US2011105573A1PendingUtilityA1
Benzimidazole acetic acids exhibiting crth2 receptor antagonism and uses thereof
Est. expirySep 21, 2024(expired)· nominal 20-yr term from priority
A61P 41/00A61P 3/10A61P 9/10A61P 37/00A61P 9/14A61P 5/14A61P 5/48A61P 43/00A61P 7/04A61P 37/06A61P 37/02A61P 37/08A61P 25/08A61P 25/00A61P 31/08A61P 29/00A61P 31/04A61P 25/14A61P 25/28A61P 25/06A61P 31/18A61P 27/02A61P 19/08A61P 11/08C07D 235/08C07D 405/12A61P 17/00A61P 21/02C07D 417/12A61P 1/00A61P 11/02C07D 417/04A61P 19/02A61P 17/04A61P 11/14C07D 235/14A61P 1/04A61P 17/06A61P 17/02A61P 19/00C07D 409/12C07D 413/12A61P 1/16C07D 235/06A61P 11/00A61P 21/04A61P 13/12A61P 11/06A61K 31/4184
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Claims
Abstract
The invention relates to benzimidazole acetic acid compounds which function as antagonists of the Chemoattractant Receptor-homologous molecule expressed on T-Helper type 2 cells (CRTH2) receptor. The invention also relates to the use of these compounds to inhibit the binding of prostaglandin D 2 and its metabolites or certain thromboxane metabolites to the CRTH2 receptor and to treat disorders responsive to such inhibition.
Claims
exact text as granted — not AI-modified1 . A compound having Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
X is NR 2 SO 2 R 3 , NR 2 COR 4 , S(O) n R 2 or H;
n is 0, 1, or 2;
R 1 is H, substituted C 1-10 alkyl, unsubstituted C 1-10 alkyl, substituted C 1-10 perhalo alkyl, unsubstituted perhalo alkyl, substituted C 2-10 alkenyl, unsubstituted C 2-10 alkenyl, substituted C 2-10 alkynyl, usubstituted C 2-10 alkynyl, substituted —C 1-10 alkyl-O—C 1-40 alkyl, or unsubstituted —C 1-10 alkyl-O—C 1-40 alkyl;
R 2 is H, substituted C 1-10 alkyl, unsubstituted C 1-10 alkyl, substituted C 1-10 perhalo alkyl, unsubstituted C 1-10 perhalo alkyl, substituted C 2-10 alkenyl, substituted C 2-10 alkenyl, substituted C 2-10 alkynyl, unsubstituted C 2-10 alkynyl, substituted —C 1-10 alkyl-O—C 2-10 alkyl, unsubstituted substituted —C 1-10 alkyl-O—C 2-10 alkyl, substituted —C 3-10 cycloalkyl, unsubstituted —C 3-10 cycloalkyl, substituted —C 1-10 alkyl-C 3-10 cycloalkyl, unsubstituted —C 1-10 alkyl-C 3-10 cycloalkyl, substituted —C 1-10 alkyl-O-aryl, unsubstituted —C 1-10 alkyl-O-aryl, substituted —C 1-10 alkyl-O-heteroaryl, unsubstituted —C 1-10 alkyl-O-heteroayl, substituted C 1-10 alkylaryl, unsubstituted C 1-10 alkylaryl, substituted C 1-10 alkylheteroaryl, unsubstituted C 1-10 alkylheteroaryl, substituted aryl, unsubstituted aryl, substituted heteroaryl, or unsubstituted heteroaryl;
R 3 is H, substituted C 1-10 alkyl, unsubstituted C 1-10 alkyl, substituted C 1-10 perhalo alkyl, substituted C 1-10 perhalo alkyl, substituted C 2-10 alkenyl, unsubstituted C 2-10 alkenyl, substituted C 2-10 alkynyl, unsubstituted C 2-10 alkynyl, substituted —C 1-10 alkyl-O—C 1-10 alkyl, unsubstituted —C 1-10 alkyl-O—C 1-10 alkyl, substituted —C 3-10 cycloalkyl, unsubstituted —C 3-10 cycloalkyl, substituted —C 1-10 alkyl-C 3-10 cycloalkyl, unsubstituted —C 1-10 alkyl-C 3-10 cycloalkyl, substituted —C 1-10 alkyl-O-aryl, unsubstituted —C 1-10 alkyl-O-aryl-C 1-10 alkyl-O-heteroaryl, substituted C 1-10 alkylaryl, unsubstituted C 1-10 alkylaryl, substituted C 1-10 alkylheteroaryl, unsubstituted C 1-10 alkylheteroaryl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, or OR 2 ;
R 4 is H, substituted C 1-10 alkyl, unsubstituted C 1-10 alkyl, substituted C 2-10 alkenyl, unsubstituted C 2-10 alkenyl, substituted C 2-10 alkynyl, unsubstituted C 2-10 alkynyl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted C 3-10 cycloalkyl, unsubstituted C 3-10 cycloalkyl, OR 2 , or NR 2 R 2 ; or
R 2 and R 3 , together with the atoms to which they are attached, form a ring; or R 2 and R 4 together with the atoms to which they are attached form a ring; and
R 5 is H, halogen, substituted C 1-10 alkyl, unsubstituted C 1-10 alkyl, substituted C 1-10 alkyl, unsubstituted C 1-10 perhaloalkyl, substituted C 1-10 perhaloalkyl, substituted C 2-10 alkenyl, unsubstituted C 2-10 alkenyl, substituted C 2-10 alkynyl, unsubstituted C 2-10 alkynyl, or OR 2 ; or
R 5 together with R 2 , R 3 , or R 4 forms a fused saturated or unsaturated ring, and wherein if R 1 , R 2 , R 3 and/or R 5 are substituted the substituents are chosen from:
alkyl;
halo.
haloalkyl;
cycloalkyl;
aryl optionally substituted with one or more lower alkyl, halo, haloalkyl or heteroaryl groups;
aryloxy optionally substituted with one or more lower alkyl, haloalkyl, or heteroaryl groups;
aralkyl;
heteroaryl optionally substituted with one or more lower alkyl, haloalkyl, and aryl groups;
heteroaryloxy optionally substituted with one or more lower alkyl, haloalkyl, and aryl groups;
alkoxy;
haloalkoxy;
alkoxycarbonyl;
alkylcarbamate;
alkylthio;
arylthio;
amino;
cyano;
acyloxy;
arylacyloxy optionally substituted with one or more lower alkyl, haloalkyl, and aryl groups;
diphenylphosphinyloxy optionally substituted with one or more lower alkyl, halo or haloalkyl groups;
heterocyclo optionally substituted with one or more lower alkyl, haloalkyl, and aryl groups;
heterocycloalkoxy optionally substituted with one or more lower alkyl, haloalkyl, and aryl groups;
partially unsaturated heterocycloalkyl optionally substituted with one or more lower alkyl, haloalkyl, and aryl groups; and
partially unsaturated heterocycloalkyloxy optionally substituted with one or more lower alkyl, haloalkyl, and aryl groups;
with the proviso that:
when X is NR 2 COR 4 in the 4 position, R 4 is not aryl.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein X is NR 2 SO 2 R 3 .
3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein X is NR 2 COR 4 .
4 . (canceled)
5 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
6 . A method of inhibiting the binding of endogenous ligands to the CRTH-2 receptor on a cell, comprising contacting the cell with a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
7 . The method of claim 6 , wherein said endogenous ligand is prostaglandin D 2 (PGD 2 ) or a metabolite thereof.
8 . The method of claim 6 , wherein said endogenous ligand is a thromboxane metabolite.
9 . A method of treating, ameliorating, or preventing a disorder responsive to inhibiting the binding of endogenous ligands to the CRTH-2 receptor in an animal, comprising administering to said animal a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
10 . The method of claim 10 , wherein said disorder is characterized by elevated levels of PGD 2 or a metabolite thereof.
11 . The method of claim 10 , wherein said endogenous ligand is a thromboxane metabolite.
12 . The method of claim 10 , wherein said disorder is asthma, chronic obstructive pulmonary disease, bronchitis, rhinitis, nasal polyposis, sarcoidosis, farmer's lung, fibroid lung, idiopathic interstitial pneumonia, cystic fibrosis, or cough.
13 . The method of claim 10 , wherein said disorder is arthritis, ankylosing spondylitis, Reiter's disease, Behcet's disease, Sjorgren's syndrome, or systemic sclerosis.
14 . The method of claim 10 , wherein said disorder is psoriasis, dermatitis, atopic dermatitis, Lichen planus, pemphigus, epidermolysis bullosa, urticaria, angiodermas, vasculitides, erythemas, cutaneous eosinophilias, chronic skin ulcers, uveitis, corneal ulcers, or conjunctivitis.
15 . The method of claim 10 , wherein said disorder is celiac disease, proctitis, gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, irritable bowel disease, or food-related allergies.
16 . The method of claim 10 , wherein said disorder is Alzheimer's disease, amyotrophic lateral sclerosis, Creutzfeldt-Jacob's disease, AIDS dementia complex, Huntingtons disease, Guillain-Barre syndrome, multiple sclerosis, encephalomyelitis, myasthenia gravis, tropical spastic paraparesis, CNS trauma, migraine, or stroke.
17 . The method of claim 10 , wherein said disorder is atherosclerosis, AIDS, lupus erythematosus, Hashimoto's thyroiditis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, leprosy, thrombocytopenia purpura, post-operative adhesions, sepsis, ischemic/reperfusion injury, hepatitis, glomerulonephritis, or chronic renal failure.
18 . The method of claim 10 , wherein said disorder is acute or chronic allograft rejection.
19 . The method of claim 10 , further comprising administering an additional therapeutic agent.
20 . A kit comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and instructions for administering said compound to an animal.
21 . The kit of claim 20 , further comprising an additional therapeutic agent.
22 . A method of preparing a compound having formula VI or VII, comprising
a) condensing a compound having Formula II with a sulfonylate to form a compound having Formula III;
b) condensing a compound having Formula III with a carboxyl-protected amino acid to form a compound having Formula IV;
c) reducing a compound having Formula IV followed by alkylation with an aldehyde R 1 CHO to form a compound having Formula V; and
d) deprotecting a compound having Formula V to form a compound having Formula VI;
e) alkylating a compound having Formula V and then deprotecting to form a compound-having Formula VII;
wherein
R 1 is H, substituted C 1-10 alkyl unsubstituted C 1-10 alkyl, substituted C 1-10 perhalo alkyl, unsubstituted C 1-10 perhalo alkyl, substituted C 2-10 alkenyl, unsubstituted C 2-10 alkenyl, substituted C 2-10 alkynyl, substituted C 2-10 alkynyl, substituted —C 1-10 alkyl-O—C 1-10 alkyl, or unsubstituted —C 1-10 alkyl-O—C 1-10 alkyl; R 2 is H, substituted C 1-10 alkyl unsubstituted C 1-10 alkyl, substituted C 1-10 perhalo alkyl, unsubstituted C 1-10 perhalo alkyl, substituted C 10 alkenyl, unsubstituted C 2-10 alkenyl, substituted C 2-10 alkynyl, substituted C 2-10 alkynyl, substituted —C 1-10 alkyl-O-aryl, unsubstituted —C 1-10 alkyl-O-aryl, substituted —C 1-10 alkyl-O-heteroaryl, unsubstituted —C 1-10 alkyl-O-heteroaryl, substituted C 1-10 alkylaryl, unsubstituted C 1-10 alkylaryl, substituted C 1-10 alkylheteroaryl, unsubstituted C 1-10 alkylheteroaryl, substituted aryl, unsubstituted aryl, substituted heteroaryl or unsubstituted heteroaryl; R 3 is H, substituted C 1-10 alkyl unsubstituted C 1-10 alkyl, substituted C 1-10 perhalo alkyl, unsubstituted C 1-10 perhalo alkyl, substituted C 2-10 alkenyl, unsubstituted C 2-10 alkenyl, substituted C 2-10 alkynyl, substituted C 2-10 alkynyl, substituted —C 1-10 alkyl-O—C 1-10 alkyl, unsubstituted —C 1-10 alkyl-O-—C 1-10 alkyl, substituted —C 3-10 cycloalkyl, unsubstituted —C 3-10 cycloalkyl, substituted —C 1-10 alkyl-C 3-10 cycloalkyl, unsubstituted —C 1-10 alkyl-C 3-10 cycloalkyl, substituted —C 1-10 -alkyl-O-aryl, unsubstituted —C 1-10 -alkyl-O-aryl, substituted —C 1-10 alkyl-O-heteroaryl, unsubstituted —C 1-10 alkyl-O-heteroaryl, substituted C 1-10 alkylaryl, unsubstituted C 1-10 alkylaryl, substituted C 1-10 alkylheteroaryl, unsubstituted C 1-10 alkylheteroaryl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, or OR 2 ; Q is a halogen; and R 6 is a carboxyl protecting group.
23 . A method of preparing a compound having formula VI or VII, comprising
a) deprotecting a compound having Formula V to form a compound having Formula VI;
b) alkylating a compound having Formula V and then deprotecting to form a compound having Formula VII;
wherein
R 1 is H, substituted C 1-10 alkyl unsubstituted C 1-10 alkyl, substituted C 1-10 perhalo alkyl, unsubstituted C 1-10 perhalo alkyl, substituted C 2-10 alkenyl, unsubstituted C 2-10 alkenyl, substituted C 2-10 alkynyl, substituted C 2-10 alkynyl, substituted —C 1-10 alkyl-O—C 1-10 alkyl, or unsubstituted —C 1-10 alkyl-O—C 1-10 alkyl; R 2 is H, substituted C 1-10 alkyl unsubstituted C 1-10 alkyl, substituted C 1-10 perhalo alkyl, unsubstituted C 1-10 perhalo alkyl, substituted C 2-10 alkenyl, unsubstituted C 2-10 alkenyl, substituted C 2-10 alkynyl, substituted C 2-10 alkynyl, substituted —C 1-10 alkyl-O-aryl, unsubstituted —C 1-10 alkyl-O-aryl, substituted —C 1-10 alkyl-O-heteroaryl, unsubstituted —C 1-10 alkyl-O-heteroaryl, substituted C 1-10 alkylaryl, unsubstituted C 1-10 alkylaryl, substituted C 1-10 alkylheteroaryl, unsubstituted C 1-10 alkylheteroaryl, substituted aryl, unsubstituted aryl, substituted heteroaryl or unsubstituted heteroaryl; R 3 is H, substituted C 1-10 alkyl unsubstituted C 1-10 alkyl, substituted C 1-10 perhalo alkyl, unsubstituted C 1-10 perhalo alkyl, substituted C 2-10 alkenyl, unsubstituted C 2-10 alkenyl, substituted C 2-10 alkynyl, substituted C 2-10 alkynyl, substituted —C 1-10 alkyl-O—C 1-10 alkyl, unsubstituted —C 1-10 alkyl-O-—C 1-10 alkyl, substituted —C 3-10 cycloalkyl, unsubstituted —C 3-10 cycloalkyl, substituted —C 1-10 alkyl-C 3-10 cycloalkyl, unsubstituted —C 1-10 alkyl-C 3-10 cycloalkyl substituted —C 1-10 -alkyl-O-aryl, unsubstituted —C 1-10 -alkyl-O-aryl, substituted —C 1-10 alkyl-O-heteroaryl, unsubstituted —C 1-10 alkyl-O-heteroaryl substituted C 1-10 alkylaryl, unsubstituted C 1-10 alkylaryl substituted C 1-10 alkylheteroaryl, unsubstituted C 1-10 alkylheteroaryl substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, or OR 2 ; Q is a halogen; and R 6 is a carboxyl protecting group.
24 . A method of preparing a compound having formula XIII, or XV, comprising
a) protecting a compound—having Formula II with an amino protecting group to form a compound having Formula VIII;
b) condensing a compound having Formula VIII with a protected amino acid to form a compound having Formula IX;
c) reducing a compound having Formula IX followed by alkylation with an aldehyde R 1 CHO to form a compound having Formula X;
d) deprotecting a compound having Formula X to form a compound having Formula XI;
e) condensing a compound having Formula XI with a sulfonylate to form a compound having Formula XII; and
wherein
R 1 is H, substituted C 1-10 alkyl unsubstituted C 1-10 alkyl, substituted C 1-10 perhalo alkyl, unsubstituted C 1-10 perhalo alkyl, substituted C 2-10 alkenyl, unsubstituted C 2-10 alkenyl substituted C 2-10 alkynyl, substituted C 2-10 alkynyl, substituted —C 1-10 alkyl-O—C 1-10 alkyl, or unsubstituted —C 1-10 alkyl-O—C 1-10 alkyl; R 2 is H, substituted C 1-10 alkyl unsubstituted C 1-10 alkyl, substituted C 1-10 perhalo alkyl, unsubstituted C 1-10 perhalo alkyl, substituted C 2-10 alkenyl, unsubstituted C 2-10 alkenyl, substituted C 2-10 alkynyl, substituted C 2-10 alkynyl, substituted —C 1-10 alkyl-O-aryl, unsubstituted —C 1-10 alkyl-O-aryl, substituted —C 1-10 alkyl-O-heteroaryl, unsubstituted —C 1-10 alkyl-O-heteroaryl, substituted C 1-10 alkylaryl, unsubstituted C 1-10 alkylaryl, substituted C 1-10 alkylheteroaryl, unsubstituted C 1-10 alkylheteroaryl, substituted aryl, unsubstituted aryl, substituted heteroaryl or unsubstituted heteroaryl; R 3 is H, substituted C 1-10 alkyl unsubstituted C 1-10 alkyl, substituted C 1-10 perhalo alkyl, unsubstituted C 1-10 perhalo alkyl, substituted C 2-10 alkenyl, unsubstituted C 2-10 alkenyl, substituted C 2-10 alkynyl, substituted C 2-10 alkynyl, substituted —C 1-10 alkyl-O—C 1-10 alkyl, unsubstituted —C 1-10 alkyl-O—C 1-10 alkyl, substituted —C 3-10 cycloalkyl, unsubstituted —C 3-10 cycloalkyl, substituted —C 1-10 alkyl-C 3-10 cycloalkyl, unsubstituted —C 1-10 alkyl-C 3-10 cycloalkyl, substituted —C 1-10 -alkyl-O-aryl, unsubstituted —C 1-10 alkyl-O-aryl, substituted —C 1-10 alkyl-O-heteroaryl, unsubstituted —C 1-10 alkyl-O-heteroaryl, substituted C 1-10 alkylaryl, unsubstituted C 1-10 alkylaryl, substituted C 1-10 alkylheteroaryl, unsubstituted C 1-10 alkylheteroaryl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, or OR 2 ; R 4 is H, substituted C 1-10 alkyl unsubstituted C 1-10 alkyl, substituted C 1-10 perhalo alkyl, unsubstituted C 1-10 perhalo alkyl, substituted C 2-10 alkenyl, unsubstituted C 2-10 alkenyl, substituted C 2-10 alkynyl, substituted C 2-10 alkynyl, substituted —C 1-10 alkyl-O—C 1-10 alkyl, unsubstituted —C 1-10 alkyl-O—C 1-10 alkyl substituted —C 3-10 cycloalkyl, unsubstituted —C 3-10 cycloalkyl, substituted —C 1-10 alkyl-C 3-10 cycloalkyl, unsubstituted —C 1-10 alkyl-C 3-10 cycloalkyl, substituted —C 1-10 -alkyl-O-aryl, unsubstituted —C 1-10 -alkyl-O-aryl, substituted —C 1-10 alkyl-O-heteroaryl, unsubstituted —C 1-10 alkyl-O-heteroaryl, substituted C 1-10 alkylaryl, unsubstituted C 1-10 alkylaryl, substituted C 1-10 alkylheteroaryl, unsubstituted C 1-10 alkylheteroaryl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, OR 2 or NR 2 R 2 ; Q is a halogen; and R 6 is a carboxyl protecting group.
25 . A method of preparing a compound having formula XIII, XIV, or XV, comprising
a) alkylating a compound having Formula XII with an alkyl halide and then deprotecting to form a compound having Formula XIII;
b) alkylating a compound having Formula XI, with an aldehyde R 2 CHO, condensing with a sulfonylate, and then deprotecting to form a compound having Formula XIV;
c) alkylating a compound having Formula XI with an aldehyde R 2 CHO, followed by condensing with an acyl halide, and then deprotecting to form a compound having Formula XV;
wherein
R 1 is H, substituted C 1-10 alkyl unsubstituted C 1-10 alkyl, substituted C 1-10 perhalo alkyl, unsubstituted C 1-10 perhalo alkyl, substituted C 2-10 alkenyl, unsubstituted C 2-10 alkenyl, substituted C 2-10 alkynyl, substituted C 2-10 alkynyl, substituted —C 1-10 alkyl-O—C 1-10 alkyl, or unsubstituted —C 1-10 alkyl-O—C 1-10 alkyl; R 2 is H, substituted C 1-10 alkyl unsubstituted C 1-10 alkyl, substituted C 1-10 perhalo alkyl, unsubstituted C 1-10 perhalo alkyl, substituted C 2-10 alkenyl, unsubstituted C 2-10 alkenyl, substituted C 2-10 alkynyl, substituted C 2-10 alkynyl, substituted —C 1-10 alkyl-O-aryl, unsubstituted —C 1-10 alkyl-O-aryl, substituted —C 1-10 alkyl-O-heteroaryl, unsubstituted —C 1-10 alkyl-O-heteroaryl, substituted C 1-10 alkylaryl, unsubstituted C 1-10 alkylaryl, substituted C 1-10 alkylheteroaryl, unsubstituted C 1-10 alkylheteroaryl, substituted aryl, unsubstituted aryl, substituted heteroaryl or unsubstituted heteroaryl; R 3 is H, substituted C 1-10 alkyl unsubstituted C 1-10 alkyl, substituted C 1-10 perhalo alkyl, unsubstituted C 1-10 perhalo alkyl, substituted C 2-10 alkenyl, unsubstituted C 2-10 alkenyl, substituted C 2-10 alkynyl, substituted C 2-10 alkynyl, substituted —C 1-10 alkyl-O—C 1-10 alkyl, unsubstituted —C 1-10 alkyl-O—C 1-10 alkyl, substituted —C 3-10 cycloalkyl, unsubstituted —C 3-10 cycloalkyl, substituted —C 1-10 alkyl-C 3-10 cycloalkyl, unsubstituted —C 1-10 alkyl-C 3-10 cycloakyl, substituted —C 1-10 -alkyl-O-aryl, unsubstituted —C 1-10 -alkyl-O-aryl, substituted —C 1-10 alkyl-O-heteroaryl, unsubstituted —C 1-10 alkyl-O-heteroaryl, substituted C 1-10 alkylaryl, unsubstituted C 1-10 alkylaryl, substituted C 1-10 alkylheteroaryl, unsubstituted C 1-10 alkylheteroaryl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, or OR 2 ; R 4 is H, substituted C 1-10 alkyl unsubstituted C 1-10 alkyl, substituted C 1-10 perhalo alkyl, unsubstituted C 1-10 perhalo alkyl, substituted C 2-10 alkenyl, unsubstituted C 2-10 alkenyl, substituted C 2-10 alkynyl, substituted C 2-10 alkynyl, substituted —C 1-10 alkyl-O—C 1-10 alkyl, unsubstituted —C 1-10 alkyl-O—C 1-10 alkyl substituted —C 3-10 cycloalkyl, unsubstituted —C 3-10 cycloalkyl, substituted —C 1-10 alkyl-C 3-10 cycloalkyl, unsubstituted —C 1-10 alkyl-C 3-10 cycloalkyl, substituted —C 1-10 -alkyl-O-aryl, unsubstituted —C 1-10 -alkyl-O-aryl, substituted —C 1-10 alkyl-O-heteroaryl, unsubstituted —C 1-10 alkyl-O-heteroaryl, substituted C 1-10 alkylaryl, unsubstituted C 1-10 alkylaryl, substituted C 1-10 alkylheteroaryl, unsubstituted C 1-10 alkylheteroaryl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, OR 2 or NR 2 R 2 ; Q is a halogen; and R 6 is a carboxyl protecting group.
26 . A method of preparing a compound having, formula XX or XXI, comprising
a) condensing a compound having Formula XVI with a carboxylic acid R 1 CO 2 H to form a compound having Formula XVII;
b) alkylating a compound having Formula XVII with a halogenated acetic acid alkyl ester to form a compound having Formula XVIII;
c) reducing a compound having Formula XVIII to form a compound; having Formula XIX;
d) condensing a compound having Formula XIX with a sulfonylate and then deprotecting to form a compound having Formula XX;
e) alkylating a compound having Formula XIX with an aldehyde R 2 CHO, condensing with a sulfonylate, and then deprotecting to form a compound having Formula XXI;
wherein
R 1 is H, substituted C 1-10 alkyl unsubstituted C 1-10 alkyl, substituted C 1-10 perhalo alkyl, unsubstituted C 1-10 perhalo alkyl, substituted C 2-10 alkenyl, unsubstituted C 2-10 alkenyl, substituted C 2-10 alkynyl, substituted C 2-10 alkynl, substituted —C 1-10 alkyl-O—C 1-10 alkyl, or unsubstituted —C 1-10 alkyl-O—C 1-10 alkyl; R 2 is H, substituted C 1-10 alkyl unsubstituted C 1-10 alkyl, substituted C 1-10 perhalo alkyl, unsubstituted C 1-10 perhalo alkyl, substituted C 2-10 alkenyl, unsubstituted C 2-10 alkenyl, substituted C 2-10 alkynyl, substituted C 2-10 alkynyl, substituted —C 1-10 alkyl-O-aryl, unsubstituted —C 1-10 alkyl-O-aryl, substituted —C 1-10 alkyl-O-heteroaryl, unsubstituted —C 1-10 alkyl-O-heteroaryl, substituted C 1-10 alkylaryl, unsubstituted C 1-10 alkylaryl, substituted C 1-10 alkylheteroaryl, unsubstituted C 1-10 alkylheteroaryl, substituted aryl, unsubstituted aryl, substituted heteroaryl or unsubstituted heteroaryl; R 3 is H, substituted C 1-10 alkyl unsubstituted C 1-10 alkyl, substituted C 1-10 perhalo alkyl, unsubstituted C 1-10 perhalo alkyl, substituted C 2-10 alkenyl, unsubstituted C 2-10 alkenyl, substituted C 2-10 alkynyl, substituted C 2-10 alkynyl, substituted —C 1-10 alkyl-O—C 1-10 alkyl, unsubstituted —C 1-10 alkyl-O—C 1-10 alkyl, substituted —C 3-10 cycloalkyl, unsubstituted —C 3-10 cycloalkyl, substituted —C 1-10 alkyl-C 3-10 cycloalkyl, unsubstituted —C 1-10 alkyl-C 3-10 cycloalkyl, substituted —C 1-10 -alkyl-O-aryl, unsubstituted —C 1-10 -alkyl-O-aryl substituted —C 1-10 alkyl-O-heteroaryl, unsubstituted —C 1-10 alkyl-O-heteroaryl, substituted C 1-10 alkylaryl, unsubstituted C 1-10 alkylaryl, substituted C 1-10 alkylheteroaryl, unsubstituted C 1-10 alkylheteroaryl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, or OR 2 ; Q is a halogen; and R 6 is a carboxyl protecting group.
27 . A method of preparing a compound having formula XX or XXI, comprising
a) condensing a compound having Formula XIX with a sulfonylate and then deprotecting to form a compound having Formula XX;
b) alkylating a compound. having Formula XIX with an aldehyde R 2 CHO, condensing with a sulfonylate, and then deprotecting to form a compound having Formula XXI;
wherein
R 1 is H, substituted C 1-10 alkyl unsubstituted C 1-10 alkyl, substituted C 1-10 perhalo alkyl, unsubstituted C 1-10 perhalo alkyl, substituted C 2-10 alkenyl, unsubstituted C 2-10 alkenyl, substituted C 2-10 alkynyl, substituted C 2-10 alkynyl, substituted —C 1-10 alkyl-O—C 1-10 alkyl, or unsubstituted —C 1-10 alkyl-O—C 1-10 alkyl; R 2 is H, substituted C 1-10 alkyl unsubstituted C 1-10 alkyl, substituted C 1-10 perhalo alkyl, unsubstituted C 1-10 perhalo alkyl, substituted C 2-10 alkenyl, unsubstituted C 2-10 alkenyl, substituted C 2-10 alkynyl, substituted C 2-10 alkynyl, substituted —C 1-10 alkyl-O-aryl, unsubstituted —C 1-10 alkyl-O-aryl substituted —C 1-10 alkyl-O-heteroaryl, unsubstituted —C 1-10 alkyl-O-heteroaryl, substituted C 1-10 alkylaryl, unsubstituted C 1-10 alkylaryl, substituted C 1-10 alkylheteroaryl, unsubstituted C 1-10 alkylheteroaryl, substituted aryl, unsubstituted aryl, substituted heteroaryl or unsubstituted heteroaryl; R 3 is H, substituted C 1-10 alkyl unsubstituted C 1-10 alkyl, substituted C 1-10 perhalo alkyl, unsubstituted C 1-10 perhalo alkyl, substituted C 2-10 alkenyl, unsubstituted C 2-10 alkenyl, substituted C 2-10 alkynyl, substituted C 2-10 alkynyl, substituted —C 1-10 alkyl-O—C 1-10 alkyl, unsubstituted —C 1-10 alkyl-O—C 1-10 alkyl, substituted —C 3-10 cycloalkyl, unsubstituted —C 3-10 cycloalkyl substituted —C 1-10 alkyl-C 3-10 cycloalkyl, unsubstituted —C 1-10 alkyl-C 3-10 cycloalkyl, substituted —C 1-10 -alkyl-O-aryl, unsubstituted —C 1-10 -alkyl-O-aryl, substituted —C 1-10 alkyl-O-heteroaryl, unsubstituted —C 1-10 alkyl-O-heteroaryl, substituted C 1-10 alkylaryl, unsubstituted C 1-10 alkylaryl, substituted C 1-10 alkylheteroaryl, unsubstituted C 1-10 alkylheteroaryl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, or OR 2 ; Q is halogen; and R 6 is a carboxyl protecting group.
28 . A method of preparing a compound having formula XXIV, XXV, or XXVI, comprising
a) condensing a compound, having formula XVI with a carboxylic acid R 1 CO 2 H to form a compound having Formula XVII;
b) alkylating a compound having Formula XVII with a halogenated acetic acid alkyl ester to form a compound having Formula XXII;
c) reducing a compound having formula XXII to form a compound having Formula XXIII;
wherein
R 1 is H, substituted C 1-10 alkyl unsubstituted C 1-10 alkyl, substituted C 1-10 perhalo alkyl, unsubstituted C 1-10 perhalo alkyl, substituted C 2-10 alkenyl, unsubstituted C 2-10 alkenyl substituted C 2-10 alkynyl, substituted C 2-10 alkynyl, substituted —C 1-10 alkyl-O—C 1-10 alkyl, or unsubstituted —C 1-10 alkyl-O—C 1-10 alkyl; R 2 is H, substituted C 1-10 alkyl unsubstituted C 1-10 alkyl, substituted C 1-10 perhalo alkyl, unsubstituted C 1-10 perhalo alkyl, substituted C 2-10 alkenyl, unsubstituted C 2-10 alkenyl, substituted C 2-10 alkynyl, substituted C 2-10 alkynyl, substituted —C 1-10 alkyl-O-aryl, unsubstituted —C 1-10 alkyl-O-aryl, substituted —C 1-10 alkyl-O-heteroaryl, unsubstituted —C 1-10 alkyl-O-heteroaryl substituted C 1-10 alkylaryl, unsubstituted C 1-10 alkylaryl, substituted C 1-10 alkylheteroaryl, unsubstituted C 1-10 alkylheteroaryl, substituted aryl, unsubstituted aryl, substituted heteroaryl or unsubstituted heteroaryl; R 3 is H, substituted C 1-10 alkyl unsubstituted C 1-10 alkyl, substituted C 1-10 perhalo alkyl, unsubstituted C 1-10 perhalo alkyl, substituted C 2-10 alkenyl, unsubstituted C 1-10 alkenyl, substituted C 2-10 alkynyl, substituted C 2-10 alkynyl, substituted —C 1-10 alkyl-O—C 1-10 alkyl, unsubstituted —C 1-10 alkyl-O—C 1-10 alkyl, substituted —C 3-10 cycloalkyl, unsubstituted —C 3-10 cycloalkyl, substituted —C 1-10 alkyl-C 3-10 cycloalkyl, unsubstituted —C 1-10 alkyl-C 3-10 cycloalkyl, substituted —C 1-10 -alkyl-O-aryl, unsubstituted —C 1-10 -alkyl-O-aryl substituted —C 1-10 alkyl-O-heteroaryl, unsubstituted —C 1-10 alkyl-O-heteroaryl, substituted C 1-10 alkylaryl, unsubstituted C 1-10 alkylaryl substituted C 1-10 alkylheteroaryl, unsubstituted C 1-10 alkylheteroaryl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, or OR 2 ; R 4 is H, substituted C 1-10 alkyl unsubstituted C 1-10 alkyl, substituted C 1-10 perhalo alkyl, unsubstituted C 1-10 perhalo alkyl, substituted C 2-10 alkenyl, unsubstituted C 2-10 alkenyl, substituted C 2-10 alkynyl, substituted C 2-10 alkynyl, substituted —C 1-10 alkyl-O—C 1-10 alkyl, unsubstituted —C 1-10 alkyl-O—C 1-10 alkyl, substituted —C 3-10 cycloalkyl, unsubstituted —C 3-10 cycloalkyl, substituted —C 1-10 alkyl-C 3-10 cycloalkyl, unsubstituted —C 1-10 alkyl-C 3-10 cycloalkyl, substituted —C 1-10 -alkyl-O-aryl, unsubstituted —C 1-10 -alkyl-O-aryl, substituted —C 1-10 alkyl-O-heteroaryl, unsubstituted —C 1-10 alkyl-O-heteroaryl, substituted C 1-10 alkylaryl, unsubstituted C 1-10 alkylaryl, substituted C 1-10 alkylheteroaryl, unsubstituted C 1-10 alkylheteroaryl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, OR 2 or NR 2 R 2 ; Q is a halogen; and R 6 is a carboxyl protecting group.
29 . A method of preparing a compound having formula XXIV, XXV, or XXVI, comprising
a) condensing a compound having Formula XXIII with an acyl halide and then deprotecting to form a compound having Formula XXIV;
b) condensing a compound having Formula XXIII with a sulfonylate and then deprotecting to form a compound having Formula XXV;
c) alkylating a compound having Formula XXIII with an aldehydc R 2 CHO, condensing with a sulfonylate, and then deprotecting to form a compound having Formula XXVI;
wherein
R 1 is H, substituted C 1-10 alkyl unsubstituted C 1-10 alkyl, substituted C 1-10 perhalo alkyl, unsubstituted C 1-10 perhalo alkyl, substituted C 2-10 alkenyl, unsubstituted C 2-10 alkenyl, substituted C 2-10 alkynyl, substituted C 2-10 alkynyl, substituted —C 1-10 alkyl-O—C 1-10 alkyl, or unsubstituted —C 1-10 alkyl-O—C 1-10 alkyl;
R 2 is H, substituted C 1-10 alkyl unsubstituted C 1-10 alkyl, substituted C 1-10 perhalo alkyl, unsubstituted C 1-10 perhalo alkyl, substituted C 2-10 alkenyl, unsubstituted C 2-10 alkenyl, substituted C 2-10 alkynyl, substituted C 2-10 alkynyl, substituted —C 1-10 alkyl-O-aryl, unsubstituted —C 1-10 alkyl-O-aryl, substituted —C 1-10 alkyl-O-heteroaryl, unsubstituted —C 1-10 alkyl-O-heteroaryl, substituted C 1-10 alkylaryl, unsubstituted C 1-10 alkylaryl, substituted C 1-10 alkylheteroaryl, unsubstituted C 1-10 alkylheteroaryl, substituted aryl, unsubstituted aryl, substituted heteroaryl or unsubstituted heteroaryl;
R 3 is H, substituted C 1-10 alkyl unsubstituted C 1-10 alkyl, substituted C 1-10 perhalo alkyl, unsubstituted C 1-10 perhalo alkyl, substituted C 2-10 alkenyl, unsubstituted C 2-10 alkenyl, substituted C 2-10 alkynyl, substituted C 2-10 alkynyl, substituted —C 1-10 alkyl-O—C 1-10 alkyl, unsubstituted —C 1-10 alkyl-O-—C 1-10 alkyl, substituted —C 3-10 cycloalkyl, unsubstituted —C 3-10 cycloalkyl, substituted —C 1-10 alkyl-C 3-10 cycloalkyl, unsubstituted —C 1-10 alkyl-C 3-10 cycloalkyl, substituted —C 1-10 -alkyl-O-aryl, unsubstituted —C 1-10 -alkyl-O-aryl, substituted —C 1-10 alkyl-O-heteroaryl, unsubstituted —C 1-10 alkyl-O-heteroaryl, substituted C 1-10 alkylaryl, unsubstituted C 1-10 alkylaryl, substituted C 1-10 alkylheteroaryl, unsubstituted C 1-10 alkylheteroaryl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, or OR 2 ;
R 4 is H, substituted C 1-10 alkyl unsubstituted C 1-10 alkyl, substituted C 1-10 perhalo alkyl, unsubstituted C 1-10 perhalo alkyl, substituted C 2-10 alkenyl, unsubstituted C 2-10 alkenyl, substituted C 2-10 alkynyl, substituted C 2-10 alkynyl, substituted —C 1-10 alkyl-O—C 1-10 alkyl, unsubstituted —C 1-10 alkyl O—C 1-10 alkyl substituted —C 3-10 cycloalkyl, unsubstituted —C 3-10 cycloalkyl, substituted —C 1-10 alkyl-C 3-10 cycloalkyl, unsubstituted —C 1-10 alkyl-C 3-10 cycloalkyl, substituted —C 1-10 -alkyl-O-aryl, unsubstituted —C 1-10 -alkyl-O-aryl substituted —C 1-10 alkyl-O-heteroaryl, unsubstituted —C 1-10 alkyl-O-heteroaryl, substituted C 1-10 alkylaryl, unsubstituted C 1-10 alkylaryl, substituted C 1-10 alkylheteroaryl, unsubstituted C 1-10 alkylheteroaryl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, OR 2 or NR 2 R 2 ;
Q is a halogen; and
R 6 is a carboxyl protecting group.
30 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is unsubstituted C 1-10 alkyl.
31 . The compound of claim 30 , or a pharmaceutically acceptable salt thereof, wherein R 1 is chosen from ethyl, propyl, isopropyl, t-butyl, sec-butyl, or 3-pentyl.
32 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is chosen from H, substituted C 1-10 alkyl, unsubstituted C 1-10 alkyl, substituted C 2-10 alkenyl, unsubstituted C 2-10 alkenyl, substituted —C 1-10 alkyl-C 3-10 cycloalkyl, unsubstituted —C 1-10 alkyl-C 3-10 cycloalkyl, substituted C 1-10 alkylheteroaryl, unsubstituted C 1-10 alkylheteroaryl, substituted C 1-10 alkyl-O—C 1-10 alkyl, unsubstituted —C 1-10 alkyl-O—C 1-10 alkyl, substituted —C 3-10 cycloalkyl, unsubstituted —C 3-10 cycloalkyl, substituted —C 1-10 alkyl-O-aryl, unsubstituted —C 1-10 alkyl-O-aryl, substituted C 1-10 alkylaryl, and unsubstituted C 1-10 alkylaryl, wherein the aryl groups on C 1-10 alkyaryl and C 1-10 alkyl-O-aryl are optionally substituted with one or more groups chosen from C 1-10 alkyl, halo, cyano, trifluoromethoxyl, and trifluoromethyl.
33 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is chosen from phenyl and C 1-10 alkylphenyl, each of which is optionally substituted on the phenyl by one or more groups chosen from halo and C 1-10 alkyl.
34 . The compound of claim 33 , or a pharmaceutically acceptable salt thereof, wherein R 3 is chosen from halophenyl and halobenzyl.
35 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is chosen from substituted C 1-10 alkyl, unsubstituted C 1-10 alkyl, substituted C 3-10 cycloalkyl, unsubstituted C 3-10 cycloalkyl, phenyl optionally substituted with one or two halo, and thienyl optionally substituted with methyl.
36 . The compound of claim 35 , or a pharmaceutically acceptable salt thereof, wherein R 4 is chosen from t-butyl, chlorophenyl, difluorophenyl, fluorophenyl, cyclopropyl, cyclopentyl, cyclohexyl, isobutyl, isopropyl, methoxymethyl, methyl, methylthienyl, phenyl, and thienyl.
37 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is H.
38 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is bonded to the benzimidazolyl moiety at the 4-position or the 5-position.
39 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 1 is unsubstituted C 1-10 alkyl; R 2 is chosen from H, unsubstituted C 1-10 alkyl, C 1-10 alkylaryl, and C 1-10 alkylaryl substituted on the aryl portion of the radical by one or more groups selected from unsubstituted C 1-10 alkyl, halo, cyano, trifluoromethoxy, and trifluoromethyl; R 3 is halophenyl or halobenzyl; R 5 is H; and X is bonded to the benzimidazolyl moiety at the 4-position or the 5-position.Cited by (0)
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