CH3)CH2C(O)OH. In some embodiments is a compound of Formula (I), or a
1 14 14
pharmaceutically acceptable salt or solvate thereof, wherein R is -R and R is -
CH CH C(O)OCH . In some embodiments is a compound of Formula (I), or a pharmaceutically
2 2 3
1 14 14
acceptable salt or solvate thereof, wherein R is -R and R is -CH CH C(O)OCH CH . In some
2 2 2 3
embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,
1 14 14
wherein R is -R and R is -CH CH C(O)OC(CH ) . In some embodiments is a compound of
2 2 3 3
1 14 14
Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -R and R is -
CH2CH2CH2C(O)OCH3. In some embodiments is a compound of Formula (I), or a pharmaceutically
1 14 14
acceptable salt or solvate thereof, wherein R is -R and R is -CH2CH2CH2C(O)OCH2CH3. In
some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate
1 14 14
thereof, wherein R is -R and R is -CH2CH2CH2C(O)OC(CH3)3. In some embodiments is a
1 14
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -R
and R is -CH CH CH CH C(O)OCH . In some embodiments is a compound of Formula (I), or a
2 2 2 2 3
1 14 14
pharmaceutically acceptable salt or solvate thereof, wherein R is -R and R is -
CH2CH2CH2CH2C(O)OCH2CH3. In some embodiments is a compound of Formula (I), or a
1 14 14
pharmaceutically acceptable salt or solvate thereof, wherein R is -R and R is -
CH CH CH CH C(O)OC(CH ) .
2 2 2 2 3 3
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt
1 14 14 6 7 6 7 8
or solvate thereof, wherein R is -R and R is -(CR R )p-Y-(CR R )q-R . In some embodiments is
a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
14 14 6 7 6 7 8 6 7
R , R is -(CR R )p-Y-(CR R )q-R , and each R and R is each independently selected from H and
C1-6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt
1 14 14 6 7 6 7 8 6 7
or solvate thereof, wherein R is -R , R is is -(CR R )p-Y-(CR R )q-R , and each R and R is H.
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate
1 14 14 6 7 6 7 8
thereof, wherein R is -R , R is is -(CR R )p-Y-(CR R )q-R , and Y is -O-. In some embodiments
is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is
14 14 6 7 6 7 8 22
-R , R is -(CR R ) -Y-(CR R ) -R , and Y is -N(R )-. In some embodiments is a compound of
1 14 14
Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -R , R is -
6 7 6 7 8 22 22 23
(CR R )p-Y-(CR R )q-R , Y is -N(R )-, and R is -SO2R . In some embodiments is a compound of
Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some
embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,
wherein p is 2. In some embodiments is a compound of Formula (I), or a pharmaceutically
acceptable salt or solvate thereof, wherein R is -C(O)OR . In some embodiments is a compound of
8 9 9
Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)OR and R
is H. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or
8 9 9
solvate thereof, wherein R is -C(O)OR and R is C1-6alkyl. In some embodiments is a compound of
8 9 9
Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)OR and R
is -CH . In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt
8 9 9
or solvate thereof, wherein R is -C(O)OR and R is -CH2CH3. In some embodiments is a
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
C(O)R . In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt
8 10 10 21
or solvate thereof, wherein R is -C(O)R and R is -NHSO2R . In some embodiments is a
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
10 21 21
C(O)R , R is -NHSO R , and R is C alkyl. In some embodiments is a compound of Formula
2 1-6
8 10 10
(I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)R , R is -
21 21
NHSO2R , and R is C3-6cycloalkyl. In some embodiments is a compound of Formula (I), or a
8 12 13 11
pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)O-(CR R )-OC(O)R . In
some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate
8 12 13 11 11
thereof, wherein R is -C(O)O-(CR R )-OC(O)R and R is C1-6alkyl. In some embodiments is a
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
12 13 11 11
C(O)O-(CR R )-OC(O)R and R is C alkoxy. In some embodiments is a compound of
1 14 14
Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -R and R is -
CH2CH2OCH2C(O)OH. In some embodiments is a compound of Formula (I), or a pharmaceutically
1 14 14
acceptable salt or solvate thereof, wherein R is -R and R is -CH CH N(SO CH )CH C(O)OH.
2 2 2 3 2
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate
1 14 14
thereof, wherein R is -R and R is -CH2CH2CH2C(O)OCH(CH3)OC(O)OCH2CH3. In some
embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,
1 14 14
wherein R is -R and R is -CH CH CH C(O)OCH(CH )OC(O)OCH(CH ) . In some
2 2 2 3 3 2
embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,
1 14 14
wherein R is -R and R is -CH2CH2CH2C(O)OCH2OC(O)OC(CH3)3. In some embodiments is a
1 14
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -R
and R is -CH CH CH C(O)OCH(CH )OC(O)CH(CH ) .
2 2 2 3 3 2
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt
1 6 7 8
or solvate thereof, wherein R is -C C-(CR R )-R . In some embodiments is a compound of
1 6 7
Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C C-(CR R )-
8 6 7
R and R and R is independently selected from H and C1-6alkyl. In some embodiments is a
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C
6 7 8 6 7
C-(CR R )-R and R and R is each independently C alkyl. In some embodiments is a
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C
6 7 8 6 7
C-(CR R )-R and R and R is -CH3. In some embodiments is a compound of Formula (I), or a
pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)OR . In some embodiments
is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is
-C(O)OR and R is H. In some embodiments is a compound of Formula (I), or a pharmaceutically
8 9 9
acceptable salt or solvate thereof, wherein R is -C(O)OR and R is C alkyl. In some embodiments
is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is
-C(O)OR and R is -CH3. In some embodiments is a compound of Formula (I), or a
8 9 9
pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)OR and R is -CH2CH3. In
some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate
8 10
thereof, wherein R is -C(O)R . In some embodiments is a compound of Formula (I), or a
8 10 10 21
pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)R and R is -NHSO2R .
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate
8 10 10 21 21
thereof, wherein R is -C(O)R , R is -NHSO R , and R is C alkyl. In some embodiments is a
2 1-6
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
10 21 21
C(O)R , R is -NHSO R , and R is C cycloalkyl. In some embodiments is a compound of
2 3-6
Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)O-
12 13 11
(CR R )-OC(O)R . In some embodiments is a compound of Formula (I), or a pharmaceutically
8 12 13 11 11
acceptable salt or solvate thereof, wherein R is -C(O)O-(CR R )-OC(O)R and R is C1-6alkyl.
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate
8 12 13 11 11
thereof, wherein R is -C(O)O-(CR R )-OC(O)R and R is C1-6alkoxy. In some embodiments is
a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt
or solvate thereof, wherein n is 0, 1, 2, or 3. In some embodiments is a compound of Formula (I), or
a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2. In some embodiments
is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1
or 2. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or
solvate thereof, wherein n is 0 or 1. In some embodiments is a compound of Formula (I), or a
pharmaceutically acceptable salt or solvate thereof, wherein n is 0. In some embodiments is a
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In
some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate
thereof, wherein n is 2. In some embodiments is a compound of Formula (I), or a pharmaceutically
acceptable salt or solvate thereof, wherein n is 3. In some embodiments is a compound of Formula
(I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 4.
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt
2 17
or solvate thereof, wherein n is 1 and R is halogen, C1-6alkyl, C1-6haloalkyl, or -OR . In some
embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,
wherein n is 1 and R is independently selected from C alkyl, halogen, -CN, or C haloalkyl. In
1-6 1-6
some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate
thereof, wherein n is 1 and R is halogen, C1-6alkyl, or C1-6haloalkyl. In some embodiments is a
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and
R is halogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable
salt or solvate thereof, wherein n is 1 and R is -Cl. In some embodiments is a compound of Formula
(I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R is -F. In some
embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,
wherein n is 1 and R is C1-6alkyl. In some embodiments is a compound of Formula (I), or a
pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R is -CH3. In some
embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,
wherein n is 1 and R is C1-6haloalkyl. In some embodiments is a compound of Formula (I), or a
pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R is -CF3. In some
embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,
wherein n is 1 and R is C alkoxy. In some embodiments is a compound of Formula (I), or a
pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R is -OCH3. In some
embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,
wherein n is 1 and R is C haloalkoxy. In some embodiments is a compound of Formula (I), or a
pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R is -OCF3. In some
embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,
wherein n is 1 and R is -OH. In some embodiments is a compound of Formula (I), or a
pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R is -CN.
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt
or solvate thereof, wherein n is 2 and each R is independently halogen, C alkyl, C haloalkyl, or -
1-6 1-6
OR . In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or
solvate thereof, wherein n is 2 and each R is independently halogen, C1-6alkyl, C1-6haloalkyl, C1-
6alkoxy, -OCF3, or -CN. In some embodiments is a compound of Formula (I), or a pharmaceutically
acceptable salt or solvate thereof, wherein n is 2 and each R is independently halogen, C alkyl, C
1-6 1-
6haloalkyl, C1-6alkoxy, or -OCF3. In some embodiments is a compound of Formula (I), or a
pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R is independently
halogen, C alkyl, C haloalkyl, or -OCF . In some embodiments is a compound of Formula (I), or
1-6 1-6 3
a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R is independently
halogen, C1-6alkyl, or C1-6haloalkyl. In some embodiments is a compound of Formula (I), or a
pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R is independently
halogen or C haloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically
acceptable salt or solvate thereof, wherein n is 2 and each R is independently halogen or C1-6alkyl.
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate
thereof, wherein n is 2 and each R is independently halogen. In some embodiments is a compound
of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R is
independently C1-6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically
acceptable salt or solvate thereof, wherein n is 2 and each R is independently C haloalkyl.
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt
or solvate thereof, wherein n is 3 and each R is independently halogen, C1-6alkyl, C1-6haloalkyl, C1-
alkoxy, C haloalkoxy, -OH, or -CN. In some embodiments is a compound of Formula (I), or a
6 1-6
pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and each R is independently
halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, -OCF3, or -CN. In some embodiments is a compound
of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and each R is
independently halogen, C alkyl, C haloalkyl, C alkoxy, or -OCF . In some embodiments is a
1-6 1-6 1-6 3
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and
each R is independently halogen, C1-6alkyl, C1-6haloalkyl, or -OCF3. In some embodiments is a
compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and
each R is independently halogen, C alkyl, or C haloalkyl. In some embodiments is a compound
1-6 1-6
of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and each R is
independently halogen or C1-6haloalkyl. In some embodiments is a compound of Formula (I), or a
pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and each R is independently
halogen or C alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically
acceptable salt or solvate thereof, wherein n is 3 and each R is independently halogen. In some
embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,
wherein n is 3 and each R is independently C alkyl. In some embodiments is a compound of
Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and each R is
independently C1-6haloalkyl.
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt
or solvate thereof, wherein n is 4 and each R is independently halogen, C1-6alkyl, C1-6haloalkyl, and
-OR .
In some embodiments is a compound of Formula (Ia):
Formula (Ia);
wherein:
each R is independently selected from C alkyl, halogen, -CN, C haloalkyl, -C
1-6 1-6 1-
17 18 19
6alkyl(heterocycloalkyl), -OR , and -C(O)NR R ;
4’ 6 7 8’ 6 7 6 7 8
R is -(CR R ) -R , -(CR R ) -Y-(CR R ) -R , -C alkyl-C(O)OH, -C cycloalkyl-C(O)OH,
m p q 4-6 3-6
or -C alkyl-C cycloalkyl-C(O)OH;
1-6 3-6
Y is -O- or -N(R )-;
6 7 6 7
each R and R is each independently selected from H, F, and C1-6alkyl; or R and R , together
with the carbon to which they are attached, form a C cycloalkyl ring;
8 9 10 12 13 11
R is -C(O)OR , -C(O)R , or -C(O)O-(CR R )-OC(O)R ;
8’ 9’ 10’ 12 13 11
R is -C(O)OR , -C(O)R , or -C(O)O-(CR R )-OC(O)R ;
R is H or C alkyl;
R is C alkyl;
21
R is C1-6alkyl or -NHSO2R ;
’ 21
R is C alkyl or -NHSO R ;
2-6 2
R is C1-6alkyl or C1-6alkoxy;
12 13
R and R is each independently H or C alkyl;
each R is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl;
18 19
each R and R is each independently selected from H, C1-6alkyl, C3-6cycloalkyl, aryl, and
18 19
heteroaryl; or R and R , together with the nitrogen to which they are attached, form a
heterocycloalkyl ring optionally substituted with one, two, or three R ;
each R is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, oxo, -CN, and C3-
cycloalkyl;
R is C alkyl or C cycloalkyl;
1-6 3-6
22 23
R is H, C1-6alkyl, or -SO2R ;
R is C1-6alkyl;
m is 1, 2, 3 or 4;
n is 0, 1, 2, 3, or 4;
p is 2, 3, or 4; and
q is 1, 2, or 3;
or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt
4’ 6 7 8’
or solvate thereof, wherein R is -(CR R ) -R . In some embodiments is a compound of Formula
4’ 6 7 8’
(Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -(CR R ) -R and each
R and R is each independently selected from H and C1-6alkyl. In some embodiments is a
compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
6 7 8’ 6 7
(CR R ) -R and each R and R is H. In some embodiments is a compound of Formula (Ia), or a
pharmaceutically acceptable salt or solvate thereof, wherein m is 1, 2, or 3. In some embodiments is
a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1.
In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or
solvate thereof, wherein m is 2. In some embodiments is a compound of Formula (Ia), or a
pharmaceutically acceptable salt or solvate thereof, wherein m is 3. In some embodiments is a
compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 4.
In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or
8’ 9’
solvate thereof, wherein R is -C(O)OR . In some embodiments is a compound of Formula (Ia), or
8’ 9’ 9’
a pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)OR and R is -CH3. In
some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate
8’ 9’ 9’
thereof, wherein R is -C(O)OR and R is -CH2CH3. In some embodiments is a compound of
8’ 10’
Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)R . In
some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate
8’ 10’ 10’ 21
thereof, wherein R is -C(O)R and R is -NHSO R . In some embodiments is a compound of
8’ 10’ 10’
Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)R , R
21 21
is -NHSO2R , and R is C1-6alkyl. In some embodiments is a compound of Formula (Ia), or a
8’ 10’ 10’ 21
pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)R , R is -NHSO R , and
R is C cycloalkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically
8’ 12 13 11
acceptable salt or solvate thereof, wherein R is -C(O)O-(CR R )-OC(O)R . In some
embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate
8’ 12 13 11 11
thereof, wherein R is -C(O)O-(CR R )-OC(O)R and R is C alkyl. In some embodiments is a
compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
12 13 11 11
C(O)O-(CR R )-OC(O)R and R is C1-6alkoxy. In some embodiments is a compound of
Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
CH2CH2C(O)OCH3. In some embodiments is a compound of Formula (Ia), or a pharmaceutically
acceptable salt or solvate thereof, wherein R is -CH2CH2C(O)OCH2CH3. In some embodiments is a
compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
CH CH C(O)OC(CH ) . In some embodiments is a compound of Formula (Ia), or a
2 2 3 3
pharmaceutically acceptable salt or solvate thereof, wherein R is -CH2CH2CH2C(O)OCH3. In some
embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate
thereof, wherein R is -CH CH CH C(O)OCH CH . In some embodiments is a compound of
2 2 2 2 3
Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
CH2CH2CH2C(O)OC(CH3)3.
In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt
4’ 6 7 6 7 8
or solvate thereof, wherein R is -(CR R )p-Y-(CR R )q-R . In some embodiments is a compound of
4’ 6 7
Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -(CR R )p-Y-
6 7 8 6 7
(CR R ) -R and each R and R is each independently selected from H and C alkyl. In some
q 1-6
embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate
4’ 6 7 6 7 8 6 7
thereof, wherein R is -(CR R )p-Y-(CR R )q-R and each R and R is H. In some embodiments is
a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
6 7 6 7 8
(CR R ) -Y-(CR R ) -R and Y is -O-. In some embodiments is a compound of Formula (Ia), or a
4’ 6 7 6 7 8
pharmaceutically acceptable salt or solvate thereof, wherein R is -(CR R )p-Y-(CR R )q-R and Y is
-N(R )-. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable
4’ 6 7 6 7 8 22 22 23
salt or solvate thereof, wherein R is -(CR R ) -Y-(CR R ) -R , Y is -N(R )-, and R is -SO R .
p q 2
In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or
solvate thereof, wherein q is 1. In some embodiments is a compound of Formula (Ia), or a
pharmaceutically acceptable salt or solvate thereof, wherein p is 2. In some embodiments is a
compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
C(O)OR . In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable
8 9 9
salt or solvate thereof, wherein R is -C(O)OR and R is H. In some embodiments is a compound of
Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)OR and
R is C alkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically
8 9 9
acceptable salt or solvate thereof, wherein R is -C(O)OR and R is -CH3. In some embodiments is
a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
C(O)OR and R is -CH CH . In some embodiments is a compound of Formula (Ia), or a
8 10
pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)R . In some embodiments is
a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
10 21
C(O)R and R is -NHSO R . In some embodiments is a compound of Formula (Ia), or a
8 10 10 21
pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)R , R is -NHSO2R , and
R is C1-6alkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically
8 10 10 21 21
acceptable salt or solvate thereof, wherein R is -C(O)R , R is -NHSO R , and R is C
2 3-
cycloalkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable
8 12 13 11
salt or solvate thereof, wherein R is -C(O)O-(CR R )-OC(O)R . In some embodiments is a
compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
12 13 11 11
C(O)O-(CR R )-OC(O)R and R is C alkyl. In some embodiments is a compound of Formula
8 12 13
(Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)O-(CR R )-
11 11
OC(O)R and R is C1-6alkoxy. In some embodiments is a compound of Formula (Ia), or a
pharmaceutically acceptable salt or solvate thereof, wherein R is -CH CH OCH C(O)OH. In some
2 2 2
embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate
thereof, wherein R is -CH2CH2N(SO2CH3)CH2C(O)OH. In some embodiments is a compound of
Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
CH CH CH C(O)OCH(CH )OC(O)OCH CH . In some embodiments is a compound of Formula
2 2 2 3 2 3
(Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
CH CH CH C(O)OCH(CH )OC(O)OCH(CH ) . In some embodiments is a compound of Formula
2 2 2 3 3 2
(Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
CH2CH2CH2C(O)OCH2OC(O)OC(CH3)3. In some embodiments is a compound of Formula (Ia), or a
pharmaceutically acceptable salt or solvate thereof, wherein R is -
CH CH CH C(O)OCH(CH )OC(O)CH(CH ) .
2 2 2 3 3 2
In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt
or solvate thereof, wherein R is -C4-6alkyl-C(O)OH. In some embodiments is a compound of
Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
CH CH CH CH C(O)OH. In some embodiments is a compound of Formula (Ia), or a
2 2 2 2
pharmaceutically acceptable salt or solvate thereof, wherein R is -CH2CH(CH3)CH2C(O)OH.
In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt
or solvate thereof, wherein R is -C cycloalkyl-C(O)OH. In some embodiments is a compound of
Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C alkyl-C
1-6 3-
6cycloalkyl-C(O)OH.
In some embodiments of a compound of Formula (Ia), or a pharmaceutically acceptable salt
or solvate thereof, wherein n is 0, 1, 2, or 3. In some embodiments of a compound of Formula (Ia),
or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2. In some
embodiments of a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate
thereof, wherein n is 1 or 2. In some embodiments of a compound of Formula (Ia), or a
pharmaceutically acceptable salt or solvate thereof, wherein n is 0 or 1. In some embodiments of a
compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
In some embodiments of a compound of Formula (Ia), or a pharmaceutically acceptable salt or
solvate thereof, wherein n is 1. In some embodiments of a compound of Formula (Ia), or a
pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments of a
compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3.
In some embodiments of a compound of Formula (Ia), or a pharmaceutically acceptable salt or
solvate thereof, wherein n is 4.
In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt
2 17
or solvate thereof, wherein n is 1 and R is halogen, C alkyl, C haloalkyl, or -OR . In some
1-6 1-6
embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate
thereof, wherein n is 1 and R is independently selected from C1-6alkyl, halogen, -CN, or C1-
haloalkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable
salt or solvate thereof, wherein n is 1 and R is halogen, C alkyl, or C haloalkyl. In some
1-6 1-6
embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate
thereof, wherein n is 1 and R is halogen. In some embodiments is a compound of Formula (Ia), or a
pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R is -Cl. In some
embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate
thereof, wherein n is 1 and R is -F. In some embodiments is a compound of Formula (Ia), or a
pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R is C alkyl. In some
embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate
thereof, wherein n is 1 and R is -CH3. In some embodiments is a compound of Formula (Ia), or a
pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R is C1-6haloalkyl. In some
embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate
thereof, wherein n is 1 and R is -CF3. In some embodiments is a compound of Formula (Ia), or a
pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R is C1-6alkoxy. In some
embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate
thereof, wherein n is 1 and R is -OCH . In some embodiments is a compound of Formula (Ia), or a
pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R is C1-6haloalkoxy. In some
embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate
thereof, wherein n is 1 and R is -OCF . In some embodiments is a compound of Formula (Ia), or a
pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R is -OH. In some
embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate
thereof, wherein n is 1 and R is -CN.
In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt
or solvate thereof, wherein n is 2 and each R is independently halogen, C1-6alkyl, C1-6haloalkyl, or –
OR . In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or
solvate thereof, wherein n is 2 and each R is independently halogen, C alkyl, C haloalkyl, C
1-6 1-6 1-
6alkoxy, -OCF3, or -CN. In some embodiments is a compound of Formula (Ia), or a
pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R is independently
halogen, C alkyl, C haloalkyl, C alkoxy, or -OCF . In some embodiments is a compound of
1-6 1-6 1-6 3
Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R is
independently halogen, C1-6alkyl, C1-6haloalkyl, or -OCF3. In some embodiments is a compound of
Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R is
independently halogen, C1-6alkyl, or C1-6haloalkyl. In some embodiments is a compound of Formula
(Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R is
independently halogen or C haloalkyl. In some embodiments is a compound of Formula (Ia), or a
pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R is independently
halogen or C1-6alkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically
acceptable salt or solvate thereof, wherein n is 2 and each R is independently halogen. In some
embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate
thereof, wherein n is 2 and each R is independently C1-6alkyl. In some embodiments is a compound
of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R
is independently C haloalkyl.
In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt
or solvate thereof, wherein n is 3 and each R is independently halogen, C1-6alkyl, C1-6haloalkyl, C1-
6alkoxy, C1-6haloalkoxy, -OH, or -CN. In some embodiments is a compound of Formula (Ia), or a
pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and each R is independently
halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, -OCF3, or -CN. In some embodiments is a compound
of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and each R
is independently halogen, C alkyl, C haloalkyl, C alkoxy, or -OCF . In some embodiments is a
1-6 1-6 1-6 3
compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3
and each R is independently halogen, C1-6alkyl, C1-6haloalkyl, or -OCF3. In some embodiments is a
compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3
and each R is independently halogen, C alkyl, or C haloalkyl. In some embodiments is a
1-6 1-6
compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3
and each R is independently halogen or C1-6haloalkyl. In some embodiments is a compound of
Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and each R is
independently halogen or C1-6alkyl. In some embodiments is a compound of Formula (Ia), or a
pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and each R is independently
halogen. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt
or solvate thereof, wherein n is 3 and each R is independently C alkyl. In some embodiments is a
compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3
and each R is independently C haloalkyl.
In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt
or solvate thereof, wherein n is 4 and each R is independently halogen, C1-6alkyl, C1-6haloalkyl, and
-OR .
In some embodiments is a compound of Formula (Ib):
Formula (Ib);
wherein:
each R is independently selected from C alkyl, halogen, -CN, C haloalkyl, -C
1-6 1-6 1-
17 18 19
6alkyl(heterocycloalkyl), -OR , and -C(O)NR R ;
3 6 7 8 6 7 6 7 8 6 7 8
R is -(CR R ) -R , -(CR R ) -Y-(CR R ) -R , or -(CR R ) -C cycloalkyl-R ;
m p q t 3-6
Y is -O- or -N(R )-;
6 7 6 7
each R and R is each independently selected from H, F, and C1-6alkyl; or R and R , together
with the carbon to which they are attached, form a C cycloalkyl ring;
8 9 10 12 13 11
R is -C(O)OR , -C(O)R , or -C(O)O-(CR R )-OC(O)R ;
R is H or C alkyl;
21
R is C1-6alkyl or -NHSO2R ;
R is C1-6alkyl or C1-6alkoxy;
12 13
R and R is each independently H or C alkyl;
each R is independently selected from H, C alkyl, C haloalkyl, and C cycloalkyl;
1-6 1-6 3-6
18 19
each R and R is each independently selected from H, C1-6alkyl, C3-6cycloalkyl, aryl, and
18 19
heteroaryl; or R and R , together with the nitrogen to which they are attached, form a
heterocycloalkyl ring optionally substituted with one, two, or three R ;
each R is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, oxo, -CN, and C3-
6cycloalkyl;
R is C alkyl or C cycloalkyl;
1-6 3-6
22 23
R is H, C1-6alkyl, or -SO2R ;
R is C1-6alkyl;
m is 1, 2, 3 or 4;
n is 0, 1, 2, 3, or 4;
p is 2, 3, or 4;
q is 1, 2, or 3; and
t is 0, 1, or 2;
or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt
3 6 7 8
or solvate thereof, wherein R is -(CR R ) -R . In some embodiments is a compound of Formula
(Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)OR . In some
embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate
8 9 9
thereof, wherein R is -C(O)OR and R is H. In some embodiments is a compound of Formula (Ib),
8 9 9
or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)OR and R is C alkyl.
In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or
8 9 9
solvate thereof, wherein R is -C(O)OR and R is -CH . In some embodiments is a compound of
Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)OR and
R is -CH2CH3. In some embodiments is a compound of Formula (Ib), or a pharmaceutically
8 10
acceptable salt or solvate thereof, wherein R is -C(O)R . In some embodiments is a compound of
8 10
Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)R and
21
R is -NHSO2R . In some embodiments is a compound of Formula (Ib), or a pharmaceutically
8 10 10 21 21
acceptable salt or solvate thereof, wherein R is -C(O)R , R is -NHSO2R , and R is C1-6alkyl. In
some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate
8 10 10 21 21
thereof, wherein R is -C(O)R , R is -NHSO R , and R is C cycloalkyl. In some embodiments
2 3-6
is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R
12 13 11
is -C(O)O-(CR R )-OC(O)R . In some embodiments is a compound of Formula (Ib), or a
8 12 13 11
pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)O-(CR R )-OC(O)R and
R is C alkyl. In some embodiments is a compound of Formula (Ib), or a pharmaceutically
8 12 13 11 11
acceptable salt or solvate thereof, wherein R is -C(O)O-(CR R )-OC(O)R and R is C1-6alkoxy.
In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or
solvate thereof, wherein R is -CH C(O)OH. In some embodiments is a compound of Formula (Ib),
or a pharmaceutically acceptable salt or solvate thereof, wherein R is -CH2CH2C(O)OH. In some
embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate
1 3 3
thereof, wherein R is -OR and R is . In some embodiments is a compound of
1 3 3
Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -OR and R is
. In some embodiments is a compound of Formula (Ib), or a pharmaceutically
acceptable salt or solvate thereof, wherein R is -CH CH CH C(O)OH. In some embodiments is a
2 2 2
compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
CH CH(CH )CH C(O)OH. In some embodiments is a compound of Formula (Ib), or a
2 3 2
pharmaceutically acceptable salt or solvate thereof, wherein R is -CH CH C(O)OCH . In some
2 2 3
embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate
thereof, wherein R is -CH2CH2C(O)OCH2CH3. In some embodiments is a compound of Formula
(Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -CH CH C(O)OC(CH ) .
2 2 3 3
In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or
solvate thereof, wherein R is -CH2CH2CH2C(O)OCH3. In some embodiments is a compound of
Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
CH CH CH C(O)OCH CH . In some embodiments is a compound of Formula (Ib), or a
2 2 2 2 3
pharmaceutically acceptable salt or solvate thereof, wherein R is -CH2CH2CH2C(O)OC(CH3)3.
In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt
3 6 7 6 7 8
or solvate thereof, wherein R is -(CR R ) -Y-(CR R ) -R . In some embodiments is a compound of
3 6 7
Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -(CR R )p-Y-
6 7 8 6 7
(CR R )q-R and each R and R is each independently selected from H and C1-6alkyl. In some
embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate
3 6 7 6 7 8 6 7
thereof, wherein R is -(CR R )p-Y-(CR R )q-R and each R and R is H. In some embodiments is a
compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein is -
6 7 6 7 8
(CR R )p-Y-(CR R )q-R and Y is -O-. In some embodiments is a compound of Formula (Ib), or a
3 6 7 6 7 8
pharmaceutically acceptable salt or solvate thereof, wherein R is -(CR R )p-Y-(CR R )q-R and Y is
-N(R )-. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable
3 6 7 6 7 8 22 22 23
salt or solvate thereof, wherein R is -(CR R ) -Y-(CR R ) -R , Y is -N(R )-, and R is -SO R . In
p q 2
some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate
thereof, wherein q is 1. In some embodiments is a compound of Formula (Ib), or a pharmaceutically
acceptable salt or solvate thereof, wherein p is 2. In some embodiments is a compound of Formula
(Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)OR . In some
embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate
8 9 9
thereof, wherein R is -C(O)OR and R is H. In some embodiments is a compound of Formula (Ib),
8 9 9
or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)OR and R is C1-6alkyl.
In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or
8 9 9
solvate thereof, wherein R is -C(O)OR and R is -CH . In some embodiments is a compound of
Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)OR and
R is -CH2CH3. In some embodiments is a compound of Formula (Ib), or a pharmaceutically
8 10
acceptable salt or solvate thereof, wherein R is -C(O)R . In some embodiments is a compound of
8 10
Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)R and
21
R is -NHSO2R . In some embodiments is a compound of Formula (Ib), or a pharmaceutically
8 10 10 21 21
acceptable salt or solvate thereof, wherein R is -C(O)R , R is -NHSO2R , and R is C1-6alkyl. In
some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate
8 10 10 21 21
thereof, wherein R is -C(O)R , R is -NHSO2R , and R is C3-6cycloalkyl. In some embodiments
is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R
12 13 11
is -C(O)O-(CR R )-OC(O)R . In some embodiments is a compound of Formula (Ib), or a
8 12 13 11
pharmaceutically acceptable salt or solvate thereof, wherein R is -C(O)O-(CR R )-OC(O)R and
R is C1-6alkyl. In some embodiments is a compound of Formula (Ib), or a pharmaceutically
8 12 13 11 11
acceptable salt or solvate thereof, wherein R is -C(O)O-(CR R )-OC(O)R and R is C alkoxy.
In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or
solvate thereof, wherein R is -CH2CH2OCH2C(O)OH. In some embodiments is a compound of
Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
CH CH N(SO CH )CH C(O)OH. In some embodiments is a compound of Formula (Ib), or a
2 2 2 3 2
pharmaceutically acceptable salt or solvate thereof, wherein R is -
CH2CH2CH2C(O)OCH(CH3)OC(O)OCH2CH3. In some embodiments is a compound of Formula
(Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
CH CH CH C(O)OCH(CH )OC(O)OCH(CH ) . In some embodiments is a compound of Formula
2 2 2 3 3 2
(Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
CH2CH2CH2C(O)OCH2OC(O)OC(CH3)3. In some embodiments is a compound of Formula (Ib), or a
pharmaceutically acceptable salt or solvate thereof, wherein R is -
CH CH CH C(O)OCH(CH )OC(O)CH(CH ) .
2 2 2 3 3 2
In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt
3 6 7 8
or solvate thereof, wherein R is -(CR R ) -C cycloalkyl-R . In some embodiments is a compound
t 3-6
3 6 7
of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -(CR R ) -C
t 3-
6cycloalkyl-R and t is 0. In some embodiments is a compound of Formula (Ib), or a
3 6 7 8
pharmaceutically acceptable salt or solvate thereof, wherein R is -(CR R )t-C3-6cycloalkyl-R and t
is 1. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or
3 6 7 8
solvate thereof, wherein R is -(CR R )t-C3-6cycloalkyl-R and t is 2. In some embodiments is a
compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
cyclopropyl-C(O)OH. In some embodiments is a compound of Formula (Ib), or a pharmaceutically
acceptable salt or solvate thereof, wherein R is -cyclobutyl-C(O)OH. In some embodiments is a
compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -
cyclopentyl-C(O)OH.
In some embodiments of a compound of Formula (Ib), or a pharmaceutically acceptable salt
or solvate thereof, wherein n is 0, 1, 2, or 3. In some embodiments of a compound of Formula (Ib),
or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2. In some
embodiments of a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate
thereof, wherein n is 1 or 2. In some embodiments of a compound of Formula (Ib), or a
pharmaceutically acceptable salt or solvate thereof, wherein n is 0 or 1. In some embodiments of a
compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
In some embodiments of a compound of Formula (Ib), or a pharmaceutically acceptable salt or
solvate thereof, wherein n is 1. In some embodiments of a compound of Formula (Ib), or a
pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments of a
compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3.
In some embodiments of a compound of Formula (Ib), or a pharmaceutically acceptable salt or
solvate thereof, wherein n is 4.
In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt
2 17
or solvate thereof, wherein n is 1 and R is halogen, C1-6alkyl, C1-6haloalkyl, or -OR . In some
embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate
thereof, wherein n is 1 and R is independently selected from C1-6alkyl, halogen, -CN, or C1-
haloalkyl. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable
salt or solvate thereof, wherein n is 1 and R is halogen, C1-6alkyl, or C1-6haloalkyl. In some
embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate
thereof, wherein n is 1 and R is halogen. In some embodiments is a compound of Formula (Ib), or a
pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R is -Cl. In some
embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate
thereof, wherein n is 1 and R is -F. In some embodiments is a compound of Formula (Ib), or a
pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R is C alkyl. In some
embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate
thereof, wherein n is 1 and R is -CH3. In some embodiments is a compound of Formula (Ib), or a
pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R is C haloalkyl. In some
embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate
thereof, wherein n is 1 and R is -CF3. In some embodiments is a compound of Formula (Ib), or a
pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R is C alkoxy. In some
embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate
thereof, wherein n is 1 and R is -OCH3. In some embodiments is a compound of Formula (Ib), or a
pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R is C haloalkoxy. In some
embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate
thereof, wherein n is 1 and R is -OCF3. In some embodiments is a compound of Formula (Ib), or a
pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R is -OH. In some
embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate
thereof, wherein n is 1 and R is -CN.
In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt
or solvate thereof, wherein n is 2 and each R is independently halogen, C alkyl, C haloalkyl, or -
1-6 1-6
OR . In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or
solvate thereof, wherein n is 2 and each R is independently halogen, C1-6alkyl, C1-6haloalkyl, C1-
alkoxy, -OCF , or -CN. In some embodiments is a compound of Formula (Ib), or a
pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R is independently
halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, or -OCF3. In some embodiments is a compound of
Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R is
independently halogen, C alkyl, C haloalkyl, or -OCF . In some embodiments is a compound of
1-6 1-6 3
Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R is
independently halogen, C1-6alkyl, or C1-6haloalkyl. In some embodiments is a compound of Formula
(Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R is
independently halogen or C haloalkyl. In some embodiments is a compound of Formula (Ib), or a
pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R is independently
halogen or C1-6alkyl. In some embodiments is a compound of Formula (Ib), or a pharmaceutically
acceptable salt or solvate thereof, wherein n is 2 and each R is independently halogen. In some
embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate
thereof, wherein n is 2 and each R is independently C1-6alkyl. In some embodiments is a compound
of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R
is independently C haloalkyl.
In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt
or solvate thereof, wherein n is 3 and each R is independently halogen, C1-6alkyl, C1-6haloalkyl, C1-
alkoxy, C haloalkoxy, -OH, or -CN. In some embodiments is a compound of Formula (Ib), or a
6 1-6
pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and each R is independently
halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, -OCF3, or -CN. In some embodiments is a compound
of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and each R
is independently halogen, C alkyl, C haloalkyl, C alkoxy, or -OCF . In some embodiments is a
1-6 1-6 1-6 3
compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3
and each R is independently halogen, C alkyl, C haloalkyl, or -OCF . In some embodiments is a
1-6 1-6 3
compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3
and each R is independently halogen, C1-6alkyl, or C1-6haloalkyl. In some embodiments is a
compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3
and each R is independently halogen or C haloalkyl. In some embodiments is a compound of
Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and each R is
independently halogen or C1-6alkyl. In some embodiments is a compound of Formula (Ib), or a
pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and each R is independently
halogen. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt
or solvate thereof, wherein n is 3 and each R is independently C1-6alkyl. In some embodiments is a
compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3
and each R is independently C haloalkyl.
In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt
or solvate thereof, wherein n is 4 and each R is independently halogen, C1-6alkyl, C1-6haloalkyl, and
-OR .
Further embodiments provided herein include combinations of one or more of the particular
embodiments set forth above.
In some embodiments, the compound disclosed herein has the structure provided in Table
TABLE 1
Chemical
Synthesis Structure Name
Example
1,1,1,3,3,3-Hexafluoropropanyl 4-(2-((4-
ethoxyoxobutyl)amino)
(trifluoromethyl)benzyl)piperazine
carboxylate
1,1,1,3,3,3-Hexafluoropropanyl 4-(2-((4-
(tert-butoxy)oxobutyl)amino)
(trifluoromethyl)benzyl)piperazine
carboxylate
4-(2-((4-(((1,1,1,3,3,3-Hexafluoropropan
yl)oxy)carbonyl)piperazinyl)methyl)
(trifluoromethyl)phenoxy)butanoic acid
4-(5-Chloro((4-(((1,1,1,3,3,3-
hexafluoropropanyl)oxy)carbonyl)piperazin-
1-yl)methyl)phenoxy)butanoic acid
Chemical
Synthesis Structure Name
Example
1,1,1,3,3,3-Hexafluoropropanyl 4-(2-((4-(1-
((ethoxycarbonyl)oxy)ethoxy)
oxobutyl)amino)
(trifluoromethyl)benzyl)piperazine
carboxylate
1,1,1,3,3,3-Hexafluoropropanyl 4-(2-((4-(1-
((isopropoxycarbonyl)oxy)ethoxy)
oxobutyl)amino)
(trifluoromethyl)benzyl)piperazine
carboxylate
1,1,1,3,3,3-Hexafluoropropanyl 4-(2-((4-
oxo((pivaloyloxy)methoxy)butyl)amino)
(trifluoromethyl)benzyl)piperazine
carboxylate
1,1,1,3,3,3-Hexafluoropropanyl 4-(2-((4-(1-
(isobutyryloxy)ethoxy)oxobutyl)amino)
(trifluoromethyl)benzyl)piperazine
carboxylate
Chemical
Synthesis Structure Name
Example
2-(2-((2-((4-(((1,1,1,3,3,3-Hexafluoropropan
yl)oxy)carbonyl)piperazinyl)methyl)
(trifluoromethyl)phenyl)amino)ethoxy)acetic
acid
2-(2-((4-Chloro((4-(((1,1,1,3,3,3-
hexafluoropropanyl)oxy)carbonyl)piperazin-
1-yl)methyl)phenyl)amino)ethoxy)acetic acid
2-(2-((2-Fluoro((4-(((1,1,1,3,3,3-
hexafluoropropanyl)oxy)carbonyl)piperazin-
1-yl)methyl)phenyl)amino)ethoxy)acetic acid
N-(2-((5-Chloro((4-(((1,1,1,3,3,3-
hexafluoropropanyl)oxy)carbonyl)piperazin-
1-yl)methyl)phenyl)amino)ethyl)-N-
(methylsulfonyl)glycine
2-(5-Chloro((4-(((1,1,1,3,3,3-
hexafluoropropanyl)oxy)carbonyl)piperazin-
1-yl)methyl)phenoxy)acetic acid
2-(2-((4-(((1,1,1,3,3,3-Hexafluoropropan
yl)oxy)carbonyl)piperazinyl)methyl)
(trifluoromethyl)phenoxy)acetic acid
Chemical
Synthesis Structure Name
Example
-(2-((4-(((1,1,1,3,3,3-Hexafluoropropan
yl)oxy)carbonyl)piperazinyl)methyl)
(trifluoromethyl)phenyl)pentanoic acid
1-(2-((4-(((1,1,1,3,3,3-Hexafluoropropan
yl)oxy)carbonyl)piperazinyl)methyl)
(trifluoromethyl)phenoxy)cyclopropane
carboxylic acid
2-(3-((4-(((1,1,1,3,3,3-hexafluoropropan
yl)oxy)carbonyl)piperazinyl)methyl)
(trifluoromethyl)phenyl)acetic acid
4-(2-((4-(((1,1,1,3,3,3-hexafluoropropan
yl)oxy)carbonyl)piperazinyl)methyl)
(trifluoromethyl)phenyl)-2,2-dimethylbut
ynoic acid
1-(3-((4-(((1,1,1,3,3,3-hexafluoropropan
yl)oxy)carbonyl)piperazinyl)methyl)
(trifluoromethyl)phenoxy)cyclopropane
carboxylic acid
1,1,1,3,3,3-hexafluoropropanyl 4-(3-fluoro-
4-methyl(2-(methylsulfonamido)
oxoethoxy)benzyl)piperazinecarboxylate
Chemical
Synthesis Structure Name
Example
1,1,1,3,3,3-hexafluoropropanyl 4-(2-(2-
(cyclopropanesulfonamido)oxoethoxy)
fluoromethylbenzyl)piperazine
carboxylate
1-(2-((4-(((1,1,1,3,3,3-Hexafluoropropan
yl)oxy)carbonyl)piperazinyl)methyl)
(trifluoromethyl)phenoxy)cyclopropane
carboxylic acid
1-((2-Chloro((4-(((1,1,1,3,3,3-
hexafluoropropan
yl)oxy)carbonyl)piperazinyl)methyl)
methylphenoxy)methyl)cyclopropane
carboxylic acid
4-(2-Fluoro((4-(((1,1,1,3,3,3-
hexafluoropropan
yl)oxy)carbonyl)piperazinyl)methyl)
methylphenyl)-2,2-dimethylbutynoic acid
4-(2-Fluoro((4-(((1,1,1,3,3,3-
hexafluoropropan
yl)oxy)carbonyl)piperazin
yl)methyl)phenyl)-2,2-dimethylbutynoic
acid
1-((2-Cyanofluoro((4-(((1,1,1,3,3,3-
hexafluoropropan
yl)oxy)carbonyl)piperazin
yl)methyl)phenoxy)methyl)cyclopropane
carboxylic acid
Chemical
Synthesis Structure Name
Example
1-((2-((4-(((1,1,1,3,3,3-hexafluoropropan
yl)oxy)carbonyl)piperazinyl)methyl)
(trifluoromethyl)phenoxy)methyl)cyclopropan
ecarboxylic acid
1-((3-((4-(((1,1,1,3,3,3-hexafluoropropan
yl)oxy)carbonyl)piperazinyl)methyl)
(trifluoromethyl)phenoxy)methyl)cyclopropan
ecarboxylic acid
1-((2-fluoro((4-(((1,1,1,3,3,3-
hexafluoropropan
29 yl)oxy)carbonyl)piperazinyl)methyl)
methylphenoxy)methyl)cyclopropane
carboxylic acid
1-((2-((4-(((1,1,1,3,3,3-hexafluoropropan
yl)oxy)carbonyl)piperazinyl)methyl)
(trifluoromethyl)phenoxy)methyl)cyclopropan
ecarboxylic acid
1,1,1,3,3,3-hexafluoropropanyl 4-(3-fluoro-
4-methyl((1-
((methylsulfonyl)carbamoyl)cyclopropyl)meth
oxy)benzyl)piperazinecarboxylate
1-((2-fluoro((4-(((1,1,1,3,3,3-
hexafluoropropan
32 yl)oxy)carbonyl)piperazinyl)methyl)
methylphenoxy)methyl)cyclopentane
carboxylic acid
Chemical
Synthesis Structure Name
Example
1-((2,3-difluoro((4-(((1,1,1,3,3,3-
hexafluoropropan
33 yl)oxy)carbonyl)piperazin
yl)methyl)phenoxy)methyl)cyclopropane
carboxylic acid
1-((4,5-difluoro((4-(((1,1,1,3,3,3-
hexafluoropropan
34 yl)oxy)carbonyl)piperazin
yl)methyl)phenoxy)methyl)cyclopropane
carboxylic acid
1-((5-cyano((4-(((1,1,1,3,3,3-
hexafluoropropan
yl)oxy)carbonyl)piperazin
yl)methyl)phenoxy)methyl)cyclopropane
carboxylic acid
1-((2-cyano((4-(((1,1,1,3,3,3-
hexafluoropropan
36 yl)oxy)carbonyl)piperazin
yl)methyl)phenoxy)methyl)cyclopropane
carboxylic acid
1-((2,3-difluoro((4-(((1,1,1,3,3,3-
hexafluoropropan
37 yl)oxy)carbonyl)piperazin
yl)methyl)phenoxy)methyl)cyclopentane
carboxylic acid
1-((3-fluoro((4-(((1,1,1,3,3,3-
hexafluoropropan
38 yl)oxy)carbonyl)piperazinyl)methyl)
methylphenoxy)methyl)cyclopropane
carboxylic acid
Chemical
Synthesis Structure Name
Example
1-((4-fluoro((4-(((1,1,1,3,3,3-
hexafluoropropan
39 yl)oxy)carbonyl)piperazinyl)methyl)
methylphenoxy)methyl)cyclopropane
carboxylic acid
1-((4-fluoro((4-(((1,1,1,3,3,3-
hexafluoropropan
40 yl)oxy)carbonyl)piperazinyl)methyl)
methylphenoxy)methyl)cyclopentane
carboxylic acid
1-((2-fluoro((4-(((1,1,1,3,3,3-
hexafluoropropan
41 yl)oxy)carbonyl)piperazin
yl)methyl)phenoxy)methyl)cyclopentane
carboxylic acid
1-((5-fluoro((4-(((1,1,1,3,3,3-
hexafluoropropan
42 yl)oxy)carbonyl)piperazin
yl)methyl)phenoxy)methyl)cyclopentane
carboxylic acid
1-((5-cyano((4-(((1,1,1,3,3,3-
hexafluoropropan
43 yl)oxy)carbonyl)piperazin
yl)methyl)phenoxy)methyl)cyclopentane
carboxylic acid
(1s,3s)(2-((4-(((1,1,1,3,3,3-
hexafluoropropan
44 yl)oxy)carbonyl)piperazinyl)methyl)
(trifluoromethyl)phenoxy)cyclobutane
carboxylic acid
Chemical
Synthesis Structure Name
Example
(1S,3R)(2-((4-(((1,1,1,3,3,3-
hexafluoropropan
45 yl)oxy)carbonyl)piperazinyl)methyl)
(trifluoromethyl)phenoxy)cyclopentane
carboxylic acid
(1R,3R)(2-((4-(((1,1,1,3,3,3-
hexafluoropropan
46 yl)oxy)carbonyl)piperazinyl)methyl)
(trifluoromethyl)phenoxy)cyclopentane
carboxylic acid
(1r,3r)(2-((4-(((1,1,1,3,3,3-
hexafluoropropan
47 yl)oxy)carbonyl)piperazinyl)methyl)
(trifluoromethyl)phenoxy)cyclobutane
carboxylic acid
4-(3-((4-(((1,1,1,3,3,3-hexafluoropropan
yl)oxy)carbonyl)piperazinyl)methyl)
(trifluoromethyl)phenyl)-2,2-dimethylbut
ynoic acid
2-(2-chloro((4-(((1,1,1,3,3,3-
hexafluoropropan
yl)oxy)carbonyl)piperazinyl)methyl)
methylphenoxy)acetic acid
1,1,1,3,3,3-hexafluoropropanyl 4-(3-chloro-
50 4-methyl(2-(methylsulfonamido)
oxoethoxy)benzyl)piperazinecarboxylate
Chemical
Synthesis Structure Name
Example
1,1,1,3,3,3-hexafluoropropanyl 4-(3-chloro-
2-(2-(cyclopropanesulfonamido)
oxoethoxy)methylbenzyl)piperazine
carboxylate
1,1,1,3,3,3-hexafluoropropanyl 4-(4-chloro-
52 2-(2-(methylsulfonamido)
oxoethoxy)benzyl)piperazinecarboxylate
1,1,1,3,3,3-hexafluoropropanyl 4-(3-chloro-
4-methyl((1-
((methylsulfonyl)carbamoyl)cyclopropyl)meth
oxy)benzyl)piperazinecarboxylate
O CF
2-(2-fluoro((4-(((1,1,1,3,3,3-
N O CF
hexafluoropropan
yl)oxy)carbonyl)piperazinyl)methyl)
methylphenoxy)acetic acid
1,1,1,3,3,3-hexafluoropropanyl 4-(2-((1-
((methylsulfonyl)carbamoyl)cyclopropyl)meth
oxy)(trifluoromethyl)benzyl)piperazine
carboxylate
Chemical
Synthesis Structure Name
Example
O CF
4-(2-chloro((4-(((1,1,1,3,3,3-
N O CF
hexafluoropropan
56 yl)oxy)carbonyl)piperazin
yl)methyl)phenyl)-2,2-dimethylbutynoic
acid
In some embodimentss the compound disclosed herein is selected from:
, , and
O CF
N O CF
; or a pharmaceutically acceptable salt or solvate thereof.
Preparation of the Compounds
The compounds used in the reactions described herein are made according to known
organic synthesis techniques, starting from commercially available chemicals and/or from
compounds described in the chemical literature. "Commercially available chemicals" are obtained
from standard commercial sources including Acros Organics (Geel, Belgium), Aldrich Chemical
(Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Ark
Pharm, Inc. (Libertyville, IL), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada),
Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Combi-blocks (San Diego, CA),
Crescent Chemical Co. (Hauppauge, NY), eMolecules (San Diego, CA), Fisher Scientific Co.
(Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN
Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham,
NH), Matrix Scientific, (Columbia, SC), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish
Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce
Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Ryan Scientific, Inc. (Mount
Pleasant, SC), Spectrum Chemicals (Gardena, CA), Sundia Meditech, (Shanghai, China), TCI America
(Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and WuXi (Shanghai, China).
Suitable reference books and treatises that detail the synthesis of reactants useful in the
preparation of compounds described herein, or provide references to articles that describe the
preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York;
S. R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York,
1983; H. O. House, "Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif.
1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J.
March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed.,
Wiley-Interscience, New York, 1992. Additional suitable reference books and treatises that detail the
synthesis of reactants useful in the preparation of compounds described herein, or provide references
to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. "Organic
Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994)
John Wiley & Sons ISBN: 329074-5; Hoffman, R.V. "Organic Chemistry, An Intermediate
Text" (1996) Oxford University Press, ISBN 0509618-5; Larock, R. C. "Comprehensive Organic
Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH,
ISBN: 019031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and
Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 060180-2; Otera, J. (editor) "Modern
Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 329871-1; Patai, S. "Patai's 1992 Guide to the
Chemistry of Functional Groups" (1992) Interscience ISBN: 093022-9; Solomons, T. W. G.
"Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 019095-0; Stowell, J.C.,
"Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 057456-2;
"Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia"
(1999) John Wiley & Sons, ISBN: 329645-X, in 8 volumes; "Organic Reactions" (1942-2000)
John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons,
in 73 volumes.
Specific and analogous reactants are also identified through the indices of known chemicals
prepared by the Chemical Abstract Service of the American Chemical Society, which are available in
most public and university libraries, as well as through on-line databases (the American Chemical
Society, Washington, D.C., may be contacted for more details). Chemicals that are known but not
commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where
many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis
services. A reference for the preparation and selection of pharmaceutical salts of the piperazine
carbamates described herein is P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts",
Verlag Helvetica Chimica Acta, Zurich, 2002.
Further Forms of Compounds Disclosed Herein
Isomers
Furthermore, in some embodiments, the compounds described herein exist as geometric
isomers. In some embodiments, the compounds described herein possess one or more double bonds.
The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z)
isomers as well as the corresponding mixtures thereof. In some situations, compounds exist as
tautomers. The compounds described herein include all possible tautomers within the formulas
described herein. In some situations, the compounds described herein possess one or more chiral
centers and each center exists in the R configuration, or S configuration. The compounds described
herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding
mixtures thereof. In additional embodiments of the compounds and methods provided herein,
mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step,
combination, or interconversion are useful for the applications described herein. In some
embodiments, the compounds described herein are prepared as optically pure enantiomers by chiral
chromatographic resolution of the racemic mixture. In some embodiments, the compounds described
herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound
with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating
the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable
complexes are preferred (e.g., crystalline diastereomeric salts). In some embodiments, the
diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities,
reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments,
the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution
techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer
is then recovered, along with the resolving agent, by any practical means that would not result in
racemization.
Labeled compounds
In some embodiments, the compounds described herein exist in their isotopically-labeled
forms. In some embodiments, the methods disclosed herein include methods of treating diseases by
administering such isotopically-labeled compounds. In some embodiments, the methods disclosed
herein include methods of treating diseases by administering such isotopically-labeled compounds as
pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include
isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one
or more atoms are replaced by an atom having an atomic mass or mass number different from the
atomic mass or mass number usually found in nature. Examples of isotopes that are incorporated into
compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,
2 3 13 14 l5 18 17 31 32 35 18 36
sulfur, fluorine and chloride, such as H, H, C, C, N, O, O, P, P, S, F, and Cl,
respectively. Compounds described herein, and the pharmaceutically acceptable salts, esters, solvate,
hydrates or derivatives thereof which contain the aforementioned isotopes and/or other isotopes of
other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for
3 14
example those into which radioactive isotopes such as H and C are incorporated, are useful in drug
3 14
and/or substrate tissue distribution assays. Tritiated, i. e., H and carbon-14, i. e., C, isotopes are
particularly preferred for their ease of preparation and detectability. Further, substitution with heavy
isotopes such as deuterium, i.e., H, produces certain therapeutic advantages resulting from greater
metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some
embodiments, the isotopically labeled compounds, pharmaceutically acceptable salt, ester, solvate,
hydrate or derivative thereof is prepared by any suitable method.
In some embodiments, the compounds described herein are labeled by other means,
including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels,
or chemiluminescent labels.
Pharmaceutically acceptable salts
In some embodiments, the compounds described herein exist as their pharmaceutically
acceptable salts. In some embodiments, the methods disclosed herein include methods of treating
diseases by administering such pharmaceutically acceptable salts. In some embodiments, the
methods disclosed herein include methods of treating diseases by administering such
pharmaceutically acceptable salts as pharmaceutical compositions.
In some embodiments, the compounds described herein possess acidic or basic groups and
therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids,
to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ
during the final isolation and purification of the compounds of the invention, or by separately
reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus
formed.
Solvates
In some embodiments, the compounds described herein exist as solvates. The invention
provides for methods of treating diseases by administering such solvates. The invention further
provides for methods of treating diseases by administering such solvates as pharmaceutical
compositions.
Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in
some embodiments, are formed during the process of crystallization with pharmaceutically
acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is
water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described
herein are conveniently prepared or formed during the processes described herein. By way of
example only, hydrates of the compounds described herein are conveniently prepared by
recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not
limited to, dioxane, tetrahydrofuran or methanol. In addition, the compounds provided herein exist in
unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the
unsolvated forms for the purposes of the compounds and methods provided herein.
Prodrugs
In some embodiments, the compounds described herein exist in prodrug form. The
invention provides for methods of treating diseases by administering such prodrugs. The invention
further provides for methods of treating diseases by administering such prodrugs as pharmaceutical
compositions.
In some embodiments, prodrugs include compounds wherein an amino acid residue, or a
polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined
through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of
the present invention. The amino acid residues include but are not limited to the 20 naturally
occurring amino acids and also includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine,
3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, cirtulline, homocysteine,
homoserine, ornithine and methionine sulfone. In other embodiments, prodrugs include compounds
wherein a nucleic acid residue, or an oligonucleotide of two or more (e.g., two, three or four) nucleic
acid residues is covalently joined to a compound of the present invention.
Pharmaceutically acceptable prodrugs of the compounds described herein also include, but
are not limited to, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives,
quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates,
phosphate esters, metal salts and sulfonate esters. In some embodiments, compounds having free
amino, amido, hydroxy or carboxylic groups are converted into prodrugs. For instance, free carboxyl
groups are derivatized as amides or alkyl esters. In certain instances, all of these prodrug moieties
incorporate groups including but not limited to ether, amine and carboxylic acid functionalities.
Hydroxy prodrugs include esters, such as though not limited to, acyloxyalkyl (e.g.
acyloxymethyl, acyloxyethyl) esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters,
phosphate esters, sulfonate esters, sulfate esters and disulfide containing esters; ethers, amides,
carbamates, hemisuccinates, dimethylaminoacetates and phosphoryloxymethyloxycarbonyls, as
outlined in Advanced Drug Delivery Reviews 1996, 19, 115.
Amine derived prodrugs include, but are not limited to the following groups and
combinations of groups:
O O O S S R' O R' O
R R R R
N R N O N S N O N S N O R N O O
H H H H H H H
O S R R' S R' S R' O
N N N R N N N S R N O R N S R
H H R H H H
R' S R' S R' O R' S R' O R' O
R R R R R R
N O S N O O N O S N S O N S S N S O
H H H H H H
as well as sulfonamides and phosphonamides.
In certain instances, sites on any aromatic ring portions are susceptible to various metabolic
reactions, therefore incorporation of appropriate substituents on the aromatic ring structures, reduce,
minimize or eliminate this metabolic pathway.
Pharmaceutical Compositions
In certain embodiments, the compound of Formula (I), (Ia), or (Ib) as described herein is
administered as a pure chemical. In some embodiments, the compound of Formula (I), (Ia), or (Ib)
described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to
herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or
acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a
chosen route of administration and standard pharmaceutical practice as described, for example, in
Remington: The Science and Practice of Pharmacy (Gennaro, 21 Ed. Mack Pub. Co., Easton, PA
(2005)).
Accordingly, provided herein is a pharmaceutical composition comprising at least one
compound of Formula (I), (Ia), or (Ib) described herein, or a pharmaceutically acceptable salt or
solvate thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or
excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the
composition and not deleterious to the recipient (i.e., the subject) of the composition.
One embodiment provides a pharmaceutical composition comprising a pharmaceutically
acceptable excipient and a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
One embodiment provides a pharmaceutical composition comprising a pharmaceutically
acceptable excipient and a compound of Formula (Ia), or a pharmaceutically acceptable salt thereof.
One embodiment provides a pharmaceutical composition comprising a pharmaceutically
acceptable excipient and a compound of Formula (Ib), or a pharmaceutically acceptable salt thereof.
One embodiment provides a pharmaceutical composition comprising a pharmaceutically
acceptable excipient and a compound of Formula (II), or a pharmaceutically acceptable salt thereof.
Another embodiment provides a pharmaceutical composition consisting essentially of a
pharmaceutically acceptable excipient and a compound of Formula (I), or a pharmaceutically
acceptable salt thereof. Another embodiment provides a pharmaceutical composition consisting
essentially of a pharmaceutically acceptable excipient and a compound of Formula (Ia), or a
pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical
composition consisting essentially of a pharmaceutically acceptable excipient and a compound of
Formula (Ib), or a pharmaceutically acceptable salt thereof. Another embodiment provides a
pharmaceutical composition consisting essentially of a pharmaceutically acceptable excipient and a
compound of Formula (II), or a pharmaceutically acceptable salt thereof.
In certain embodiments, the compound of Formula (I), (Ia), or (Ib) as described herein is
substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about
0.1%, of other organic small molecules, such as contaminating intermediates or by-products that are
created, for example, in one or more of the steps of a synthesis method.
These pharmaceutical compositions include those suitable for oral, rectal, topical, buccal,
parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) vaginal, ophthalmic, or
aerosol administration.
Exemplary pharmaceutical compositions are used in the form of a pharmaceutical
preparation, for example, in solid, semisolid or liquid form, which includes one or more of a
disclosed compound, as an active ingredient, in a mixture with an organic or inorganic carrier or
excipient suitable for external, enteral or parenteral applications. In some embodiments, the active
ingredient is compounded, for example, with the usual non-toxic, pharmaceutically acceptable
carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other
form suitable for use. The active object compound is included in the pharmaceutical composition in
an amount sufficient to produce the desired effect upon the process or condition of the disease.
In some embodiments for preparing solid compositions such as tablets, the principal active
ingredient is mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as
corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or
gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition
containing a homogeneous mixture of a disclosed compound or a non-toxic pharmaceutically
acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is
meant that the active ingredient is dispersed evenly throughout the composition so that the
composition is readily subdivided into equally effective unit dosage forms such as tablets, pills and
capsules.
In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders,
granules and the like), the subject composition is mixed with one or more pharmaceutically
acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1)
fillers or extenders, such as starches, cellulose, microcrystalline cellulose, silicified microcrystalline
cellulose, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example,
carboxymethylcellulose, hypromellose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or
acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as crospovidone,
croscarmellose sodium, sodium starch glycolate, agar-agar, calcium carbonate, potato or tapioca
starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as
paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents,
such as, for example, docusate sodium, cetyl alcohol and glycerol monostearate; (8) absorbents, such
as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid
polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the
case of capsules, tablets and pills, in some embodiments, the compositions comprise buffering
agents. In some embodiments, solid compositions of a similar type are also employed as fillers in
soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high
molecular weight polyethylene glycols and the like.
In some embodiments, a tablet is made by compression or molding, optionally with one or
more accessory ingredients. In some embodiments, compressed tablets are prepared using binder
(for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative,
disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),
surface-active or dispersing agent. In some embodiments, molded tablets are made by molding in a
suitable machine a mixture of the subject composition moistened with an inert liquid diluent. In
some embodiments, tablets, and other solid dosage forms, such as dragees, capsules, pills and
granules, are scored or prepared with coatings and shells, such as enteric coatings and other coatings.
Compositions for inhalation or insufflation include solutions and suspensions in
pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. Liquid
dosage forms for oral administration include pharmaceutically acceptable emulsions,
microemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject composition, in
some embodiments, the liquid dosage forms contain inert diluents, such as, for example, water or
other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils
(in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol,
tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and
mixtures thereof.
In some embodiments, suspensions, in addition to the subject composition, contain
suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and
sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and
tragacanth, and mixtures thereof.
In some embodiments, formulations for rectal or vaginal administration are presented as a
suppository, which are prepared by mixing a subject composition with one or more suitable non-
irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a
suppository wax or a salicylate, and which is solid at room temperature, but liquid at body
temperature and, therefore, will melt in the body cavity and release the active agent.
Dosage forms for transdermal administration of a subject composition include powders,
sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In some
embodiments, the active component is mixed under sterile conditions with a pharmaceutically
acceptable carrier, and with any preservatives, buffers, or propellants as required.
In some embodiments, the ointments, pastes, creams and gels contain, in addition to a
subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch,
tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and
zinc oxide, or mixtures thereof.
In some embodiments, powders and sprays contain, in addition to a subject composition,
excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide
powder, or mixtures of these substances. In some embodiments, sprays additionally contain
customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,
such as butane and propane.
In some embodiments, the compounds described herein are formulated as eye drops for
ophthalmic administration.
Compositions and compounds disclosed herein alternatively are administered by aerosol.
This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles
containing the compound. In some embodiments, a non-aqueous (e.g., fluorocarbon propellant)
suspension is used. In some embodiments, sonic nebulizers are used because they minimize
exposing the agent to shear, which results in degradation of the compounds contained in the subject
compositions. Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or
suspension of a subject composition together with conventional pharmaceutically acceptable carriers
and stabilizers. The carriers and stabilizers vary with the requirements of the particular subject
composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol),
innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as
glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic
solutions.
Pharmaceutical compositions suitable for parenteral administration comprise a subject
composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous
or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which are
reconstituted into sterile injectable solutions or dispersions just prior to use, which, in some
embodiments, contain antioxidants, buffers, bacteriostats, solutes which render the formulation
isotonic with the blood of the intended recipient or suspending or thickening agents.
Examples of suitable aqueous and non-aqueous carriers which are employed in the
pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol,
polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and
injectable organic esters, such as ethyl oleate and cyclodextrins. Proper fluidity is maintained, for
example, by the use of coating materials, such as lecithin, by the maintenance of the required particle
size in the case of dispersions, and by the use of surfactants
Also contemplated are enteral pharmaceutical formulations including a disclosed compound
and an enteric material; and a pharmaceutically acceptable carrier or excipient thereof. Enteric
materials refer to polymers that are substantially insoluble in the acidic environment of the stomach,
and that are predominantly soluble in intestinal fluids at specific pHs. The small intestine is the part
of the gastrointestinal tract (gut) between the stomach and the large intestine, and includes the
duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is
about 6.5 and the pH of the distal ileum is about 7.5. Accordingly, enteric materials are not soluble,
for example, until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, of about 5.8, of about
6.0, of about 6.2, of about 6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about 7.4, of
about 7.6, of about 7.8, of about 8.0, of about 8.2, of about 8.4, of about 8.6, of about 8.8, of about
9.0, of about 9.2, of about 9.4, of about 9.6, of about 9.8, or of about 10.0. Exemplary enteric
materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate
(HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate
(HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate
succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate
maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methylmethacrylic
acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic
acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate-
methylmethacrylate-chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein,
shellac and copal collophorium, and several commercially available enteric dispersion systems (e.g.,
Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl
30D, Coateric, and Aquateric). The solubility of each of the above materials is either known or is
readily determinable in vitro.
The dose of the composition comprising at least one compound of Formula (I), (Ia), or (Ib)
as described herein differs, depending upon the patient's (e.g., human) condition, that is, stage of the
disease, general health status, age, and other factors.
Pharmaceutical compositions are administered in a manner appropriate to the disease to be
treated (or prevented). An appropriate dose and a suitable duration and frequency of administration
will be determined by such factors as the condition of the patient, the type and severity of the
patient's disease, the particular form of the active ingredient, and the method of administration. In
general, an appropriate dose and treatment regimen provides the composition(s) in an amount
sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome,
such as more frequent complete or partial remissions, or longer disease-free and/or overall survival,
or a lessening of symptom severity. Optimal doses are generally determined using experimental
models and/or clinical trials. In some embodiments, the optimal dose depends upon the body mass,
weight, or blood volume of the patient.
Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more,
per day.
Methods
Disclosed herein are methods of modulating the activity of MAGL. Contemplated
methods, for example, comprise exposing said enzyme to a compound described herein. In some
embodiments, the compound utilized by one or more of the foregoing methods is one of the generic,
subgeneric, or specific compounds described herein, such as a compound of Formula (I), (Ia), or (Ib),
or a pharmaceutically acceptable salt or solvate thereof. The ability of compounds described herein
to modulate or inhibit MAGL is evaluated by procedures known in the art and/or described herein.
Another aspect of this disclosure provides methods of treating a disease associated with expression
or activity of MAGL in a patient.
Also disclosed herein are methods of treating and/or preventing in a patient in need thereof
a disorder such as one or more of acute or chronic pain and neuropathy. Disclosed methods include
administering a pharmaceutically effective amount of a compound described herein.
In another embodiment is a method of treating pain in a patient, comprising administering a
therapeutically effective amount of a compound of Formula (I), (Ia), or (Ib) described herein, or a
pharmaceutically acceptable salt or solvate thereof, to a patient in need thereof to treat said pain. In
another embodiment is a method of treating neuropathic pain in a patient, comprising administering a
therapeutically effective amount of a compound of Formula (I), (Ia), or (Ib) described herein, or a
pharmaceutically acceptable salt or solvate thereof, to a patient in need thereof to treat said
neuropathic pain. In another embodiment is a method of treating inflammatory pain in a patient,
comprising administering a therapeutically effective amount of a compound of Formula (I), (Ia), or
(Ib) described herein, or a pharmaceutically acceptable salt or solvate thereof, to a patient in need
thereof to treat said inflammatory pain. In another embodiment is a method of treating complex
regional pain syndrome in a patient in need thereof, comprising administering to the patient a
therapeutically effective amount of a compound of Formula (I), (Ia), or (Ib) described herein, or a
pharmaceutically acceptable salt or solvate thereof.
In another embodiment is a method of treating a disease or disorder in a patient comprising
administering to the patient in need thereof a therapeutically effective amount of a compound of
Formula (I), (Ia), or (Ib) described herein, or a pharmaceutically acceptable salt or solvate thereof,
wherein the disease or disorder is selected from the group consisting of epilepsy/seizure disorder,
multiple sclerosis, neuromyelitis optica (NMO), Tourette syndrome, Alzheimer’s disease, and
abdominal pain associated with irritable bowel syndrome. In another embodiment is a method of
treating epilepsy/seizure disorder in a patient comprising administering to the patient in need thereof
a therapeutically effective amount of a compound of Formula (I), (Ia), or (Ib) described herein, or a
pharmaceutically acceptable salt or solvate thereof. In another embodiment is a method of treating
multiple sclerosis in a patient comprising administering to the patient in need thereof a
therapeutically effective amount of a compound of Formula (I), (Ia), or (Ib) described herein, or a
pharmaceutically acceptable salt or solvate thereof. In another embodiment is a method of treating
neuromyelitis optica (NMO) in a patient comprising administering to the patient in need thereof a
therapeutically effective amount of a compound of Formula (I), (Ia), or (Ib) described herein, or a
pharmaceutically acceptable salt or solvate thereof. In another embodiment is a method of treating
Tourette syndrome in a patient comprising administering to the patient in need thereof a
therapeutically effective amount of a compound of Formula (I), (Ia), or (Ib) described herein, or a
pharmaceutically acceptable salt or solvate thereof. In another embodiment is a method of treating
Alzheimer’s disease in a patient comprising administering to the patient in need thereof a
therapeutically effective amount of a compound of Formula (I), (Ia), or (Ib) described herein, or a
pharmaceutically acceptable salt or solvate thereof. In another embodiment is a method of treating
abdominal pain associated with irritable bowel syndrome in a patient comprising administering to the
patient in need thereof a therapeutically effective amount of a compound of Formula (I), (Ia), or (Ib)
described herein, or a pharmaceutically acceptable salt or solvate thereof.
In another embodiment is a method of treating acute pain, inflammatory pain, cancer pain,
pain caused by peripheral neuropathy, central pain, fibromyalgia, migraine, vasoocclussive painful
crises in sickle cell disease, spasticity or pain associated with multiple sclerosis, functional chest
pain, rheumatoid arthritis, osteoarthritis, or functional dyspepsia in a patient in need thereof,
comprising administering to the patient a therapeutically effective amount of a compound of Formula
(I), (Ia), or (Ib) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another
embodiment is a method of treating acute pain in a patient in need thereof, comprising administering
to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), or (Ib) described
herein, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment is a method
of treating inflammatory pain in a patient in need thereof, comprising administering to the patient a
therapeutically effective amount of a compound of Formula (I), (Ia), or (Ib) described herein, or a
pharmaceutically acceptable salt or solvate thereof. In another embodiment is a method of treating
cancer pain in a patient in need thereof, comprising administering to the patient a therapeutically
effective amount of a compound of Formula (I), (Ia), or (Ib) described herein, or a pharmaceutically
acceptable salt or solvate thereof. In another embodiment is a method of treating pain caused by
peripheral neuropathy in a patient in need thereof, comprising administering to the patient a
therapeutically effective amount of a compound of Formula (I), (Ia), or (Ib) described herein, or a
pharmaceutically acceptable salt or solvate thereof. In another embodiment is a method of treating
central pain in a patient in need thereof, comprising administering to the patient a therapeutically
effective amount of a compound of Formula (I), (Ia), or (Ib) described herein, or a pharmaceutically
acceptable salt or solvate thereof. In another embodiment is a method of treating fibromyalgia in a
patient in need thereof, comprising administering to the patient a therapeutically effective amount of
a compound of Formula (I), (Ia), or (Ib) described herein, or a pharmaceutically acceptable salt or
solvate thereof. In another embodiment is a method of treating migraine in a patient in need thereof,
comprising administering to the patient a therapeutically effective amount of a compound of Formula
(I), (Ia), or (Ib) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another
embodiment is a method of treating vasoocclussive painful crises in sickle cell disease in a patient in
need thereof, comprising administering to the patient a therapeutically effective amount of a
compound of Formula (I), (Ia), or (Ib) described herein, or a pharmaceutically acceptable salt or
solvate thereof. In another embodiment is a method of treating spasticity or pain associated with
multiple sclerosis in a patient in need thereof, comprising administering to the patient a
therapeutically effective amount of a compound of Formula (I), (Ia), or (Ib) described herein, or a
pharmaceutically acceptable salt or solvate thereof. In another embodiment is a method of treating
functional chest pain in a patient in need thereof, comprising administering to the patient a
therapeutically effective amount of a compound of Formula (I), (Ia), or (Ib) described herein, or a
pharmaceutically acceptable salt or solvate thereof. In another embodiment is a method of treating
rheumatoid arthritis in a patient in need thereof, comprising administering to the patient a
therapeutically effective amount of a compound of Formula (I), (Ia), or (Ib) described herein, or a
pharmaceutically acceptable salt or solvate thereof. In another embodiment is a method of treating
osteoarthritis in a patient in need thereof, comprising administering to the patient a therapeutically
effective amount of a compound of Formula (I), (Ia), or (Ib) described herein, or a pharmaceutically
acceptable salt or solvate thereof. In another embodiment is a method of treating functional
dyspepsia in a patient in need thereof, comprising administering to the patient a therapeutically
effective amount of a compound of Formula (I), (Ia), or (Ib) described herein, or a pharmaceutically
acceptable salt or solvate thereof.
In some embodiments, disclosed herein is a method of treating Persistent Motor Tic Disorder
in a patient in need thereof, comprising administering to the patient a therapeutically effective
amount of a compound of Formula (I), (Ia), or (Ib) described herein, or a pharmaceutically
acceptable salt or solvate thereof. In some embodiments, disclosed herein is a method of treating
Persistent Vocal Tic Disorder in a patient in need thereof, comprising administering to the patient a
therapeutically effective amount of a compound of Formula (I), (Ia), or (Ib) described herein, or a
pharmaceutically acceptable salt or solvate thereof.
In another embodiment is a method of lowering intraocular eye pressure (IOP) in a patient in
need thereof, comprising administering to the patient a therapeutically effective amount of a
compound of Formula (I), (Ia), or (Ib) described herein, or a pharmaceutically acceptable salt or
solvate thereof. In another embodiment is a method of treating glaucoma in a patient in need thereof,
comprising administering to the patient a therapeutically effective amount of a compound of Formula
(I), (Ia), or (Ib) described herein, or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, disclosed herein is a method of treating attention deficit and
hyperactivity disorder (ADHD) in a patient in need thereof, comprising administering to the patient a
therapeutically effective amount of a compound of Formula (I), (Ia), or (Ib) described herein, or a
pharmaceutically acceptable salt or solvate thereof. In some embodiments, disclosed herein is a
method of treating obsessive–compulsive disorder (OCD) in a patient in need thereof, comprising
administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), or
(Ib) described herein, or a pharmaceutically acceptable salt or solvate thereof.
In another embodiment is a method of treating atopic dermatitis in a patient in need thereof,
comprising administering to the patient a therapeutically effective amount of a compound of Formula
(I), (Ia), or (Ib) described herein, or a pharmaceutically acceptable salt or solvate thereof.
In another embodiment is a method of treating pruritis in a patient in need thereof,
comprising administering to the patient a therapeutically effective amount of a compound of Formula
(I), (Ia), or (Ib) described herein, or a pharmaceutically acceptable salt or solvate thereof.
In another embodiment is a method of treating Down’s syndrome in a patient in need
thereof, comprising administering to the patient a therapeutically effective amount of a compound of
Formula (I), (Ia), or (Ib) described herein, or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, disclosed herein is a method of synergistically potentiating the
activity of an opioid analgesic in a patient being treated with an opioid analgesic, comprising
administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), or
(Ib) described herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments,
disclosed herein is a method of reducing the acute side-effects associated with an opioid analgesic in
a patient being treated with an opioid analgesic, comprising administering to the patient a
therapeutically effective amount of a compound of Formula (I), (Ia), or (Ib) described herein, or a
pharmaceutically acceptable salt or solvate thereof.
In another embodiment is a method of treating dystonia in a patient in need thereof,
comprising administering to the patient a therapeutically effective amount of a compound of Formula
(I), (Ia), or (Ib) described herein, or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, disclosed herein is a method of treating Amyotrophic Lateral
Sclerosis (ALS) or ALS-related symptoms in a patient in need thereof, comprising administering to
the patient a therapeutically effective amount of a compound of Formula (I), (Ia), or (Ib) described
herein, or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, disclosed herein is a method of treating agitation in autism in a
patient in need thereof, comprising administering to the patient a therapeutically effective amount of
a compound of Formula (I), (Ia), or (Ib) described herein, or a pharmaceutically acceptable salt or
solvate thereof.
In another embodiment is a method of treating sleep disturbance or bladder dysfunction
associated with multiple sclerosis in a patient in need thereof, comprising administering to the patient
a therapeutically effective amount of a compound of Formula (I), (Ia), or (Ib) described herein, or a
pharmaceutically acceptable salt or solvate thereof.
In some embodiments, disclosed herein is a method of treating Huntington’s Disease in a
patient in need thereof, comprising administering to the patient a therapeutically effective amount of
a compound of Formula (I), (Ia), or (Ib) described herein, or a pharmaceutically acceptable salt or
solvate thereof.
In some embodiments, disclosed herein is a method of Parkinson’s Disease in a patient in
need thereof, comprising administering to the patient a therapeutically effective amount of a
compound of Formula (I), (Ia), or (Ib) described herein, or a pharmaceutically acceptable salt or
solvate thereof.
In some embodiments, disclosed herein is a method of improving functional outcome
following stroke in a patient in need thereof, comprising administering to the patient a
therapeutically effective amount of a compound of Formula (I), (Ia), or (Ib) described herein, or a
pharmaceutically acceptable salt or solvate thereof.
In some embodiments, disclosed herein is a method of treating traumatic brain injury in a
patient in need thereof, comprising administering to the patient a therapeutically effective amount of
a compound of Formula (I), (Ia), or (Ib) described herein, or a pharmaceutically acceptable salt or
solvate thereof.
In some embodiments, disclosed herein is a method of treating trigeminal neuralgia in a
patient in need thereof, comprising administering to the patient a therapeutically effective amount of
a compound of Formula (I), (Ia), or (Ib) described herein, or a pharmaceutically acceptable salt or
solvate thereof. In some embodiments, disclosed herein is a method of treating glossopharyngeal
neuralgia in a patient in need thereof, comprising administering to the patient a therapeutically
effective amount of a compound of Formula (I), (Ia), or (Ib) described herein, or a pharmaceutically
acceptable salt or solvate thereof.
In certain embodiments, a disclosed compound utilized by one or more of the foregoing
methods is one of the generic, subgeneric, or specific compounds described herein, such as a
compound of Formula (I), (Ia), or (Ib).
Disclosed compounds are administered to patients (animals and humans) in need of such
treatment in dosages that will provide optimal pharmaceutical efficacy. It will be appreciated that
the dose required for use in any particular application will vary from patient to patient, not only with
the particular compound or composition selected, but also with the route of administration, the nature
of the condition being treated, the age and condition of the patient, concurrent medication or special
diets then being followed by the patient, and other factors, with the appropriate dosage ultimately
being at the discretion of the attendant physician. For treating clinical conditions and diseases noted
above, a contemplated compound disclosed herein is administered orally, subcutaneously, topically,
parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-
toxic pharmaceutically acceptable carriers, adjuvants and vehicles. Parenteral administration include
subcutaneous injections, intravenous or intramuscular injections or infusion techniques.
Also contemplated herein are combination therapies, for example, co-administering a
disclosed compound and an additional active agent, as part of a specific treatment regimen intended
to provide the beneficial effect from the co-action of these therapeutic agents. The beneficial effect
of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action
resulting from the combination of therapeutic agents. Administration of these therapeutic agents in
combination typically is carried out over a defined time period (usually weeks, months or years
depending upon the combination selected). Combination therapy is intended to embrace
administration of multiple therapeutic agents in a sequential manner, that is, wherein each
therapeutic agent is administered at a different time, as well as administration of these therapeutic
agents, or at least two of the therapeutic agents, in a substantially simultaneous manner.
Substantially simultaneous administration is accomplished, for example, by administering
to the subject a single formulation or composition, (e.g., a tablet or capsule having a fixed ratio of
each therapeutic agent or in multiple, single formulations (e.g., capsules) for each of the therapeutic
agents. Sequential or substantially simultaneous administration of each therapeutic agent is effected
by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular
routes, and direct absorption through mucous membrane tissues. The therapeutic agents are
administered by the same route or by different routes. For example, a first therapeutic agent of the
combination selected is administered by intravenous injection while the other therapeutic agents of
the combination are administered orally. Alternatively, for example, all therapeutic agents are
administered orally or all therapeutic agents are administered by intravenous injection.
Combination therapy also embraces the administration of the therapeutic agents as
described above in further combination with other biologically active ingredients and non-drug
therapies. Where the combination therapy further comprises a non-drug treatment, the non-drug
treatment is conducted at any suitable time so long as a beneficial effect from the co-action of the
combination of the therapeutic agents and non-drug treatment is achieved. For example, in
appropriate cases, the beneficial effect is still achieved when the non-drug treatment is temporally
removed from the administration of the therapeutic agents, perhaps by days or even weeks.
The components of the combination are administered to a patient simultaneously or
sequentially. It will be appreciated that the components are present in the same pharmaceutically
acceptable carrier and, therefore, are administered simultaneously. Alternatively, the active
ingredients are present in separate pharmaceutical carriers, such as conventional oral dosage forms,
that are administered either simultaneously or sequentially.
For example, e.g., for contemplated treatment of pain, a disclosed compound is co-
administered with another therapeutic for pain such as an opioid, a cannabinoid receptor (CB-1 or
CB-2) modulator, a COX-2 inhibitor, acetaminophen, and/or a non-steroidal anti-inflammatory
agent. Additional therapeutics e.g., for the treatment of pain that are co-administered, include
morphine, codeine, hydromorphone, hydrocodone, oxymorphone, fentanyl, tramadol, and
levorphanol.
Other contemplated therapeutics for co-administration include aspirin, naproxen, ibuprofen,
salsalate, diflunisal, dexibuprofen, fenoprofen, ketoprofen, oxaprozin, loxoprofen, indomethacin,
tolmetin, sulindac, etodolac, ketorolac, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam,
celecoxib, parecoxib, rimonabant, and/or etoricoxib.
The following examples are provided merely as illustrative of various embodiments and
shall not be construed to limit the invention in any way.
EXAMPLES
List of abbreviations
As used above, and throughout the description of the invention, the following
abbreviations, unless otherwise indicated, shall be understood to have the following meanings:
ACN or MeCN acetonitrile
Bn benzyl
BOC or Boc tert-butyl carbamate
CDI 1,1'-carbonyldiimidazole
Cy cyclohexyl
DCE dichloroethane (ClCH CH Cl)
DCM dichloromethane (CH Cl )
DIPEA or DIEA diisopropylethylamine
DMAP 4-(N,N-dimethylamino)pyridine
DMF dimethylformamide
DMA N,N-dimethylacetamide
DMSO dimethylsulfoxide
equiv equivalent(s)
Et ethyl
EtOH ethanol
EtOAc ethyl acetate
HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxid hexafluorophosphate
HFIP 1,1,1,3,3,3-hexafluoropropanol
HPLC high performance liquid chromatography
LAH lithium aluminum hydride
LCMS liquid chromatography-mass spectrometry
Me methyl
MeOH methanol
MS mass spectroscopy
NMM N-methylmorpholine
NMR nuclear magnetic resonance
PMB para-methoxybenzyl
rt room temperature
TEA triethylamine
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin layer chromatography
I. Chemical Synthesis
Unless otherwise noted, reagents and solvents were used as received from commercial
suppliers. Anhydrous solvents and oven-dried glassware were used for synthetic transformations
sensitive to moisture and/or oxygen. Yields were not optimized. Reaction times are approximate and
were not optimized. Column chromatography and thin layer chromatography (TLC) were performed
on silica gel unless otherwise noted. Spectra are given in ppm ( ) and coupling constants (J) are
reported in Hertz. For proton spectra the solvent peak was used as the reference peak.
Example 1: 1,1,1,3,3,3-Hexafluoropropanyl 4-(2-((4-ethoxyoxobutyl)amino)
(trifluoromethyl)benzyl)piperazinecarboxylate
Step 1: Preparation of ethyl 4-((4-methoxybenzyl)amino)butanoate
A flask was charged with ethyl 4-aminobutanoate (1.00 g, 7.62 mmol, 1.00 equiv), EtOH
(15 mL), and 4-methoxybenzaldehyde (1.04 mg, 7.62 mmol, 1.00 equiv). The resulting solution was
stirred for 5 h at 70 °C. Sodium borohydride (176 mg, 4.65 mmol, 0.60 equiv) was added and the
resulting solution was stirred overnight at rt and quenched with water (30 mL). The resulting solution
was extracted with DCM (2 x 50 mL) and the organic layers were combined, washed with brine (2 x
mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was
chromatographed on a silica gel column with EtOAc/petroleum ether (3/17) to provide 800 mg (42%
yield) of ethyl 4-((4-methoxybenzyl)amino)butanoate as a white oil. LCMS (ESI, m/z): 252 [M+H] .
Step 2: Preparation of ethyl 4-((2-formyl(trifluoromethyl)phenyl)(4-
methoxybenzyl)amino)butanoate
A flask was charged with ethyl 4-((4-methoxybenzyl)amino)butanoate (400 mg, 1.59
mmol, 1.00 equiv), 2-fluoro(trifluoromethyl)benzaldehyde (304 mg, 1.59 mmol, 1.00 equiv),
DMSO (15 mL), and DIPEA (620 mg, 4.77 mmol, 3.00 equiv). The resulting solution was stirred
overnight at 110 °C and quenched with water (30 mL). The resulting solution was extracted with
EtOAc (2 x 50 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried
over anhydrous sodium sulfate, filtered and concentrated. The residue was chromatographed on a
silica gel column with EtOAc/petroleum ether (1/4) to provide 110 mg (16% yield) of ethyl 4-((2-
formyl(trifluoromethyl)phenyl)(4-methoxybenzyl)amino)butanoate as a light yellow oil. LCMS
(ESI, m/z): 424 [M+H] .
Step 3: Preparation of 1-(tert-butyl) 4-(1,1,1,3,3,3-hexafluoropropanyl) piperazine-1,4-
dicarboxylate
A flask was charged with triphosgene (7.98 g, 26.9 mmol, 0.50 equiv), DCM (150 mL), and
HFIP (18.1 g, 108 mmol, 2.00 equiv) under nitrogen. DIPEA (20.8 g, 161 mmol, 3.00 equiv) was
added at 0 °C and the resulting solution was stirred for 2 h at 0 °C. tert-Butyl piperazine
carboxylate (10.0 g, 53.7 mmol, 1.00 equiv) was added and the resulting solution was stirred
overnight at rt and quenched with water (150 mL). The resulting solution was extracted with DCM
(2 x 200 mL) and the organic layers were combined, washed with brine (2 x 150 mL), dried over
anhydrous sodium sulfate, filtered and concentrated. The residue was chromatographed on a silica
gel column with EtOAc/petroleum ether (1/4) to provide 15.5 g (76% yield) of 1-(tert-butyl) 4-
(1,1,1,3,3,3-hexafluoropropanyl) piperazine-1,4-dicarboxylate as a white solid. LCMS (ESI, m/z):
381 [M+H] .
Step 4: Preparation of 1,1,1,3,3,3-hexafluoropropanyl piperazinecarboxylate, 2,2,2-
trifluoroacetate salt
A flask was charged with 1-(tert-butyl) 4-(1,1,1,3,3,3-hexafluoropropanyl) piperazine-
1,4-dicarboxylate (200 mg, 0.530 mmol, 1.00 equiv), DCM (10 mL), and TFA (2 mL). The resulting
solution was stirred for 3 h at rt and concentrated to provide 250 mg of 1,1,1,3,3,3-hexafluoropropan-
2-yl piperazinecarboxylate, 2,2,2-trifluoroacetate salt as a light yellow oil. LCMS (ESI, m/z): 281
[M+H] .
Step 5: Preparation of 1,1,1,3,3,3-hexafluoropropanyl 4-(2-((4-ethoxyoxobutyl)(4-
methoxybenzyl)amino)(trifluoromethyl)benzyl)piperazinecarboxylate
A flask was charged with ethyl 4-((2-formyl(trifluoromethyl)phenyl)(4-
methoxybenzyl)amino)butanoate (110 mg, 0.260 mmol, 1.00 equiv), DCE (10 mL), TEA (79.0 mg,
0.780 mmol, 3.00 equiv), and 1,1,1,3,3,3-hexafluoropropanyl piperazinecarboxylate, 2,2,2-
trifluoroacetate salt (73.0 mg, 0.260 mmol, 1.00 equiv). The mixture was stirred for 1 h at rt and
sodium triacetoxyborohydride (129 mg, 0.780 mmol, 3.00 equiv) was added. The resulting solution
was stirred overnight at rt and quenched with water (30 mL). The resulting solution was extracted
with DCM (2 x 50 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried
over anhydrous sodium sulfate, filtered and concentrated. The residue was chromatographed on a
silica gel column with DCM/MeOH (96/4) to provide 170 mg (95% yield) of 1,1,1,3,3,3-
hexafluoropropanyl 4-(2-((4-ethoxyoxobutyl)(4-methoxybenzyl)amino)
(trifluoromethyl)benzyl)piperazinecarboxylate as a light yellow oil. LCMS (ESI, m/z): 688
[M+H] .
Step 6: Preparation of 1,1,1,3,3,3-hexafluoropropanyl 4-(2-((4-ethoxyoxobutyl)amino)
(trifluoromethyl)benzyl)piperazinecarboxylate
A flask was charged with 1,1,1,3,3,3-hexafluoropropanyl 4-(2-((4-ethoxyoxobutyl)(4-
methoxybenzyl)amino)(trifluoromethyl)benzyl)piperazinecarboxylate (170 mg, 0.250 mmol,
1.00 equiv), DCM (10 mL), and TFA (2 mL). The resulting solution was stirred for 3 h at rt and
concentrated. The crude product (180 mg) was purified by preparative HPLC to provide 28.9 mg
(21% yield) of 1,1,1,3,3,3-hexafluoropropanyl 4-(2-((4-ethoxyoxobutyl)amino)
(trifluoromethyl)benzyl)piperazinecarboxylate as a light yellow oil. H NMR (300 MHz,
Methanol-d ) 7.15 - 7.18 (m, 1H), 6.84 - 6.87 (m, 2H), 6.13 - 6.21 (m, 1H), 4.11 - 4.18 (m, 2H),
3.57 - 3.60 (m, 6H), 3.24 (t, J = 6 Hz, 2H), 2.46 - 2.53 (m, 6H), 1.95 - 2.04 (m, 2H) 1.26 (t, J = 3 Hz,
3H). LCMS (ESI, m/z): 568 [M+H] .
Example 2: 1,1,1,3,3,3-Hexafluoropropanyl 4-(2-((4-(tert-butoxy)oxobutyl)amino)
(trifluoromethyl)benzyl)piperazinecarboxylate
Step 1: Preparation of 1,1,1,3,3,3-Hexafluoropropanyl 4-(2-((4-(tert-butoxy)
oxobutyl)amino)(trifluoromethyl)benzyl)piperazinecarboxylate
A flask was charged with EtOAc (10 mL) and 1,1,1,3,3,3-hexafluoropropanyl 4-(2-((4-
(tert-butoxy)oxobutyl)(4-methoxybenzyl)amino)(trifluoromethyl)benzyl)piperazine
carboxylate (200 mg, 0.280 mmol, 1.00 equiv, prepared as described in Example 1, Steps 1-5 using
tert-butyl 4-aminobutanoate in Step 1). Hydrogen was introduced and the resulting solution was
stirred for 5 h at rt before the solids were filtered and the filtrate concentrated. The crude product was
purified by preparative HPLC to provide 64.6 mg (39% yield) of 1,1,1,3,3,3-hexafluoropropanyl
4-(2-((4-(tert-butoxy)oxobutyl)amino)(trifluoromethyl)benzyl)piperazinecarboxylate as a
light yellow oil. H NMR (400 MHz, Chloroform-d) 7.05 (d, J = 7.2 Hz, 1H), 6.86 (d, J = 7.6 Hz,
1H), 6.78 (s, 1H), 6.13 (br s, 1H), 5.73 - 5.76 (m, 1H), 3.56 (br s, 6H), 3.19 (t, J = 6.6 Hz, 2H), 2.45
(s, 4H), 2.37 (t, J = 7.2 Hz, 2H), 1.93 - 1.97 (m, 2H), 1.45 (s, 9H). LCMS (ESI, m/z): 596 [M+H] .
Example 3: 4-(2-((4-(((1,1,1,3,3,3-Hexafluoropropanyl)oxy)carbonyl)piperazinyl)methyl)-
-(trifluoromethyl)phenoxy)butanoic acid
Step 1: Preparation of 2-hydroxy(trifluoromethyl)benzaldehyde
A flask was charged with 2-fluoro(trifluoromethyl)benzaldehyde (1.00 g, 5.21 mmol,
1.00 equiv), water (2 mL), DMSO (10 mL), and potassium carbonate (2.16 g, 15.6 mmol, 3.00
equiv) under nitrogen. The resulting solution was stirred overnight at 110 °C and quenched with
water (50 mL). The resulting solution was extracted with EtOAc (2 x 80 mL) and the organic layers
were combined, washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered and
concentrated. The residue was chromatographed on a silica gel column with EtOAc/petroleum ether
(1/19) to provide 500 mg (51% yield) of 2-hydroxy(trifluoromethyl)benzaldehyde as a light
yellow oil.
Step 2: Preparation of tert-butyl 4-(2-formyl(trifluoromethyl)phenoxy)butanoate
K CO , DMF
100 °C, overnight
A flask was charged with 2-hydroxy(trifluoromethyl)benzaldehyde (300 mg, 1.58 mmol,
1.00 equiv), DMF (10 mL), potassium carbonate (654 mg, 4.73 mmol, 3.00 equiv), and tert-butyl 4-
bromobutanoate (702 mg, 3.15 mmol, 2.00 equiv). The resulting solution was stirred overnight at
100 °C and quenched with water (30 mL). The resulting solution was extracted with DCM (2 x 50
mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous
sodium sulfate, filtered and concentrated. The residue was chromatographed on a silica gel column
with EtOAc/petroleum ether (1/10) to provide 450 mg (86% yield) of tert-butyl 4-(2-formyl
(trifluoromethyl)phenoxy)butanoate as a light yellow solid. H NMR (300 MHz, Chloroform-d)
.5 (s, 1H), 7.96 (d, J = 7.5 Hz, 1H), 7.29 - 7.33 (m, 2H), 4.22 (t, J = 6.0 Hz, 2H), 2.50 (t, J = 6.0
Hz, 2H), 2.18 - 2.25 (m, 2H), 1.49 (s, 9H).
Step 3: Preparation of 1,1,1,3,3,3-hexafluoropropanyl 4-(2-(4-(tert-butoxy)oxobutoxy)
(trifluoromethyl)benzyl)piperazinecarboxylate
A flask was charged with 1,1,1,3,3,3-hexafluoropropanyl piperazinecarboxylate,
2,2,2-trifluoroacetate salt (202 mg, 0.720 mmol, 1.20 equiv, prepared as described in Example 1,
Steps 3-4), DCE (10 mL), TEA (183 mg, 1.80 mmol, 3.00 equiv), and tert-butyl 4-(2-formyl
(trifluoromethyl)phenoxy)butanoate (200 mg, 0.600 mmol, 1.00 equiv). The mixture was stirred for
1 h at rt. Sodium triacetoxyborohydride (382 mg, 1.80 mmol, 3.00 equiv) was added and the reaction
mixture was stirred overnight at rt and quenched with water (30 mL). The resulting solution was
extracted with DCM (2 x 50 mL) and the organic layers were combined, washed with brine (2 x 30
mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was
chromatographed on a silica gel column with DCM/MeOH (97/3) to provide 230 mg (64% yield) of
1,1,1,3,3,3-hexafluoropropanyl 4-(2-(4-(tert-butoxy)oxobutoxy)
(trifluoromethyl)benzyl)piperazinecarboxylate as a light yellow oil. LCMS (ESI, m/z): 597
[M+H] .
Step 4: Preparation of 4-(2-((4-(((1,1,1,3,3,3-hexafluoropropanyl)oxy)carbonyl)piperazin
yl)methyl)(trifluoromethyl)phenoxy)butanoic acid
A flask was charged with 1,1,1,3,3,3-hexafluoropropanyl 4-(2-(4-(tert-butoxy)
oxobutoxy)(trifluoromethyl)benzyl)piperazinecarboxylate (200 mg, 0.340 mmol, 1.00 equiv),
1,4-dioxane (10 mL), and hydrochloric acid (3 mL). The resulting solution was stirred for 3 h at rt
and concentrated. The crude product (400 mg) was purified by preparative HPLC to provide 46.4 mg
(26% yield) of 4-(2-((4-(((1,1,1,3,3,3-hexafluoropropanyl)oxy)carbonyl)piperazinyl)methyl)
(trifluoromethyl)phenoxy)butanoic acid as a white solid. H NMR (300 MHz, Methanol-d4) 7.53
(d, J = 7.8 Hz, 1H), 7.19 - 7.24 (m, 2H), 6.10 - 6.18 (m, 1H), 4.11 (t, J = 6.2 Hz, 2H), 3.68 (s, 2H),
3.56 - 3.62 (m, 4H), 2.58 - 2.61 (m, 4H), 2.49 (t, J = 7.2 Hz, 2H), 2.08 - 2.17 (m, 2H). LCMS (ESI,
m/z): 541 [M+H] .
Example 4: 4-(5-Chloro((4-(((1,1,1,3,3,3-hexafluoropropanyl)oxy)carbonyl)piperazin
yl)methyl)phenoxy)butanoic acid
The title compound was prepared according to the representative procedure of Example 3
using commercially available 4-chlorohydroxybenzaldehyde in Step 2 to provide 4-(5-chloro
((4-(((1,1,1,3,3,3-hexafluoropropanyl)oxy)carbonyl)piperazinyl)methyl)phenoxy)butanoic acid
as an off-white solid. H NMR (300 MHz, Methanol-d ) 7.29 (d, J = 8.1 Hz, 1H), 7.01 (s, 1H), 6.92
- 6.96 (m, 1H), 6.10 - 6.19 (m, 1H), 4.07 (t, J = 6.0 Hz, 2H), 3.70 (s, 2H), 3.63 (br s, 4H), 2.67 - 2.68
(m, 4H), 2.48 (t, J = 7.0 Hz, 2H), 2.07 - 2.16 (m, 2H). LCMS (ESI, m/z): 507 [M+H] .
Example 5: 1,1,1,3,3,3-Hexafluoropropanyl 4-(2-((4-(1-((ethoxycarbonyl)oxy)ethoxy)
oxobutyl)amino)(trifluoromethyl)benzyl)piperazinecarboxylate
Step 1: Preparation of tert-butyl 4-(benzyl(2-formyl
(trifluoromethyl)phenyl)amino)butanoate
A flask was charged with tert-butyl 4-(benzylamino)butanoate (230 mg, 0.920 mmol, 1.00
equiv, prepared as described in Example 1, Step 1 using benzaldehyde and tert-butyl 4-
aminobutanoate), 2-fluoro(trifluoromethyl)benzaldehyde (177 mg, 0.920 mmol, 1.00 equiv),
DMSO (10 mL), and DIPEA (356 mg, 2.75 mmol, 3.00 equiv). The reaction mixture was stirred
overnight at 110 °C and quenched with water (30 mL). The resulting solution was extracted with
EtOAc (2 x 50 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried
over anhydrous sodium sulfate, filtered and concentrated. The residue was chromatographed on a
silica gel column with EtOAc/petroleum ether (1/9) to provide 135 mg (35% yield) of tert-butyl 4-
(benzyl(2-formyl(trifluoromethyl)phenyl)amino)butanoate as a yellow oil. LCMS (ESI, m/z): 422
[M+H] .
Step 2: Preparation of 4-(benzyl(2-formyl(trifluoromethyl)phenyl)amino)butanoic acid,
2,2,2-trifluoroacetate salt
A flask was charged with tert-butyl 4-(benzyl(2-formyl
(trifluoromethyl)phenyl)amino)butanoate (800 mg, 1.90 mmol, 1.00 equiv), DCM (2 mL), and TFA
(10 mL). The resulting solution was stirred for 5 h at rt and concentrated to provide 830 mg (crude)
of 4-(benzyl(2-formyl(trifluoromethyl)phenyl)amino)butanoic acid, 2,2,2-trifluoroacetate salt as a
yellow oil. LCMS (ESI, m/z): 366 [M+H] .
Step 3: Preparation of 1-((ethoxycarbonyl)oxy)ethyl 4-(benzyl(2-formyl
(trifluoromethyl)phenyl)amino)butanoate
O Bn
O O Cl
Pr NEt, NaI, EtOAc
60 °C, overnight
O OH
A flask was charged with 4-(benzyl(2-formyl(trifluoromethyl)phenyl)amino)butanoic
acid, 2,2,2-trifluoroacetate salt (300 mg, 0.820 mmol, 1.00 equiv), EtOAc (10 mL), 1-chloroethyl
ethyl carbonate (138 mg, 0.900 mmol, 1.10 equiv), DIPEA (99.0 mg, 0.770 mmol, 1.20 equiv), and
sodium iodide (49.0 mg, 0.328 mmol, 0.400 equiv) under nitrogen. The reaction mixture was stirred
overnight at 60 °C and quenched with water (30 mL). The resulting solution was extracted with
DCM (2 x 50 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over
anhydrous sodium sulfate, filtered and concentrated. The residue was chromatographed on a silica
gel column with EtOAc/petroleum ether (1/4) to provide 330 mg (83% yield) of 1-
((ethoxycarbonyl)oxy)ethyl 4-(benzyl(2-formyl(trifluoromethyl)phenyl)amino)butanoate as a
yellow oil. LCMS (ESI, m/z): 482 [M+H] .
Step 4: Preparation of 1,1,1,3,3,3-hexafluoropropanyl 4-(2-(benzyl(4-(1-
((ethoxycarbonyl)oxy)ethoxy)oxobutyl)amino)(trifluoromethyl)benzyl)piperazine
carboxylate
A flask was charged with 1-((ethoxycarbonyl)oxy)ethyl 4-(benzyl(2-formyl
(trifluoromethyl)phenyl)amino)butanoate (250 mg, 0.520 mmol, 1.00 equiv), DCE (10 mL), and
1,1,1,3,3,3-hexafluoropropanyl piperazinecarboxylate, 2,2,2-trifluoroacetate salt (145 g, 0.520
mmol, 1.00 equiv, prepared as described in Example 1, Steps 3-4). The mixture was stirred for 1 h at
rt and then sodium triacetoxyborohydride (330 mg, 1.56 mmol, 3.00 equiv) was added. The resulting
solution was stirred overnight at rt and quenched with water (30 mL). The resulting solution was
extracted with DCM (2 x 50 mL) and the organic layers were combined, washed with brine (2 x 30
mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was
chromatographed on a silica gel column with DCM/MeOH (97/3) to provide 320 mg (83% yield) of
1,1,1,3,3,3-hexafluoropropanyl 4-(2-(benzyl(4-(1-((ethoxycarbonyl)oxy)ethoxy)
oxobutyl)amino)(trifluoromethyl)benzyl)piperazinecarboxylate as a yellow oil. LCMS (ESI,
m/z): 746 [M+H] .
Step 5: Preparation of 1,1,1,3,3,3-hexafluoropropanyl 4-(2-((4-(1-
((ethoxycarbonyl)oxy)ethoxy)oxobutyl)amino)(trifluoromethyl)benzyl)piperazine
carboxylate
A flask was charged with 1,1,1,3,3,3-hexafluoropropanyl 4-(2-(benzyl(4-(1-
((ethoxycarbonyl)oxy)ethoxy)oxobutyl)amino)(trifluoromethyl)benzyl)piperazine
carboxylate (320 mg, 0.430 mmol, 1.00 equiv), EtOAc (10 mL) and palladium on carbon (107 mg).
Hydrogen was introduced into the reaction mixture. After 5 h at rt, the solids were removed by
filtration. The filtrate was then concentrated and purified by preparative HPLC to provide 133.6 mg
(47% yield) of 1,1,1,3,3,3-hexafluoropropanyl 4-(2-((4-(1-((ethoxycarbonyl)oxy)ethoxy)
oxobutyl)amino)(trifluoromethyl)benzyl)piperazinecarboxylate as a colorless oil. H NMR
(300 MHz, Chloroform-d) 7.05 - 7.07 (m, 1H), 6.86 - 6.91 (m, 1H), 6.75 - 6.80 (m, 2H), 6.13 (br s,
1H), 5.70 - 5.79 (m, 1H), 4.15 - 4.25 (m, 2H), 3.55 (br s, 6H), 3.19 - 3.23 (m, 2H), 2.47 - 2.52 (m,
6H), 1.99 - 2.03 (m, 2H), 1.51 (d, J = 5.4 Hz, 3H), 1.30 (t, J = 7.2 Hz, 3H). LCMS (ESI, m/z): 656
[M+H] .
Example 6: 1,1,1,3,3,3-Hexafluoropropanyl 4-(2-((4-(1-((isopropoxycarbonyl)oxy)ethoxy)
oxobutyl)amino)(trifluoromethyl)benzyl)piperazinecarboxylate
The title compound was prepared according to the representative procedure of Example 5
using hydrochloric acid and 1,4-dioxane in Step 2 and 1-chloroethyl isopropyl carbonate in Step 3 to
provide 1,1,1,3,3,3-hexafluoropropanyl 4-(2-((4-(1-((isopropoxycarbonyl)oxy)ethoxy)
oxobutyl)amino)(trifluoromethyl)benzyl)piperazinecarboxylate as a solid. H NMR (300 MHz,
Chloroform-d) 7.05 - 7.07 (m, 1H), 6.87 (d, J = 6.0 Hz, 1H), 6.77 - 6.80 (m, 2H), 6.12 (br s, 1H),
.70 - 5.79 (m, 1H), 4.82 - 4.91 (m, 1H), 3.56 (br s, 6H), 3.19 - 3.23 (m, 2H), 2.47 - 2.52 (m, 6H),
1.99 - 2.03 (m, 2H), 1.51 (d, J = 5.7 Hz, 3H), 1.27 - 1.31 (m, 6H). LCMS (ESI, m/z): 670 [M+H] .
Example 7: 1,1,1,3,3,3-Hexafluoropropanyl 4-(2-((4-oxo
((pivaloyloxy)methoxy)butyl)amino)(trifluoromethyl)benzyl)piperazinecarboxylate
Step 1: Preparation of 4-(benzyl(2-formyl(trifluoromethyl)phenyl)amino)butanoic acid
hydrochloride
A flask was charged with tert-butyl 4-(benzyl(2-formyl
(trifluoromethyl)phenyl)amino)butanoate hydrochloride (350 mg, 0.830 mmol, 1.00 equiv, prepared
as described in Example 5, Step 1), 1,4-dioxane (10 mL), and hydrochloric acid (2 mL). The
resulting solution was stirred overnight at rt and concentrated to provide 360 mg (crude) of 4-
(benzyl(2-formyl(trifluoromethyl)phenyl)amino)butanoic acid hydrochloride as a light yellow oil.
LCMS (ESI, m/z): 366 [M+H] .
Step 2: Preparation of 1-(pivaloyloxy)methyl 4-(benzyl(2-formyl
(trifluoromethyl)phenyl)amino)butanoate
A flask was charged with 4-(benzyl(2-formyl(trifluoromethyl)phenyl)amino)butanoic
acid hydrochloride (303 mg, 0.830 mmol, 1.00 equiv), MeOH (10 mL), and cesium carbonate (270
mg, 0.830 mmol, 1.00 equiv). The resulting solution was stirred for 3 h at rt and concentrated. MeCN
(10 mL) and iodomethyl pivalate (602 mg, 2.49 mmol, 3.00 equiv) were added. The resulting
solution was stirred overnight at rt and quenched with water (30 mL). The resulting solution was
extracted with DCM (2 x 50 mL) and the organic layers were combined, washed with brine (2 x 30
mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was
chromatographed on a silica gel column with EtOAc/petroleum ether (1/4) to provide 300 mg (75%
yield) of 1-(pivaloyloxy)methyl 4-(benzyl(2-formyl(trifluoromethyl)phenyl)amino)butanoate as a
yellow oil. LCMS (ESI, m/z): 480 [M+H] .
Step 3: Preparation of 1,1,1,3,3,3-hexafluoropropanyl 4-(2-(benzyl(4-oxo
((pivaloyloxy)methoxy)butyl)amino)(trifluoromethyl)benzyl)piperazinecarboxylate
O CF
N O CF
O CF
N O CF Bn
NaBH(OAc) , Et N, DCE
rt, overnight
A flask was charged with 1-(pivaloyloxy)methyl 4-(benzyl(2-formyl
(trifluoromethyl)phenyl)amino)butanoate (300 mg, 0.630 mmol, 1.00 equiv), DCE (10 mL), TEA
(199 mg, 1.97 mmol, 3.00 equiv), and 1,1,1,3,3,3-hexafluoropropanyl piperazinecarboxylate,
2,2,2-trifluoroacetate salt (175 mg, 0.620 mmol, 1.00 equiv, prepared as described in Example 1,
Steps 3-4). The mixture was stirred for 1 h at rt and sodium triacetoxyborohydride (398 mg, 1.97
mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at rt and quenched with
water (30 mL). The resulting solution was extracted with DCM (2 x 50 mL) and the organic layers
were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered, and
concentrated. The residue was chromatographed on a silica gel column with DCM/MeOH (96/4) to
provide 200 mg (43% yield) of 1,1,1,3,3,3-hexafluoropropanyl 4-(2-(benzyl(4-oxo
((pivaloyloxy)methoxy)butyl)amino)(trifluoromethyl)benzyl)piperazinecarboxylate as a yellow
oil. LCMS (ESI, m/z): 744 [M+H] .
Step 4: Preparation of 1,1,1,3,3,3-hexafluoropropanyl 4-(2-((4-oxo
((pivaloyloxy)methoxy)butyl)amino)(trifluoromethyl)benzyl)piperazinecarboxylate
A flask was charged with 1,1,1,3,3,3-hexafluoropropanyl 4-(2-(benzyl(4-oxo
((pivaloyloxy)methoxy)butyl)amino)(trifluoromethyl)benzyl)piperazinecarboxylate (200 mg,
0.270 mmol, 1.00 equiv), EtOAc (10 mL), and 10% palladium on carbon (67.0 mg). Hydrogen was
introduced into the reaction mixture. After 5 h at rt, the reaction was filtered and the filtrate was
concentrated and purified by preparative HPLC to provide 22.4 mg (13% yield) of 1,1,1,3,3,3-
hexafluoropropanyl 4-(2-((4-oxo((pivaloyloxy)methoxy)butyl)amino)
(trifluoromethyl)benzyl)piperazinecarboxylate as a colorless oil. H NMR (300 MHz,
Chloroform-d) 7.06 (d, J = 7.5 Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 6.77 (s, 1H), 6.15 (br s, 1H), 5.73
- 5.77 (m, 3H), 3.55 (s, 6H), 3.20 (t, J = 6.8 Hz, 2H), 2.45 - 2.54 (m, 6H), 1.99 - 2.03 (m, 2H), 1.19
(s, 9H). LCMS (ESI, m/z): 654 [M+H] .
Example 8: 1,1,1,3,3,3-Hexafluoropropanyl 4-(2-((4-(1-(isobutyryloxy)ethoxy)
oxobutyl)amino)(trifluoromethyl)benzyl)piperazinecarboxylate
Step 1: Preparation of 1-(isobutyryloxy)ethyl 4-(benzyl(2-formyl
(trifluoromethyl)phenyl)amino)butanoate
A flask was charged with 4-(benzyl(2-formyl(trifluoromethyl)phenyl)amino)butanoic
acid (260 mg, 0.710 mmol, 1.00 equiv, prepared as described in Example 7, Step 1), DMF (10 mL),
1-chloroethyl isobutyrate (215 mg, 1.43 mmol, 2.00 equiv), and potassium carbonate (295 mg, 2.13
mmol, 3.00 equiv). The resulting solution was stirred overnight at rt and quenched with water (30
mL). The resulting solution was extracted with EtOAc (2 x 50 mL) and the organic layers were
combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and
concentrated. The residue was chromatographed on a silica gel column with EtOAc/petroleum ether
(1/9) to provide 170 mg (50% yield) of 1-(isobutyryloxy)ethyl 4-(benzyl(2-formyl
(trifluoromethyl)phenyl)amino)butanoate as a yellow oil. LCMS (ESI, m/z): 480 [M+H] .
Step 2: Preparation of 1,1,1,3,3,3-hexafluoropropanyl 4-(2-(benzyl(4-(1-
(isobutyryloxy)ethoxy)oxobutyl)amino)(trifluoromethyl)benzyl)piperazinecarboxylate
A flask was charged with 1-(isobutyryloxy)ethyl 4-(benzyl(2-formyl
(trifluoromethyl)phenyl)amino)butanoate (170 mg, 0.350 mmol, 1.00 equiv), 1,1,1,3,3,3-
hexafluoropropanyl piperazinecarboxylate, 2,2,2-trifluoroacetate salt (99.0 mg, 0.350 mmol,
1.00 equiv, prepared as described in Example 1, Steps 3-4), DCE (10 mL), and TEA (108 mg, 1.07
mmol, 3.00 equiv). The mixture was stirred for 1 h at rt and then sodium triacetoxyborohydride (226
mg, 3.00 equiv) was added. The resulting solution was stirred overnight at rt and quenched with
water (30 mL). The resulting solution was extracted with DCM (2 x 50 mL) and the organic layers
were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and
concentrated. The residue was chromatographed on a silica gel column with DCM/MeOH (97/3) to
provide 200 mg (76% yield) of 1,1,1,3,3,3-hexafluoropropanyl 4-(2-(benzyl(4-(1-
(isobutyryloxy)ethoxy)oxobutyl)amino)(trifluoromethyl)benzyl)piperazinecarboxylate as
yellow oil. LCMS (ESI, m/z): 744 [M+H] .
Step 3: Preparation of 1,1,1,3,3,3-hexafluoropropanyl 4-(2-((4-(1-(isobutyryloxy)ethoxy)
oxobutyl)amino)(trifluoromethyl)benzyl)piperazinecarboxylate
O CF O CF
F C F C
N O CF N O CF
N NH
Bn H , Pd/C
EtOAc
rt, 5 h
O O O O
A flask was charged with 1,1,1,3,3,3-hexafluoropropanyl 4-(2-(benzyl(4-(1-
(isobutyryloxy)ethoxy)oxobutyl)amino)(trifluoromethyl)benzyl)piperazinecarboxylate (200
mg, 0.270 mmol, 1.00 equiv), EtOAc (10 mL), and palladium on carbon (100 mg). Hydrogen was
introduced into the reaction and the resulting mixture was stirred for 5 h at rt. The solids were
filtered out and the filtrate was concentrated. The crude product (180 mg) was purified by
preparative HPLC to provide 59.9 mg (34% yield) of 1,1,1,3,3,3-hexafluoropropanyl 4-(2-((4-(1-
(isobutyryloxy)ethoxy)oxobutyl)amino)(trifluoromethyl)benzyl)piperazinecarboxylate as a
light yellow oil. H NMR (300 MHz, Methanol-d4) 7.05 (d, J = 7.5 Hz, 1H), 6.84 - 6.89 (m, 2H),
6.77 (s, 1H), 6.13 (br s, 1H), 5.71 - 5.79 (m, 1H), 3.54 (br s, 6H), 3.20 (t, J = 6.6 Hz, 2H), 2.44 - 2.60
(m, 7H), 1.94 - 2.04 (m, 2H), 1.46 (d, J = 5.4 Hz, 3H), 1.13 - 1.16 (m, 6H). LCMS (ESI, m/z): 654
[M+H] .
Example 9: 2-(2-((2-((4-(((1,1,1,3,3,3-Hexafluoropropanyl)oxy)carbonyl)piperazin
yl)methyl)(trifluoromethyl)phenyl)amino)ethoxy)acetic acid
Step 1: Preparation of tert-butyl 2-(2-(((benzyloxy)carbonyl)amino)ethoxy)acetate
A flask was charged with tert-butyl 2-bromoacetate (6.00 g, 30.8 mmol, 1.00 equiv),
toluene (180 mL), benzyl (2-hydroxyethyl)carbamate (12.0 g, 61.5 mmol, 2.00 equiv),
tetrabutylammonium hydrogen sulfate (5.22 g, 15.40 mmol, 0.50 equiv), and 30% sodium hydroxide
aqueous solution (90 mL), The resulting solution was stirred overnight at rt and quenched with water
(80 mL). The resulting solution was extracted with EtOAc (2 x 100 mL) and the organic layers were
combined, washed with brine (2 x 80 mL), dried over anhydrous sodium sulfate, filtered and
concentrated. The residue was chromatographed on a silica gel column with EtOAc/petroleum ether
(1/3) to provide 3.70 g (39% yield) of tert-butyl 2-(2-(((benzyloxy)carbonyl)amino)ethoxy)acetate as
a light yellow oil. LCMS (ESI, m/z): 332 [M+Na] .
Step 2: Preparation of tert-butyl 2-(2-aminoethoxy)acetate
A flask was charged with tert-butyl 2-(2-(((benzyloxy)carbonyl)amino)ethoxy)acetate (3.80
g, 12.3 mmol, 1.00 equiv), EtOAc (40 mL), and palladium on carbon (2.00 g). Hydrogen was
introduced and the resulting solution was stirred overnight at rt. The reaction mixture was filtered
and the filtrate concentrated under vacuum to provide 1.80 g (84% yield) of tert-butyl 2-(2-
aminoethoxy)acetate as a colorless oil. LCMS (ESI, m/z): 176 [M+H] .
Step 3: Preparation of tert-butyl 2-(2-((2-formyl(trifluoromethyl)phenyl)(4-
methoxybenzyl)amino)ethoxy)acetate
A flask was charged with tert-butyl 2-(2-((4-methoxybenzyl)amino)ethoxy)acetate (300
mg, 1.02 mmol, 1.00 equiv, prepared as described in Example 1, Step 1 using tert-butyl 2-(2-
aminoethoxy)acetate), DMSO (10 mL), 2-fluoro(trifluoromethyl)benzaldehyde (235 mg, 1.22
mmol, 1.20 equiv), and DIPEA (395 mg, 3.06 mmol, 3.00 equiv). The resulting solution was stirred
overnight at 110 °C and quenched with water (30 mL). The resulting solution was extracted with
EtOAc (2 x 50 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried
over anhydrous sodium sulfate, filtered and concentrated. The residue was chromatographed on a
silica gel column with ethyl acetate/petroleum ether (1/10) to provide 160 mg (34% yield) of tert-
butyl 2-(2-((2-formyl(trifluoromethyl)phenyl)(4-methoxybenzyl)amino)ethoxy)acetate as a yellow
oil. LCMS (ESI, m/z): 468 [M+H] .
Step 4: Preparation of 1,1,1,3,3,3-hexafluoropropanyl 4-(2-((2-(2-(tert-butoxy)
oxoethoxy)ethyl)(4-methoxybenzyl)amino)(trifluoromethyl)benzyl)piperazinecarboxylate
A flask was charged with 1,1,1,3,3,3-hexafluoropropanyl piperazinecarboxylate,
2,2,2-trifluoroacetate salt (115 mg, 0.410 mmol, 1.20 equiv, prepared as described in Example 1,
Steps 3-4), DCE (10 mL), TEA (104 mg, 1.03 mmol, 3.00 equiv), and tert-butyl 2-(2-((2-formyl
(trifluoromethyl)phenyl)(4-methoxybenzyl)amino)ethoxy)acetate (160 mg, 0.340 mmol, 1.00 equiv).
The mixture was stirred for 1 h at rt and then sodium triacetoxyborohydride (218 mg, 1.03 mmol,
3.00 equiv) was added. The reaction mixture was stirred overnight at rt and quenched with water (30
mL). The resulting solution was extracted with DCM (2 x 50 mL) and the organic layers were
combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and
concentrated. The residue was chromatographed on a silica gel column with DCM/MeOH (97/3) to
provide 160 mg (64% yield) of 1,1,1,3,3,3-hexafluoropropanyl 4-(2-((2-(2-(tert-butoxy)
oxoethoxy)ethyl)(4-methoxybenzyl)amino)(trifluoromethyl)benzyl)piperazinecarboxylate as a
yellow oil. LCMS (ESI, m/z): 732 [M+H] .
Step 5: Preparation of 2-(2-((2-((4-(((1,1,1,3,3,3-hexafluoropropan
yl)oxy)carbonyl)piperazinyl)methyl)(trifluoromethyl)phenyl)amino)ethoxy)acetic acid
A flask was charged with 1,1,1,3,3,3-hexafluoropropanyl 4-(2-((2-(2-(tert-butoxy)
oxoethoxy)ethyl)(4-methoxybenzyl)amino)(trifluoromethyl)benzyl)piperazinecarboxylate (160
mg, 0.220 mmol, 1.00 equiv), 1,4-dioxane (10 mL), and hydrochloric acid (3 mL). The resulting
solution was stirred for 5 h at rt and concentrated. The crude product (300 mg) was purified by
preparative HPLC to provide 17.0 mg (14%) of 2-(2-((2-((4-(((1,1,1,3,3,3-hexafluoropropan
yl)oxy)carbonyl)piperazinyl)methyl)(trifluoromethyl)phenyl)amino)ethoxy)acetic acid as an
off-white solid. H NMR (400 MHz, Methanol-d ) 7.16 (d, J = 7.6 Hz, 1H), 6.84 - 6.88 (m, 2H),
6.09 - 6.18 (m, 1H), 3.94 (s, 2H), 3.82 (t, J = 5.2 Hz, 2H), 3.60 (br s, 6H), 3.35 - 3.36 (m, 2H), 2.45 -
2.51 (m, 4H). LCMS (ESI, m/z): 556 [M+H] .
Example 10: 2-(2-((4-Chloro((4-(((1,1,1,3,3,3-hexafluoropropan
yl)oxy)carbonyl)piperazinyl)methyl)phenyl)amino)ethoxy)acetic acid
The title compound was prepared according to the representative procedure of Example 9
using 5-chlorofluorobenzaldehyde in Step 3 to provide 2-(2-((4-chloro((4-(((1,1,1,3,3,3-
hexafluoropropanyl)oxy)carbonyl)piperazinyl)methyl)phenyl)amino)ethoxy)acetic acid as a
yellow solid. H NMR (400 MHz, Methanol-d ) 7.12 - 7.14 (m, 1H), 7.02 (s, 1H), 6.64 (d, J = 8.4
Hz, 1H), 6.11 - 6.17 (m, 1H), 4.05 (s, 2H), 3.82 (t, J = 6.8 Hz, 2H), 3.54 - 3.66 (m, 6H), 3.29 - 3.32
(m, 2H), 2.46 - 2.48 (m, 4H). LCMS (ESI, m/z): 522 [M+H] .
Example 11: 2-(2-((2-Fluoro((4-(((1,1,1,3,3,3-hexafluoropropanyl)oxy)carbonyl)piperazin-
1-yl)methyl)phenyl)amino)ethoxy)acetic acid
The title compound was prepared according to the representative procedure of Example 9
using 2,3-difluorobenzaldehyde in Step 3 to provide 2-(2-((2-fluoro((4-(((1,1,1,3,3,3-
hexafluoropropanyl)oxy)carbonyl)piperazinyl)methyl)phenyl)amino)ethoxy)acetic acid as a
light yellow oil. H NMR (300 MHz, Methanol-d ) 6.86 - 6.99 (m, 2H), 6.69 - 6.78 (m, 1H), 6.08 -
6.18 (m, 1H), 3.98 (s, 2H), 3.62 - 3.65 (m, 4H), 3.56 (br s, 4H), 3.45 - 3.46 (m, 2H), 2.46 (br s, 4H).
LCMS (ESI, m/z): 506 [M+H] .
Example 12: N-(2-((5-Chloro((4-(((1,1,1,3,3,3-hexafluoropropan
yl)oxy)carbonyl)piperazinyl)methyl)phenyl)amino)ethyl)-N-(methylsulfonyl)glycine
Step 1: Preparation of N-(2-(1,3-dioxoisoindolinyl)ethyl)methanesulfonamide
A flask was charged with 2-(2-aminoethyl)isoindoline-1,3-dione (2.00 g, 10.5 mmol, 1.00
equiv), DCM (20 mL), TEA (2.12 g, 21.0 mmol, 2.00 equiv), and methanesulfonyl chloride (1.44 g,
12.6 mmol, 1.20 equiv). The resulting solution was stirred overnight at rt and quenched with water
(80 mL). The resulting solution was extracted with EtOAc (2 x 100 mL) and the organic layers were
combined, washed with brine (2 x 80 mL), dried over anhydrous sodium sulfate, filtered and
concentrated to provide 800 mg (crude) of N-(2-(1,3-dioxoisoindolinyl)ethyl)methanesulfonamide
as a light yellow solid. LCMS (ESI, m/z): 269 [M+H] .
Step 2: Preparation of tert-butyl N-(2-(1,3-dioxoisoindolinyl)ethyl)-N-
(methylsulfonyl)glycinate
A flask was charged with N-(2-(1,3-dioxoisoindolinyl)ethyl)methanesulfonamide (750
mg, 2.80 mmol, 1.00 equiv), MeCN (10 mL), potassium carbonate (1.16 g, 8.40 mmol, 3.00 equiv),
and tert-butyl 2-bromoacetate (652 mg, 3.36 mmol, 1.20 equiv). The resulting solution was stirred
overnight at 60 °C. The solids were filtered out and concentrated. The residue was chromatographed
on a silica gel column with DCM/MeOH (3/97) to provide 700 mg (65% yield) of tert-butyl N-(2-
(1,3-dioxoisoindolinyl)ethyl)-N-(methylsulfonyl)glycinate as an off-white solid. LCMS (ESI,
m/z): 383 [M+H] .
Step 3: Preparation of tert-butyl N-(2-aminoethyl)-N-(methylsulfonyl)glycinate
A flask was charged with tert-butyl N-(2-(1,3-dioxoisoindolinyl)ethyl)-N-
(methylsulfonyl)glycinate (500 mg, 1.31 mmol, 1.00 equiv), EtOH (10 mL), and hydrazine hydrate
(328 mg, 6.55 mmol, 5.00 equiv). The resulting solution was stirred overnight at 50 °C and
concentrated to provide 300 mg (crude) of tert-butyl N-(2-aminoethyl)-N-(methylsulfonyl)glycinate
as a light yellow solid. LCMS (ESI, m/z): 253 [M+H] .
Step 4: Preparation of tert-butyl N-(2-((4-methoxybenzyl)amino)ethyl)-N-
(methylsulfonyl)glycinate
A flask was charged with tert-butyl N-(2-aminoethyl)-N-(methylsulfonyl)glycinate (300
mg, 1.19 mmol, 1.00 equiv), EtOH (10 mL), and 4-methoxybenzaldehyde (162 mg, 1.19 mmol, 1.00
equiv) The resulting solution was stirred for 5 h at 60 °C. Sodium borohydride (27.0 mg, 0.714
mmol, 0.60 equiv) was added. The resulting solution was stirred overnight at rt and quenched with
water (30 mL). The resulting solution was extracted with DCM (2 x 50 mL) and the organic layers
were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and
concentrated. The residue was chromatographed on a silica gel column with DCM/MeOH (96/4) to
provide 240 mg (54% yield) of tert-butyl N-(2-((4-methoxybenzyl)amino)ethyl)-N-
(methylsulfonyl)glycinate as a yellow oil. LCMS (ESI, m/z): 373 [M+H] .
Step 5: Preparation of tert-butyl N-(2-((5-chloroformylphenyl)(4-
methoxybenzyl)amino)ethyl)-N-(methylsulfonyl)glycinate
A flask was charged with tert-butyl N-(2-((4-methoxybenzyl)amino)ethyl)-N-
(methylsulfonyl)glycinate (200 mg, 0.540 mmol, 1.00 equiv), DMSO (10 mL), and 4-chloro
fluorobenzaldehyde (128 mg, 0.810 mmol, 1.50 equiv) under nitrogen. The resulting solution was
stirred overnight at 120 °C and quenched with water (30 mL). The resulting solution was extracted
with EtOAc (2 x 50 mL) and the organic layers were combined, washed with brine (2 x 30 mL),
dried over anhydrous sodium sulfate, filtered and concentrated. The residue was chromatographed on
a silica gel column with EtOAc/petroleum ether (1/4) to provide 80.0 mg (29% yield) of tert-butyl N-
(2-((5-chloroformylphenyl)(4-methoxybenzyl)amino)ethyl)-N-(methylsulfonyl)glycinate as a
yellow oil. LCMS (ESI, m/z): 511 [M+H] .
Step 6: Preparation of 1,1,1,3,3,3-hexafluoropropanyl 4-(2-((2-(N-(2-(tert-butoxy)
oxoethyl)methylsulfonamido)ethyl)(4-methoxybenzyl)amino)chlorobenzyl)piperazine
carboxylate
A flask was charged with 1,1,1,3,3,3-hexafluoropropanyl piperazinecarboxylate,
2,2,2-trifluoroacetate salt (53.0 mg, 0.190 mmol, 1.20 equiv, prepared as described in Example 1,
Steps 3-4), DCE (10 mL), TEA (48.0 mg, 0.470 mmol, 3.00 equiv), and tert-butyl N-(2-((5-chloro
formylphenyl)(4-methoxybenzyl)amino)ethyl)-N-(methylsulfonyl)glycinate (80.0 mg, 0.160 mmol,
1.00 equiv). The mixture was stirred for 1 h at rt and then sodium triacetoxyborohydride (100 mg,
0.470 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at rt and quenched
with water (30 mL). The resulting solution was extracted with DCM (2 x 50 mL) and the organic
layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered
and concentrated. The residue was chromatographed on a silica gel column with DCM/MeOH (96/4)
to provide 100 mg (82% yield) of 1,1,1,3,3,3-hexafluoropropanyl 4-(2-((2-(N-(2-(tert-butoxy)
oxoethyl)methylsulfonamido)ethyl)(4-methoxybenzyl)amino)chlorobenzyl)piperazine
carboxylate as a yellow oil. LCMS (ESI, m/z): 775 [M+H] .
Step 7: Preparation of N-(2-((5-chloro((4-(((1,1,1,3,3,3-hexafluoropropan
yl)oxy)carbonyl)piperazinyl)methyl)phenyl)amino)ethyl)-N-(methylsulfonyl)glycine
A flask was charged with 1,1,1,3,3,3-hexafluoropropanyl 4-(2-((2-(N-(2-(tert-butoxy)
oxoethyl)methylsulfonamido)ethyl)(4-methoxybenzyl)amino)chlorobenzyl)piperazine
carboxylate (100 mg, 0.130 mmol, 1.00 equiv), DCM (10 mL), and TFA (5 mL). The resulting
solution was stirred overnight at rt and concentrated. The crude product was purified by preparative
HPLC to provide 6.4 mg (8% yield) of N-(2-((5-chloro((4-(((1,1,1,3,3,3-hexafluoropropan
yl)oxy)carbonyl)piperazinyl)methyl)phenyl)amino)ethyl)-N-(methylsulfonyl)glycine as a white
solid. H NMR (300 MHz, Methanol-d ) 6.95 (d, J = 7.8 Hz, 1H), 6.63 (s, 1H), 6.57- 6.58 (m, 1H),
6.17 - 6.15 (m, 1H), 3.98 (s, 2H), 3.60 - 3.64 (m, 4H), 3.52 (s, 2H), 3.25 - 3.30 (m, 4H), 3.06 (s, 3H),
2.46 - 2.48 (m, 4H). LCMS (ESI, m/z): 599 [M+H] .
Example 13: 2-(5-Chloro((4-(((1,1,1,3,3,3-hexafluoropropanyl)oxy)carbonyl)piperazin
yl)methyl)phenoxy)acetic acid
Step 1: Preparation of tert-butyl 4-(4-chlorohydroxybenzyl)piperazinecarboxylate
A flask was charged with 4-chlorohydroxybenzaldehyde (1.00 g, 6.39 mmol, 1.00
equiv), DCE (15 mL), and tert-butyl piperazinecarboxylate (1.43 g, 7.67 mmol, 1.20 equiv). The
mixture was stirred for 1 h at rt and then sodium triacetoxyborohydride (4.08 g, 19.2 mmol, 3.00
equiv) was added. The resulting solution was stirred overnight at rt and quenched with water (30
mL). The resulting solution was extracted with DCM (2 x 50 mL) and the organic layers were
combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and
concentrated. The residue was chromatographed on a silica gel column with DCM/MeOH (95/5) to
provide 1.20 g (57% yield) of tert-butyl 4-(4-chlorohydroxybenzyl)piperazinecarboxylate as a
yellow oil. LCMS (ESI, m/z): 327 [M+H] .
Step 2: Preparation of tert-butyl 4-(2-(2-(tert-butoxy)oxoethoxy)chlorobenzyl)piperazine-
1-carboxylate
A flask was charged with tert-butyl 4-(4-chlorohydroxybenzyl)piperazinecarboxylate
(300 mg, 0.920 mmol, 1.00 equiv), DMF (10 mL), tert-butyl 2-bromoacetate (215 mg, 1.10 mmol,
1.20 equiv), and potassium carbonate (381 mg, 2.76 mmol, 3.00 equiv). The resulting solution was
stirred overnight at 100 °C and quenched with water (30 mL). The resulting solution was extracted
with DCM (2 x 50 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried
over anhydrous sodium sulfate, filtered and concentrated. The residue was chromatographed on a
silica gel column with DCM/MeOH (97/3) to provide 200 mg (49% yield) of tert-butyl 4-(2-(2-(tert-
butoxy)oxoethoxy)chlorobenzyl)piperazinecarboxylate as a yellow oil. LCMS (ESI, m/z):
441 [M+H] .
Step 3: Preparation of 2-(5-chloro(piperazinylmethyl)phenoxy)acetic acid hydrochloride
Cl Boc
1,4-dioxane
O HCl
rt,overnight
O OH
A flask was charged with tert-butyl 4-(2-(2-(tert-butoxy)oxoethoxy)
chlorobenzyl)piperazinecarboxylate (200 mg, 0.450 mmol, 1.00 equiv), 1,4-dioxane (10 mL), and
hydrochloric acid (3 mL). The resulting solution was stirred overnight at rt and concentrated to
provide 300 mg (crude) of 2-(5-chloro(piperazinylmethyl)phenoxy)acetic acid hydrochloride as
a yellow semi-solid. LCMS (ESI, m/z): 285 [M+H] .
Step 4: Preparation of 2-(5-chloro((4-(((1,1,1,3,3,3-hexafluoropropan
yl)oxy)carbonyl)piperazinyl)methyl)phenoxy)acetic acid
A flask was charged with triphosgene (94.0 mg, 0.315 mmol, 0.70 equiv), DCM (10 mL),
and HFIP (152 mg, 0.900 mmol, 2.00 equiv) under nitrogen. DIPEA (175 mg, 1.35 mmol, 3.00
equiv) was added at 0 °C. The mixture was stirred for 1 h at rt. 2-(5-Chloro(piperazin
ylmethyl)phenoxy)acetic acid hydrochloride (128 mg, 0.450 mmol, 1.00 equiv) was added. The
resulting solution was stirred for 3 h at rt and quenched with water (30 mL). The resulting solution
was extracted with DCM (2 x 50 mL) and the organic layers were combined, washed with brine (2 x
mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product (300 mg)
was purified by preparative HPLC to provide 145.3 mg (68% yield) of 2-(5-chloro((4-
(((1,1,1,3,3,3-hexafluoropropanyl)oxy)carbonyl)piperazinyl)methyl)phenoxy)acetic acid as a
white solid. H NMR (300 MHz, Methanol-d4) 7.36 (d, J = 7.8 Hz, 1H), 7.25 (s, 1H), 7.07 - 7.10
(m, 1H), 6.17 - 6.30 (m, 1H), 4.68 (s, 2H), 4.21 (s, 2H), 3.86 (br s, 4H), 3.19 (br s, 4H). LCMS (ESI,
m/z): 479 [M+H] .
Example 14: 2-(2-((4-(((1,1,1,3,3,3-Hexafluoropropanyl)oxy)carbonyl)piperazin
yl)methyl)(trifluoromethyl)phenoxy)acetic acid
The title compound was prepared according to the representative procedure of Example 13
using 2-hydroxy(trifluoromethyl)benzaldehyde, prepared as described in Step 1 of Example 3, in
Step 1 to provide 2-(2-((4-(((1,1,1,3,3,3-hexafluoropropanyl)oxy)carbonyl)piperazin
yl)methyl)(trifluoromethyl)phenoxy)acetic acid as a white solid. H NMR (300 MHz, Methanol-
d ) 7.57 (d, J = 7.8 Hz, 1H), 7.45 (s, 1H), 7.35 (d, J = 7.8 Hz, 1H), 6.15 - 6.28 (m, 1H), 4.88 (s,
2H), 4.26 (br s, 2H), 3.83 (br s, 4H), 3.83 (br s, 4H). LCMS (ESI, m/z): 513 [M+H] .
Example 15: 5-(2-((4-(((1,1,1,3,3,3-Hexafluoropropanyl)oxy)carbonyl)piperazin
yl)methyl)(trifluoromethyl)phenyl)pentanoic acid
Step 1: Preparation of tert-butyl 4-(2-bromo(trifluoromethyl)benzyl)piperazine
carboxylate
A flask was charged with 2-bromo(trifluoromethyl)benzaldehyde (1.00 g, 3.95 mmol,
1.00 equiv), DCE (15 mL), and tert-butyl piperazinecarboxylate (813 mg, 4.35 mmol, 1.10 equiv).
The mixture was stirred for 1 h at rt and then sodium triacetoxyborohydride (2.52 g, 11.9 mmol, 3.00
equiv) was added. The resulting solution was stirred overnight at rt and quenched with water (30
mL). The resulting solution was extracted with DCM (2 x 50 mL) and the organic layers were
combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and
concentrated. The residue was chromatographed on a silica gel column with DCM/MeOH (98/2) to
provide 1.50 g (90% yield) of tert-butyl 4-(2-bromo(trifluoromethyl)benzyl)piperazine
carboxylate as a light yellow oil. LCMS (ESI, m/z): 423 [M+H] .
Step 2: Preparation of tert-butyl 4-(2-formyl(trifluoromethyl)benzyl)piperazine
carboxylate
A flask was charged with tert-butyl 4-(2-bromo(trifluoromethyl)benzyl)piperazine
carboxylate (2.00 g, 4.73 mmol, 1.00 equiv) and THF (15 mL) under nitrogen. The mixture was
cooled to -78 °C, and n-butyllithium (2.5 M in hexane, 2.30 mL, 5.68 mmol, 1.20 equiv) was added
dropwise over 20 min. After 1 h at -78 °C, DMF (1.73 g, 23.7 mmol, 5.00 equiv) was added. The
mixture was stirred for 1 h at -78 °C and concentrated to provide 1.20 g (68% yield) of tert-butyl 4-
(2-formyl(trifluoromethyl)benzyl)piperazinecarboxylate as a red oil. LCMS (ESI, m/z): 373
[M+H] .
Step 3: Preparation of (4-(tert-butoxy)oxobutyl)triphenylphosphonium bromide
A flask was charged with tert-butyl 4-bromobutanoate (500 mg, 2.24 mmol, 1.00 equiv),
MeCN (15 mL), triphenylphosphine (590 mg, 2.25 mmol, 1.00 equiv), and sodium bicarbonate (378
mg, 4.50 mmol, 2.00 equiv). The resulting solution was stirred overnight at 85 °C and cooled to rt.
The mixture was filtered and the filtrate was concentrated. The residue was triturated with diethyl
ether to provide 650 mg (60% yield) of (4-(tert-butoxy)oxobutyl)triphenylphosphonium bromide
as a white solid. LCMS (ESI, m/z): 405 [M-Br] .
Step 4: Preparation of tert-butyl (E)(2-(5-(tert-butoxy)oxopentenyl)
(trifluoromethyl)benzyl)piperazinecarboxylate
A flask was charged with (4-(tert-butoxy)oxobutyl)triphenylphosphonium bromide (650
mg, 1.34 mmol, 1.00 equiv) and THF (15 mL) under nitrogen. The mixture was cooled to -78 °C and
n-butyllithium (2.5 M in hexane, 0.540 mL, 1.34 mmol, 1.00 equiv) was added dropwise over 10
min. The mixture was stirred for 30 min at -78 °C and tert-butyl 4-(2-formyl
(trifluoromethyl)benzyl)piperazinecarboxylate (500 mg, 1.34 mmol, 1.00 equiv) was added. The
reaction mixture was stirred overnight at 50 °C and quenched with water (30 mL). The resulting
solution was extracted with DCM (2 x 50 mL) and the organic layers were combined, washed with
brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was
chromatographed on a silica gel column with DCM/MeOH (95/5) to provide 210 mg (31% yield) of
tert-butyl (E)(2-(5-(tert-butoxy)oxopentenyl)(trifluoromethyl)benzyl)piperazine
carboxylate as a yellow oil. LCMS (ESI, m/z): 499 [M+H] .
Step 5: Preparation of tert-butyl 4-(2-(5-(tert-butoxy)oxopentyl)
(trifluoromethyl)benzyl)piperazinecarboxylate
A flask was charged with tert-butyl (E)(2-(5-(tert-butoxy)oxopentenyl)
(trifluoromethyl)benzyl)piperazinecarboxylate (150 mg, 0.300 mmol, 1.00 equiv), MeOH (10
mL), and palladium on carbon (100 mg). Hydrogen was introduced into the reaction and the mixture
was stirred overnight at rt and the solids were removed by filtration. The filtrate was concentrated to
provide 100 mg (crude) of tert-butyl 4-(2-(5-(tert-butoxy)oxopentyl)
(trifluoromethyl)benzyl)piperazinecarboxylate as a light yellow oil. LCMS (ESI, m/z): 501
[M+H] .
Step 6: Preparation of 5-(2-(piperazinylmethyl)(trifluoromethyl)phenyl)pentanoic acid
hydrochloride
A flask was charged with tert-butyl 4-(2-(5-(tert-butoxy)oxopentyl)
(trifluoromethyl)benzyl)piperazinecarboxylate (100 mg, 0.220 mmol, 1.00 equiv), 1,4-dioxane (10
mL), and hydrochloric acid (2 mL). The resulting solution was stirred for 3 h at rt and concentrated
to provide 150 mg (crude) of 5-(2-(piperazinylmethyl)(trifluoromethyl)phenyl)pentanoic acid
hydrochloride as a light yellow oil. LCMS (ESI, m/z): 345 [M+H] .
Step 7: Preparation of 5-(2-((4-(((1,1,1,3,3,3-hexafluoropropanyl)oxy)carbonyl)piperazin
yl)methyl)(trifluoromethyl)phenyl)pentanoic acid
A flask was charged with triphosgene (39.0 mg, 0.130 mmol, 0.70 equiv), DCM (10 mL),
and HFIP (64.0 mg, 0.380 mmol, 2.00 equiv) under nitrogen. DIPEA (73.0 mg, 0.560 mmol, 3.00
equiv) was added at 0 °C and the mixture was stirred for 1 h at rt. 5-(2-(Piperazinylmethyl)
(trifluoromethyl)phenyl)pentanoic acid hydrochloride (65.0 mg, 0.190 mmol, 1.00 equiv) was added.
The resulting solution was stirred overnight at rt and quenched with water (30 mL). The resulting
solution was extracted with DCM (2 x 50 mL) and the organic layers were combined, washed with
brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product
(300 mg) was purified by preparative HPLC to provide 21.5 mg (21% yield) of 5-(2-((4-
(((1,1,1,3,3,3-hexafluoropropanyl)oxy)carbonyl)piperazinyl)methyl)
(trifluoromethyl)phenyl)pentanoic acid as a colorless oil. H NMR (300 MHz, Methanol-d ) 7.41 -
7.50 (m, 3H), 6.07 - 6.19 (m, 1H), 3.60 (s, 2H), 3.47 - 3.58 (m, 4H), 2.79 - 2.84 (m, 2H), 2.47 - 2.49
(m, 4H), 2.30 (t, J = 6.9 Hz, 2H), 1.64 - 1.75 (m, 4H). LCMS (ESI, m/z): 539 [M+H] .
Example 16: 1-(2-((4-(((1,1,1,3,3,3-Hexafluoropropanyl)oxy)carbonyl)piperazin
yl)methyl)(trifluoromethyl)phenoxy)cyclopropanecarboxylic acid
Step 1: Preparation of methyl 1-(2-formyl(trifluoromethyl)phenoxy)cyclopropane
carboxylate
A flask was charged with methyl 1-hydroxycyclopropanecarboxylate (362 mg, 3.12
mmol, 1.50 equiv) and THF (10 mL). Sodium hydride (125 mg, 3.12 mmol, 1.50 equiv, 60% in
mineral oil) was added at 0 °C. The mixture was stirred for 20 min at rt before 2-fluoro
(trifluoromethyl)benzaldehyde (400 mg, 2.08 mmol, 1.00 equiv) was added. The resulting solution
was stirred for 1 h at rt and quenched with water (30 mL). The resulting solution was extracted with
DCM (2 x 50 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over
anhydrous sodium sulfate, filtered and concentrated. The residue was chromatographed on a silica
gel column with EtOAc/petroleum ether (1/10) to provide 180 mg (29% yield) of methyl 1-(2-
formyl(trifluoromethyl)phenoxy)cyclopropanecarboxylate as a light yellow oil.
Step 2: Preparation of tert-butyl 4-(2-(1-(methoxycarbonyl)cyclopropoxy)
(trifluoromethyl)benzyl)piperazinecarboxylate
A flask was charged with methyl 1-(2-formyl(trifluoromethyl)phenoxy)cyclopropane
carboxylate (200 mg, 0.690 mmol, 1.00 equiv), DCE (10 mL), and tert-butyl piperazine
carboxylate (155 mg, 0.828 mmol, 1.20 equiv). The mixture was stirred for 1 h at rt and sodium
triacetoxyborohydride (441 mg, 2.07 mmol, 3.00 equiv) was added. The resulting solution was
stirred overnight at rt and quenched with water (30 mL). The resulting solution was extracted with
DCM (2 x 50 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over
anhydrous sodium sulfate, filtered and concentrated. The residue was chromatographed on a silica
gel column with DCM/MeOH (97/3) to provide 250 mg (79% yield) of tert-butyl 4-(2-(1-
(methoxycarbonyl)cyclopropoxy)(trifluoromethyl)benzyl)piperazinecarboxylate as a colorless
oil. LCMS (ESI, m/z): 459 [M+H] .
Step 3: Preparation of 1-(2-((4-(tert-butoxycarbonyl)piperazinyl)methyl)
(trifluoromethyl)phenoxy)cyclopropanecarboxylic acid
A flask was charged with tert-butyl 4-(2-(1-(methoxycarbonyl)cyclopropoxy)
(trifluoromethyl)benzyl)piperazinecarboxylate (200 mg, 0.440 mmol, 1.00 equiv), THF (5 mL),
water (5 mL), and lithium hydroxide (157 mg, 6.56 mmol, 15.0 equiv). The resulting solution was
stirred overnight at rt, and then pH value of the solution was adjusted to 5 with hydrochloric acid (1
mol/L). The resulting solution was extracted with DCM (2 x 50 mL) and the organic layers were
combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and
concentrated to provide 190 mg (crude) of 1-(2-((4-(tert-butoxycarbonyl)piperazinyl)methyl)
(trifluoromethyl)phenoxy)cyclopropanecarboxylic acid as a light yellow solid. LCMS (ESI, m/z):
445 [M+H] .
Step 4: Preparation of 1-(2-(piperazinylmethyl)(trifluoromethyl)phenoxy)cyclopropane
carboxylic acid hydrochloride
A flask was charged with 1-(2-((4-(tert-butoxycarbonyl)piperazinyl)methyl)
(trifluoromethyl)phenoxy)cyclopropanecarboxylic acid (190 mg, 0.430 mmol, 1.00 equiv), 1,4-
dioxane (10 mL), and hydrochloric acid (3 mL). The resulting solution was stirred for 5 h at rt and
concentrated to provide 140 mg (crude) of 1-(2-(piperazinylmethyl)
(trifluoromethyl)phenoxy)cyclopropanecarboxylic acid hydrochloride as a light yellow solid.
LCMS (ESI, m/z): 345 [M+H] .
Step 5: Preparation of 1-(2-((4-(((1,1,1,3,3,3-hexafluoropropanyl)oxy)carbonyl)piperazin
yl)methyl)(trifluoromethyl)phenoxy)cyclopropanecarboxylic acid
A flask was charged with triphosgene (85.0 mg, 0.290 mmol, 0.70 equiv), DCM (10 mL),
1,1,1,3,3,3-hexafluoropropanol (137 mg, 0.820 mmol, 2.00 equiv) under nitrogen. DIPEA (158
mg, 1.22 mmol, 3.00 equiv) was added at 0 °C. The mixture was stirred for 1 h at rt and 1-(2-
(piperazinylmethyl)(trifluoromethyl)phenoxy)cyclopropanecarboxylic acid hydrochloride
(140 mg, 0.410 mmol, 1.00 equiv) was added. The resulting solution was stirred overnight at rt and
quenched with water (30 mL). The resulting solution was extracted with DCM (2 x 50 mL) and the
organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate,
filtered and concentrated. The crude product (300 mg) was purified by preparative HPLC to provide
84.9 mg (39% yield) of 1-(2-((4-(((1,1,1,3,3,3-hexafluoropropanyl)oxy)carbonyl)piperazin
yl)methyl)(trifluoromethyl)phenoxy)cyclopropanecarboxylic acid as a white solid. H NMR
(300 MHz, Methanol-d ) 7.55 (d, J = 7.8 Hz, 1H), 7.41 (s, 1H), 7.30 (d, J = 7.8 Hz, 1H), 6.10 -
6.19 (m, 1H), 3.86 (s, 2H), 3.65 - 3.66 (m, 4H), 2.78 (br s, 4H), 1.50 - 1.54 (m, 2H), 1.16 - 1.20 (m,
2H). LCMS (ESI, m/z): 539 [M+H] .
Example 17: 2-(3-((4-(((1,1,1,3,3,3-hexafluoropropanyl)oxy)carbonyl)piperazin
yl)methyl)(trifluoromethyl)phenyl)acetic acid
Step 1: Synthesis of tert-butyl 4-(3-bromo(trifluoromethyl)benzyl)piperazinecarboxylate
A flask was charged with 3-bromo(trifluoromethyl)benzaldehyde (2.53 g, 10.0 mmol,
1.00 equiv), tert-butyl piperazinecarboxylate (2.23 g, 12.0 mmol, 1.20 equiv), DCE (25 mL), and
triethylamine (3.03 g, 29.9 mmol, 3.00 equiv). The mixture was stirred for 30 min at rt prior to
addition of sodium triacetoxyborohydride (6.36 g, 30.0 mmol, 3.00 equiv). The resulting solution
was stirred overnight at rt and quenched with water (25 mL), as described in Example 1, Step 5. The
residue was chromatographed on a silica gel column to provide 1.90 g (45% yield) of tert-butyl 4-(3-
bromo(trifluoromethyl)benzyl)piperazinecarboxylate. LCMS (ESI, m/z): 423 [M+H] .
Step 2: Synthesis of tert-butyl 4-(3-(2-(tert-butoxy)oxoethyl)
(trifluoromethyl)benzyl)piperazinecarboxylate
A flask was charged with tert-butyl 4-(3-bromo(trifluoromethyl)benzyl)piperazine
carboxylate (2.00 g, 4.73 mmol, 1.00 equiv), (2-tert-butoxyoxoethyl)zinc(II) chloride (28.4 mL,
14.2 mmol, 3.00 equiv, 0.5M in ethylether), tris(dibenzylideneacetone)dipalladium (433 mg, 0.473
mmol, 0.10 equiv), 2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (451 mg, 0.946 mmol,
0.20 equiv), and THF (30 mL) under nitrogen. The resulting solution was stirred overnight at 60 °C
and quenched with water (30 mL). The resulting solution was extracted with DCM (3 x 30 mL), and
the organic layers were combined, washed with brine (2 x 10 mL), dried over anhydrous sodium
sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a
silica gel column to provide 1.00 g (46% yield) of tert-butyl 4-(3-(2-(tert-butoxy)oxoethyl)
(trifluoromethyl)benzyl)piperazinecarboxylate. LCMS (ESI, m/z): 459 [M+H] .
Step 3: Synthesis of 2-(3-(piperazinylmethyl)(trifluoromethyl)phenyl)acetic acid
A flask was charged with tert-butyl 4-(3-(2-(tert-butoxy)oxoethyl)
(trifluoromethyl)benzyl)piperazinecarboxylate (200 mg, 0.436 mmol, 1.00 equiv), 1,4-dioxane (4
mL), and concentrated hydrogen chloride (1 mL). The resulting solution was stirred for 2 h at rt and
concentrated under reduced pressure, as described in Example 3, Step 4 to provide 180 mg (crude) of
2-(3-(piperazinylmethyl)(trifluoromethyl)phenyl)acetic acid. LCMS (ESI, m/z): 303 [M+H] .
Step 4: Synthesis of 2-(3-((4-(((1,1,1,3,3,3-hexafluoropropanyl)oxy)carbonyl)piperazin
yl)methyl)(trifluoromethyl)phenyl)acetic acid
A flask was charged with triphosgene (63.9 mg, 0.215 mmol, 0.50 equiv), DCM (5 mL),
and 1,1,1,3,3,3-hexafluoropropanol (145 mg, 0.861 mmol, 2.00 equiv). DIPEA (222 mg, 1.72
mmol, 4.00 equiv) was added dropwise at 0 °C, and the mixture was stirred for 2 h at room
temperature. 2-(3-(Piperazinylmethyl)(trifluoromethyl)phenyl)acetic acid (130 mg, 0.430
mmol, 1.00 equiv) was added and the resulting solution was stirred for 2 h at rt before quenching
with saturated sodium bicarbonate solution (20 mL), as described in Example 1, Step 1. The crude
product (200 mg) was purified by preparative HPLC to provide 54.9 mg (26% yield) of 2-(3-((4-
(((1,1,1,3,3,3-hexafluoropropanyl)oxy)carbonyl)piperazinyl)methyl)
(trifluoromethyl)phenyl)acetic acid. H NMR (300 MHz, Methanol-d ) 7.58 - 7.53 (m, 3H), 6.18 -
6.08 (m, 1H), 3.72 (br s, 2H), 3.64 - 3.56 (m, 6H), 2.52 - 2.51 (m, 4H). LCMS (ESI, m/z): 497
[M+H] .
Example 18: 4-(2-((4-(((1,1,1,3,3,3-hexafluoropropanyl)oxy)carbonyl)piperazin
yl)methyl)(trifluoromethyl)phenyl)-2,2-dimethylbutynoic acid
Step 1: Synthesis of tert-butyl 4-(2-iodo(trifluoromethyl)benzyl)piperazinecarboxylate
A flask was charged with 2-iodo(trifluoromethyl)benzaldehyde (1.00 g, 3.33 mmol, 1.00
equiv), tert-butyl piperazinecarboxylate (0.744 g, 3.99 mmol, 1.20 equiv), and DCE (15 mL). The
mixture was stirred for 1 h at rt prior to addition of sodium triacetoxyborohydride (2.12 g, 10.0
mmol, 3.00 equiv). The resulting solution was stirred overnight at rt and quenched with water (20
mL), as described in Example 15, Step 1. The residue was chromatographed on a silica gel column to
provide 1.39 g (89% yield) of tert-butyl 4-(2-iodo(trifluoromethyl)benzyl)piperazine
carboxylate. LCMS (ESI, m/z): 471 [M+H] .
Step 2: Synthesis of tert-butyl 4-(2-(4-ethoxy-3,3-dimethyloxobutynyl)
(trifluoromethyl)benzyl)piperazinecarboxylate
A flask was charged with tert-butyl 4-(2-iodo(trifluoromethyl)benzyl)piperazine
carboxylate (400 mg, 0.851 mmol, 1.00 equiv), ethyl 2,2-dimethylbutynoate (238 mg, 1.70 mmol,
2.00 equiv), bis(triphenylphosphine)palladium(II) chloride (59.6 mg, 0.0851 mmol, 0.10 equiv),
copper(I) iodide (32.3 mg, 0.170 mmol, 0.20 equiv), triethylamine (258 mg, 2.55 mmol, 3.00 equiv),
and THF (10 mL) under nitrogen. The reaction mixture was stirred overnight at 60 °C and quenched
with water (15 mL). The resulting solution was extracted with DCM (3 x 20 mL), and the organic
layers were combined, washed with brine (1 x 50 mL), dried over anhydrous Na SO , filtered and
concentrated under reduced pressure. The residue was chromatographed on a silica gel column to
provide 320 mg (78% yield) of tert-butyl 4-(2-(4-ethoxy-3,3-dimethyloxobutynyl)
(trifluoromethyl)benzyl)piperazinecarboxylate. LCMS (ESI, m/z): 483 [M+H] .
Step 3: Synthesis of 4-(2-((4-(tert-butoxycarbonyl)piperazinyl)methyl)
(trifluoromethyl)phenyl)-2,2-dimethylbutynoic acid
A flask was charged with tert-butyl 4-(2-(4-ethoxy-3,3-dimethyloxobutynyl)
(trifluoromethyl)benzyl)piperazinecarboxylate (320 mg, 0.660 mmol, 1.00 equiv), THF (10 mL),
lithium hydroxide (313 mg, 13.1 mmol, 20.00 equiv), and water (2 mL). The resulting solution was
stirred overnight at 35 °C and quenched with water (10 mL). The pH value of the solution was
adjusted to 6 with hydrochloric acid (1M), as described in Example 16, Step 3 to provide 280 mg
(93% yield) of 4-(2-((4-(tert-butoxycarbonyl)piperazinyl)methyl)(trifluoromethyl)phenyl)-2,2-
dimethylbutynoic acid. LCMS (ESI, m/z): 455 [M+H] .
Step 4: Synthesis of 2,2-dimethyl(2-(piperazinylmethyl)(trifluoromethyl)phenyl)but
ynoic acid
A flask was charged with 4-(2-((4-(tert-butoxycarbonyl)piperazinyl)methyl)
(trifluoromethyl)phenyl)-2,2-dimethylbutynoic acid (280 mg, 0.620 mmol, 1.00 equiv), 1,4-
dioxane (10 mL), and concentrated hydrochloric acid (2 mL). The resulting solution was stirred for 2
h at rt and concentrated under reduced pressure to provide 300 mg (crude) of 2,2-dimethyl(2-
(piperazinylmethyl)(trifluoromethyl)phenyl)butynoic acid as a yellow solid. LCMS (ESI,
m/z): 355 [M+H] .
Step 5: Synthesis of 4-(2-((4-(((1,1,1,3,3,3-hexafluoropropanyl)oxy)carbonyl)piperazin
yl)methyl)(trifluoromethyl)phenyl)-2,2-dimethylbutynoic acid
A flask was charged with triphosgene (117 mg, 0.390 mmol, 0.70 equiv), DCM (10 mL).
1,1,1,3,3,3-hexafluoropropanol (190 mg, 1.13 mmol, 2.00 equiv) was added at 0 °C. N,N-DIPEA
(292 mg, 2.26 mmol, 4.00 equiv) was added at 0 °C. The mixture was stirred for 2 h at 0 °C. 2,2-
Dimethyl(2-(piperazinylmethyl)(trifluoromethyl)phenyl)butynoic acid (200 mg, 0.560
mmol, 1.00 equiv) was added. The resulting solution was stirred for 1 h at rt and quenched with
water (10 mL), as described in Example 1, Step 1. The crude product (400 mg) was purified by
preparative HPLC to provide 21.1 mg (7% yield) of 4-(2-((4-(((1,1,1,3,3,3-hexafluoropropan
yl)oxy)carbonyl)piperazinyl)methyl)(trifluoromethyl)phenyl)-2,2-dimethylbutynoic acid. H
NMR (400 MHz, Methanol-d ) 7.69 - 7.68 (m, 2H), 7.63 - 7.61 (m, 1H), 6.19 - 6.13 (m, 1H), 3.84
(s, 2H), 3.63 - 3.60 (m, 4H), 2.63 - 2.59 (m, 4H), 1.60 (s, 6H). LCMS (ESI, m/z): 549 [M+H] .
Example 19: 1-(3-((4-(((1,1,1,3,3,3-hexafluoropropanyl)oxy)carbonyl)piperazin
yl)methyl)(trifluoromethyl)phenoxy)cyclopropanecarboxylic acid
Step 1: Synthesis of tert-butyl 4-(3-hydroxy(trifluoromethyl)benzyl)piperazine
carboxylate
A flask was charged with 3-bromo(trifluoromethyl)phenol (400 mg, 1.66 mmol, 1.00
equiv), palladium acetate (18.6 mg, 0.0830 mmol, 0.05 equiv), 2-(dicyclohexylphosphino)-2',4',6'-
triisopropylbiphenyl (79.2 mg, 0.166 mmol, 0.10 equiv), cesium carbonate (1.62 g, 4.98 mmol, 3.00
equiv), potassium (4-[(tert-butoxy)carbonyl]piperazinylmethyl)trifluoroboranuide (765 mg, 2.50
mmol, 1.50 equiv), dioxane (10 mL), and water (2 mL) under nitrogen. The reaction mixture was
stirred overnight at 80 °C and quenched with water (10 mL). The resulting solution was extracted
with DCM (3 x 20 mL), and the organic layers were combined, washed with brine (1 x 20 mL), dried
over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was
chromatographed on a silica gel column to provide 580 mg (97% yield) of tert-butyl 4-(3-hydroxy
(trifluoromethyl)benzyl)piperazinecarboxylate. LCMS (ESI, m/z): 361 [M+H] .
Step 2: Synthesis of tert-butyl 4-(3-((4-bromomethoxyoxobutanyl)oxy)
(trifluoromethyl)benzyl)piperazinecarboxylate
A flask was charged with tert-butyl 4-(3-hydroxy(trifluoromethyl)benzyl)piperazine
carboxylate (500 mg, 1.39 mmol, 1.00 equiv), methyl 4-bromooxobutanoate (723 mg, 2.78 mmol,
2.00 equiv), potassium carbonate (384 mg, 2.78 mmol, 2.00 equiv), and DMF (10 mL) under
nitrogen. The resulting solution was stirred overnight at 50 °C and quenched with water (10 mL), as
described in Example 3, Step 4. The residue was chromatographed on a silica gel column to provide
500 mg (67% yield) of tert-butyl 4-(3-((4-bromomethoxyoxobutanyl)oxy)
(trifluoromethyl)benzyl)piperazinecarboxylate. LCMS (ESI, m/z): 539 [M+H] .
Step 3: Synthesis of 1-(3-((4-(tert-butoxycarbonyl)piperazinyl)methyl)
(trifluoromethyl)phenoxy)cyclopropanecarboxylic acid
A flask was charged with tert-butyl 4-(3-((4-bromomethoxyoxobutanyl)oxy)
(trifluoromethyl)benzyl)piperazinecarboxylate (500 mg, 0.930 mmol, 1.00 equiv), potassium tert-
butoxide (208 mg, 1.86 mmol, 2.00 equiv), and THF (5 mL). The reaction mixture was stirred
overnight at rt and quenched with water (10 mL). The resulting solution was extracted with DCM (3
x 30 mL), and the organic layers were combined, washed with brine (1 x 20 mL), dried over
anhydrous Na SO , filtered and concentrated under reduced pressure. The residue was
chromatographed on a silica gel column to provide 150 mg (36% yield) of 1-(3-((4-(tert-
butoxycarbonyl)piperazinyl)methyl)(trifluoromethyl)phenoxy)cyclopropanecarboxylic acid.
LCMS (ESI, m/z): 445 [M+H] .
Step 4: Synthesis of 1-(3-(piperazinylmethyl)(trifluoromethyl)phenoxy)cyclopropane
carboxylic acid
A flask was charged with 1-(3-((4-(tert-butoxycarbonyl)piperazinyl)methyl)
(trifluoromethyl)phenoxy)cyclopropanecarboxylic acid (100 mg, 0.220 mmol, 1.00 equiv),
concentrated hydrochloride acid (1 mL), and 1,4-dioxane (4 mL). The resulting solution was stirred
overnight at rt and concentrated under reduced pressure to provide 110 mg (crude) of 1-(3-
(piperazinylmethyl)(trifluoromethyl)phenoxy)cyclopropanecarboxylic acid. LCMS (ESI,
m/z): 345 [M+H] .
Step 5: Synthesis of 1-(3-((4-(((1,1,1,3,3,3-hexafluoropropanyl)oxy)carbonyl)piperazin
yl)methyl)(trifluoromethyl)phenoxy)cyclopropanecarboxylic acid
A flask was charged with triphosgene (42.2 mg, 0.142 mmol, 0.70 equiv), and DCM (5
mL). 1,1,1,3,3,3-Hexafluoropropanol (68.2 mg, 0.406 mmol, 2.00 equiv) was added at 0 °C
followed by DIPEA (105 mg, 0.812 mmol, 4.00 equiv). The mixture was stirred for 2 h at room
temperature prior to addition of 1-(3-(piperazinylmethyl)
(trifluoromethyl)phenoxy)cyclopropanecarboxylic acid (70.0 mg, 0.203 mmol, 1.00 equiv). The
resulting solution was stirred overnight at rt and quenched with water (10 mL), as described in
Example 1, Step 1. The crude product (400 mg) was purified by preparative HPLC to provide 7.40
mg (7% yield) of 1-(3-((4-(((1,1,1,3,3,3-hexafluoropropanyl)oxy)carbonyl)piperazin
yl)methyl)(trifluoromethyl)phenoxy)cyclopropanecarboxylic acid. H NMR (300 MHz,
Methanol-d4) δ 7.26 (s, 2H), 7.08 (s, 1H), 6.19 - 6.10 (m, 1H), 3.67 - 3.59 (m, 6H), 2.55 (br s, 4H),
1.65 - 1.61 (m, 2H), 1.33 - 1.28 (m, 2H). LCMS (ESI, m/z): 539 [M+H] .
Example 20: 1,1,1,3,3,3-hexafluoropropanyl 4-(3-fluoromethyl(2-
(methylsulfonamido)oxoethoxy)benzyl)piperazinecarboxylate
O CF
N O CF
O NH
O S O
Step 1: Synthesis of tert-butyl 2-(6-bromofluoromethylphenoxy)acetate
A flask was charged with 6-bromofluoromethylphenol (1.00 g, 4.90 mmol, 1.00
equiv), DMF (10 mL), cesium carbonate (4.79 g, 14.7 mmol, 3.00 equiv), and tert-butyl 2-
bromoacetate (1.43 g, 7.35 mmol, 1.50 equiv). The reaction mixture was stirred overnight at 80 °C
and quenched with water (30 mL). The resulting solution was extracted with EtOAc (2 x 50 mL),
and the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on a
silica gel column to provide 0.950 g (61% yield) of tert-butyl 2-(6-bromofluoro
methylphenoxy)acetate. LCMS (ESI, m/z): 319 [M+H] .
Step 2. Synthesis of tert-butyl 4-(2-(2-(tert-butoxy)oxoethoxy)fluoro
methylbenzyl)piperazinecarboxylate
A flask was charged with tert-butyl 2-(6-bromofluoromethylphenoxy)acetate (900
mg, 2.82 mmol, 1.00 equiv), 1,4-dioxane (10 mL), water (2 mL), potassium ((4-(tert-
butoxycarbonyl)piperazinyl)methyl)trifluoroborate (1004 mg, 3.38 mmol, 1.20 equiv), palladium
acetate (21.0 mg, 0.0850 mmol, 0.03 equiv), 2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl
(81.0 mg, 0.170 mmol, 0.06 equiv), and cesium carbonate (2770 mg, 8.50 mmol, 3.00 equiv) under
nitrogen. The resulting solution was stirred overnight at 80 °C and quenched with water (30 mL), as
described in Example 19, Step 1. The residue was chromatographed on a silica gel column to provide
1.00 g (81% yield) of tert-butyl 4-(2-(2-(tert-butoxy)oxoethoxy)fluoro
methylbenzyl)piperazinecarboxylate. LCMS (ESI, m/z): 439 [M+H] .
Step 3: Synthesis of 2-(2-fluoromethyl(piperazinylmethyl)phenoxy)acetic acid
A flask was charged with tert-butyl 4-(2-(2-(tert-butoxy)oxoethoxy)fluoro
methylbenzyl)piperazinecarboxylate (650 mg, 1.48 mmol, 1.00 equiv), 1,4-dioxane (10 mL), and
concentrated hydrochloric acid (2 mL) as described in Example 3, Step 4. The resulting solution was
stirred for 2 h at rt and concentrated under reduced pressure to provide 417 mg (quantitative) of 2-(2-
fluoromethyl(piperazinylmethyl)phenoxy)acetic acid. LCMS (ESI, m/z): 283 [M+H] .
Step 4: Synthesis of 2-(2-fluoro((4-(((1,1,1,3,3,3-hexafluoropropan
yl)oxy)carbonyl)piperazinyl)methyl)methylphenoxy)acetic acid
A flask was charged with triphosgene (220 mg, 0.740 mmol, 0.50 equiv), DCM (10 mL),
and 1,1,1,3,3,3-hexafluoropropanol (497 mg, 2.96 mmol, 2.00 equiv), DIPEA (573 mg, 4.43
mmol, 3.00 equiv) was added at 0 °C. The mixture was stirred for 1 h at rt prior to addition of 2-(2-
fluoromethyl(piperazinylmethyl)phenoxy)acetic acid (417 mg, 1.48 mmol, 1.00 equiv). The
resulting solution was stirred for 2 h at rt and quenched with saturated NaHCO3 solution (30 mL)
under nitrogen, as described in Example 1, Step 1. The crude product (300 mg) was purified by
preparative HPLC to provide 400 mg (57% yield) of 2-(2-fluoro((4-(((1,1,1,3,3,3-
hexafluoropropanyl)oxy)carbonyl)piperazinyl)methyl)methylphenoxy)acetic acid. H NMR
(400 MHz, Chloroform-d) δ 6.89 (d, J = 7.2 Hz, 1H), 6.83 (d, J = 7.6 Hz, 1H), 5.79 - 5.73 (m, 1H),
4.92 (s, 2H), 3.82 (br s, 4H), 3.73 (s, 2H), 2.78 (br s, 4H), 2.31 (s, 3H). LCMS (ESI, m/z): 477
[M+H] .
Step 5: Synthesis of 1,1,1,3,3,3-hexafluoropropanyl 4-(3-fluoromethyl(2-
(methylsulfonamido)oxoethoxy)benzyl)piperazinecarboxylate
A flask was charged with 2-(2-fluoro((4-(((1,1,1,3,3,3-hexafluoropropan
yl)oxy)carbonyl)piperazinyl)methyl)methylphenoxy)acetic acid (300 mg, 0.630 mmol, 1.00
equiv), DCM (10 mL), DMAP (230 mg, 1.89 mmol, 3.00 equiv), methanesulfonamide (180 mg, 1.89
mmol, 3.00 equiv), and N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (242 mg,
1.26 mmol, 2.00 equiv). The reaction mixture was stirred overnight at rt and quenched with water
(30 mL). The resulting solution was extracted with DCM (2 x 50 mL), and the organic layers were
combined, washed with brine (2 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated
under reduced pressure. The crude product (400 mg) was purified by preparative HPLC to provide
17.3 mg (5% yield) of 1,1,1,3,3,3-hexafluoropropanyl 4-(3-fluoromethyl(2-
(methylsulfonamido)oxoethoxy)benzyl)piperazinecarboxylate. H NMR (300MHz,
Chloroform-d) δ 6.95 - 6.85 (m, 2H), 5.75 - 5.71 (m, 1H), 4.76 (s, 2H), 3.76 - 3.72 (m, 6H), 3.31 (s,
3H), 2.75 (br s, 4H), 2.29 (s, 3H). LCMS (ESI, m/z): 554 [M+H] .
Example 21: 1,1,1,3,3,3-hexafluoropropanyl 4-(2-(2-(cyclopropanesulfonamido)
oxoethoxy)fluoromethylbenzyl)piperazinecarboxylate
Step 1: Synthesis of tert-butyl 2-(6-bromofluoromethylphenoxy)acetate
A flask was charged with 6-bromofluoromethylphenol (1.00 g, 4.90 mmol, 1.00
equiv), DMF (10 mL), cesium carbonate (4.79 g, 14.7 mmol, 3.00 equiv), and tert-butyl 2-
bromoacetate (1.43 g, 7.35 mmol, 1.50 equiv). The resulting solution was stirred overnight at 80 °C
and quenched with water (30 mL), as described in Example 3, Step 4. The residue was
chromatographed on a silica gel column to provide 0.950 g (61% yield) of tert-butyl 2-(6-bromo
fluoromethylphenoxy)acetate. LCMS (ESI, m/z): 319 [M+H] .
Step 2: Synthesis of tert-butyl 4-(2-(2-(tert-butoxy)oxoethoxy)fluoro
methylbenzyl)piperazinecarboxylate
A flask was charged with tert-butyl 2-(6-bromofluoromethylphenoxy)acetate (900
mg, 2.82 mmol, 1.00 equiv), 1,4-dioxane (10 mL), water (2 mL), potassium ((4-(tert-
butoxycarbonyl)piperazinyl)methyl)trifluoroborate (1004 mg, 3.38 mmol, 1.20 equiv), palladium
acetate (21.0 mg, 0.0850 mmol, 0.03 equiv), 2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl
(81.0 mg, 0.170 mmol, 0.06 equiv), and cesium carbonate (2770 mg, 8.50 mmol, 3.00 equiv) under
nitrogen. The resulting solution was stirred overnight at 80 °C and quenched with water (30 mL), as
described in Example 19, Step 1. The residue was chromatographed on a silica gel column to provide
1.00 g (81% yield) of tert-butyl 4-(2-(2-(tert-butoxy)oxoethoxy)fluoro
methylbenzyl)piperazinecarboxylate. LCMS (ESI, m/z): 439 [M+H] .
Step 3: Synthesis of 2-(2-fluoromethyl(piperazinylmethyl)phenoxy)acetic acid
A flask was charged with tert-butyl 4-(2-(2-(tert-butoxy)oxoethoxy)fluoro
methylbenzyl)piperazinecarboxylate (650 mg, 1.48 mmol, 1.00 equiv), 1,4-dioxane (10 mL), and
concentrated hydrochloric acid (2 mL). The resulting solution was stirred for 2 h at rt and
concentrated under reduced pressure as described in Example 3, Step 4 to provide 417 mg
(quantitative) of 2-(2-fluoromethyl(piperazinylmethyl)phenoxy)acetic acid. LCMS (ESI,
m/z): 283 [M+H]
Step 4: Synthesis of 2-(2-fluoro((4-(((1,1,1,3,3,3-hexafluoropropan
yl)oxy)carbonyl)piperazinyl)methyl)methylphenoxy)acetic acid
A flask was charged with triphosgene (220 mg, 0.740 mmol, 0.50 equiv), DCM (10 mL),
and 1,1,1,3,3,3-hexafluoropropanol (497 mg, 2.96 mmol, 2.00 equiv). DIPEA (573 mg, 4.43
mmol, 3.00 equiv) was added at 0 °C. The mixture was stirred for 1 h at rt prior to addition of 2-(2-
fluoromethyl(piperazinylmethyl)phenoxy)acetic acid (417 mg, 1.48 mmol, 1.00 equiv). The
resulting solution was stirred for 2 h at rt and quenched with saturated NaHCO solution (30 mL)
under nitrogen, as described in Example 1, Step 1. The crude product (300 mg) was purified by
preparative HPLC to provide 400 mg (57% yield) of 2-(2-fluoro((4-(((1,1,1,3,3,3-
hexafluoropropanyl)oxy)carbonyl)piperazinyl)methyl)methylphenoxy)acetic acid. H NMR
(400 MHz, Chloroform-d) δ 6.89 (d, J = 7.2 Hz, 1H), 6.83 (d, J = 7.6 Hz, 1H), 5.79 - 5.73 (m, 1H),
4.92 (s, 2H), 3.82 (br s, 4H), 3.73 (s, 2H), 2.78 (br s, 4H), 2.31 (s, 3H). LCMS (ESI, m/z): 477
[M+H] .
Step 5: Synthesis of 1,1,1,3,3,3-hexafluoropropanyl 4-(2-(2-chlorooxoethoxy)fluoro
methylbenzyl)piperazinecarboxylate
A flask was charged with 2-(2-fluoro((4-(((1,1,1,3,3,3-hexafluoropropan
yl)oxy)carbonyl)piperazinyl)methyl)methylphenoxy)acetic acid (300 mg, 0.630 mmol, 1.00
equiv), and DCM (10 mL). Oxalyl dichloride (234 mg, 1.86 mmol, 3.00 equiv) was added at 0 °C.
The resulting solution was stirred for 2 h at rt and concentrated under reduced pressure to provide
311 mg (crude) of 1,1,1,3,3,3-hexafluoropropanyl 4-(2-(2-chlorooxoethoxy)fluoro
methylbenzyl)piperazinecarboxylate.
Step 6: Synthesis of 1,1,1,3,3,3-hexafluoropropanyl 4-(2-(2-(cyclopropanesulfonamido)
oxoethoxy)fluoromethylbenzyl)piperazinecarboxylate
A flask was charged with cyclopropanesulfonamide (229 mg, 1.89 mmol, 3.00 equiv), and
THF (10 mL) under nitrogen. The mixture was cooled to -78 °C and lithium bis(trimethylsilyl)amide
(2.52 mL, 2.52 mmol, 4.00 equiv, 1M in tetrahydrofuran) was added dropwise at -78 °C. The
mixture was stirred for 30 min at -78 °C prior to drop-wise addition of 1,1,1,3,3,3-hexafluoropropan-
2-yl 4-(2-(2-chlorooxoethoxy)fluoromethylbenzyl)piperazinecarboxylate (311 mg, 0.630
mmol, 1.00 equiv) over 10 min at -78 °C. The reaction mixture was stirred overnight at rt and
quenched with saturated NH Cl solution (30 mL). The resulting solution was extracted with DCM (2
x 50 mL), and the organic layers were combined, washed with brine (2 x 30 mL), dried over
anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product (200 mg)
was purified by preparative HPLC to provide 77.6 mg (21% yield) of 1,1,1,3,3,3-hexafluoropropan-
2-yl 4-(2-(2-(cyclopropanesulfonamido)oxoethoxy)fluoromethylbenzyl)piperazine
carboxylate. H NMR (300MHz, Chloroform-d) δ 6.94 - 6.84 (m, 2H), 5.78 - 5.69 (m, 1H), 4.72 (s,
2H), 3.61 (br s, 6H), 3.02 - 2.96 (m, 1H), 2.56 - 2.55 (m, 4H), 2.28 (s, 3H), 1.39 - 1.38 (m, 2H), 1.17
- 1.10 (m, 2H). LCMS (ESI, m/z): 580 [M+H] .
Example 22: 1-(2-((4-(((1,1,1,3,3,3-Hexafluoropropanyl)oxy)carbonyl)piperazin
yl)methyl)(trifluoromethyl)phenoxy)cyclopropanecarboxylic acid
O CF
N O CF
COOH
Step 1: Synthesis of tert-butyl 4-bromo(2-bromo(trifluoromethyl)phenoxy)butanoate
A round-bottom flask was charged with 2-bromo(trifluoromethyl)phenol (0.500 g, 2.07
mmol, 1.00 equiv), tert-butyl 2,4-dibromobutanoate (1.25 g, 4.14 mmol, 2.00 equiv), potassium
carbonate (0.857 g, 6.21 mmol, 3.00 equiv) and DMF (15 mL) under nitrogen. The reaction mixture
was stirred overnight at 100 °C and quenched with water (10 mL). The resulting solution was
extracted withEtOAc(3 x 20 mL), and the organic layers were combined, washed with brine (20 mL),
dried over anhydrous Na SO , filtered and concentrated under reduced pressure. The residue was
chromatographed on a silica gel column to provide 0.200 g (21% yield) of tert-butyl 4-bromo(2-
bromo(trifluoromethyl)phenoxy)butanoate. LCMS (ESI, m/z): 461 [M+H] .
Step 2: Synthesis of tert-butyl 1-(2-bromo(trifluoromethyl)phenoxy)cyclopropane
carboxylate
A round-bottom flask was charged with tert-butyl 4-bromo(2-bromo
(trifluoromethyl)phenoxy)butanoate (1.50 g, 3.26 mmol, 1.00 equiv), potassium tert-butoxide (0.730
g, 6.52 mmol, 2.00 equiv) and THF (20 mL) under nitrogen. The reaction mixture was stirred
overnight at rt and quenched with water (30 mL). The resulting solution was extracted with EtOAc(3
x 40 mL), and the organic layers were combined, washed with brine (40 mL), dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on a
silica gel column to provide 0.600 g (49% yield) of tert-butyl 1-(2-bromo
(trifluoromethyl)phenoxy)cyclopropanecarboxylate. LCMS (ESI, m/z): 381 [M+H] .
Step 3: Synthesis of potassium trifluoro((4-(((1,1,1,3,3,3-hexafluoropropan
yl)oxy)carbonyl)piperazinyl)methyl)borate
A round-bottom flask was charged with 1,1,1,3,3,3-hexafluoropropanyl piperazine
carboxylate (7.30 g, 26.1 mmol, 1.00 equiv, Example 1, Step 2), potassium
(bromomethyl)trifluoroboranuide (5.30 g, 26.1 mmol, 1.00 equiv) and THF (120 mL) under nitrogen.
The mixture was stirred overnight at 80 °C and concentrated under reduced pressure. Potassium
carbonate (3.56 g, 26.1 mmol, 1.00 equiv) and acetone (150 mL) were added, and the resulting
solution was stirred for 2 h at rt prior to dilution with acetone (400 mL). The mixture was filtered and
the filtrate was concentrated under reduced pressure to provide 10.1 g (97% yield) of potassium
trifluoro((4-(((1,1,1,3,3,3-hexafluoropropanyl)oxy)carbonyl)piperazinyl)methyl)borate. H
NMR (300MHz, Chloroform-d) 6.56 - 6.45 (m, 1H), 3.38 - 3.33 (m, 4H), 2.28 - 2.22 (m, 4H), 1.28
- 1.22 (m, 2H). LCMS (ESI, m/z): 361 [M-K] .
Step 4: Synthesis of 1,1,1,3,3,3-hexafluoropropanyl 4-(2-(1-(tert-
butoxycarbonyl)cyclopropoxy)(trifluoromethyl)benzyl)piperazinecarboxylate
A round-bottom flask was charged with tert-butyl 1-(2-bromo
(trifluoromethyl)phenoxy)cyclopropanecarboxylate (500 mg, 1.31 mmol, 1.00 equiv), potassium
trifluoro((4-(((1,1,1,3,3,3-hexafluoropropanyl)oxy)carbonyl)piperazinyl)methyl)borate (632
mg, 1.58 mmol, 1.20 equiv), palladium acetate (20.2 mg, 0.0660 mmol, 0.05 equiv), 2-
dicyclohexylphosphino-2',6'-dimethoxybiphenyl (54.3 mg, 0.132 mmol, 0.10 equiv), cesium
carbonate (1.28 g, 3.93 mmol, 3.00 equiv), cyclopentyl methyl ether (10 mL), and water (2 mL)
under nitrogen. The reaction mixture was stirred overnight at 100 °C and quenched with water (10
mL). The resulting solution was extracted with dichloromethane (3 x 20 mL), and the organic layers
were combined, washed with brine (20 mL), dried over anhydrous Na SO , filtered and concentrated
under reduced pressure. The residue was chromatographed on a silica gel column to provide 90.0 mg
(12% yield) of 1,1,1,3,3,3-hexafluoropropanyl 4-(2-(1-(tert-butoxycarbonyl)cyclopropoxy)
(trifluoromethyl)benzyl)piperazinecarboxylate. LCMS (ESI, m/z): 595 [M+H] .
Step 5: Synthesis of 1-(2-((4-(((1,1,1,3,3,3-hexafluoropropanyl)oxy)carbonyl)piperazin
yl)methyl)(trifluoromethyl)phenoxy)cyclopropanecarboxylic acid
A round-bottom flask was charged with 1,1,1,3,3,3-hexafluoropropanyl 4-(2-(1-(tert-
butoxycarbonyl)cyclopropoxy)(trifluoromethyl)benzyl)piperazinecarboxylate (90.0 mg, 0.150
mmol, 1.00 equiv), 1,4-dioxane (5 mL), and concentrated hydrochloric acid (2 mL). The resulting
solution was stirred for 2 h at rt and concentrated under reduced pressure. The crude product was
dissolved in saturated NaHCO solution (10 mL) and extracted with DCM (3 x 20 mL). The organic
layers were combined, washed with brine (30 mL), dried over anhydrous Na SO , filtered and
concentrated under reduced pressure. The crude product (78 mg) was purified by preparative HPLC
to afford 4.7 mg (6% yield) of 1-(2-((4-(((1,1,1,3,3,3-hexafluoropropanyl)oxy)carbonyl)piperazin-
1-yl)methyl)(trifluoromethyl)phenoxy)cyclopropanecarboxylic acid. H NMR (400MHz,
Methanol-d4) δ 7.88 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 6.31 - 6.11
(m, 1H), 3.82 (s, 2H), 3.61 - 3.50 (m, 4H), 2.62 - 2.45 (m, 4H), 1.38 (br s, 2H), 0.98 - 0.94 (m, 2H).
LCMS (ESI, m/z): 539 [M+H] .
Example 23: 1-((2-Chloro((4-(((1,1,1,3,3,3-hexafluoropropanyl)oxy)carbonyl)piperazin
yl)methyl)methylphenoxy)methyl)cyclopropanecarboxylic acid
O CF
N O CF
Step 1: Synthesis of ethyl 1-(((methylsulfonyl)oxy)methyl)cyclopropanecarboxylate
A 100-mL round-bottom flask was charged with ethyl 1-(hydroxymethyl)cyclopropane
carboxylate (1.91 g, 13.3 mmol, 1.00 equiv), TEA (4.03 g, 39.9 mmol, 3.00 equiv) , and DCM (40
mL). Methanesulfonyl chloride (2.27 g, 20.0 mmol, 1.50 equiv) was added at 0 °C, and the reaction
mixture was stirred for 1 h at rt prior to quenching with saturated NH Cl (30 mL). The resulting
solution was extracted with dichloromethane (2 x 50 mL), and the organic layers were combined,
washed with saturated NaHCO (30 mL) and brine (30 mL), dried over anhydrous Na SO , filtered
3 2 4
and concentrated under reduced pressure to provide 2.83 g (crude) of ethyl 1-
(((methylsulfonyl)oxy)methyl)cyclopropanecarboxylate.
Step 2: Synthesis of ethyl 1-((6-bromochloromethylphenoxy)methyl)cyclopropane
carboxylate
A round-bottom flask was charged with 6-bromochloromethylphenol (0.900 g, 4.09
mmol, 1.00 equiv), ethyl 1-(((methylsulfonyl)oxy)methyl)cyclopropanecarboxylate (1.36 g, 6.14
mmol, 1.50 equiv), cesium carbonate (4.00 g, 12.3 mmol, 3.00 equiv), and DMF (20 mL). The
reaction mixture was stirred overnight at 80 °C and quenched with water (30 mL). The resulting
solution was extracted with EtOAc(2 x 50 mL), and the organic layers were combined, washed with
brine (2 x 30 mL), dried over anhydrous Na SO , filtered and concentrated under reduced pressure.
The residue was chromatographed on a silica gel column to provide 1.18 g (84% yield) of ethyl 1-
((6-bromochloromethylphenoxy)methyl)cyclopropanecarboxylate. LCMS (ESI, m/z): 347
[M+H] .
Step 3: Synthesis of tert-butyl 4-(3-chloro((1-(ethoxycarbonyl)cyclopropyl)methoxy)
methylbenzyl)piperazinecarboxylate
A round-bottom flask was charged with ethyl 1-((6-bromochloro
methylphenoxy)methyl)cyclopropanecarboxylate (700 mg, 2.02 mmol, 1.00 equiv), palladium
acetate (90.0 mg, 0.202 mmol, 0.10 equiv), 2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl
(181 mg, 0.404 mmol, 0.20 equiv, Xphos), cesium carbonate (1980 mg, 6.06 mmol, 3.00 equiv),
potassium ((4-(tert-butoxycarbonyl)piperazinyl)methyl)trifluoroborate (927 mg, 3.03 mmol, 1.50
equiv), THF (8 mL), and water (2 mL) under nitrogen. The reaction mixture was stirred for 4 h at
80 °C and quenched with water (30 mL). The resulting solution was extracted with DCM (2 x 50
mL), and the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on a
silica gel column to provide 700 mg (74% yield) of tert-butyl 4-(3-chloro((1-
(ethoxycarbonyl)cyclopropyl)methoxy)methylbenzyl)piperazinecarboxylate. LCMS (ESI, m/z):
467 [M+H] .
Step 4: Synthesis of 1-((6-((4-(tert-butoxycarbonyl)piperazinyl)methyl)chloro
methylphenoxy)methyl)cyclopropanecarboxylic acid
A round-bottom flask was charged with tert-butyl 4-(3-chloro((1-
(ethoxycarbonyl)cyclopropyl)methoxy)methylbenzyl)piperazinecarboxylate (700 mg, 1.50
mmol, 1.00 equiv), tetrahydrofuran (3 mL), ethanol (3 mL), water (5 mL), and sodium hydroxide
(600 mg, 15.0 mmol, 10.0 equiv). The reaction mixture was stirred for 3 h at 50 °C. The pH value of
the solution was adjusted to 5 with hydrochloric acid (1 mol/L). The resulting solution was extracted
with dichloromethane (2 x 50 mL), and the organic layers were combined, washed with brine (2 x 30
mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide 610
mg (93% yield) of 1-((6-((4-(tert-butoxycarbonyl)piperazinyl)methyl)chloro
methylphenoxy)methyl)cyclopropanecarboxylic acid. LCMS (ESI, m/z): 439 [M+H] .
Step 5: Synthesis of 1-((2-chloromethyl(piperazin
ylmethyl)phenoxy)methyl)cyclopropanecarboxylic acid
A round-bottom flask was charged with 1-((6-((4-(tert-butoxycarbonyl)piperazin
yl)methyl)chloromethylphenoxy)methyl)cyclopropanecarboxylic acid (630 mg, 1.44 mmol,
1.00 equiv), 1,4-dioxane (10 mL), and concentrated hydrochloric acid (3 mL). The resulting solution
was stirred overnight at rt and concentrated under reduced pressure to provide 600 mg (crude) of 1-
((2-chloromethyl(piperazinylmethyl)phenoxy)methyl)cyclopropanecarboxylic acid.
LCMS (ESI, m/z): 339 [M+H] .
Step 6: Synthesis of 1-((2-chloro((4-(((1,1,1,3,3,3-hexafluoropropan
yl)oxy)carbonyl)piperazinyl)methyl)methylphenoxy)methyl)cyclopropanecarboxylic
acid
A round-bottom flask was charged with triphosgene (270 mg, 0.910 mmol, 0.70 equiv),
dichloromethane (10 mL), and 1,1,1,3,3,3-hexafluoropropanol (437 mg, 2.60 mmol, 2.00 equiv).
N,N-Diisopropylethylamine (503 mg, 3.90 mmol, 3.00 equiv) was added at 0 °C, and the mixture
was stirred for 1 h at rt prior to addition of 1-((2-chloromethyl(piperazin
ylmethyl)phenoxy)methyl)cyclopropanecarboxylic acid (440 mg, 1.30 mmol, 1.00 equiv). The
reaction mixture was stirred overnight at rt and quenched with saturated NaHCO (30 mL). The
resulting solution was extracted with DCM (2 x 50 mL), and the organic layers were combined,
washed with brine (2 x 30 mL), dried over anhydrous Na SO , filtered and concentrated under
reduced pressure. The crude product (200 mg) was purified by preparative HPLC to provide 155 mg
(22% yield) of 1-((2-chloromethyl(piperazinylmethyl)phenoxy)methyl)cyclopropane
carboxylic acid. H NMR (300MHz, Methanol-d ) 7.21 (d, J = 7.8 Hz, 1H), 7.07 (d, J = 8.1 Hz,
1H), 6.18 - 6.09 (m, 1H), 4.11 (s, 2H), 3.89 (s, 2H), 3.63 - 3.54 (m, 4H), 2.69 - 2.68 (m, 4H), 2.35 (s,
3H), 1.32 - 1.28 (m, 2H), 1.11 - 1.08 (m, 2H). LCMS (ESI, m/z): 533 [M+H] .
Example 24: 4-(2-Fluoro((4-(((1,1,1,3,3,3-hexafluoropropanyl)oxy)carbonyl)piperazin
yl)methyl)methylphenyl)-2,2-dimethylbutynoic acid
Step 1: Synthesis of tert-butyl 4-(3-fluorohydroxymethylbenzyl)piperazinecarboxylate
A round-bottom flask was charged with 6-bromofluoromethylphenol (2.00 g, 9.75
mmol, 1.00 equiv), potassium (4-[(tert-butoxy)carbonyl]piperazinylmethyl)trifluoroboranuide
(3.90 g, 12.7 mmol, 1.30 equiv), palladium acetate (0.439 g, 1.96 mmol, 0.20 equiv), 2-
(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (1.87 g, 3.93 mmol, 0.40 equiv, Xphos),
cesium carbonate (9.59 g, 29.4 mmol, 3.00 equiv), 1,4-dioxane (20 mL), and water (4 mL) under
nitrogen. The reaction mixture was stirred overnight at 80 °C and quenched with water (20 mL). The
resulting solution was extracted with EtOAc(3 x 30 mL), and the organic layers were combined,
washed with brine (1 x 50 mL), dried over anhydrous Na SO , filtered and concentrated under
reduced pressure. The residue was chromatographed on a silica gel column to provide 2.20 g (70%
yield) of tert-butyl 4-(3-fluorohydroxymethylbenzyl)piperazinecarboxylate. LCMS (ESI,
m/z): 325 [M+H]
Step 2: Synthesis of tert-butyl 4-(3-fluoromethyl
(((trifluoromethyl)sulfonyl)oxy)benzyl)piperazinecarboxylate
A round-bottom flask was charged with tert-butyl 4-(3-fluorohydroxy
methylbenzyl)piperazinecarboxylate (2.00 g, 6.17 mmol, 1.00 equiv), TEA (1.87 g, 18.5 mmol,
3.00 equiv), and DCM (40 mL). Trifluoromethanesulfonic anhydride (2.61 g, 9.25 mmol, 1.50 equiv)
was added at 0 °C, and the reaction mixture was stirred for 2 h at rt before quenching with water (30
mL). The resulting solution was extracted with DCM (3 x 50 mL), and the organic layers were
combined, washed with brine (1 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated
under reduced pressure. The residue was chromatographed on a silica gel column to provide 1.80 g
(64% yield) of tert-butyl 4-(3-fluoromethyl(((trifluoromethyl)sulfonyl)oxy)benzyl)piperazine-
1-carboxylate. LCMS (ESI, m/z): 457 [M+H] .
Step 3: Synthesis of tert-butyl 4-(2-(4-ethoxy-3,3-dimethyloxobutynyl)fluoro
methylbenzyl)piperazinecarboxylate
A round-bottom flask was charged with tert-butyl 4-(3-fluoromethyl
(((trifluoromethyl)sulfonyl)oxy)benzyl)piperazinecarboxylate (850 mg, 1.86 mmol, 1.00 equiv),
ethyl 2,2-dimethylbutynoate (522 mg, 3.72 mmol, 2.00 equiv), copper(I) iodide (70.8 mg, 0.370
mmol, 0.20 equiv), bis(triphenylphosphine)palladium(II) chloride (130 mg, 0.190 mmol, 0.10 equiv),
TEA (565 mg, 5.58 mmol, 3.00 equiv), and DMF (10 mL) under nitrogen. The reaction mixture was
stirred overnight at 80 °C and quenched with water (20 mL). The resulting solution was extracted
with EtOAc(3 x 30 mL), and the organic layers were combined, washed with brine (1 x 50 mL),
dried over anhydrous Na SO , filtered and concentrated under reduced pressure. The residue was
chromatographed on a silica gel column to provide 100 mg (12% yield) of tert-butyl 4-(2-(4-ethoxy-
3,3-dimethyloxobutynyl)fluoromethylbenzyl)piperazinecarboxylate. LCMS (ESI,
m/z): 447 [M+H]
Step 4: Synthesis of 4-(6-((4-(tert-butoxycarbonyl)piperazinyl)methyl)fluoro
methylphenyl)-2,2-dimethylbutynoic acid
A round-bottom flask was charged with tert-butyl 4-(2-(4-ethoxy-3,3-dimethyloxobut
ynyl)fluoromethylbenzyl)piperazinecarboxylate (100 mg, 0.224 mmol, 1.00 equiv),
lithium hydroxide (322 mg, 13.4 mmol, 60.00 equiv), tetrahydrofuran (5 mL), and water (1 mL). The
reaction mixture was stirred overnight at 35 °C and quenched with water (10 mL), prior to
adjustment of the pH value to pH 6 with hydrochloric acid (1M). The resulting solution was
extracted with DCM (3 x 15 mL), and the organic layers were combined, washed with brine (1 x 20
mL), dried over anhydrous Na SO , filtered and concentrated under reduced pressure to provide 90.0
mg (96% yield) of 4-(6-((4-(tert-butoxycarbonyl)piperazinyl)methyl)fluoromethylphenyl)-
2,2-dimethylbutynoic acid. LCMS (ESI, m/z): 419 [M+H] .
Step 5: Synthesis of 4-(2-fluoromethyl(piperazinylmethyl)phenyl)-2,2-dimethylbut
ynoic acid
A round-bottom flask was charged with 4-(6-((4-(tert-butoxycarbonyl)piperazin
yl)methyl)fluoromethylphenyl)-2,2-dimethylbutynoic acid (90.0 mg, 0.220 mmol, 1.00
equiv), 1,4-dioxane (8 mL), and concentrated hydrochloric acid (1 mL). The resulting solution was
stirred for 2 h at rt and concentrated under reduced pressure to provide 100 mg (crude) of 4-(2-
fluoromethyl(piperazinylmethyl)phenyl)-2,2-dimethylbutynoic acid. LCMS (ESI, m/z):
319 [M+H]
Step 6: Synthesis of 4-(2-fluoro((4-(((1,1,1,3,3,3-hexafluoropropan
yl)oxy)carbonyl)piperazinyl)methyl)methylphenyl)-2,2-dimethylbutynoic acid
O CF
N O CF
HO CF
triphosgene
Pr NEt, CH Cl
2 2 2
rt, 3h
COOH
COOH
A round-bottom flask was charged with triphosgene (42.5 mg, 0.143 mmol, 0.70 equiv) and
DCM (10 mL). 1,1,1,3,3,3-Hexafluoropropanol (85.8 mg, 0.510 mmol, 2.50 equiv) and DIPEA
(105 mg, 0.816 mmol, 4.00 equiv) were added sequentially at 0 °C. The mixture was stirred for 1 h
at rt prior to addition of 4-(2-fluoromethyl(piperazinylmethyl)phenyl)-2,2-dimethylbut
ynoic acid (65.0 mg, 0.204 mmol, 1.00 equiv). The reaction mixture was stirred for 2 h at rt and
quenched with water (10 mL). The resulting solution was extracted with DCM (3 x 15 mL), and the
organic layers were combined, washed with brine (1 x 40 mL), dried over anhydrous Na2SO4,
filtered and concentrated under reduced pressure. The crude product (200 mg) was purified by
preparative HPLC to afford 34.2 mg (33% yield) of 4-(2-fluoro((4-(((1,1,1,3,3,3-
hexafluoropropanyl)oxy)carbonyl)piperazinyl)methyl)methylphenyl)-2,2-dimethylbut
ynoic acid. H NMR (300 MHz, Methanol-d4) 7.23 - 7.13 (m, 2H), 6.20 - 6.11 (m, 1H), 3.83 (s,
2H), 3.63 - 3.60 (m, 4H), 2.68 - 2.67 (m, 4H), 2.27 (s, 3H), 1.58 (s, 6H). LCMS (ESI, m/z): 513
[M+H] .
Example 25: 4-(2-Fluoro((4-(((1,1,1,3,3,3-hexafluoropropanyl)oxy)carbonyl)piperazin
yl)methyl)phenyl)-2,2-dimethylbutynoic acid
Step 1: Synthesis of 2-(trimethylsilyl)ethyl 2,2-dimethylbutynoate
A round-bottom flask was charged with 2,2-dimethylbutynoic acid (1.00 g, 8.93 mmol,
1.00 equiv), 2-(trimethylsilyl)ethanol (1.05 g, 8.93 mmol, 1.00 equiv), 2-(1H-benzotriazoleyl)-
1,1,3,3-tetramethyluronium tetrafluoroborate (3.72 g, 11.6 mmol, 1.30 equiv), TEA (1.81 g, 17.9
mmol, 2.00 equiv), and DMF (10 mL). The resulting solution was stirred overnight at room
temperature. The reaction mixture was diluted with ethyl ether (30 mL), and the resulting solution
was washed with water (1 x 30 mL) and brine (1 x 20 mL), dried over anhydrous Na SO , filtered
and concentrated under reduced pressure. The residue was chromatographed on a silica gel column
to provide 1.30 g (69% yield) of 2-(trimethylsilyl)ethyl 2,2-dimethylbutynoate as yellow oil. H
NMR (300 MHz, Chloroform-d) 4.28 - 4.22 (m, 2H), 2.27 (s, 1H), 1.50 (s, 6H), 1.08 - 1.02 (m,
2H), 0.07 (s, 9H).
Step 2: Synthesis of 2-(trimethylsilyl)ethyl 4-(2-fluoroformylphenyl)-2,2-dimethylbut
ynoate
A round-bottom flask was charged with 2-bromofluorobenzaldehyde (300 mg, 1.49
mmol, 1.00 equiv), 2-(trimethylsilyl)ethyl 2,2-dimethylbutynoate (475 mg, 2.24 mmol, 1.50
equiv), bis(triphenylphosphine)palladium(II) chloride(52.3 mg, 0.0745 mmol, 0.05 equiv), copper(I)
iodide (28.3 mg, 0.149 mmol, 0.10 equiv), TEA (451 mg, 4.46 mmol, 3.00 equiv), and DMF (10 mL)
under nitrogen. The reaction mixture was stirred overnight at 80 °C and then quenched with water
(10 mL). The resulting solution was extracted with DCM (3 x 15 mL), and the organic layers were
combined, washed with brine (1 x 20 mL), dried over anhydrous Na SO , filtered and concentrated
under reduced pressure. The residue was chromatographed on a silica gel column to provide 340 mg
(72% yield) of 2-(trimethylsilyl)ethyl 4-(2-fluoroformylphenyl)-2,2-dimethylbutynoate. LCMS
(ESI, m/z): 357 [M+Na] .
Step 3: Synthesis of 1,1,1,3,3,3-hexafluoropropanyl 4-(2-(3,3-dimethyloxo(2-
(trimethylsilyl)ethoxy)butynyl)fluorobenzyl)piperazinecarboxylate
A round-bottom flask was charged with 2-(trimethylsilyl)ethyl 4-(2-fluoro
formylphenyl)-2,2-dimethylbutynoate (334 mg, 1.00 mmol, 1.00 equiv), 1,1,1,3,3,3-
hexafluoropropanyl piperazinecarboxylate (364 mg, 1.30 mmol, 1.30 equiv), and DCE (15
mL). The mixture was stirred for 1 h at rt prior to addition of sodium triacetoxyborohydride (848 mg,
4.00 mmol, 4.00 equiv). The resulting solution was stirred overnight at rt and then quenched with
water (10 mL). The mixture was extracted with DCM (3 x 15 mL), and the organic layers were
combined, washed with brine (1 x 20 mL), dried over anhydrous Na2SO4, filtered and concentrated
under reduced pressure. The residue was chromatographed on a silica gel column to provide 350 mg
(59% yield) of 1,1,1,3,3,3-hexafluoropropanyl 4-(2-(3,3-dimethyloxo(2-
(trimethylsilyl)ethoxy)butynyl)fluorobenzyl)piperazinecarboxylate. LCMS (ESI, m/z):
599 [M+H] .
Step 4: Synthesis of 4-(2-fluoro((4-(((1,1,1,3,3,3-hexafluoropropan
yl)oxy)carbonyl)piperazinyl)methyl)phenyl)-2,2-dimethylbutynoic acid
A round-bottom flask was charged with 1,1,1,3,3,3-hexafluoropropanyl 4-(2-(3,3-
dimethyloxo(2-(trimethylsilyl)ethoxy)butynyl)fluorobenzyl)piperazinecarboxylate
(350 mg, 0.584 mmol, 1.00 equiv), tetrabutylammonium fluoride (0.9 mL, 1M in tetrahydrofuran,
0.900 mmol, 1.50 equiv) , and THF (10 mL). The reaction mixture was stirred for 1 h at rt and
quenched with water (10 mL). The resulting solution was extracted with DCM (3 x 15 mL), and the
organic layers were combined, washed with brine (1 x 20 mL), dried over anhydrous Na SO ,
filtered and concentrated under reduced pressure. The crude product (280 mg) was purified by
preparative HPLC to afford 107.6 mg (37% yield) of 4-(2-fluoro((4-(((1,1,1,3,3,3-
hexafluoropropanyl)oxy)carbonyl)piperazinyl)methyl)phenyl)-2,2-dimethylbutynoic acid.
H NMR (400 MHz, Methanol-d ) 7.34 - 7.25 (m, 2H), 7.08 - 7.04 (m, 1H), 6.17 - 6.10 (m, 1H),
3.81 (s, 2H), 3.62 - 3.57 (m, 4H), 2.62 (br s, 4H), 1.56 (s, 6H). LCMS (ESI, m/z): 499 [M+H] .
Example 26: 1-((2-Cyanofluoro((4-(((1,1,1,3,3,3-hexafluoropropan
yl)oxy)carbonyl)piperazinyl)methyl)phenoxy)methyl)cyclopropanecarboxylic acid
Step 1: Synthesis of ethyl 1-((2-bromofluoroformylphenoxy)methyl)cyclopropane
carboxylate
A round-bottom flask was charged with 3-bromofluorohydroxybenzaldehyde (1.00 g,
4.59 mmol, 1.00 equiv), ethyl 1-[(methanesulfonyloxy)methyl]cyclopropanecarboxylate (1.53 g,
6.88 mmol, 1.50 equiv), cesium carbonate (4.49 g, 13.8 mmol, 3.00 equiv), and DMF (10 mL). The
reaction mixture was stirred overnight at 80 °C and quenched with water (30 mL). The resulting
solution was extracted with EtOAc(2 x 50 mL), and the organic layers were combined, washed with
brine (2 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.
The residue was chromatographed on a silica gel column to provide 0.600 g (38% yield) of ethyl 1-
(2-bromofluoroformylphenoxymethyl)cyclopropanecarboxylate. LCMS (ESI, m/z): 345
[M+H] .
Step 2: Synthesis of tert-butyl 4-(3-bromo((1-(ethoxycarbonyl)cyclopropyl)methoxy)
fluorobenzyl)piperazinecarboxylate
Boc N NH
Br Br
NaBH(OAc) , Et N, DCE
rt, overnight
A round-bottom flask was charged with ethyl 1-(2-bromofluoro
formylphenoxymethyl)cyclopropanecarboxylate (600 mg, 1.74 mmol, 1.00 equiv), TEA (527 mg,
.22 mmol, 3.00 equiv), tert-butyl piperazinecarboxylate (390 mg, 2.09 mmol, 1.20 equiv), and
DCE (10 mL). The solution was stirred for 1 h at rt prior to addition of sodium triacetoxyborohydride
(1110 mg, 5.22 mmol, 3.00 equiv). The reaction mixture was stirred overnight at rt and quenched
with water (30 mL). The resulting solution was extracted with DCM (2 x 50 mL), and the organic
layers were combined, washed with brine (2 x 30 mL), dried over anhydrous Na2SO4, filtered and
concentrated under reduced pressure. The residue was chromatographed on a silica gel column to
provide 540 mg (60% yield) of tert-butyl 4-(3-bromo((1-(ethoxycarbonyl)cyclopropyl)methoxy)-
-fluorobenzyl)piperazinecarboxylate. LCMS (ESI, m/z): 515 [M+H] .
Step 3: Synthesis of tert-butyl 4-(3-cyano((1-(ethoxycarbonyl)cyclopropyl)methoxy)
fluorobenzyl)piperazinecarboxylate
A round-bottom flask was charged with tert-butyl 4-(3-bromo((1-
(ethoxycarbonyl)cyclopropyl)methoxy)fluorobenzyl)piperazinecarboxylate (240 mg, 0.470
mmol, 1.00 equiv), zinc cyanide (108 mg, 0.940 mmol, 2.00 equiv),
tetrakis(triphenylphosphine)palladium (58.0 mg, 0.0500 mmol, 0.10 equiv), and DMF (10 mL) under
nitrogen. The reaction mixture was stirred overnight at 120 °C and quenched with water (30 mL).
The resulting solution was extracted with EtOAc(2 x 50 mL), and the organic layers were combined,
washed with brine (2 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated under
reduced pressure. The residue was chromatographed on a silica gel column to provide 125 mg (58%
yield) of tert-butyl 4-(3-cyano((1-(ethoxycarbonyl)cyclopropyl)methoxy)
fluorobenzyl)piperazinecarboxylate. LCMS (ESI, m/z): 462 [M+H] .
Step 4: Synthesis of 1-((2-((4-(tert-butoxycarbonyl)piperazinyl)methyl)cyano
fluorophenoxy)methyl)cyclopropanecarboxylic acid
A round-bottom flask was charged with tert-butyl 4-(3-cyano((1-
(ethoxycarbonyl)cyclopropyl)methoxy)fluorobenzyl)piperazinecarboxylate (125 mg, 0.270
mmol, 1.00 equiv), lithium hydroxide (130 mg, 5.43 mmol, 20.0 equiv), THF (5 mL), and water (5
mL). The reaction mixture was stirred overnight at room temperature. The pH value of the solution
was adjusted to 5 with hydrochloric acid (1 mol/L). The resulting solution was extracted with DCM
(2 x 50 mL), and the organic layers were combined, washed with brine (2 x 30 mL), dried over
anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide 110 mg (94% yield)
of 1-((2-((4-(tert-butoxycarbonyl)piperazinyl)methyl)cyano
fluorophenoxy)methyl)cyclopropanecarboxylic acid. LCMS (ESI, m/z): 434 [M+H] .
Step 5: Synthesis of 1-((2-cyanofluoro(piperazin
ylmethyl)phenoxy)methyl)cyclopropanecarboxylic acid
A round-bottom flask was charged with 1-((2-((4-(tert-butoxycarbonyl)piperazin
yl)methyl)cyanofluorophenoxy)methyl)cyclopropanecarboxylic acid (160 mg, 0.370 mmol,
1.00 equiv), concentrated hydrochloric acid (2 mL), and 1,4-dioxane (8 mL). The resulting solution
was stirred for 3 h at rt and concentrated under reduced pressure to provide 123 mg (quantitative) of
1-((2-cyanofluoro(piperazinylmethyl)phenoxy)methyl)cyclopropanecarboxylic acid.
LCMS (ESI, m/z): 334 [M+H] .
Step 6: Synthesis of 1-((2-cyanofluoro((4-(((1,1,1,3,3,3-hexafluoropropan
yl)oxy)carbonyl)piperazinyl)methyl)phenoxy)methyl)cyclopropanecarboxylic acid
A round-bottom flask was charged with triphosgene (77.0 mg, 0.260 mmol, 0.700 equiv),
1,1,1,3,3,3-hexafluoropropanol (124 mg, 0.740 mmol, 2.00 equiv), and DCM (5 mL). N,N-
Diisopropylethylamine (143 mg, 1.11 mmol, 3.00 equiv)was added at 0 °C and the mixture was
stirred for 1 h at rt prior to addition of 1-((2-cyanofluoro(piperazin
ylmethyl)phenoxy)methyl)cyclopropanecarboxylic acid (123 mg, 0.370 mmol, 1.00 equiv) was
added. The reaction mixture was stirred overnight at rt and quenched with water (30 mL). The
resulting solution was extracted with DCM (2 x 50 mL), and the organic layers were combined,
washed with brine (2 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated under
reduced pressure. The crude product (250 mg) was purified by preparative HPLC to afford 39.9 mg
(21% yield) of 1-((2-cyanofluoro((4-(((1,1,1,3,3,3-hexafluoropropan
yl)oxy)carbonyl)piperazinyl)methyl)phenoxy)methyl)cyclopropanecarboxylic acid. H NMR
(400 MHz, Chloroform-d) δ 7.46 - 7.43 (m, 1H), 7.24 - 7.22 (m, 1H), 5.81 - 5.73 (m, 1H), 4.22 (s,
2H), 3.73 (s, 2H), 3.61 - 3.60 (m, 4H), 2.56 - 2.53 (m, 4H), 1.57 - 1.54 (m, 2H), 1.32 - 1.29 (m, 2H).
LCMS (ESI, m/z): 528 [M+H] .
Examples 27-56 : Examples 27-56 were prepared by similar procedures as described in Examples 1-
NMR ( H NMR, 300 MHz or MS
Ex Name Structure
400 MHz, Chloroform-d) [M+H]
1-((2-((4-(((1,1,1,3,3,3- (Methanol-d ) 7.53 (d, J = 7.5
hexafluoropropan
Hz, 1H), 7.26 - 7.23 (m, 2H),
yl)oxy)carbonyl)piperazin
6.16 - 6.10 (m, 1H), 4.19 (s,
27 yl)methyl) 553.4
2H), 3.80 (s, 2H), 3.65 - 3.62
(trifluoromethyl)phenoxy) (m, 4H), 2.70 - 2.67 (m, 4H),
methyl)cyclopropane
1.33 - 1.30 (m, 2H), 1.05 - 1.02
carboxylic acid
(m, 2H)
1-((3-((4-(((1,1,1,3,3,3-
(Methanol-d ) δ 7.22 - 7.13 (m,
hexafluoropropan
2H), 7.08 (s, 1H), 6.17 - 6.09
yl)oxy)carbonyl)piperazin
(m, 1H), 4.17 (s, 2H), 3.58 1-yl)methyl) 553.5
3.55 (m, 6H), 2.49 - 2.48 (m,
(trifluoromethyl)phenoxy)
4H), 1.34 - 1.25 (m, 2H), 1.07 -
methyl)cyclopropane
1.03 (m, 2H)
carboxylic acid
1-((2-fluoro((4-
(Methanol-d ) 7.02 (d, J = 8.7
(((1,1,1,3,3,3-
Hz, 1H), 6.91 (t, J = 7.4 Hz,
hexafluoropropan
1H), 6.21 - 6.10 (m, 1H), 4.21
yl)oxy)carbonyl)piperazin
29 517.1
(s, 2H), 3.85 (s, 2H), 3.68 (br s,
yl)methyl)
4H), 2.75 - 2.67 (m, 4H), 2.25
methylphenoxy)methyl)cy
(s, 3H), 1.25 - 1.22 (m, 2H),
clopropanecarboxylic
0.94 - 0.92 (m, 2H)
acid
(Methanol-d ) δ 7.74 (d, J = 7.8
1-((2-((4-(((1,1,1,3,3,3-
Hz, 1H), 7.61 (d, J = 7.8 Hz,
hexafluoropropan
1H), 7.29 (t, J = 7.6 Hz, 1H),
yl)oxy)carbonyl)piperazin
6.19 - 6.11 (m, 1H), 4.18 (s,
yl)methyl) 553.2
2H), 3.93 (s, 2H), 3.61(br s,
(trifluoromethyl)phenoxy)
4H), 2.63 (br s, 4H), 1.35 -
methyl)cyclopropane
1.32 (m, 2H), 1.14 - 1.04 (m,
carboxylic acid
1,1,1,3,3,3-
hexafluoropropanyl 4-
(3-fluoromethyl((1-
31 ((methylsulfonyl)carbamo 594.2
yl)cyclopropyl)methoxy)b
enzyl)piperazine
carboxylate
1-((2-fluoro((4-
(Methanol-d ) δ 7.02 (d, J = 8.4
(((1,1,1,3,3,3-
Hz, 1H), 6.92 (t, J = 7.4 Hz,
hexafluoropropan
1H), 6.20 - 6.10 (m, 1H), 4.16
yl)oxy)carbonyl)piperazin
32 (s 2H), 3.68 (s, 2H), 3.60 (br s, 544.9
yl)methyl)
4H), 2.61 - 2.59 (m, 4H), 2.26
methylphenoxy)methyl)cy
(s, 3H), 2.20 - 2.16 (m, 2H),
clopentanecarboxylic
1.82 - 1.75 (br s, 6H)
acid
1-((2,3-difluoro((4-
(((1,1,1,3,3,3- δ 7.02 - 6.96 (m, 1H), 6.93 -
hexafluoropropan 6.84 (m, 1H), 5.76 - 5.66 (m,
yl)oxy)carbonyl)piperazin 1H), 4.21 (s, 2H), 3.87 (s, 2H),
33 520.8
3.59 (br s, 4H), 2.59 (br s,
yl)methyl)phenoxy)methy 4H), 1.46 - 1.42 (m, 2H), 1.09 -
l)cyclopropane 1.01 (m, 2H)
carboxylic acid
1-((4,5-difluoro((4-
(((1,1,1,3,3,3- (Methanol-d ) δ 7.34 - 7.27 (m,
hexafluoropropan 1H), 7.03 - 6.97 (m, 1H), 6.21 -
yl)oxy)carbonyl)piperazin 6.12 (m, 1H), 4.12 (s, 2H), 3.76
34 521.1
(s, 2H), 3.69 (br s, 4H), 2.72 -
yl)methyl)phenoxy)methy 2.68 (m, 4H), 1.36 - 1.32 (m,
l)cyclopropane 2H), 1.06 - 1.02 (m, 2H)
carboxylic acid
1-((5-cyano((4-
(((1,1,1,3,3,3- 7.45 (d, J = 7.8 Hz, 1H), 7.28
hexafluoropropan
- 7.25 (m, 1H), 7.09 (s, 1H),
yl)oxy)carbonyl)piperazin
.80 - 5.70 (m, 1H), 4.14 (s,
510.1
2H), 3.61 - 3.56 (m, 6H), 2.51
yl)methyl)phenoxy)methy (br s, 4H), 1.47 (br s, 2H),
l)cyclopropane
1.12 (br s, 2H)
carboxylic acid
1-((2-cyano((4-
(Methanol-d ) 7.77 - 7.74 (m,
(((1,1,1,3,3,3-
1H), 7.65 - 7.62 (m, 1H), 7.28
hexafluoropropan
(t, J = 7.6 Hz, 1H), 6.20 - 6.11
yl)oxy)carbonyl)piperazin
36 510.2
(m, 1H), 4.33 (s, 2H), 3.83 (s,
2H), 3.62 (br s, 4H), 2.63 -
yl)methyl)phenoxy)methy
2.62 (m, 4H), 1.40 - 1.36 (m,
l)cyclopropane
2H), 1.21 - 1.17 (m, 2H)
carboxylic acid
1-((2,3-difluoro((4-
(((1,1,1,3,3,3-
6.97 - 6.93 (m, 1H), 6.92 -
hexafluoropropan 6.80 (m, 1H), 5.76 - 5.65 (m,
yl)oxy)carbonyl)piperazin 1H), 4.24 (s, 2H), 3.64 (s, 2H),
37 549.1
3.55 (br s, 4H), 2.52 (br s,
yl)methyl)phenoxy)methy
4H), 2.20 - 2.18 (m, 2H), 1.78 -
l)cyclopentane 1.71 (m, 6H)
carboxylic acid
1-((3-fluoro((4-
δ 7.10 (t, J = 7.4 Hz, 1H), 6.85
(((1,1,1,3,3,3-
(t, J = 8.6 Hz, 1H), 5.76 - 5.68
hexafluoropropan
(m, 1H), 3.96 (s, 2H), 3.92 (s,
yl)oxy)carbonyl)piperazin
38 2H), 3.77 (br s, 4H), 2.64 1-yl)methyl)
2.62 (m, 4H), 2.23 (s, 3H), 1.50
methylphenoxy)methyl)cy
- 1.44 (m, 2H), 1.09 - 1.06 (m,
clopropanecarboxylic
acid
1-((4-fluoro((4-
(((1,1,1,3,3,3-
δ 6.92 - 6.84 (m, 2H), 5.77 -
hexafluoropropan
.71 (m, 1H), 3.96 (s, 2H), 3.91
yl)oxy)carbonyl)piperazin
39 (br s, 2H), 3.61 (br s, 4H), 517.1
yl)methyl)
2.60 (br s, 4H), 2.31 (s, 3H),
methylphenoxy)methyl)cy
1.46 (br s, 2H), 1.07 (br s, 2H)
clopropanecarboxylic
acid
1-((4-fluoro((4-
δ 6.93 - 6.90 (m, 1H), 6.84 -
(((1,1,1,3,3,3-
6.82 (m, 1H), 5.79 - 5.72 (m,
hexafluoropropan
1H), 3.88 (s, 2H), 3.64 (s, 2H),
yl)oxy)carbonyl)piperazin
40 3.59 - 3.58 (m, 4H), 2.54 - 2.47 545.2
yl)methyl)
(m, 4H), 2.31 (s, 3H), 2.26 -
methylphenoxy)methyl)cy
2.23 (m, 2H), 1.82 - 1.72 (m,
clopentanecarboxylic
acid
1-((2-fluoro((4-
(((1,1,1,3,3,3-
δ 7.10 - 6.97 (m, 3H), 5.78 -
hexafluoropropan
.63 (m, 1H), 4.22 (s, 2H), 3.74
yl)oxy)carbonyl)piperazin
(s, 2H), 3.60 - 3.58 (m, 4H), 531.2
2.59 - 2.56 (m, 4H), 2.23 - 2.21
yl)methyl)phenoxy)methy
(m, 2H), 1.80 - 1.73 (m, 6H)
l)cyclopentane
carboxylic acid
1-((5-fluoro((4-
(((1,1,1,3,3,3- δ 7.16 (t, J = 7.4 Hz, 1H), 6.68
hexafluoropropan - 6.64 (m, 2H), 5.78 - 5.71 (m,
yl)oxy)carbonyl)piperazin 1H), 4.05 (s, 2H), 3.66 - 3.61
42 531.2
(m, 6H), 2.61 (br s, 4H), 2.29 -
yl)methyl)phenoxy)methy 2.23 (m, 2H), 1.81 - 1.72 (m,
l)cyclopentane 6H)
carboxylic acid
1-((5-cyano((4-
(((1,1,1,3,3,3- δ 7.40 (d, J = 7.6 Hz, 1H), 7.26
hexafluoropropan - 7.24 (m, 1H), 7.11 (s, 1H),
yl)oxy)carbonyl)piperazin 5.76 - 5.69 (m, 1H), 4.07 (s,
43 538.2
2H), 3.56 - 3.49 (m, 6H), 2.48 -
yl)methyl)phenoxy)methy 2.47 (m, 4H), 2.24 - 2.22 (m,
l)cyclopentane 2H), 1.81 - 1.73 (m, 6H)
carboxylic acid
(1s,3s)(2-((4-
(Methanol-d ) 7.55 (d, J = 7.8
(((1,1,1,3,3,3-
Hz, 1H), 7.24 (d, J = 7.8 Hz,
hexafluoropropan
1H), 7.03 (s, 1H), 6.19 - 6.09
yl)oxy)carbonyl)piperazin
44 (m, 1H), 4.78 - 4.74 (m, 1H), 553.4
yl)methyl)
3.66 - 3.55 (m, 6H), 2.90 - 2.73
(trifluoromethyl)phenoxy)
(m, 3H), 2.56 - 2.52 (m, 4H),
cyclobutanecarboxylic
2.39 - 2.30(m, 2H)
acid
(1S,3R)(2-((4-
(Methanol-d ) 7.58 (d, J = 7.8
(((1,1,1,3,3,3-
Hz, 1H), 7.29 - 7.27 (m, 2H),
hexafluoropropan
6.21 - 6.17 (m, 1H), 5.08 - 5.06
yl)oxy)carbonyl)piperazin
45 567.2
(m, 1H), 4.08 - 3.95 (m, 2H),
yl)methyl)
3.73 (br s, 4H), 3.98 (br s,
(trifluoromethyl)phenoxy)
5H), 2.33 - 2.26 (m, 2H), 2.13 -
cyclopentane
1.99 (m, 4H)
carboxylic acid
(1R,3R)(2-((4-
(Methanol-d ) 7.66 (d, J = 7.8
(((1,1,1,3,3,3-
Hz, 1H), 7.34 - 7.31 (m, 2H),
hexafluoropropan
6.26 - 6.18 (m, 1H), 5.12 - 5.11
yl)oxy)carbonyl)piperazin
(m, 1H), 4.20 (s, 2H), 3.78 (br 567.2
yl)methyl)
s, 4H), 3.17 - 3.07 (m, 5H),
(trifluoromethyl)phenoxy)
2.29 - 2.13 (m, 4H), 1.99 - 1.92
cyclopentane
(m, 2H)
carboxylic acid
(1r,3r)(2-((4- (Methanol-d ) 7.59 (d, J = 7.2
(((1,1,1,3,3,3-
Hz, 1H), 7.26 (d, J = 7.2 Hz,
hexafluoropropan
1H), 6.98 (s, 1H), 6.19 - 6.11
yl)oxy)carbonyl)piperazin
(m, 1H), 5.03 - 4.95 (m, 1H),
47 553.2
yl)methyl) 3.70 (s, 2H), 3.61 - 3.55 (m,
(trifluoromethyl)phenoxy)
4H), 3.25 - 3.16 (m, 1H), 2.81 -
cyclobutanecarboxylic
2.73 (m, 2H), 2.60 - 2.44 (m,
acid
4-(3-((4-(((1,1,1,3,3,3-
hexafluoropropan
(Methanol-d ) 7.64 - 7.57 (m,
yl)oxy)carbonyl)piperazin
3H), 6.17 - 6.08 (m, 1H), 3.62 1-yl)methyl) 549.4
3.52 (m, 6H), 2.49 (br s, 4H),
(trifluoromethyl)phenyl)-
1.55 (s, 6H)
2,2-dimethylbutynoic
acid
2-(2-chloro((4-
(((1,1,1,3,3,3- (Methanol-d ) δ 7.21 - 7.12 (m,
hexafluoropropan 2H), 6.28 - 6.20 (m, 1H), 4.78
49 yl)oxy)carbonyl)piperazin (s, 2H), 4.25 (s, 2H), 3.90 (br s, 493.1
yl)methyl) 4H), 3.22 (br s, 4H), 2.43 (s,
methylphenoxy)acetic 3H)
acid
1,1,1,3,3,3-
δ 7.07 - 7.01 (m, 2H), 5.77 -
hexafluoropropanyl 4-
.69 (m, 1H), 4.69 (s, 2H), 3.56
(3-chloromethyl(2 3.49 (m, 6H), 3.37 (s, 3H), 570.1
(methylsulfonamido)
2.49 (t, J = 5.0 Hz, 4H), 2.39 (s,
oxoethoxy)benzyl)piperaz
inecarboxylate
1,1,1,3,3,3-
δ 7.07 - 7.02 (m, 2H), 5.77 -
hexafluoropropanyl 4-
.69 (m, 1H), 4.70 (s, 2H), 3.53
(3-chloro(2-
- 3.49 (m, 6H), 3.07 - 2.99 (m,
51 (cyclopropanesulfonamid 595.9
1H), 2.46 - 2.39 (m, 7H), 1.48 -
o)oxoethoxy)
1.45 (m, 2H), 1.21 - 1.14 (m,
methylbenzyl)piperazine-
1-carboxylate
1,1,1,3,3,3-
7.12 (d, J = 8.1 Hz, 1H), 7.04
hexafluoropropanyl 4-
- 7.00 (m, 1H), 6.90 (s, 1H),
(4-chloro(2-
52 5.76 - 5.72 (m, 1H), 4.68 (s, 556.4
(methylsulfonamido)
2H), 3.69 - 3.67 (m, 6H), 3.24
oxoethoxy)benzyl)piperaz
(s, 3H), 2.68 - 2.66 (m, 5H)
inecarboxylate
1,1,1,3,3,3-
7.12 - 7.05 (m, 2H), 5.78 -
hexafluoropropanyl 4-
.70 (m, 1H), 4.13 (s, 2H), 3.56
(3-chloromethyl((1-
- 3.53 (m, 6H), 3.34 (s, 3H),
53 ((methylsulfonyl)carbamo 609.9
2.50 - 2.47 (m, 4H), 2.39 (s,
yl)cyclopropyl)methoxy)b
3H), 1.56 - 1.52 (m, 2H), 1.07 -
enzyl)piperazine
1.03 (m, 2H)
carboxylate
2-(2-fluoro((4-
(((1,1,1,3,3,3-
δ 6.91 - 6.82 (m, 2H), 5.79 -
hexafluoropropan
.73 (m, 1H), 4.92 (s, 2H), 3.82
54 yl)oxy)carbonyl)piperazin 477.4
- 3.73 (m, 6H), 2.78 (br s, 4H),
yl)methyl)
2.31 (s, 3H)
methylphenoxy)acetic
acid
1,1,1,3,3,3-
7.51 (d, J = 8.1 Hz, 1H), 7.32
hexafluoropropanyl 4-
(d, J = 8.1 Hz, 1H), 7.05 (s,
(2-((1-
1H), 5.79 - 5.71 (m, 1H), 4.11
((methylsulfonyl)carbamo
55 630.1
(s, 2H), 3.64 - 3.55 (m, 6H),
yl)cyclopropyl)methoxy)-
3.31 (s, 3H), 2.45 - 2.45 (m,
4H), 1.58 - 1.54 (m, 2H), 1.05 -
(trifluoromethyl)benzyl)pi
1.01 (m, 2H)
perazinecarboxylate
4-(2-chloro((4-
(Methanol-d ) 7.40 - 7.37 (m,
(((1,1,1,3,3,3-
2H), 7.30 - 7.26 (m, 1H), 6.17 -
hexafluoropropan
56 515.2
6.11 (m, 1H), 3.83 (s, 2H), 3.63
yl)oxy)carbonyl)piperazin
- 3.58 (m, 4H), 2.65 - 2.61 (m,
yl)methyl)phenyl)-2,2-
4H), 1.57 (s, 6H)
dimethylbutynoic acid
II. Biological Evaluation
Compounds were tested to assess their MAGL and serine hydrolase activity using the
following in vitro and in vivo assays.
In vitro competitive activity-based protein profiling (human)
Proteomes (human prefrontal cortex or cell membrane fractions) (50 µL, 1.0-2.0 mg/mL
total protein concentration) were preincubated with varying concentrations of inhibitors at 37 ºC.
After 30 min, FP-Rh or JW912 (1.0 µL, 50 µM in DMSO) was added and the mixture was incubated
for another 30 min at room temperature. Reactions were quenched with SDS loading buffer (15 µL -
4X) and run on SDS-PAGE. Following gel imaging, serine hydrolase activity was determined by
measuring fluorescent intensity of gel bands corresponding to MAGL using ImageJ 1.49k software.
IC data from this assay are shown in Table 2.
TABLE 2
Example MAGL Human Example MAGL Human
(IC50) (IC50)
1 *** 29 ***
2 *** 30 ***
3 *** 31 ***
*** ***
4 32
*** 33 ***
6 *** 34 ***
7 *** 35 ***
8 *** 36 ***
*** ***
9 37
*** 38 ***
11 *** 39 ***
12 *** 40 ***
13 *** 41 ***
14 *** 42 ***
*** 43 ***
16 *** 44 ***
17 *** 45 ***
18 *** 46 ***
*** ***
19 47
*** 48 ***
21 *** 49 ***
22 *** 50 ***
23 *** 51 ***
*** ***
24 52
*** 53 ***
26 *** 54 **
27 *** 55 ***
28 *** 56 ***
*** IC is less than or equal to 100 nM; ** IC is greater than 100 nM and less than 1
50 50
M; * IC is greater than or equal to 1 M and less or equal to 10 M.
In vitro competitive activity-based protein profiling (mouse)
Proteomes (mouse brain membrane fraction or cell lysates) (50 L, 1.0 mg/mL total protein
concentration) were preincubated with varying concentrations of inhibitors at 37 ºC. After 30 min,
FP-Rh (1.0 L, 50 M in DMSO) was added and the mixture was incubated for another 30 min at 37
ºC. Reactions were quenched with SDS loading buffer (50 µL - 4X) and run on SDS-PAGE.
Following gel imaging, serine hydrolase activity was determined by measuring fluorescent intensity
of gel bands corresponding to MAGL using ImageJ 1.49k software.
Preparation of mouse brain proteomes from inhibitor treated mice
Inhibitors were administered to wild-type C57Bl/6J by oral gavage in a vehicle of
polyethylene glycol. Each animal was sacrificed 4 h following administration and brain proteomes
were prepared and analyzed according to previously established methods (See Niphakis, M. J., et al.
(2011) ACS Chem. Neurosci. and Long, J. Z., et al. Nat. Chem. Biol. 5:37-44). Percent inhibition
data are shown in Table 3.
TABLE 3
Example MGLL % Inhibition Example MGLL % Inhibition
at 5 mg/kg (Mouse) at 5 mg/kg (Mouse)
NT ###
1 29
2 NT 30 #
3 ### 31 #
4 NT 32 ###
NT 33 NT
NT NT
6 34
7 NT 35 NT
8 NT 36 #
9 NT 37 NT
NT 38 ###
NT ###
11 39
12 ## 40 ###
13 # 41 NT
14 # 42 ###
NT 43 NT
16 # 44 NT
17 NT 45 NT
NT NT
18 46
19 NT 47 NT
NT 48 NT
21 # 49 #
22 # 50 #
23 ### 51 #
24 NT 52 #
NT 53 #
26 # 54 NT
27 ### 55 NT
NT NT
28 56
% Inhibition: ### is > 75%; ## is between 25 and 75%; # is < 25%; NT is not tested
Claims (10)
1. A compound having the structure of Formula (I): Formula (I); wherein: R isOR ; each R is independently selected from C1-6alkyl, halogen, and C1-6haloalkyl; 3 6 7 8 R is -(CR R ) -R ; 6 7 6 7 each R and R is each independently selected from H, F, and C alkyl; or R and R , together with the carbon to which they are attached, form a C3-6cycloalkyl ring; R is -C(O)OR ; R is H or C alkyl; m is 1, 2, 3 or 4; and n is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 1, 2, or 3.
3. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt thereof, wherein each R and R is each independently selected from H and C alkyl.
4. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt or solvate thereof, wherein R and R , together with the carbon to which they are attached, form a C3- cycloalkyl ring.
5. The compound of any one of claims 1-4 , or a pharmaceutically acceptable salt thereof, wherein R is H.
6. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R is C alkyl.
7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein n is 1.
8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein R is -CF .
9. A compound of claim 1 having the structure selected from: , , , , and , or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising a compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201662423099P | 2016-11-16 | 2016-11-16 | |
US62/423,099 | 2016-11-16 | ||
PCT/US2017/061868 WO2018093947A1 (en) | 2016-11-16 | 2017-11-15 | Magl inhibitors |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ753264A NZ753264A (en) | 2020-12-18 |
NZ753264B2 true NZ753264B2 (en) | 2021-03-19 |
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